Short tandem repeat polymorphism markers on the short arm of chromosome 8 were used to search for loss of heterozygosity (LOH) in colorectal carcinoma and dysplasia complicating ulcerative colitis, in prostatic carcinoma, and in malignant fibrous histiocytoma (MFH). Fifty percent of prostatic carcinomas (13/26), 44% of carcinomas or dysplasias arising in ulcerative colitis (7/16), and 30% (4/12) of MFH cases showed LOH for markers on 8p. Detailed mapping demonstrated variability in the size of the chromosomal region showing LOH; however, the data suggest a common 30-centimorgan region of LOH on chromosome 8p between the LPL locus and pter in colorectal and prostatic cancers. In addition, LOH was observed on 8p in both high-grade and low-grade dysplasia in ulcerative colitis, indicating that LOH on 8p may occur at an early stage of neoplastic development in this disorder. In contrast, MFH cases exhibited LOH for marker D8S87, which has been identified as being near the putative Werner's syndrome locus. These results suggest that a tumor suppressor gene, located on the distal portion of chromosome 8p, exists in common for prostatic and colorectal carcinomas, and a second tumor suppressor gene may exist linked to the Werner's syndrome locus.
Objective. To study effect and its mechanism of Bifid Triple Viable for initially treating ulcerative colitis with 5-aminosalicylic acid. Methods. 82 patients, who were firstly diagnosed as ulcerative colitis, were randomized into experiment group (41 cases, treated with Bifid Triple Viable and Etiasa) and control group (41 cases, treated with Etiasa). The clinic symptom score, colon mucosa inflammation score, and some immune indices were detected and compared between two groups before and two months after treatment. Results. Two months after treatment, the clinical symptom score, colon mucosa inflammation score, and IL-1β expression in colon mucosa decreased significantly (P < 0.01), and IL-10 and IgA expressions in colon mucosa increased significantly (P < 0.01). Those differences were more marked in experiment group than control group (P < 0.05). However, peripheral blood T cell subgroup, immunoglobulins, and complements had no significant difference between two groups two months after treatment, but the ratio of peripheral blood CD4+ T cell to CD8+ T cell in experiment group increased more than that in control group (P < 0.05). Conclusion. Bifid Triple Viable contributed to Etiasa to treat ulcerative colitis in inducing remission period...
Pyoderma gangrenosum is strongly associated with inflammatory bowel disease and exhibits pathergy, occurring at sites of previous minor trauma. A patient is presented with a 21 year history of extensive ulcerative colitis, who developed pyoderma gangrenosum and arthralgia while receiving high dose corticosteroids for active ulcerative colitis. The arthralgia exhibited pathergy affecting particularly the left temporomandibular joint, which was stressed by an asymmetric bite, and the left elbow, which had been fractured many years previously. This prompted the hypothesis that neutrophils in this condition may be marginated, as a result of increased stickiness of either the neutrophil or the vascular endothelium. The introduction of heparin therapy was associated with rapid resolution of the arthralgia, pyoderma gangrenosum, and ulcerative colitis.
Several retrospective studies have reported seasonal variations in the relapse of ulcerative colitis, and two studies have found seasonality in the onset of ulcerative colitis, with a peak from August to January. This study was designed to investigate possible seasonal variations of onset of ulcerative colitis (UC) and Crohn's disease (CD). Patients with symptoms of one year or less were recruited from a prospective study of the incidence of inflammatory bowel disease, and the onset of symptoms was recorded month by month for four consecutive years. A total of 420 patients with UC and 142 patients with CD were included. There was monthly seasonality (p = 0.028) in symptomatic onset in December and January for UC but not for CD. It was found that environmental agents with known seasonality can be of importance for the seasonal variations of disease onset in UC.
To compare the efficacy of Asacol (mesalazine coated with Eudraget-S) as a maintenance therapy with that of sulphasalazine, relapse rates of patients with ulcerative colitis and Crohn's disease, treated with sulphasalazine or Asacol were assessed in a retrospective study. A total of 164 patients were investigated, 127 on sulphasalazine and 37 on Asacol. None of the patients on Asacol was changed from sulphasalazine because of lack of efficacy to sulphasalazine. Relapse rates were measured over a 4 year period. In ulcerative colitis these were sulphasalazine 10/77 (13.0%), Asacol 5/20 (25.0%), NS; in all Crohn's disease patients, sulphasalazine 12/50 (24.0%), Asacol 11/17 (64.7%); P less than 0.0025. In patients with Crohn's disease with ileal involvement, relapse rates were sulphasalazine 9/28 (32.1%), Asacol 9/11 (81.6%), P less than 0.0125; without ileal involvement, sulphasalazine 3/22 (13.6%), Asacol 2/6 (33.4%), NS. This study suggests that Asacol is as effective as sulphasalazine in maintaining remission in ulcerative colitis and in patients with Crohn's disease without ileal involvement. Sulphasalazine seems to be more effective than Asacol in maintaining remission in patients with Crohn's disease with terminal ileal involvement.
It has been suggested that antibodies to a colonocyte protein of 40 kD (an intestinal isoform of tropomyosin) are specifically found in the serum and mucosa of patients with ulcerative colitis, which has important pathogenic implications. This study isolated and purified tropomyosin from the colonic mucosa, but no specific binding to this protein has been detected in serum samples or immunoglobulins isolated from mucosal washings of 20 ulcerative colitis (UC) patients by enzyme linked immunosorbent assay (ELISA) compared with 21 controls or 17 Crohn's disease (CD) patients. Samples from a further 12 patients with UC and primary sclerosing cholangitis (it is proposed that cross reactivity against the intestinal tropomyosin isoform accounts for the extraintestinal disease) also did not show binding to tropomyosin, whereas monoclonal antitropomyosin antisera bound both ELISAs and western blots. This study also examined the proteins in the normal colonic biopsy specimens on western blots that are bound by both serum samples and mucosal immunoglobulin preparations from these patients groups; there was no specific IgG or IgA binding to patients with UC or UC/primary sclerosing cholangitis, whereas binding to mitochondrial proteins of 70...
Fluticasone propionate is a corticosteroid with the potential for topical treatment of ulcerative colitis because of low systemic bioavailability. The drug was compared with prednisolone in the management of active left sided or total ulcerative colitis. Two hundred and five patients were studied in the multicentre four week double blind study. Prednisolone was given in a dose of 40 mg daily orally, reducing over four weeks to 10 or 20 mg. Fluticasone propionate was given in an oral daily dose of 20 mg. The primary end point was the investigator's overall assessment of response. Patient's assessment, sigmoidoscopic appearance, and histology were also studied. Patients improved more rapidly with prednisolone. Differences between the two groups were significant at two weeks. At four weeks differences were not significant, but there was a trend in favour of prednisolone. Corticosteroid side effects were minimal in the fluticasone propionate group, and there was minimal suppression of the hypothalamic pituitary adrenal axis. Fluticasone propionate 20 mg daily is not as effective in the treatment of active ulcerative colitis as prednisolone tapering from 40 mg daily to 10 or 20 mg. The complete absence of suppression of the corticoadrenal axis by fluticasone propionate was encouraging...
Pyoderma gangrenosum (PG) is an immune-mediated inflammatory skin condition representing one of the most distinct extraintestinal manifestations of inflammatory bowel disease (IBD). PG occurs independently from intestinal disease activity in about 1–2% of patients suffering from ulcerative colitis or Crohn's disease and is characterized by chronic deep skin ulcers whose exact pathogenesis is still unknown. So far, patients with ulcerative colitis have only been reported to develop PG during the course of IBD but not at the initial manifestation of bowel symptoms. This is the first report demonstrating the simultaneous onset of ulcerative colitis and severe multifocal PG. In addition, we provide first evidence that infliximab may have a particularly powerful effect in early disseminated PG compared to late-onset PG, advocating an early application of this drug.
Cerebral venous thrombosis developing concurrently with active ulcerative colitis poses a therapeutic dilemma. We report the case of a 31-year-old woman who developed dural venous sinus thrombosis during the course of active ulcerative colitis in whom we accomplished clot lysis using intrasinus urokinase. The success of the procedure was assessed by improvement in the patient's neurological condition and resolution of imaging features without any bleeding complications. We also reviewed literature on various modalities of treatment of sinus venous thrombosis in patients with ulcerative colitis and outcome.
A 25-year-old Japanese man showed symptoms of common cold and digestive problems for 1 month. He later developed hypoesthesia ascending from the lower extremities and consulted the emergency outpatient department with the chief complaint of generalised dysesthesia. Because of a history of ulcerative colitis, his condition was initially treated as acute aggravation of the disease; however, after admission, his consciousness level gradually deteriorated. Physical findings showed weakened tendon reflexes, and anti-GQ1b antibodies were strongly positive in the cerebrospinal fluid. Therefore, the patient was diagnosed with Bickerstaff's brainstem encephalitis (BBE). Plasmapheresis was performed 8 times, resulting in an improvement of the symptoms; the patient was discharged 1 month later. Campylobacter infections are the main cause of BBE, and its incidence is high among patients with ulcerative colitis. Therefore, in cases where patients with ulcerative colitis develop disturbance in consciousness, BBE should be included in the differential diagnosis.
The effect of olsalazine, an analogue of sulphasalazine, consisting of two molecules 5-aminosalicylic acid linked by an azobond has been investigated for the treatment of ulcerative colitis. In a randomised double blind trial we compared 2 g olsalazine with placebo for four weeks. Of the 105 patients, with mild to moderate ulcerative colitis, entered in the trial 52 received olsalazine, and 53 placebo. Treatment had to be terminated prematurely because of untoward effects of olsalazine (mainly diarrhoea) in three patients and treatment failure--that is, increased rectal bleeding in four patients (olsalazine group: one placebo group: three). After four weeks' treatment, a statistically significant improvement in the endoscopic findings in rectum and a positive trend in the reduction of rectal mucus and blood discharge was observed in the patients treated with olsalazine. No statistically significant difference was found for other factors, including stool frequency, consistency, urge to defecate, abdominal pain, and biopsy findings. A comparison between these clinical and endoscopic parameters at study entry and those at study completion (within drug evaluation) showed significant improvement in six of 10 parameters during treatment with olsalazine and in two of 10 during placebo treatment. This difference suggests the significant effect of olsalazine. We conclude that 2 g olsalazine was tolerated as well as placebo...
The incidence of cold-reactive lymphocytotoxins in the serum of patients with Crohn's disease or ulcerative colitis has been investigated. Twenty-seven percent of patients with Crohn's disease and twenty-two percent of those with ulcerative colitis had circulating lymphocytotoxins. This is significantly higher than the 4% found in a normal control population. The presence of lymphocytotoxins did not correlate with age or sex of the subjects studied nor with clinical parameters. As in previous studies, the lymphocytotoxin is an antibody of IgM class, is optimally effective at 15 degrees C in the presence of complement and reacts with both T and B lymphocytes. The lymphocytes from patients with active Crohn's disease or ulcerative colitis are poorly susceptible to lysis by lymphocytotoxins but lymphocytes from patients in remission are as susceptible as normal lymphocytes. This implies that the lymphocyte surface is altered during active disease although the pathogenetic significance of this is unclear.
Random motility and chemotaxis of peripheral blood neutrophils and monocytes from patients with Crohn's disease and ulcerative colitis have been measured using a modified Boyden Chamber filter assay. Increased random motility and chemotaxis of monocytes were found in patients with active ulcerative colitis. Monocyte motility was normal in Crohn's disease and no abnormality of neutrophil motility or chemotaxis was found in either disease. Drug therapy with prednisolone or sulphasalazine received in vivo was found to have no effect on the motility of the washed neutrophils and monocytes in vitro. This work adds to the evidence that monocytes are activated in ulcerative colitis but does not support the hypothesis that Crohn's disease is due to an inherent defect in phagocyte motility.
Heat-shock proteins (HSPs) are highly conserved immunogenic intracellular molecules that are induced by inflammatory mediators and may induce autoimmune phenomena in vivo. We have recently demonstrated the increased expression of HSP-60 in the colonocytes of patients with ulcerative colitis. To study further the role of HSP-60 in inflammatory bowel disease, we have now measured antibodies to recombinant mycobacterial HSP-65 (a member of the HSP-60 family) in patients with Crohn's disease, ulcerative colitis, healthy volunteers and, as disease controls, patients with confirmed bacterial diarrhoea. In comparison with healthy controls (n = 20; median level of 89 ELISA units; range 24-292), serum IgA HSP-60 antibodies were elevated in Crohn's disease (n = 21; 157; 57-364; P < 0.05) and active ulcerative colitis (n = 16; 188; 58-373; P < 0.01) but not bacterial diarrhoea (n = 10; 106; 51-285). Increased IgA HSP-60 antibody levels in patients with inflammatory bowel disease may occur as the result of HSP release from injured gut epithelium; alternatively, increased intestinal permeability could facilitate mucosal access of luminal antigens and the generation of cross-reactive anti-bacterial HSP antibodies.
We investigated the pattern of proliferation of epithelial cells in rectal mucosa taken from normal individuals and patients with ulcerative colitis by incubating mucosa with tritiated thymidine in vitro and processing for autoradiography. We found that patients with ulcerative colitis in remission showed a proliferative pattern similar to that seen in both regenerating and "precancerous' mucosa. Patients with a short history were as likely to show this pattern as those with a long history, and this shows that the abnormal pattern does not signify impending malignant change. We also found that mucosa from patients with ulcerative colitis in remission showed an increased proportion of cells synthesising DNA, a proportion surprisingly close to that seen in an active phase; this suggests that the abnormal pattern seen in remission is the pattern of a regenerating mucosa. We feel that this high rate of mucosal turnover, sustained not just during clinically active disease but throughout remission, leads to the increased incidence of carcinoma and to the development of carcinoma in flat mucosa.
The incidence of lactose malabsorption was investigated in 85 patients with ulcerative colitis and 71 patients with Crohn's disease by means of lactose tolerance tests and disaccharidase determinations in small intestinal mucosa. Eight patients with ulcerative colitis (9%) and four with Crohn's disease (6%) had lactose malabsorption. A control group displayed a similar incidence. It is concluded that lactose malabsorption is not particularly common in ulcerative colitis and Crohn's disease. If it is present, its aetiology seems to be unrelated to the intestinal disease.
Two histochemical techniques, the PAT/KOH/PAS and the PBT/KOH/PAS, were used to investigate the side chain O-acyl substitution patterns of the sialic acids of the colonic epithelial mucins in cases of ulcerative colitis and Crohn's disease. In both diseases there was, as compared to normal, a reduction in the proportion of sialic acids O-acylated at C7C8, the reduction being greater in ulcerative colitis. Further, there appeared to be an association between the severity of the disease and the reduction in the staining of O-acylated sialic acids. This relationship was more marked in ulcerative colitis. In some cases of both diseases there was evidence for epithelial mucins containing predominantly C7-substituted sialic acids. This study has confirmed our previous conclusion that, in Crohn's disease of the terminal ileum, the disease is associated with an increase in the proportion of sialic acids bearing side chain substituents.
Linear IgA dermatosis has been increasingly associated with inflammatory bowel diseases, particularly ulcerative colitis. A 13-year-old male patient with an 11-month history of ulcerative colitis developed vesicles, pustules and erosions on the skin of the face, trunk and buttocks and in the oral mucosa. The work-up revealed a neutrophil-rich sub-epidermal bullous disease and linear deposition of IgA along the dermoepidermal junction, establishing the diagnosis of linear IgA dermatosis. The patient experienced unsatisfactory partial control of skin and intestinal symptoms despite the use of adalimumab, mesalazine, prednisone and dapsone for some months. After total colectomy, he presented complete remission of skin lesions, with no need of medications during two years of follow-up. A review of previously reported cases of the association is provided here and the role of ulcerative colitis in triggering linear IgA dermatosis is discussed.
This is the author accepted manuscript. The final version is available from NPG at http://www.nature.com/ng/journal/v47/n2/full/ng.3176.html#acknowledgments; Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules1. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles2, 3. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.; J.D.R. holds a Canada Research Chair...
The overall goal of our Demonstration Project is to address the hypothesis that the gut microbiota plays a critical role in the pathogenesis of inflammatory bowel disease (IBD). To circumvent the confounding effects of mucosal inflammation and medications that independently bias microbial selection, we have set out to study a unique clinical model of ulcerative colitis (pouchitis) where the development and status of the gut microbiota can be assessed prospectively and relative to the outcome of disease. Pouchitis is an inflammatory condition of a surgically-created pseudorectum that is unique to ulcerative colitis and rarely occurs when this procedure is performed for treatment of other non-IBD diseases. Since the incidence of developing pouchitis within one year is over 50%, the likelihood of detecting antecedent changes in microbiota is high. Our multi-center study involves an integrated team of researchers with expertise in clinical manifestations of pouchitis (Univ. Chicago), cultivation of diverse microorganisms (MSU), molecular microbial ecology (MSU/UMich/MBL), and metagenomics (ANL). Our goal is to enroll up to 50 patients with pouchitis who will be followed clinically and endoscopically (sampling from the unprepped pouch) for a period of 18 months each. Though the use of high-throughput...