Browsing by Author "Jewell, D.P."

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Acute inflammation in ideal pouches(pouchitis)
(Lippincott Williams And Wilkins, 1991) de Silva, H.J.; Kettlewell, M.; Mortensen, N.J.; Jewell, D.P.
The Association of autoimmune disorders with inflammatory bowel disease
(Oxford University Press, 1989) Snook, J.A.; de Silva, H.J.; Jewell, D.P.
Medical records of patients with ulcerative colitis (n = 858), Crohn's disease (n = 378) and coeliac disease (n = 148) were examined to determine the prevalence of associated autoimmune disorders. Of outpatient controls (n = 300), 2 per cent had at least one autoimmune disorder, compared to 7 per cent with ulcerative colitis, 2 per cent with Crohn's disease and 6 per cent with coeliac disease. Inclusion of primary sclerosing cholangitis with the autoimmune disorders increased the overall prevalence in ulcerative colitis to over 9 per cent. The results provide further indirect evidence of involvement of autoimmune mechanisms in the pathogenesis of ulcerative colitis
Clinical and functional outcome after restorative proctocolectomy
(1991) de Silva, H.J.; de Angelis, C.P.; Soper, N.; Kettlewell, M.G.; Mortensen, N.J.; Jewell, D.P.
Restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) has been carried out on 88 patients since 1982. Three different pouch designs (J, S and W) were used. Ten pouches had to be removed. Detailed analysis was performed on 61 patients (J = 23, S = 15, W = 23) whose pouches had been functioning for at least 6 months. There was no significant difference in surgical complications before or after ileostomy closure between pouch designs but the hospital stay was greater after construction of an S pouch (P less than 0.05). There were no significant differences in stool frequency, degree of continence or urgency between the three types. Twelve patients with J pouches required antidiarrhoeal medication compared with only one with S and five with W pouches. Only seven patients with S pouches could defaecate spontaneously compared with 22 with W pouches and all patients with J pouches (P less than 0.001). Twenty-five of 29 patients who had preservation of the anal transition zone had perfect continence compared with 23 of 32 with a mucosal proctectomy (P = n.s.). Pouchitis occurred in 13 patients, all of whom had ulcerative colitis. In a subgroup of 23 patients, pouch evacuation was assessed scintigraphically. There was no difference in pouch capacity or total volume evacuated, but spontaneous evacuation was better in J and W pouches compared with S pouches
Crypt cell proliferation and HLA-DR expression in pelvic ileal pouches
(BMJ Publishing Group, 1990) de Silva, H.J.; Gatter, K.C.; Millard, P.R.; Kettlewell, M.; Mortensen, N.J.; Jewell, D.P.
To investigate the nature of the morphological changes that occur in ileal pouches, 26 biopsy specimens from patients with functioning ileo-anal pouches (eight with pouchitis) were studied. Normal ileum (n = 10) was used as a control. Mucosal morphometry (using linear measurements), crypt cell proliferation (CCP) (using the monoclonal antibody Ki67), and epithelial HLA-DR expression (monoclonal antibody CR3/43) were assessed. CCP (expressed as the percentage of Ki67 positive nuclei for each crypt) was significantly higher in pouches with pouchitis, compared with those without, and in pouches without pouchitis compared with normal ileum. CCP values in some pouches without pouchitis approached values found in those with pouchitis. CCP was related inversely to villous height and an index of villous atrophy (VH/TMT), and directly to crypt depth. In the presence of pouchitis there was intense epithelial HLA-DR expression that extended into the crypts. In some pouches with high CCP values, but without clinically important inflammation, surface epithelial HLA-DR expression was weak and patchy. It is concluded that villous atrophy and crypt hyperplasia in ileal pouches are associated with high CCP values. These may be increased even in the absence of active inflammation, and this increase may occur as a response to the new luminal environment.
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.
Effects of the faecal stream and stasis on the ileal pouch mucosa
(British Medical Assosiation, 1991) de Silva, H.J.; Millard, P.R.; Soper, N.; Kettlewell, M.; Mortensen, N.; Jewell, D.P.
This study aimed to investigate the effects of the faecal stream and stasis on the mucosa of ileal pouches. Nine patients were followed up. Two pouch biopsy specimens were obtained from each at the time of pouch formation, ileostomy closure, and three, six, and 12 months after operation. None developed pouchitis. Two pouch biopsy specimens each were also obtained from 20 patients (six with pouchitis), whose pouches had been functioning for at least a year and in whom pouch evacuation was assessed by radioisotope labelled artificial stool. Biopsy specimens were assessed for the degree of acute and chronic inflammation, mucin type (high iron diamine-alcian blue stain), a morphometric index of villous atrophy (villous height:total mucosal thickness), and crypt cell proliferation (using the monoclonal antibody Ki67). Mean values from the two biopsy specimens were obtained for each parameter. After three months of pouch function, the scores for acute and chronic inflammation, the degree of sulphomucin, and crypt cell proliferation were significantly higher, and the index of villous atrophy was significantly lower (indicating a greater degree of villous atrophy), than at pouch formation or at ileostomy closure. The values at pouch formation and ileostomy closure were similar. For all parameters, the changes seen at six and 12 months were not significantly different from those at three months. There was no significant correlation between the efficiency of pouch evacuation and any of the mucosal changes. It is concluded that exposure to the faecal stream is necessary for changes to take place in the pouch mucosa, although the amount of stasis, as measured by radioisotopic evacuation studies, seems to be irrelevant. The mucosal changes occur soon after ileostomy closure and then remain stable for at least one year.
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.
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 available
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.
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.
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.
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.
Mucosal characteristics of pelvic ileal pouches
(British Medical Assosiation, 1991) de Silva, H.J.; Millard, P.R.; Kettlewell, M.; Mortensen, N.J.; Prince, C.; Jewell, D.P.
This study aimed to investigate the degree of colonic metaplasia in ileo - anal pouches. Biopsy specimens from 25 patients with functioning pouches, eight of whom had pouchitis, were studied using routine histology, mucosal morphometry, mucin histochemistry, and immunoperoxidase staining with monoclonal antibodies directed towards a 40kD colonic protein and a small bowel specific disaccharidase-sucrase isomaltase. Thirteen patients (including all eight with pouchitis) had subtotal or total villous atrophy and crypt hyperplasia. In this group, nine had colorectal type sulphomucin and the 40kD colonic protein was detected in two. These changes were not observed in patients with less severe villous abnormalities. Sucrase-isomaltase activity was, however, present in all 25 pouch specimens. We conclude that although some ileal pouches acquire certain colonic characteristics, complete colonic metaplasia does not occur.
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 remission
Short-chain fatty acid irrigation in severe pouchitis
(Massachusetts Medical Society, 1989) de Silva, H.J.; Ireland, A.; Kettlewell, M.; Mortensen, N.; Jewell, D.P.
No Abstract available
Sub clinical intestinal mucosal inflammation in diarrhea predominant Irritable Bowel Syndrome (IBS) in a tropical setting
(American Gastroenterological Association(AGA) Institute, Published by Elsevier Inc., 2010) de Silva, A.P.; Manamperi, A.; Hewavisenthi, S.J.de S.; Ariyasinghe, M.P.; Dassanayake, A.S.; Jewell, D.P.; de Silva, H.J.
BACKGROUND: There is evidence for potential roles for gut flora and the host immune response in the pathophysiology of IBS, and especially, for low grade colonic mucosal inflammation in the pathophysiology of post-infectious IBS. AIM: To investigate for evidence of sub-clinical intestinal mucosal inflammation in diarrhea- predominant IBS (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. None had alarm symptoms: unintentional significant loss of weight, bleeding per rectum or malaena. None were on NSAIDS or proton pump inhibitors. All patients had normal ESR, CRP, TSH and stools reports. 14 individuals with a family history of colon cancer [median age 46.5 years (range 23-56); median 46.5, M:F 6:8] were selected as controls. Stools of patients and controls were tested for calprotectin. During colonoscopy, serial biopsies were obtained from the ileum, caecum, ascending, transverse and descending colon, and rectum. In addition to histology, 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). Histology was normal in others. A history suggestive of an episode of infectious diarrhea (ID) was seen in 16/49 cases and 0/14 controls (p=0.013). There was no significant association between ID and the presence of MNOS. 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 (0.63-1.3), 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). In patients with IBS-D, cytokine abnormalities were not significantly different in those with or without a history of ID or the presence or absence of MNOS. CONCLUSION: There is evidence for subclinical intestinal mucosal inflammation in patients with IBS-D in a tropical setting, whether or not a history of ID or MNOS was present or absent.
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.
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.