Biomedical subjects

Peter R Gibson

Publications and source records attributed to Peter R Gibson.

11 recordsLinked to original sources

PubMed2006

Microscopic colitis demonstrates a T helper cell type 1 mucosal cytokine profile.

BACKGROUND: Microscopic colitis (MC) is an inflammatory disorder of unknown aetiology. AIM: To characterise the mucosal cytokine profile of MC, with a view to understanding its potential pathogenic mechanisms. METHODS: Cytokine profiles of mucosal biopse specimens taken at flexible sigmoidoscopy from 18 patients (8 with lymphocytic colitis and 10 with collagenous colitis) were analysed using real-time reverse transcriptase-PCR, in comparison with those from 13 aged-matched controls with diarrhoea-predominant irritable bowel syndrome. Biopsy specimens from six patients with histologically documented remission were available for comparative analysis. Biopsy specimens were also taken to determine the cellular expression of cytokine and cytokine-related proteins using immunohistochemistry. RESULTS: Mucosal mRNA levels were 100 times greater for interferon (IFN)gamma and interleukin (IL) 15, 60 times greater for tumour necrosis factor alpha, and 35 times greater for inducible nitric oxide synthase in MC compared with controls. Apart from a trend for increased levels of IL10, levels of other T helper cell type 2 (T(H)2) cytokines including IL2 and IL4 were too low to be accurately quantified. Mucosal IFNgamma mRNA levels correlated with the degree of diarrhoea, and returned to normal in remission. The immunohistochemical expression of cell junction proteins E-cadherin and ZO-1 was reduced in active disease. No differences were noted between lymphocytic and collagenous colitis for any of the above parameters. CONCLUSIONS: MC demonstrates a T(H)1 mucosal cytokine profile with IFNgamma as the predominantly upregulated cytokine, with concurrent induction of nitric oxide synthase and down regulation of IFNgamma-related cell junction proteins. This pattern is similar to that in coeliac disease and suggests that it might represent a response to a luminal antigen.

Aged↗

PubMed2006

Fructose malabsorption and symptoms of irritable bowel syndrome: guidelines for effective dietary management.

Dietary fructose induces abdominal symptoms in patients with fructose malabsorption, but there are no published guidelines on its dietary management. The objective was to retrospectively evaluate a potentially successful diet therapy in patients with irritable bowel syndrome and fructose malabsorption. Tables detailing the content of fructose and fructans in foods were constructed. A dietary strategy comprising avoidance of foods containing substantial free fructose and short-chain fructans, limitation of the total dietary fructose load, encouragement of foods in which glucose was balanced with fructose, and co-ingestion of free glucose to balance excess free fructose was devised. Sixty-two consecutively referred patients with irritable bowel syndrome and fructose malabsorption on breath hydrogen testing underwent dietary instruction. Dietary adherence and effect on abdominal symptoms were evaluated via telephone interview 2 to 40 months (median 14 months) later. Response to the diet was defined as improvement of all symptoms by at least 5 points on a -10- to 10-point scale. Forty-eight patients (77%) adhered to the diet always or frequently. Forty-six (74%) of all patients responded positively in all abdominal symptoms. Positive response overall was significantly better in those adherent than nonadherent (85% vs 36%; P<0.01), as was improvement in individual symptoms (P<0.01 for all symptoms). This comprehensive fructose malabsorption dietary therapy achieves a high level of sustained adherence and good symptomatic response.

Adolescent↗

PubMed2006

Does butyrate protect from colorectal cancer?

Butyrate, the four-carbon fatty acid, is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber), and putatively suppresses colorectal cancer (CRC). Butyrate has diverse and apparently paradoxical effects on cellular proliferation, apoptosis and differentiation that may be either pro-neoplastic or anti-neoplastic, depending upon factors such as the level of exposure, availability of other metabolic substrate and the intracellular milieu. In humans, the relationship between luminal butyrate exposure and CRC has been examined only indirectly in case-control studies, by measuring fecal butyrate concentrations, although this may not accurately reflect effective butyrate exposure during carcinogenesis. Perhaps not surprisingly, results of these investigations have been mutually contradictory. The direct effect of butyrate on tumorigenesis has been assessed in a number of in vivo animal models, which have also yielded conflicting results. In part, this may be explained by methodological differences in the amount and route of butyrate administration, which are likely to significantly influence delivery of butyrate to the distal colon. Nonetheless, there appears to be some evidence that delivery of an adequate amount of butyrate to the appropriate site protects against early tumorigenic events. Future study of the relationship between butyrate and CRC in humans needs to focus on risk stratification and the development of feasible strategies for butyrate delivery.

Animals↗

PubMed2006

Hepatitis B and C virus infections and anti-tumor necrosis factor-alpha therapy: guidelines for clinical approach.

Anti-tumor necrosis factor-alpha (TNF) therapy has recently been recognized to be associated with activation of hepatitis B virus (HBV) infection, with a potentially fatal outcome, mirroring experience in the setting of immune suppression and subsequent reconstitution in cancer chemotherapy and transplantation. Although there is no current evidence that anti-TNF therapy influences the natural history of hepatitis C virus (HCV) infection, the involvement of TNF in the pathogenesis of hepatic injury and extrapolation from other clinical situations heighten awareness of a potential conflict. Preventive strategies should be mandatory. These include screening of all patients for HBV and HCV infection prior to commencement of anti-TNF therapy, and active monitoring of aminotransferases and, for HBV, viral load during and for 3 months after therapy has terminated. Prophylactic or early intervention strategies with nucleoside analogs are recommended for patients with evidence of HBV infection.

Anti-Inflammatory Agents↗

PubMed2005

The influence of specific luminal factors on the colonic epithelium: high-dose butyrate and physical changes suppress early carcinogenic events in rats.

INTRODUCTION: Although luminal delivery of butyrate is one putative mechanism by which biology of the colonic epithelium might be influenced by changes in luminal contents, there is a paucity of supportive cause-effect evidence. This study aimed to directly establish whether distal colonic butyrate delivery is able to alter the response of the distal colonic epithelium to a carcinogen. METHODS: Groups of male Sprague-Dawley rats with chronically intubated colons received infusions of 80 mM butyrate or 0.9 percent saline into distal colon two or five times daily. Three weeks after exposure to azoxymethane (15 mg/kg subcutaneously), the density of aberrant crypts was quantified in distal colon. RESULTS: Infusions of 0.5 ml twice daily, whether containing saline or butyrate, decreased the number of aberrant crypt foci by 45 percent compared with rats receiving no infusions (P = 0.004, analysis of variance). Similar results were obtained when infusions were restricted to the post-initiation phase. When infusions were increased to 1 ml five times daily, saline infusions similarly suppressed aberrant crypt formation (38 percent), but butyrate infusions suppressed it to a greater degree (by 64 percent; P = 0.02 compared with saline infusion, t-test). CONCLUSIONS: High levels of butyrate delivery to the distal colonic lumen alter the epithelial response to a carcinogen in otherwise healthy rats. This finding directly supports the notion that the effects of butyrate on cells in vitro do occur in vivo provided a sufficient dose is delivered. The effect of infusion of liquid per se on the epithelial response highlights the potential impact physical changes alone can have on the colonic epithelium.

Animals↗

PubMed2005

Comprehensive clinical assessment improves the accuracy of predicting cirrhosis in chronic hepatitis C.

BACKGROUND: The diagnosis of cirrhosis in chronic hepatitis C (CHC) is important but difficult in those who are unable to undergo liver biopsy. Thus, the aims of the present study were to compare separately and in combination, clinical markers of liver disease, the discriminant score (DS) and serum hyaluronic acid (HA) for their ability to predict cirrhosis in CHC. METHODS: Two groups of consecutive patients (groups 1 and 2) with CHC were analyzed. Clinical data and routine laboratory results at the time of liver biopsy were collected, and serum HA levels were assayed. A clinical examination score (CES) was constructed using the sum of clinical markers of liver disease in group 1 and was validated in group 2, the DS was calculated, and a serum HA score (HAS) was produced. Combination scores were constructed using the sum of the CES, DS and HAS. Histological analysis of liver biopsies was performed by hepatopathologists blinded to clinical results. RESULTS: One hundred and fifty-one patients with CHC (group 1, n = 47; group 2, n = 104) including 27 with cirrhosis were assessed. Serum HA was more accurate than either CES or DS in the prediction of cirrhosis. The combination of CES, DS and HAS enabled the most accurate prediction of cirrhosis with a sensitivity and specificity of 78% and 93%, and a positive predictive value and negative predictive value of 75% and 94%, respectively. CONCLUSIONS: A comprehensive clinical assessment utilizing clinical and laboratory data more accurately predicts the presence and absence of cirrhosis in CHC than individual markers.

Adult↗

PubMed2005

Inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is increasing in frequency in Australia. General practitioners play an important role in early diagnosis and in a multidisciplinary approach to managing such patients. Keeping abreast of evolving concepts, particularly in treatment, is challenging. OBJECTIVE: This article aims to address key issues in diagnosis and management to better equip general practitioners for their role in multidisciplinary management of patients with IBD. DISCUSSION: Making the diagnosis can be difficult, but is facilitated by appropriate clinical suspicion and sensible judgment as to who undergoes diagnostic tests such as colonoscopy. Treatment of ulcerative colitis has changed little in recent years, except for our improved ability to deliver mesalazine to the large bowel via the recent availability of several oral and rectal preparations. Prevention of relapse using these is an important strategy in the majority of patients. Treatment of Crohn disease is changing due to more realistic concepts of the natural history of the disease and the development of new, powerful anti-inflammatory therapies. Attention to issues other than intestinal inflammation such as nutrition, education and counselling, remain important in achieving optimal management.

Adrenal Cortex Hormones↗

PubMed2004

Apoptosis or necrosis--colonic epithelial cell survival.

The organization of the colonic epithelium is directed towards maintaining a continuous layer of cells with functional maturity at the surface, with a constant supply of epithelial cells of sufficient maturity from the crypts. Cells die by shedding at the surface or by undergoing apoptosis in situ, followed by shedding or phagocytosis. The nature of the predominant form of cell death in the normal colon remains uncertain but probably involves more than one route. Death of abnormal cells in the crypt is an important process to prevent clonal expansion and tumour formation. Apoptosis of normal cells is largely secondary to the effects of exposure to luminal factors, such as short-chain fatty adds and surfactants; loss of cell-substratum adhesion (anoikis) in the surface compartment; or cytokine-, oxidant stress- or lymphocyte-mediated death in association with inflammation. In inflammatory bowel disease (IBD) cell death can directly or indirectly compromise barrier function, impair effective epithelial restitution, lead to loss of stem cells and regenerative capacity, and has relevance to carcinogenesis. Therapeutic targeting of cell death in IBD is a double-edged sword--promotion of cell survival may favour more effective healing for active inflammation, while promotion of apoptosis may be protective from carcinogenesis.

Apoptosis↗

PubMed2003

The trophic effect of dietary fibre is not associated with a change in total crypt number in the distal colon of rats.

Soluble fibres, such as guar gum, promote and wheat bran or methylcellulose protect from chemically induced colon carcinogenesis, relative to the effect of a fibre-free diet in rats. Mechanisms are poorly understood. Whereas all fibres are trophic to the colonic epithelium, the heterogeneity of effects on carcinogenesis may reflect different effects on the total number of crypts and, therefore, the size of the stem cell population. This study aimed to assess this hypothesis. Sprague-Dawley rats were fed one of fibre-free diets with or without 10% wheat bran, methylcellulose or guar gum for 4 weeks. The distal colons were stained with methylene blue and quantified for the number and density of crypts using an image analysis system. Epithelial proliferative kinetics was measured stathmokinetically. Methodology for quantifying crypts was valid and reproducible. Rats fed a fibre-free diet had atrophic distal colon, as shown by a decrease in crypt column height and a lower mitotic index. Fibre supplementation prevented the atrophy and was associated with crypt mouth areas that were 30-60% larger than those in the fibre-free group (P < 0.001, ANOVA), with the methylcellulose group being the largest (1.16 microm(2)). The crypt density of the fibre-free group was 16-19% greater than those in fibre fed groups (P + 0.006), due to the smaller size of the crypts. However, there was no difference in the total number of crypts across the four dietary groups (P > 0.1). Distal colons in all of the dietary groups contained approximately 10(5) crypts. In conclusion, although variation in the amount or type of dietary fibre exerts heterogeneous effects on the growth of the colonic epithelium and on colon carcinogenesis, the total number of crypts in the distal colon remains constant. It is, therefore, unlikely that fibres influence carcinogenic events by altering the size of the stem cell population.

Animals↗

PubMed2002

Development of a chronic colonic intubation model in rats for the study of luminal factors in colonic diseases.

INTRODUCTION: A rat model of long-term colonic intubation has been developed to facilitate the in vivo study of colonic biology. This study aims to characterize this model. METHODS: The effects of intubation and sham surgery on animal behavior and weight gain were measured and compared with unoperated controls. The reproducibility of the model was assessed by comparing complication and failure rates for three operators. The distribution and excretion of infused materials were studied using radiology and gas chromatography of feces, respectively. The effects of the colonic tube and infusions on the mucosa were assessed histologically. RESULTS: There was about 10 percent weight loss postoperatively, more marked in those rats undergoing more extensive surgery. Subsequent weight gain was similar in all groups, and no behavioral effects of surgery were noted. There were no differences in histologic appearances or proliferative indices among the groups. All three operators had similar complication and tube dislodgement rates. Radiologic examination showed even distribution of infusate regardless of fecal consistency. Infusion through the two tubes allowed the cecum and the distal bowel to be targeted differentially. The infusions did not alter the consistency of the fecal pellets or induce defecation. Gas chromatography at various time points after butyrate infusion showed a small, but statistically insignificant, rise in fecal excretion, representing less than 10 percent of the infused butyrate. CONCLUSIONS: A highly reproducible in vivo rat model, with an experimental life span of five to six weeks, has been achieved. Biological agents can be accurately delivered via the colonic tubes and are retained in the colonic segment of interest. This intubation model should provide a valuable tool in the future for in vivo studies of colonic biology.

Animals↗

PubMed2002

Colonic epithelial atrophy induced by a fibre-free diet in rats is reversed by minimal amounts of luminal butyrate, but only in the short term.

BACKGROUND: Luminal butyrate may be trophic to the colonic epithelium, but this effect is poorly characterized. The aim of the present study was to define the dose-response, time-course, site-specificity and the dependence on background diet of the effects of butyrate on epithelial proliferation in normal distal colon, using an in vivo rat model of colonic substrate delivery. METHODS: Male Sprague-Dawley rats, maintained on a fibre-free diet, had butyrate infused twice daily into the colonic lumen via polyethylene tubes placed at laparotomy. Varying dose levels (0-80 micro mol/d; 4 d), site (caecal vs distal colonic), duration of infusions (1-5 weeks; 80 micro mol/d), or dietary fibre intake were investigated. Epithelial proliferative indices were assessed stathmokinetically. RESULTS: Four-day infusions of butyrate led to a progressive trophic effect (cells/crypt column increased from 37.9 +/- 1.6 at 0 micro mol/d to 44.7 +/- 1.2 at 80 micro mol/d) on fibre-deprived colonic mucosa, related linearly to the daily butyrate dose (P < 0.001, linear regression). This effect was mediated by increases in the number and proportion of mitoses, related to the square of the butyrate dose (P < 0.001 in each case, polynomial regression). Butyrate (80 micro mol/d) was associated with significantly higher cellularity (59.9 +/- 1.4) and mitotic activity (4.9 +/- 0.6) per crypt column compared to vehicle controls (50.3 +/- 1.6 and 0.9 +/- 0.2, respectively; P < 0.05, t-tests), at 1 and 3 weeks, but not at 5 weeks. Butyrate had similar effects on distal colonic crypt cellularity (62.0 +/- 1.5) when delivered caecally, but in rats fed a fibre-containing diet, colonic crypt cellularity (55.3 +/- 3.2) was similar to baseline (59.6 +/- 1.9). CONCLUSIONS: Trophic effects of butyrate are concentration-dependent and occur at low doses in the short term, but are not sustained over longer periods. They are seen only in a fibre-deprived state and appear to be independent of the site of administration.

Animals↗