Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Subclinical intestinal mucosal inflammation in diarrhoea predominant irritable bowel syndrome in a tropical setting(Sri Lanka Medical Association, 2010) de Silva, A.P.; Mannamperi, A.; Ariyasinghe, M.P.; Nandaslri, A.S.D.; Hewavisenthi, J.; Dassanayake, A.S.; Jewell, D.P.; de Silva, H.J.OBJECTIVES: There has been increasing evidence to support an inflammatory pathology in irritable bowel syndrome (IBS), especially diarrhoea predominant type (IBS-D).The aim of this study was to investigate for evidence of intestinal mucosal inflammation in IBS-D in a tropical setting. METHODS: In a prospective study over one year, we investigated 49 patients with IBS-D [median age 34 years (range 18-59; M: F 36:13], based on Rome III criteria and 14 controls [median age 46.5 years (range 23-56); M: F 6:8]. None had alarm symptoms, were on NSAIDS or PPIs. All patients had normal ESR, CRP, TSH and stools reports. Stools of all subjects were tested for calprotectin. During colonoscopy, serial biopsies were obtained.Tissue expression of IL-8 and IL-10 were assessed in biopsy specimens using semi-quantitative RT-PCR. RESULTS: Colono-ileoscopy was macroscopically normal and faecal calprotectin was undetectable in cases and controls. Microscopic colitis not otherwise specified (MNOS) was seen in 10/49 cases and 1/14 controls (p=0.43, Fisher's Exact test). A history suggestive of an episode of infectious diarrhoea (ID) was seen in 16/49 cases and 0/14 controls (p=0.013). Tissue expression of IL-8 was significantly higher and IL-10 significantly lower in cases compared to controls (target/standard cDNA ratio, median (range) IL-8: 1.25 (0.75-2) vs 0.85 (0.63-1.37), p<0.0001, Mann-Whitney U test; IL-10: 0.33 (0-0.63) vs 0.55 (0.5-0.7), p<0.0001). There was a significant inverse correlation between IL-8 and IL-10 expression (Pearson Correlation, (-) 0.509; p<0.01). CONCLUSIONS: There is evidence for sub-clinical intestinal mucosal inflammation in patients with IBS-D in a tropical setting, whether a history of ID or MNOS was present or absent.Item Subclinical mucosal inflammation in diarrhea-predominant irritable bowel syndrome (IBS) in a tropical setting(Informa Healthcare, 2012) de Silva, A.P.; Nandasiri, S.D.; Hewavisenthi, J.; Manamperi, A.; Ariyasinghe, M.P.; Dassanayake, A.S.; Jewell, D.P.; de Silva, H.J.BACKGROUND AND AIMS: There is evidence for low-grade inflammation in the pathophysiology of post-infectious irritable bowel syndrome (IBS). We assessed the degree of subclinical intestinal mucosal inflammation in diarrhea-predominant IBS (IBS-D) in a tropical setting. MATERIAL AND METHODS: In a prospective study over 1 year, we investigated 49 patients with IBS-D (cases; median age 34 years (range 18-59); M:F 36:13), diagnosed on Rome III criteria. 14 individuals with a family history of colon cancer (median age 46.5 years (range 23-56); M:F 6:8) were selected as controls. Stools of cases and controls were tested for calprotectin. During colonoileoscopy, serial biopsies were obtained. Mucosal mast cells, neutrophils, eosinophils and lymphocytes/plasma cell infiltrate were quantified. Tissue expression of IL-8 and IL-10 was assessed in biopsies by semi-quantitative RT-PCR. RESULTS: A history suggestive of an episode of infectious diarrhea (ID) was present in 16/49 cases and 0/14 controls (p = 0.013). In cases, there were significantly more mucosal mast cells in the ileum and all segments of colon and significantly more eosinophils in the cecum. Tissue expression of IL-8 was significantly higher and IL-10 significantly lower in cases compared with controls (target/standard cDNA ratio, median (range) IL-8: 1.25 (0.75-2) vs. 0.85 (0.63-1.3), p < 0.0001, Mann-Whitney U test; IL-10: 0.33 (0-0.63) vs. 0.55 (0.5-0.7), p < 0.0001). There was a significant inverse correlation between IL-8 and IL-10 expression (Pearson correlation, (-) 0.509; p < 0.01). CONCLUSION: There was evidence of subclinical intestinal mucosal inflammation in patients with IBS-D. The finding of increased eosinophils is novel, and may be of special relevance to IBS-D in the tropics.Item Emergence of inflammatory bowel disease 'beyond the West': do prosperity and improved hygiene have a role?(Oxford University Press, 2008) de Silva, H.J.; de Silva, N.R.; de Silva, A.P.; Jewell, D.P.Inflammatory bowel disease (IBD) is increasing in many countries 'beyond the West'. This increase may be due to an increased rate of diagnosis but might also represent a true increase in incidence. Economic development, leading to improved hygiene and other changes in lifestyle, may play a role in the increase in IBD. However, the marked difference in prevalence between ethnic groups suggests that the genetic background of populations may also be relevant and supports the current hypothesis that IBD represents an interaction between environmental factors and a genetically susceptible host. Investigating the early stages of IBD as it emerges in new populations may provide new clues to its pathophysiology.Item Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors(Oxford University Press, 2002) van Heel, D.A.; Udalova, I.A.; de Silva, A.P.; McGovern, D.P.; Kinouchi, Y.; Hull, J.; Lench, N.J.; Cardon, L.R.; Carey, A.H.; Jewell, D.P.; Kwiatkowski, D.Tumour necrosis factor-alpha (TNF) expression is increased in inflammatory bowel disease (IBD), and TNF maps to the IBD3 susceptibility locus. Transmission disequilibrium and case-control analyses, in two independent Caucasian cohorts, showed a novel association of the TNF(-857C) promoter polymorphism with IBD (overall P=0.001 in 587 IBD families). Further genetic associations of TNF(-857C) with IBD sub-phenotypes were seen for ulcerative colitis and for Crohn's disease, but only in patients not carrying common NOD2 mutations. The genetic data suggest a recessive model of inheritance, and we observed ex vivo lipopolysaccharide-stimulated whole-blood TNF production to be higher in healthy TNF(-857C) homozygotes. We show the transcription factor OCT1 binds TNF(-857T) but not TNF(-857C), and interacts in vitro and in vivo with the pro-inflammatoryNF(-kappa)B transcription factor p65 subunit at an adjacent binding site. Detailed functional analyses of these interactions in gut macrophages, in addition to further genetic mapping of this gene-dense region, will be critical to understand the significance of the observed association of TNF(-857C) with IBD.Item The Molecular classification of the clinical manifestations of Crohn's Disease.(Elsevier-W.B. Saunders, 2002) Ahamad, T.; Armuzzi, A.; Bunce, M.; Mulcahy-Hawes, K.; Marshall, S.E.; Orchard, T.R.; Crawshaw, J.; Large, O.; de Silva, A.; Cook, J.T.; Barnardo, M.; Cullen, S.; Welsh, K.I.; Jewell, D.P.BACKGROUND & AIMS: Crohn's disease is a common inflammatory disorder of the gut characterized by variation in both location and behavior. Chromosome 16 and the HLA region on chromosome 6 have been implicated in susceptibility to disease. Mutations in the NOD2/CARD15 gene, recently identified on chromosome 16, have been associated with disease overall but are found in only 25% of patients. No data regarding their contribution to specific disease subtypes exist. Here we report a detailed genotype-phenotype analysis of 244 accurately characterized patients. METHODS: A total of 244 white patients with Crohn's disease recruited from a single center in the United Kingdom were studied. All patients were rigorously phenotyped and followed-up for a median time of 16 years. By using linkage disequilibrium mapping we studied 340 polymorphisms in 24 HLA genes and 3 NOD2/CARD15 polymorphisms. RESULTS: We show that NOD2/CARD15 mutations determine ileal disease only. We confirm that alleles on specific long-range HLA haplotypes determine overall susceptibility and describe novel genetic associations with susceptibility, location, and behavior of Crohn's disease. CONCLUSIONS: The clinical pattern of Crohn's disease may be defined by specific genotypes. This study may provide the basis for a future molecular classification of disease.Item Eosinophilic granulomatous vasculitis mimicking a gastric neoplasmn(Blackwell Scientific Publications, 1999) Premaratna, R.; Saparamadu, A.; Samarasekera, D.N.; Warren, B.; Jewell, D.P.; de Silva, H.J.No Abstract availableItem Optimum dose of olsalazine for maintaining remission in ulcerative colitis(British Medical Assosiation, 1994) Travis, S.P.L.; Tysk, C.; de Silva, H.J.; Sandberg-Gertzen, H.; Jewell, D.P.; Jarnerot, G.To evaluate the optimum dose of olsalazine for maintaining remission in ulcerative colitis, 198 patients in remission for more than three months were randomly assigned to receive 0.5 g, 1.0 g, or 2.0 g/day for 12 months. A dose-ranging effect was detected in the per protocol analysis, with remission rates of 60% (0.5 g), 70% (1.0 g), and 78% (2.0 g) (p = 0.03, trend in proportions). The higher dose was most effective in patients with proctitis (90% remission on 2 g/day, p = 0.03) or those in remission for less than 12 months before the trial (88% remission on 2 g/day, p = 0.0006). There was little dose-ranging effect in patients with extensive colitis or those in remission for more than 12 months. Diarrhoea necessitated treatment withdrawal in 12%. The optimal dose of olsalazine for maintaining remission in ulcerative colitis is 1 g/day. For patients with proctitis or recent relapse, 2 g/day may be preferable, although the dose seems to be less important in patients with more extensive disease or those in long term remissionItem Cytokine production by human colonic intraepithelial lymphocytes in controls and ulcerative colitis(Hindawi Publishing Cooperation, 1994) Hoang, P.; Dalton, H.R.; de Silva, H.J.; Jewell, D.P.Using an ELISA technique, concentrations of gamma-interferon and interleukin-2 were assayed in the supernatants of colonic intraepithelial lymphocytes cultured with or without phytohaemagglutinin (PHA). IntraepitheHal lymphocytes produced low concentrations of gamma-interferon and interleukin-2 when stimulated with PHA, but significantly more than when unstimulated (p < 0.05). There was no difference in production of these cytokines by IEL from control or inflammatory bowel disease.Item Immune activation during cerebellar dysfunction following Plasmodium falciparum malaria(Oxford University Press, 1992) de Silva, H.J.; Hoang, P.; Dalton, H.; de Silva, N.R.; Jewell, D.P.; Peiris, J.B.Evidence for immune activation was investigated in 12 patients with a rare syndrome of self-limiting, delayed onset cerebellar dysfunction following an attack of falciparum malaria which occurred 18-26 d previously. Concentrations of tumour necrosis factor, interleukin 6 and interleukin 2 were all significantly higher in serum samples of patients during cerebellar ataxia than in recovery sera and in the sera of 8 patients who did not develop delayed cerebellar dysfunction following an attack of falciparum malaria. Cytokine concentrations in the cerebrospinal fluid were also significantly higher in ataxic patients than in controls. These findings suggest that immunological mechanisms may play a role in delayed cerebellar dysfunction following falciparum malaria.Item Lymphocyte and macrophage subpopulations in pelvic ileal pouches(British Medical Assosiation, 1991) de Silva, H.J.; Jones, M.; Prince, C.; Kettlewell, M.; Mortensen, N.J.; Jewell, D.P.This study aimed to characterise the mucosal cellular infiltrate in ileal reservoirs with and without pouchitis (reservoir ileitis). Intraepithelial lymphocyte counts were performed in biopsy specimens obtained from ileal pouches and compared with counts in normal ileum and normal colon. T lymphocyte and macrophage subpopulations were characterised immunohistochemically in pouch biopsy specimens using a panel of monoclonal antibodies. Normal ileum was used as a control. Intraepithelial lymphocyte densities (expressed as intraepithelial lymphocyte/100 epithelial cells) in pouches with and without pouchitis were significantly less than in normal ileum, and approached counts found in normal colon. There was no significant increase in counts even in pouchitis. There were no significant differences in the helper/inducer to suppressor/cytotoxic T cell (CD4:CD8) ratios between normal ileum and pouches with or without pouchitis, either in the epithelium or in the lamina propria. The proportions of RFD9+ (epithelioid cells and tingible body macrophages) and 3G8+ (CD16) macrophages were significantly higher in pouchitis compared with pouches without pouchitis or normal ileum. There were no significant differences between the three groups in the proportions of cells positive for the other macrophage markers (CD68, RFD1-dendritic cells, and RFD7-mature macrophages). The significance of low intraepithelial lymphocyte counts in ileal pouches is unknown, but this may be an adaptive response to the new luminal environment. Since an increase in RFD9+ macrophages occurs in inflammatory bowel disease, but does not occur as a non-specific response to an acute infective process, their presence in pouchitis suggests that effector mechanisms similar to those triggering the original ulcerative colitis may be operating in pouchitis.