Strains of Bacteroides vulgatus from a variety of sources were tested for their abilities to enhance the inflammatory response in an experimental model for ulcerative colitis. Although there were considerable differences noted in inflammatory responses when guinea pigs were immunized with the various strains, there did not appear to be any correlation between the source of the isolates and the severity of the carrageenan-induced lesions. Strains from patients with ulcerative colitis were no more active in the model system than were strains from patients with antibiotic-associated colitis or strains from a healthy human source. The antibody titer to the strain used for immunization did not correlate with the severity of the cecal ulcerations, as determined by histopathologic evaluation.
Previous experiments with the carrageenan model for ulcerative colitis have shown that the inflammatory response in guinea pigs can be enhanced by immunization with and subsequent feeding of Bacteroides vulgatus to experimental animals. The present studies showed that only certain strains of B. vulgatus are capable of provoking immune enhancement of ulcerative colitis. Animals were fed carrageenan and various strains of viable B. vulgatus after immunization with a strain of B. vulgatus isolated from a guinea pig with experimentally induced colitis. Histological comparison of immune and nonimmune groups revealed that immune animals which received B. vulgatus from a patient with inflammatory bowel disease had a significantly (P less than 0.025) greater number of histopathological lesions at 21 days than did nonimmune animals. Immune animals receiving B. vulgatus isolated from a clinically normal source did not show any significant difference in disease status when compared to nonimmune animals. Additional experiments showed that adoptive transfer of spleen cells from animals immunized with B. vulgatus to nonimmune recipient animals is effective in transferring the immune enhancement demonstrated in actively immunized animals. Animals which received immune spleen cells with concurrent feeding of B. vulgatus showed a significant (P less than 0.005) increase in inflammation over control groups...
To investigate the theory of hypersensitivity in the colonic mucosa of Asian patients with ulcerative colitis the rectal biopsy specimens of Asian and Caucasian patients presenting with colitis were selectively stained for both eosinophils and mast cells. Comparisons between ethnic groups were made as well as the correlation to the blood eosinophil count and two variables of active ulcerative colitis--the blood leucocyte count and serum orosomucoid concentration. No correlation was found in either group between circulating and tissue eosinophils and no ethnic difference was identified in the lamina propria differential cell densities. The leucocyte count and serum orosomucoid concentrations, however, were significantly higher in the Caucasians. In the Asian group a strong negative association was found between the lamina propria eosinophil density and serum orosomucoids; in the Caucasian group there was a positive association between all blood variables. It is concluded that different mechanisms occur in the two ethnic groups and in Asians these might not be reflected by the more orthodox indices of colonic inflammation.
In a prospective study of 100 patients with ulcerative colitis, 82 of whom had extensive colitis, carcinoma and dysplasia were distinguished cytologically from reactive hyperplasia. Six patients had carcinoma complicating colitis and satisfactory samples were obtained from five; the cytological appearances were interpreted as carcinoma in three and as dysplasia in two. Seventy eight patients had not developed carcinoma or dysplasia; the cytological appearances were interpreted as negative for dysplasia in 75 and indefinite for dysplasia in three. In patients who had developed dysplasia the changes seemed to be more widespread on cytological rather than on histological examination. Brush cytology may complement histological assessment in patients with ulcerative colitis who have developed strictures or in whom there is a high suspicion of neoplastic change.
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.
The deoxyribonucleic (DNA) content was measured by microspectrophotometry in 100 specimens from 60 patients with ulcerative colitis, including six patients in whom the colitis was associated with carcinoma. Some 23 of 30 (77%) specimens of dysplastic tissue showed aneuploidy or polyploidy, whereas 50 of 53 (94%) specimens of non-dysplastic tissue showed diploidy. The difference was statistically significant (p less than 0.001). Polyploidy was often observed in non-dysplastic mucosa from patients who had carcinoma or dysplasia. In the non-dysplastic patients all samples of inflamed tissue showed diploidy. Some 10% of samples without inflammation, however, also showed polyploidy. A good correlation was found between the frequency of polyploid cells and the grade of dysplasia. Microspectrophotometric measurement of DNA content proved useful in the assessment and diagnosis of dysplasia in ulcerative colitis and could be considered for screening high risk patients.
Proximal faecal stasis may occur when faecal matter accumulates in the uninflamed colon above an area of active ulcerative colitis. This phenomenon is thought to be the cause of symptoms in some patients with distal disease. It is not known, however, how often patients with active distal colitis exhibit slow colonic transit. Fifty two consecutive patients with active ulcerative colitis each ingested 10 radio-opaque markers nightly for 14 days. Minimum colonic transit times were derived from counts of retained markers shown by plain abdominal radiography on the 15th day. The transit times for each patient were related to their disease extent and bowel frequency. Four patients had colonic transit times greater than one week and two others had evidence of relative stasis. The results indicate that approximately 10% of attacks of distal colitis are associated with faecal stasis.
Two hundred thirty-four patients with extensive ulcerative colitis from the city of Göteborg, Sweden have been followed up and the cumulative risk of development of cancer of the large bowel was estimated. These patients constitute all persons in this region who developed an extensive ulcerative colitis between 1951 and 1974. All patients were followed up until December 1975. The mean observation time was 8.5 years, median value six years. Fifteen patients developed carcinoma of the large bowel. Five of the 15 patients were still alive in December 1975. The expected number of colorectal carcinomas in a matched reference group was 0.49. The cumulative incidence of carcinoma 25 years after the onset of colitis for the whole group of patients was 34% and for those who developed the disease before 25 years of age it was 43%.
A case of pyostomatitis vegetans and ulcerative colitis in a 26-year-old African is described. The colitis, confirmed clinically and radiologically, antedated the development of pyostomatitis. Systemic corticosteroids apparently cured the pyostomatitis but only caused an improvement in the ulcerative colitis.
The relationship of pyoderma gangrenosum and ulcerative colitis remains uncertain. We investigating 14 patients with pyoderma gangrenosum by colonoscopy with multiple biopsies. Six patients had ulcerative colitis and all of these had disease affecting the whole colon. There were no correlations between exacerbations of the colitis and the onset or course of pyoderma gangrenosum. The remaining eight patients with pyoderma gangrenosum had no other disease and they were found to be significantly older than those patients with coexisting colitis (P less than 0.002).
Ulcerative colitis has a number of associated skin lesions. We report the case of a patient with active ulcerative disease presenting with rapidly progressive necrotic skin lesions, identified as thrombotic and requiring skin grafting. Thrombotic cutaneous gangrene is a rare but potentially serious manifestation of uncontrolled ulcerative colitis.
Two cases of co-existing thyroid disease and ulcerative colitis are reported. Thyroid disorder preceded ulcerative colitis in each case. The presence of acute colitis delayed and obscured the clinical diagnosis of thyrotoxicosis in one case and the colitis could not be controlled until her thyrotoxicosis was treated. Although the specific factors involved in this relationship are now known, an interplay of immunological factors is most probable.
Dextran sodium sulfate (DSS)-induced colitis is widely used to study pathological mechanisms and potential treatments of inflammatory bowel disease. Because temporal changes in genome expression profiles remain unknown in this model, we performed whole genome expression profile analysis during the development of DSS colitis in comparison with ulcerative colitis (UC) specimens to identify novel and common responses during disease. Colon tissue from DSS-treated mice was collected at days 0, 2, 4, and 6. Half of each specimen was used for histopathological analysis and half for Affymetrix whole genome expression profiling and qRT-PCR validation. Genesifter and Ingenuity software analysis was used to identify differentially expressed genes and perform interactive network analysis. Identified DSS-associated genes in mice were also compared with UC patient data. We identified 1,609 genes that were significantly altered during DSS colitis; the majority were functionally related to inflammation, angiogenesis, metabolism, biological adhesion, cellular growth and proliferation, and cell-to-cell signaling responses. Five hundred and one genes were progressively upregulated, while one hundred seventy-three genes were progressively downregulated. Changes in gene expression were validated in a subset of 33 genes by qRT-PCR...
Intestinal epithelial cell (IEC) apoptosis contributes to the development of ulcerative colitis (UC), an inflammatory bowel disease (IBD) that affects the colon and rectum. Therapies that target the inflammatory cytokine TNF have been found to inhibit IEC apoptosis in patients with IBD, although the mechanism of IEC apoptosis remains unclear. We therefore investigated the role of p53-upregulated modulator of apoptosis (PUMA), a p53 target and proapoptotic BH3-only protein, in colitis and IEC apoptosis, using patient samples and mouse models of UC. In UC patient samples, PUMA expression was elevated in colitis tissues relative to that in uninvolved tissues, and the degree of elevation of PUMA expression correlated with the severity of colitis and the degree of apoptosis induction. In mice, PUMA was markedly induced in colonic epithelial cells following induction of colitis by either dextran sulfate sodium salt (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). The induction of PUMA was p53-independent but required NF-κB. Absence of PUMA, but neither absence of p53 nor that of another BH3-only protein (Bid), relieved DSS- and TNBS-induced colitis and inhibited IEC apoptosis. Furthermore, treating mice with infliximab (Remicade), a clinically used TNF-specific antibody...
A case of Hodgkin lymphoma located in the rectum of a patient with ulcerative colitis is described. The patient was a 44 year old male treated with thiopurines for ulcerative colitis for ten years. He was admitted with malaise, weight loss and abdominal pain. Endoscopy revealed a large ulcerative lesion involving the rectum and distal part of the sigmoid colon. Although it macroscopically resembled a rectal cancer, repeated biopsies did not reveal any malignancy. In order to resolve the symptoms of stenosis and to get the final diagnosis a recto-sigmoid resection was performed. Pathologic examination revealed nodular sclerosis classical Hodgkin lymphoma, positive for Epstein Barr Virus. Subsequent examination revealed disseminated disease involving the pelvic wall, liver, and bone marrow. The patient is currently receiving chemotherapeutic treatment, and follow-up shows disease remission.
The results of the first 9 patients with proctocolectomy and ileal pouch operated on between 1983 and 1990 were analysed. This procedure was carried out in 8 patients with adenomatous polyposis. Three of these patients had an associated rectal cancer and one a degenerated sigmoid polyp. One patient had ulcerative colitis and was previously submitted to a colectomy related with perforated fulminant colitis. Three types of pouches were constructed: 3 S, 3 J and 3W, all with a temporary ileostomy. A circular stapler was used in 2 cases for ileoanal anastomosis. Three postoperative complications were observed: two patients with pouchitis during the presence of a diverting ileostomy and an ileal fistula following ileostomy closure, all medically treated. Clinical and functional results were evaluated 1 to 7 years after the procedure. The average daytime stool frequency was 4 with 1 nocturnal. All patients indicated normal continence. One patient had her professional life affected due to the increased number of defecations. Differences in the clinical results of the patients with S, J and W pouches were not statistically different. The functional results expressed as median and range were as follows: resting and pressure 45 cm H2O (20-60)...
An eight year endoscopical and histological cancer surveillance programme comprising 71 patients with ulcerative colitis is presented. Forty one patients had total colitis and 30 substantial colitis. Mean duration of the disease was 19.7 years (range 9-46 years). An average of 2.6 colonoscopies per patient in the total colitis group were carried out, and at least two biopsies were taken at 10 locations in the colon. In the total colitis group, seven had either low (four), or high grade dysplasia (two), or Dukes' A cancer (one). In the group with substantial colitis two patients with low grade dysplasia were found. Dysplasia or cancer leading to operation was found above the rectum in four of five operated patients, all having had total colitis for 25 to 44 years. The dysplasia and cancer findings at the colonoscopy preceding surgery corresponded well with the surgical specimens. In three operated patients a sequence of dysplasia development was recorded. With the exception of long duration and dysplasia, nothing in the clinical course distinguished the operated cases. Using this surveillance programme prophylactic colectomy can be limited to patients in a high risk group developing dysplasia. The risk of missing a cancer before it becomes incurable seems to be low.
To examine pharmacokinetics and tolerance of long term administration of olsalazine (azodisalicylate), increasing doses of the drug were given for one year to 31 patients with ulcerative colitis (UC) and nine patients with Crohn's colitis (CC), refractory to, or intolerant of sulphasalazine, until sustained remission was obtained or a maximum of 4 g/day was reached. Colonic drug metabolism was studied by equilibrium in vivo dialysis of faeces. Complete azoreduction occurred in most cases. Concentrations of 5-aminosalicylic acid, but not N-acetyl-5-aminosalicylic acid, in faecal dialysates increased dose dependently. Serum concentrations disclosed no cumulation in the long term and olsalazine was well tolerated, although loose stools occurred transiently in some patients with extensive disease: this was associated with a larger proportion of unsplit olsalazine in the faecal dialysates. Patients with ulcerative colitis having a high prostaglandin E2 concentration (greater than ng/ml) determined by equilibrium dialysis of rectum, were less likely to benefit from treatment. Olsalazine is a very effective means of delivery of 5-aminosalicylic acid to the colonic mucosa in active disease. Use of the drug in controlled trials may be considered safe even in prolonged high dosage.
Morphological and functional changes in the enteric nervous system (ENS) have been reported in inflammatory bowel disease. We examined the effects of inflammation on the expression of choline acetyltransferase (ChAT) and nNOS in the muscularis externae of two models of colonic inflammation, trinitrobenzene sulfonic acid (TNBS)-induced colitis, which models Crohn's disease-like inflammation, and DSS-induced colitis, which models ulcerative Colitis-like inflammation. In TNBS colitis, we observed significant decline in ChAT, nNOS, and protein gene product (PGP) 9.5 protein and mRNA levels. In DSS colitis, ChAT and PGP9.5 were significantly upregulated while nNOS levels did not change. The nNOS dimer-to-monomer ratio decreased significantly in DSS- but not in TNBS-induced colitis. No differences were observed in the percentage of either ChAT (31 vs. 33%)- or nNOS (37 vs. 41%)-immunopositive neurons per ganglia or the mean number of neurons per ganglia (55 ± 5 vs. 59 ± 5, P > 0.05). Incubation of the distal colon muscularis externae in vitro with different types of inflammatory mediators showed that cytokines decreased ChAT and nNOS expression, whereas H2O2, a component of oxidative stress, increased their expression. NF-κB inhibitor MG-132 did not prevent the IL-1β-induced decline in either ChAT or nNOS expression. These findings showed that TNBS- and DSS-induced inflammation differentially regulates the expression of two critical proteins expressed in the colonic myenteric neurons. These differences are likely due to the exposure of the myenteric plexus neurons to different combinations of Th1-type inflammatory mediators and H2O2 in each model.
An immunological study of B cells in patients with colitis that was associated with Hirschsprung's disease was undertaken and compared with that in patients with ulcerative colitis and in normal controls. There was an appreciable increase in IgA and a decrease in IgG in both disease groups. Humoral reaction in colitis associated with Hirschsprung's disease seems to be indistinguishable from that in ulcerative colitis and possibly in other inflammatory bowel diseases.