Sho Takagi

Effectiveness of an ‘half elemental diet’ as maintenance therapy for Crohn's disease: a randomized-controlled trial

Although thiopurines have a proven role in maintenance therapy for Crohns disease, an alternative therapy is needed for patients intolerant or resistant to thiopurines.

Telomere shortening in the colonic mucosa of patients with ulcerative colitis.

Abstract: Telomere length in human somatic cells gradually decreases with the number of cell divisions and is regarded as a marker of somatic cell turnover. Mucosal cells of the affected colon show rapid turnover in individuals with active ulcerative colitis (UC). Telomere length was determined by Southern blot analysis of terminal restriction fragments (TRFs) from the colonic mucosa of 17 patients with UC in remission, two of whom showed dysplasia, and 17 control subjects without colitis. For each individual, mean TRF length was compared between rectal mucosa and unaffected cecal mucosa. The mean TRF length of the rectal mucosa was significantly less than that of cecal mucosa in UC patients (7.87 ± 0.36 kb versus 8.77 ± 0.21 kb; P = 0.0015, Wilcoxon signed rank test), whereas no significant difference was detected in the control subjects. The extent of telomere shortening was 10.6 ± 3.35% in UC patients, compared with 0.8 ± 0.64% in noncolitis controls (P = 0.0024, Mann-Whitney U-test). Four UC patients, two of whom had dysplasia, showed telomere shortening of more than 20% in the rectal mucosa. These observations suggest that telomere shortening in the colonic mucosa of individuals with UC may represent the history of mucosal inflammation during disease of long duration, and that it may contribute to aneuploidy in UC.

Clinical course and longterm prognosis of Japanese patients with Crohn's disease: predictive factors, rates of operation, and mortality.

BackgroundThe purpose of this study was to clarify the long-term course of Crohn’s disease (CD) and predictors of its prognosis in Japan.MethodsThis was a historical cohort study of 276 patients with CD who had been diagnosed between 1965 and 1998. The clinical course was evaluated by the course of the CD score (CCDS) according to the required treatments. The predictive factors were examined by stepwise regression test. The cumulative rates of operation and survival were calculated by the Kaplan-Meier method.ResultsPatients with colitis-type CD had significantly lower annual and cumulative operation rates than those with other types, and showed significantly better progress, estimated by the CCDS, than patients with ileocolitis type. Reliable predictors for the 2- to 5-year clinical course after starting treatment were the CCDS, the presence of laparotomy during the initial year, and onset at age 30 years or more. The predictors for the 6- to 10-year clinical course were the duration of symptoms at diagnosis and onset at age 16 years or less. The predictors for the 11- to 15-year clinical course were the CCDS, the maximum International Organization of the Study of Inflammatory Bowel Disease (IOIBD) assessment score during the first year after starting treatment, and the effectiveness of the initial treatment. Relative survival rates at 5, 10, 15, and 20 years after the onset were 98.9%, 98.1%, 97.7%, and 94.9%, respectively.ConclusionsCD patients with colitis type showed a better clinical course and had significantly different clinical features compared with the patients with ileitis and ileocolitis type. Prediction of the longterm course of CD is possible by using clinical factors during the first year after starting treatment. The relative survival rates in Japanese patients with CD are not different from those seen in Western countries.

CARD15/NOD2 mutational analysis in Japanese patients with Crohn's disease

To the Editor: Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract and is considered to be a complex, multifactorial disease partly determined by a genetic predisposition. Among the putative CD-susceptibility loci, the pericentromeric region of chromosome 16, designated as IBD1, is most widely and consistently confirmed in Western populations (1, 2). Recently, three independent studies, one from the United States (3) and two from Europe (4, 5), have demonstrated that the three main variants (R702W, G908R, 3020insC) of CARD15/NOD2 (CARD15), located on chromosome 16q12, are associated with CD. In Japanese patients with CD, however, a genome-wide linkage analysis has not yet been performed and our collaborative research could not find any of the main variants of CARD15 (6). As our previous collaborative research was limited to

TNFSF15 transcripts from risk haplotype for Crohn's disease are overexpressed in stimulated T cells

TNFSF15 is a susceptibility gene for Crohns disease (CD). It remains to be elucidated how the associated single nucleotide polymorphisms (SNPs) in TNFSF15 affect the susceptibility to CD. Because there are no non-synonymous SNPs in TNFSF15, we speculated that one or more of the SNPs associated with CD may act as cis-regulatory SNPs. To reveal the effects of the SNPs on the transcriptional activity of TNFSF15, we first examined the allelic expression imbalance of TNFSF15 in peripheral blood mononuclear cells (PBMCs). When PBMCs stimulated by phytohemagglutinin (PHA) were examined, the allelic ratio of mRNA transcribed from the risk haplotype to the non-risk haplotype increased, compared with the ratio without stimulation. When peripheral blood T cells and Jurkat cells stimulated by phorbol 12-myristate 13-acetate + ionomycin were examined, an allelic expression imbalance similar to that observed in PBMCs stimulated by PHA was confirmed. The promoter assay in stimulated Jurkat cells showed that the luciferase activity of the promoter region (-979 to +35) of the risk haplotype was significantly higher than that of the non-risk haplotype, and deletion and mutagenesis analysis demonstrated that this difference resulted from the -358T/C SNP. The promoter activity of -358C (risk allele) was higher than that of -358T (non-risk allele) in stimulated T cells. This effect of -358T/C on the transcriptional activity in stimulated T cells may confer susceptibility to CD.

Lack of association between IBD5 and Crohn's disease in Japanese patients demonstrates population-specific differences in inflammatory bowel disease

Objective. Population-specific differences in the genetic susceptibility to inflammatory bowel disease (IBD) are indicated by the fact that Crohns disease (CD) in Japanese patients does not have any of the common CARD15 variants that are associated with CD in Caucasians. Recently, the disease-causing mutation in the IBD5 haplotype was identified. The TC haplotype, composed of L503F in SLC22A4 and −207G/C in SLC22A5 promoters, was reported to alter the function of the organic cation transporter and to be associated with CD in Caucasians. To determine whether the TC haplotype is also associated with IBD in a Japanese population, we genotyped L503F and −207G/C variants in Japanese subjects. Furthermore, we also performed a case-control association study with all representative single nucleotide polymorphisms (SNPs) in IBD5 using previous information of linkage disequilibrium extension reported in Japanese patients to determine whether there were variants in IBD5 specifically associated with IBD in Japanese patients. Material and methods. A total of 758 Japanese individuals, 241 patients with CD, 247 patients with ulcerative colitis (UC) and 270 healthy controls, were analyzed in this study. Genotyping for SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Results. We found L503F and −207G/C to be very rare (<1% frequency) in CD, UC and HC in the Japanese population. Furthermore, we also found that none of the representative SNPs in IBD5 was associated with CD or UC in the Japanese subjects. Conclusions. In contrast to Caucasians, IBD5 is not a major component of the susceptibility to IBD in the Japanese population.

Telomere shortening and the clinicopathologic characteristics of human colorectal carcinomas

It has been reported that shortening of telomeres and strong activation of telomerase occur frequently in colorectal carcinomas. In the current study, the authors examined the correlations between the telomere length of colorectal carcinomas and their clinicopathologic characteristics as well as the activity of telomerase to clarify whether telomere length might represent the biologic behavior of tumors and the mode of tumor development.

Changes of faecal microbiota in patients with Crohn's disease treated with an elemental diet and total parenteral nutrition.

BACKGROUND Intestinal microbiota contributes to the pathogenesis of Crohns disease. Elemental diet and total parenteral nutrition are effective therapies for Crohns disease; however, changes of microbiota as a result of both treatments have not been fully elucidated. AIM To elucidate changes of faecal microbiota in Crohns disease patients treated with elemental diet and total parenteral nutrition. METHODS Stool samples were collected from 33 active Crohns disease patients and 17 healthy subjects, and recollected after elemental diet (8 patients) and total parenteral nutrition (9 patients). Terminal restriction fragment length polymorphism analysis of bacterial 16srDNA was performed to evaluate the whole microbiota. Specific quantitative PCR was then used to determine populations of predominant bacterial groups. RESULTS In Crohns disease patients, the number of terminal restriction fragments, which reflects bacterial species, was significantly lower. Populations of total bacteria and Bifidobacterium were significantly lower and the ratio of Enterococcus was higher. The number of terminal restriction fragments was significantly decreased after total parenteral nutrition, but not after elemental diet. Population of Bacteroides fragilis significantly decreased after elemental diet, while population of Enterococcus significantly increased after total parenteral nutrition. CONCLUSION Faecal microbiota in Crohns disease patients was markedly different from healthy subjects. Species diversity was reduced by total parenteral nutrition, but not by elemental diet.

Effect of weekend 5-aminosalicylic acid (Mesalazine) enema as maintenance therapy for ulcerative colitis : Results from a randomized controlled study

Background: 5‐Aminosalicylic acid (5‐ASA) is known to be effective in the treatment of active ulcerative colitis (UC). The aim of the current study was to investigate the effect of 5‐ASA enemas, as a maintenance therapy for UC, when administered twice weekly as a weekend treatment regimen, compared to daily oral 5‐ASA alone. We hypothesized that the weekend enema therapy would be better tolerated by patients who worked or attended school. Methods: Between January 2004 and August 2005, patients with UC, in whom remission of the condition had just been induced, were randomly assigned to either: the weekend 5‐ASA enema group (n = 11), who received 1 g 5‐ASA enemas twice a week on Saturday and Sunday plus oral 5‐ASA 3 g/day for 7 days, or to the daily oral 5‐ASA use only group (n = 13), who received only oral 5‐ASA 3 g/day for 7 days. The primary endpoint of the study was defined as the incidence of relapse. The study was stopped after 24 patients had been enrolled because an interim analysis showed a significant benefit of the weekend 5‐ASA enema group. Results: In the weekend enema group, 2 patients (18.2%) had relapses compared with 10 (76.9%) in the oral 5‐ASA only group. The multivariate hazard ratio of relapse associated with weekend 5‐ASA enema, relative to the oral alone group, was 0.19 (95% confidence interval, 0.04–0.94). Conclusions: This study demonstrated the beneficial effects of adding weekend 1 g 5‐ASA enema to daily 3 g oral 5‐ASA as maintenance therapy for UC.

Analysis of the pten gene mutation in polyposis syndromes and sporadic gastrointestinal tumors in Japanese patients

PURPOSE:PTEN is a candidate tumor suppressor gene for mutations which are responsible for Cowden disease. Recently, it has been shown thatPTEN is mutated in several human neoplasms. To investigate the role ofPTEN in tumorigenesis, we screened its mutation in Japanese patients with gastrointestinal polyposis and various sporadic tumors. METHODS: The entire coding region ofPTEN was screened by single strand conformational polymorphism or direct sequencing for somatic mutations in 16 gingival papillomas, 4 juvenile polyps, 10 esophageal papillomas, and 20 colorectal cancers and for germline mutations in three patients with Cowden disease (including one with Lhermitte-Duclos disease) and one patient each with juvenile polyposis syndrome, Turcots syndrome, and Cronkhite-Canada syndrome. RESULTS: Germline mutations were found in all cases of Cowden disease. One mutation was a nonsense mutation at codon 130 (CGA→TGA), and the other two were splice site mutations at the 5′ site of intron 4 and the 3′ site of intron 8. We could not detect germline mutations in other patients with gastrointestinal polyposis or somatic mutations in sporadic tumors. CONCLUSIONS: We confirmed previous reports that germline mutations inPTEN are responsible for Cowden disease. However, somatic mutations ofPTEN may not play a major role in tumorigenesis, at least in colorectal cancers, esophageal papillomas and gingival papillomas.