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Colonic mucins in ulcerative colitis: evidence for loss of sulfation.

Colonic tissue obtained at surgery from control individuals and patients with ulcerative colitis was used to isolate mucins and to prepare mucin glycopolypeptides by pronase digestion. These were compared with mucins labelled with [35S] sulfate and [3H]-glucosamine after organ culture tissue samples from the same patients. A significant loss of mucin sulfation was detected in the colitis patients by both metabolic labelling and chemical analysis of the glycopolypeptides. A change in the size distribution of purified mucin oligosaccharides fractionated on BioGel P6 after release by beta-elimination was seen in both radiolabelled and non-labelled colitis mucins compared with controls. Amino acid analysis of the glycopolypeptides showed a close similarity to the expected ratio of serine:threonine:proline for MUC2 and did not vary between control and colitis groups. Analysis of the mucins confirmed > 90% purity in the labelling experiments, characteristic behaviour on density gradient centrifugation and agarose gel electrophoresis in control and ulcerative colitis groups and differences in sulfation and turnover at various sites in the normal colon.

Amino Acids↗

Increased phospholipase A2 activity in peritoneal leukocytes in rat experimental colitis.

Activated leukocytes in the peritoneal cavity have been shown to release phospholipase A2(PLA2) activity and increased production of eicosanoids. It is not known whether a similar phenomenon occurs in inflammatory bowel diseases. We measured PLA2 activity in the peritoneal leukocytes and eicosanoid content in the peritoneal cavity of rats with experimental colitis induced by dinitrochlorobenzene, immune complex-mediated colitis, and acetic acid-induced colitis. In all models of colitis, proteins in the peritoneal cavity were increased by 60-260% above control, leukocyte number was elevated by 3- to 10-fold, the PLA2 activity by 4- to 32-fold, and anti-PLA2 activity was absent. Eicosanoid concentrations were 3- to 4-fold higher than controls. In vitro studies confirmed that the peritoneal leukocytes were the source of PLA2. Treatment of rats with dexamethasone and leukocytes in vitro reduced PLA2 significantly, but they were well above control rats without colitis. However, dexamethasone did not improve the histology. These studies suggest that peritoneal leukocytes may serve as an additional source of inflammatory mediators, which may further enhance the inflammatory response in the rat colon.

Acetates↗

Chemical and histochemical studies of normal and diseased human gastrointestinal tract. I. A comparison between histologically normal colon, colonic tumours, ulcerative colitis and diverticular disease of the colon.

Chemical and histochemical methods were used to compare the epithelial glycoproteins from formalin-fixed surgical specimens of normal human large intestine, colonic tumours, ulcerative colitis and diverticular disease. All the epithelial glycoproteins contained fucose, galactose, glucosamine, galactosamine and, in addition, sialic acids both with and without O-acyl substituents in the side chain and/or at position C4. The glycoproteins of the normal ascending and descending colons differed significantly with respect to the percentage of the sialic acids released following digestion of the de-O-acylated glycoprotein with Vibrio cholera neuraminidase and to the molar fucose-sialic acid ratio. Statistical analysis of the chemical data showed that (a) compared to normal, the sialic acids of the tumour and ulcerative colitis glycoproteins from the descending colon were significantly less substituted in the side chain and at position C4; (b) the O-acetyl substitution pattern of the sialic acids of the ulcerative colitis glycoproteins from the ascending colon and the quantitative composition of the carbohydrate prosthetic groups of the ulcerative colitis glycoproteins from both ascending and descending colons differed from normal; (c) it was not always possible to distinguish between the ulcerative colitis and tumour glycoproteins on the basis of the O-acetyl substitution pattern of their sialic acids; and (d), there were minor differences between normal glycoproteins and those from cases of diverticular disease.

Colitis, Ulcerative↗

Experimental models for ulcerative colitis.

Animal model systems have been used extensively to study both experimental and naturally occurring ulcerative colitis syndromes. Interestingly, despite a variety of different animal species and a broad range of inducing agents, the response of the large intestine has been somewhat predictable. Although there is suggestive evidence for transmissible agents in several of these animal model systems, documentation of a bacterial or viral etiology has remained elusive. Perhaps the best evidence to suggest that bacteria play a role in the development of naturally occurring ulcerative colitis resides in the studies utilizing the rabbit-dinitrochlorobenzine model and the carrageenin-induced ulcerative colitis model in the guinea pig. The evidence for microbial involvement in these model systems includes the use of single bacterial species in the carrageenin model to produce an ulcerative colitis like disease and the use of antimicrobial agents to alter the experimental model system in the guinea pig and hamster with proliferative ileitis and evidence of transmissibility. Recent reports of transmissible agents for both ulcerative colitis and Crohn's disease in studies utilizing immunologically deficient mice also suggest that the search for the "agent" and mechanism should continue in model systems. The many differences between animal model systems and the human disease cannot be ignored. These differences make establishing what appears to be a complicated etiology even more difficult. Despite the difference in anatomy, physiology, and nutritional factors between animal model systems and the human disease process, the fact remains that one or more of these model systems may reflect the same mechanism or etiologic agent which occurs in the human disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Inflammatory bowel disease and leukemia. A report of seven cases of leukemia in ulcerative colitis and Crohn's disease and review of the literature.

In a review of a large number of patients with inflammatory bowel disease, leukemia was observed in five patients with chronic ulcerative colitis and in two patients with Crohn's disease. In ulcerative colitis patients, there were three cases of acute myelocytic leukemia and one case each of acute lymphoblastic leukemia and chronic granulocytic leukemia. In Crohn's disease patients, there was one case each of chronic granulocytic leukemia and chronic lymphocytic leukemia associated with thrombocythemia. Sixteen other cases of leukemia have been reported to date in inflammatory bowel disease. All types of leukemia, but particularly acute myelocytic leukemia, have been described. There has been no single common feature as to type (whether ulcerative colitis or Crohn's disease), extent and course, or medical and surgical treatment of the bowel disease. The relative risk of leukemia in patients with ulcerative colitis was 5.3 [95% confidence interval 1.7 to 12.3 (P less than 0.01)] and of acute myelocytic leukemia 11.4 [95% confidence interval 2.3 to 24.9 (P less than 0.01)]. Our data on patients with Crohn's disease were not sufficient to assess the statistical significance of leukemia in this disease. This study suggests that there may be an increased risk of leukemia, particularly acute myelocytic leukemia, in ulcerative colitis. The causal relationship, if any, remains undetermined.

Adult↗

Circulating neutrophils from patients with ulcerative colitis have a normal respiratory burst.

The hallmark of ulcerative colitis is a diffuse infiltration of neutrophils from the circulation into the colonic mucosa. The underlying mechanism for neutrophil tissue infiltration is unknown. One possible hypothesis is abnormal circulating neutrophils. This hypothesis has been previously tested with conflicting results. The aim of our study was to re-evaluate circulating neutrophil function in the absence of several possible confounding factors. To this end, we measured the respiratory burst of circulating neutrophils in response to two different stimuli by chemiluminescence in patients with active and inactive ulcerative colitis being off all medications. Our results show no significant difference between ulcerative colitis patients and controls in peak chemiluminescence, area-under-the-curve and time to peak comparisons. However, 27% of patients with active ulcerative colitis had an abnormally elevated chemiluminescence to stimuli. In addition, no correlations were seen between disease activity and peak chemiluminescence. Thus circulating neutrophils in the majority of patients with ulcerative colitis do not appear to be either "primed" or hyperactive. This may suggest the presence of local colonic factors that lead to neutrophil tissue infiltration and activation.

Adult↗

Collagenous colitis in setting of nonsteroidal antiinflammatory drugs and antibiotics.

Collagenous colitis is a clinicopathologic syndrome characterized by chronic watery diarrhea and a mucosal inflammatory process with increased subepithelial collagen band on colonic biopsy. This disorder occurs primarily in females, and the etiology is unknown. We report the atypical presentation of collagenous colitis in two older-aged men following prolonged use of nonsteroidal antiinflammatory agents and short-term use of antibiotics. Although one patient had colonic pseudomembranes, neither patient had microbiological evidence of C. difficile toxin or infection. A variety of medications were initially given to these patients without resolution of diarrhea. Only after the diagnosis of collagenous colitis was made and antiinflammatory drugs directed at the colitis given did the diarrhea abate. These cases illustrate an unusual presentation of collagenous colitis with possible implications for pathogenesis.

Aged↗

Dysplasia and cancer complicating strictures in ulcerative colitis.

Previous studies have found a widely variable prevalence of dysplasia and cancer in colonic strictures in patients with ulcerative colitis. Consequently, therapeutic recommendations are conflicting. To better assess the prevalence, we reviewed the clinical and pathological findings in all 27 patients with ulcerative colitis complicated by stricture who were entered into our Inflammatory Bowel Disease Registry. A true stricture was defined as a persistent localized narrowing of the colon found on air-contrast barium enema or on colonoscopy. Upon careful review, 12 of 27 patients were found to have transient colonic spasm, not a stricture, and were excluded. The remaining 15 patients with true strictures represented 3.2% of all ulcerative colitis patients in the registry. Strictures were identified at 13.3 +/- 9.9 years following the diagnosis of ulcerative colitis. Eleven patients had multiple strictures that were principally located in the left colon. Of the 15 patients, 11 had dysplasia and two had cancer found on colonoscopic biopsy. Ultimately, six patients had carcinoma found at colonoscopy or colectomy (three modified Dukes' stage A, one stage B, and two stage D). All cancers were at the site of a stricture. These findings indicate that a true colonic stricture in ulcerative colitis is frequently associated with dysplasia and cancer, which can be diagnosed with colonoscopic biopsy. A stricture should be considered a strong risk factor for cancer, requiring intensive colonoscopic surveillance. If dysplasia is discovered, or if the stricture cannot be adequately biopsied, consideration should be given to total colectomy.

Adult↗

Coombs-positive autoimmune hemolytic anemia in ulcerative colitis.

Coombs-positive autoimmune hemolytic anemia is a rare complication of ulcerative colitis, occurring in fewer than 1% of cases. We have found eight patients with autoimmune hemolytic anemia in a series of 1150 hospitalized patients with ulcerative colitis (0.7%). There was a marked preponderance of female patients F:M = 7:1, in accord with previous reports. The hemolytic anemia appeared at a mean of 10 years after the onset of colitis, apparently independent of the age of the patient. Although seven of the eight patients had active colitis at the time of diagnosis of anemia, there was no consistent relationship to the extent of the bowel disease. Seven of the eight patients survived. One patient showed a partial response to steroid therapy, two responded to splenectomy, but four required both colectomy and splenectomy. Steroids should be the first line of therapy followed by splenectomy, if necessary. For those patients who have severe colitis, which in itself would merit surgery, a total proctocolectomy combined with splenectomy seems advisable.

Adolescent↗

Role of inflammatory mediators in colonic smooth muscle function in ulcerative colitis.

Patients with ulcerative colitis have a decrease in colonic motility which may increase their diarrheal symptoms. Studies in patients with ulcerative colitis showed that the postprandial spike response was slightly decreased and the intraluminal pressure response was absent. In vitro studies showed that the circular smooth muscle, obtained from patients with ulcerative colitis or from a rabbit model of experimental colitis, generated decreased force compared to muscle not associated with mucosal inflammation. The decrease in muscle contraction was observed with bethanechol stimulation or electrical field stimulation. Since the response to an increased extracellular concentration of potassium [( K+]0) was also diminished, the decreased response appears to be caused by an abnormality in the intrinsic contractile mechanism of colonic smooth muscle. Further studies are necessary to determine if metabolic abnormalities are present in the colonic muscle in patients with colitis.

Animals↗

Actions of anticolitic drugs on a guinea-pig model of immune colitis.

A cell-mediated immune colitis in guinea-pigs was examined for its response to several drugs used in the management of colitis as an attempt to obtain an appropriate model for evaluating potentially new anticolitic drugs. The experimentally-induced colitis was readily reproducible and possessed several features in common with the clinical disease: diarrhoea, rectal bleeding and body weight loss, together with ulceration and haemorrhage of the distal colon. Sulphasalazine, prednisolone and disodium chromoglycate appeared not to influence the manifestations of the colitis nor the macroscopic features of the inflamed colon. Azathioprine (AZA) at 100 mg/kg but not at 30 mg/kg modified the colitis in some but not all animals. This model appears to be of little value for the screening of anti-colitic agents.

Animals↗

Ischemic colitis.

Ischemic colitis represents the most common form of gastrointestinal ischemia. The presumed etiologies are numerous; however, it typically develops "spontaneously," in the absence of major vasculature occlusion, and in the presence of viable intestine elsewhere. It is most usefully classified into gangrenous and nongangrenous forms, the latter of which may be subdivided into transient and chronic types. Ischemic colitis may develop in people who are otherwise healthy, although a variety of clinical settings, such as shock, predispose to its occurrence. It usually presents as an acute abdominal illness with bloody diarrhea. Diagnosis is confirmed by colonoscopy. Therapy and outcome are dependent on the severity of disease. Nongangrenous colonic ischemia usually requires only medical management and is associated with a good prognosis. The chronic subtype may lead to the sequelae of persistent segmental colitis or colonic strictures, occasionally requiring surgery. Urgent operative intervention and a high morbidity and mortality are the hallmarks of gangrenous colonic ischemia. Special considerations must be given to those patients in whom ischemic colitis develops in the context of colon carcinoma or obstructing colon lesions, after abdominal aortic surgery, and following cardiopulmonary bypass. This review will discuss the clinical spectrum of ischemic colitis.

Colitis, Ischemic↗

Management of fulminant ulcerative colitis by primary restorative proctocolectomy.

UNLABELLED: Severe acute ulcerative colitis unresponsive to medical management is characterized by multiple associated risk factors including anemia, hypoproteinemia, and high steroid requirements when urgent surgery is required. Current surgical options include use of primary ileal pouch-anal anastomosis (IPAA) vs. historic trends favoring colectomy with ileostomy. PURPOSE: To evaluate the efficacy of primary IPAA in patients with severe colitis, we reviewed our own experience in 20 patients with this condition. METHODS: Patients undergoing primary restorative proctocolectomy included 13 males and 7 females (mean age, 30.5 +/- 2.4 years). Exclusion criteria for primary reconstruction included septic patients and patients with associated medical conditions such as pulmonary or cardiovascular disease. History of ulcerative colitis averaged 3.1 +/- 1.1 years (range, 1 month to 19 years). Preoperative mean total serum protein concentration was 5.0 +/- 0.2 g/dl, and mean albumin concentration was 2.1 +/- 0.2 g/dl, reflecting disease severity. The average daily steroid requirement at the time of urgent colectomy was 58.0 +/- 4.4 mg of prednisone (or intravenous equivalent). Primary IPAA included 18 "W" reservoirs, 1 "S" reservoir, and 1 "J" reservoir. RESULTS: Major surgical complications included mild pancreatitis (10 percent), anastomotic leak (5 percent), adrenal insufficiency (15 percent), an upper gastrointestinal bleed (5 percent), and small bowel obstruction (15 percent). There were no deaths, and no patients developed pelvic sepsis or required IPAA removal. At three and twelve months, 24-hr stool frequency averaged 7.3 +/- 0.4 and 4.9 +/- 0.3, respectively. Overall day and night continence was excellent and not different from patients who underwent elective IPAA procedures for ulcerative colitis. CONCLUSIONS: Improved options such as primary IPAA may be safely used in selected patients requiring urgent surgery for severe or fulminant ulcerative colitis. Medical management should be abbreviated when disease control cannot be promptly achieved.

Acute Disease↗

Pneumocystis carinii pneumonia postrestorative proctocolectomy for ulcerative colitis: a role for perioperative prophylaxis in the cyclosporine era? Report of a case and review of the literature.

PURPOSE: Medical management of severe ulcerative colitis has used cyclosporine with increasing frequency as an adjuvant to systemic steroids and mercaptopurine. However, the effects of combined management with cyclosporine and prednisone may lead to significant immune compromise and adversely affect operative morbidity in the event urgent surgery is required. METHODS: A case is reported of a 43-year-old white male who presented with severe ulcerative colitis. The patient had been initially treated with prednisone and cyclosporine for six weeks before surgical intervention. The intractability of his ulcerative colitis caused the patient to present to surgery, where he underwent restorative proctocolectomy. RESULTS: On initial presentation, the patient manifested systemic signs of severe ulcerative colitis with hypoalbuminemia, anemia, and weight loss, despite continuous prednisone and cyclosporine management. Before surgical intervention, a chest x-ray and the patient's respiratory status were normal. A total abdominal colectomy with ileal pouch reconstruction and temporary loop ileostomy were performed without incident. On the fifth postoperative day, the patient developed respiratory failure, which was subsequently diagnosed as Pneumocystis carinii pneumonia. Although ventilator support and both aggressive medical and surgical management eventually resulted in successful outcome, significant perioperative morbidity occurred. CONCLUSIONS: In the era of aggressive medical management for ulcerative colitis with both steroids and cyclosporine, the complications of immunosuppression may be significant, including opportunistic pneumonia. Prophylaxis against P. carinii pneumonia with sulfa antibiotics should be considered, especially in patients for whom proctocolectomy is a potential end point.

Adult↗

Mucosal cell proliferation of the rectal stump in ulcerative colitis patients after ileorectal anastomosis.

The proliferative activity and polyamine levels of the rectal epithelium in unoperated ulcerative colitis patients and in ulcerative colitis patients after total colectomy and ileorectal anastomosis were determined and compared with control subjects. Cell proliferation was evaluated in rectal biopsies by in vitro 3H thymidine incorporation by measuring the labeling index and the position of labeled cells along the crypt; polyamines were determined with a chromatographic method. In ulcerative colitis patients the labeling index was significantly increased, and labeled cells were shifted toward the upper part of the crypt when compared with controls. Ileorectal anastomosis patients showed a normalization of the labeling index and a distribution of labeled cells similar to controls. Polyamine levels were also increased in ulcerative colitis patients; in ileorectal anastomosis patients, the level of polyamines was decreased in respect to unoperated patients and return to normal values except for spermine. Because the increased proliferation and higher polyamine levels are related to increased colon cancer risk, our results confirm that ulcerative colitis is a risk factor for the development of carcinoma. Ileorectal anastomosis may reduce this risk through a normalization of mucosal cell proliferative activity and of some polyamine levels.

Adolescent↗

Previous subtotal colectomy with ileostomy and sigmoidostomy improves the morbidity and early functional results after ileal pouch-anal anastomosis in ulcerative colitis.

The aim of this work was to study the effects of previous subtotal colectomy (STC) with ileostomy and sigmoidostomy on the outcome of ileal J-pouch-anal anastomosis (IPAA) in patients with acute ulcerative colitis. Between 1983 and 1991, we conducted a prospective, nonrandomized study of 156 patients who underwent IPAA in our center. Fifty-five patients (34.3 percent) had undergone STC with ileostomy and sigmoidostomy for either severe acute colitis (36.5 percent of cases) or nonresolving acute colitis (63.5 percent) up to six months before IPAA with covering ileostomy. There were no perioperative deaths; six patients (11 percent) developed complications requiring reoperation (three cases of pelvic sepsis, two occlusions, and one stenosis of the ileostomy). IPAA was successfully carried out at a later stage in all cases. The results of IPAA in these patients were compared with those in 78 patients who underwent the classical two-stage IPAA procedure. The rates of pelvic sepsis and postoperative occlusion were lower in the subgroup of patients who underwent the three-step procedure. Three months after closure of the ileostomy, the mean number of daily stools was significantly lower in the patients who had undergone prior STC (5.09 vs. 5.9), but there was no significant difference between the two groups with regard to diurnal and nocturnal continence, the need to wear a pad, discrimination between gas and stools, or the use of antidiarrheal medication. In addition, there was no significant difference at one year in terms of functional parameters. We conclude that STC is a simple and safe procedure for the treatment of a severe attack of colitis and that it does not compromise the results of later IPAA. Because it does not increase the morbidity of subsequent IPAA and is associated with more rapid functional recovery, STC appears to be suitable for the treatment of patients with nonresolving acute colitis before the onset of malnutrition or steroid dependency.

Adolescent↗

Preoperative diagnosis of a small, depressed rectal cancer complicating ulcerative colitis. Report of a case.

PURPOSE: This study was designed to clarify the importance of detecting small, depressed colorectal cancer complicating ulcerative colitis. METHODS: A 39-year-old Japanese male, who had an 18-year history of left-sided ulcerative colitis, was admitted to Fukuoka University Hospital for further evaluation of his colitis. Colonoscopy with a dye spraying method clearly revealed a small, depressed lesion and flat plaque-like lesions in the rectum. Biopsies taken from a depressed lesion and plaque-like lesions revealed a signet-ring cell carcinoma and dysplasia, respectively. Total colectomy was performed. RESULTS: Sections from the depressed rectal lesion, measuring 7 x 8 mm in size, revealed a signet-ring cell carcinoma that diffusely invaded the muscularis propria. Lymph node metastasis was evident. Flat plaques and mucosa around the depressed lesion were positive for dysplasia. CONCLUSION: This is the first report of a case of small, depressed rectal cancer complicating ulcerative colitis diagnosed by preoperative colonoscopy. To improve outcome of colonoscopic surveillance in ulcerative colitis, detecting such small, depressed lesions are important, and colonoscopy with a dye spraying method would be useful in detecting them.

Adult↗

Phenotypic and functional characterization of T-cell lines generated from colonoscopic biopsy specimens in patients with ulcerative colitis.

Intestinal T-cell lines were generated from lamina propria mononuclear cells isolated from colonoscopic biopsies in ulcerative colitis patients and controls. In both ulcerative colitis and controls, expanded cells were constituted largely by T-cell receptor alpha beta+, CD4+, CD45RA- (helper), and CD8+, CD11b- (cytotoxic) phenotypes. T-cell receptor V beta gene usage was not significantly changed after cell expansion and no difference was observed between ulcerative colitis and controls. Ulcerative colitis cells, especially those derived from the patients with long-standing disease, showed significantly higher levels of cytotoxicity against the target cells, including those of colonic epithelial origin, and enhanced production of tumor necrosis factor-alpha and interferon-gamma after short incubation with anti-CD3 antibody. Generation of T-cell lines from colonoscopic biopsy specimens may be useful for detailed functional characterization of locally infiltrating T cells in ulcerative colitis patients.

Adolescent↗