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Biomedical subjects

Simon Murch

Publications and source records attributed to Simon Murch.

14 recordsLinked to original sources
PubMed2006

Heparan sulfate plays a central role in a dynamic in vitro model of protein-losing enteropathy.

Protein-losing enteropathy (PLE), the loss of plasma proteins through the intestine, is a symptom in ostensibly unrelated diseases. Emerging commonalities indicate that genetic insufficiencies predispose for PLE and environmental insults, e.g. viral infections and inflammation, trigger PLE onset. The specific loss of heparan sulfate (HS) from the basolateral surface of intestinal epithelial cells only during episodes of PLE suggests a possible mechanistic link. In the first tissue culture model of PLE using a monolayer of intestinal epithelial HT29 cells, we proved that HS loss directly causes protein leakage and amplifies the effects of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha). Here, we extend our in vitro model to assess the individual and combined effects of HS loss, interferon gamma (IFNgamma), TNFalpha, and increased pressure, and find that HS plays a central role in the patho-mechanisms underlying PLE. Increased pressure, mimicking venous hypertension seen in post-Fontan PLE patients, substantially increased protein leakage, but HS loss, IFNgamma, or TNFalpha alone had only minor effects. However, IFNgamma up-regulated TNFR1 expression and amplified TNFalpha-induced protein leakage. IFNgamma and TNFalpha compromised the integrity of the HT29 monolayer and made it more susceptible to increased pressure. HS loss itself compromises the integrity of the monolayer, amplifying the effects of pressure, but also amplifies the effects of both cytokines. In the absence of HS a combination of increased pressure, IFNgamma, and TNFalpha caused maximum protein leakage. Soluble heparin fully compensated for HS loss, providing a reasonable explanation for patient favorable response to heparin therapy.

Albumins↗
PubMed2006

Allergy and intestinal dysmotility--evidence of genuine causal linkage?

PURPOSE OF REVIEW: The relationship between allergy and motility has been controversial. There is, however, accumulating evidence demonstrating that mucosal allergic responses may disrupt gut motility, and may also potentially alter nociceptive pathways to cause visceral hyperalgesia. RECENT FINDINGS: Experimental studies implicate T helper 2 cells and the cytokines interleukin-4 and -13 in antigen-induced dysmotility, and interleukin-5 in the pathogenesis of mucosal eosinophilia. Both mast cells and eosinophils play obligatory roles in different forms of experimental antigen-induced dysmotility. Overall clinical findings appear to implicate eosinophil infiltration in proximal and distal dysmotility syndromes (oesophageal, gastric and colorectal), and induced mast cell degranulation in mid-gut dysmotility. There is also evidence that mucosal allergic responses may induce long-term changes in visceral perception, including alteration of limbic response, leading to sustained abnormality in visceral sensation. SUMMARY: Clinical evidence implicating mucosal allergic responses in dysmotility has been extended to include disorders considered previously entirely functional, such as in some cases of irritable bowel syndrome. Only a proportion of cases are, however, caused by food allergy and a future challenge is to differentiate patients with similar symptoms, but induced by different mechanisms.

Animals↗
PubMed2006

Acquisition of competence in paediatric ileocolonoscopy with virtual endoscopy training.

This study prospectively compared the rates of skill acquisition in ileocolonoscopy in 2 consecutive groups of trainees in paediatric gastroenterology, with 1 cohort exposed to virtual endoscopy. All paediatric gastroenterology trainees rotating through our department during a 7-year period between 1997 and 2004 were formally assessed while performing ileocolonoscopies using a trainer case-by-case method. Fourteen consecutive trainees with no previous experience of ileocolonoscopy were assessed. Comparison of rates of skill acquisition and lesion recognition using multiple linear regressions revealed a significant acceleration of achievement of endoscopic goals (P < 0.0001) in the group with prior exposure to virtual endoscopy.

Child↗
PubMed2005

Carboxylated glycans mediate colitis through activation of NF-kappa B.

The role of carbohydrate modifications of glycoproteins in leukocyte trafficking is well established, but less is known concerning how glycans influence pathogenesis of inflammation. We previously identified a carboxylate modification of N-linked glycans that is recognized by S100A8, S100A9, and S100A12. The glycans are expressed on macrophages and dendritic cells of normal colonic lamina propria, and in inflammatory infiltrates in colon tissues from Crohn's disease patients. We assessed the contribution of these glycans to the development of colitis induced by CD4(+)CD45RB(high) T cell transfer to Rag1(-/-) mice. Administration of an anti-carboxylate glycan Ab markedly reduced clinical and histological disease in preventive and early therapeutic protocols. Ab treatment reduced accumulation of CD4(+) T cells in colon. This was accompanied by reduction in inflammatory cells, reduced expression of proinflammatory cytokines and of S100A8, S100A9, and receptor for advanced glycation end products. In vitro, the Ab inhibited expression of LPS-elicited cytokines and induced apoptosis of activated macrophages. It specifically blocked activation of NF-kappaB p65 in lamina propria cells of colitic mice and in activated macrophages. These results indicate that carboxylate-glycan-dependent pathways contribute to the early onset of colitis.

Animals↗
PubMed2005

Colonic Crohn's disease in children does not respond well to treatment with enteral nutrition if the ileum is not involved.

Data supporting a response to treatment with exclusive enteral nutrition in pediatric colonic Crohn's disease are few. We examined clinical and biochemical responses of ileal, colonic, and ileocolonic Crohn's disease and assessed the endoscopic and histological colonic mucosal response in the colonic and ileocolonic groups. We prospectively enrolled 65 children (age: 8-17 years) with acute intestinal Crohn's disease (Pediatric Crohn's Disease Activity Index [PCDAI] >20). After ileocolonoscopy, gastroscopy, and a barium meal and follow-through, they were distributed into three groups (ileal, n = 12, ileocolonic, n = 39; and colonic, n = 14). All patients received exclusive polymeric feed as treatment, with a repeat endoscopy at completion of treatment. At enrollment the ileal group had significantly less severe disease (P = 0.05) compared to the colonic and ileocolonic groups. However, the colonic disease group showed the least fall in PCDAI scores at completion of treatment with enteral nutrition (P = 0.03), with the lowest remission rate (50%, vs 82.1% in the ileocolonic and 91.7% in the ileal group [chi2 test, P = 0.021]). Endoscopic and histologic colonic mucosal assessment showed a post-treatment improvement in the ileocolonic (P < or = 0.01) but not in the colonic disease group (P = ns). Children with disease in the colon respond better to enteral nutrition if the ileum is also involved. This may be due to different underlying inflammatory mechanisms. Detailed pretreatment assessment in studies of Crohn's disease according to disease distribution with appropriate individualized tailoring of treatment may be important in this regard.

Adolescent↗
PubMed2004

Heparan sulfate depletion amplifies TNF-alpha-induced protein leakage in an in vitro model of protein-losing enteropathy.

Protein-losing enteropathy (PLE), the excessive loss of plasma proteins through the intestine, often correlates with the episodic loss of heparan sulfate (HS) proteoglycans (HSPG) from the basolateral surface of intestinal epithelial cells. PLE onset is often associated with a proinflammatory state. We investigated whether loss of HS or treatment with the proinflammatory cytokine TNF-alpha directly causes protein leakage and whether a combination of both exacerbates this process. We established the first in vitro model of PLE and measured the flux of albumin/FITC through a monolayer of intestinal HT29 or Caco-2 cells grown on transwells and determined the integrity by transepithelial electrical resistance (TER). Loss of HS from the basolateral surface, either by heparanase digestion or by inhibition of HS synthesis, increased albumin flux 1.58 +/- 0.09-fold and reduced TER by 23.4 +/- 6.5%. TNF-alpha treatment increased albumin flux 4.04 +/- 0.03-fold and reduced TER by 75.7 +/- 4.7% but only slightly decreased HS content. The combined effects of HS loss and TNF-alpha treatment were not only additive, but synergistic, with a 7.00 +/- 0.11-fold increase in albumin flux and a 83.9 +/- 8.1% reduction of TER. Coincubation of TNF-alpha with soluble HS or heparin abolished these synergistic effects. Loss of basolateral HS directly causes protein leakage and amplifies the effects of the proinflammatory cytokine TNF-alpha. Our findings imply that loss of HSPGs renders patients more susceptible to PLE and offer a potential explanation for the favorable response some PLE patients have to heparin therapy.

Albumins↗
PubMed2004

A clinical, microbiological, and pathological study of intestinal perforation associated with typhoid fever.

One of the most serious complications of typhoid fever is intestinal perforation. Of 27 patients admitted to a provincial hospital in the Mekong Delta region of Vietnam who had gastrointestinal perforation secondary to suspected typhoid fever, 67% were male, with a median age of 23 years and a median duration of illness of 10 days. Salmonella enterica subspecies enterica serotype Typhi (S. Typhi) was isolated from 11 (41%) of 27 patients; of 27 patients, only 4 (15%) had positive cultures from gut biopsies. S. Typhi DNA was detected by polymerase chain reaction for all perforation biopsy samples. Detailed histological examination of the gastrointestinal mucosa at the site of perforation in all cases showed a combination of discrete acute and chronic inflammation. Acute inflammation at the serosal surface indicated additional tissue damage after perforation. Immunohistochemical results showed that the predominant infiltrating cell types at the site of perforation were CD68+ leukocytes (macrophages) or CD3+ leukocytes (T lymphocytes).

Adult↗
PubMed2003

Human intestinal tissue tropism of intimin epsilon O103 Escherichia coli.

Human intestinal in vitro organ culture was used to assess the tissue tropism of human isolates of Escherichia coli O103:H2 and O103:H- that express intimin epsilon. Both strains showed tropism for follicle associated epithelium and limited adhesion to other regions of the small and large intestine. This is similar to the tissue tropism shown by intimin gamma enterohaemorrhagic (EHEC) O157:H7, but distinct from that of intimin alpha enteropathogenic (EPEC) O127:H6.

Amino Acid Sequence↗
PubMed2003

Constipation with acquired megarectum in children with autism.

OBJECTIVE: Recent evidence suggests that autistic children may have significant gastrointestinal symptoms. Although constipation occurs in 2% to 5% of healthy children, its clinical diagnosis is often difficult in children with behavioral disorders. We thus aimed to assess the prevalence of fecal loading in autistic children with gastrointestinal symptoms and to identify possible predictors of constipation. METHODS: We studied abdominal radiographs of 103 autistic children (87 boys) who were referred for gastroenterological assessment, in comparison with 29 control radiographs from children who were referred to the emergency department, most with abdominal pain. Radiographs were scored independently, in blinded manner, by 4 pediatric gastroenterologists and a radiologist. The severity of constipation was determined using a validated index. Details of stool habit, abdominal pain, dietary history, and laxative use were obtained from case notes. RESULTS: The incidence of constipation in the control subjects with abdominal pain was higher than reported for normal children. Despite this, moderate or severe constipation was more frequent in the autistic group than in the control subjects (36% vs 10%). Analysis of rectosigmoid loading showed more striking differences (54.4% of autistic children had moderate/severe loading or acquired megarectum compared with 24.1% of control subjects). Multivariate regression analysis showed consumption of milk to be the strongest predictor of constipation in the autistic group, whereas stool frequency, gluten consumption, soiling, and abdominal pain were not predictive of constipation. CONCLUSIONS: Constipation is a frequent finding in children with gastrointestinal symptoms and autism, particularly in the rectosigmoid colon, often with acquired megarectum. The absence of any correlation between the clinical history and the degree of fecal impaction in autistic children confirms the importance of an abdominal radiograph in the assessment of their degree of constipation.

Abdominal Pain↗