Ulcerative Colitis: Tahara T

Tomomasa T, Kobayashi A, Ushijima K, Uchida K, Kagimoto S, Shimizu T, Tajiri H, Tahara T, Yoden A, Anonymous00348. · Department of Pediatrics, Gunma University Graduate School, Japan. · Pediatr Int. · Pubmed #15310325 No free full text.

Abstract: This paper introduces the guidelines for treatment of ulcerative colitis in children, created by the working group of the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (Chair: Yuichiro Yamashiro) and the Japanese Society for Pediatric Inflammatory Bowel Disease (IBD) (Chair: Akio Kobayashi). The ideas of the working group, with regard to the fundamental differences in medical treatment between children and adults, included: (1) for children, intensive medical treatment including appropriate systemic management is important during the acute phase of illness. (2) Treatment with steroids, which can cause growth disturbances, should not be continued for long periods of time. (3) Pulsed steroid therapy, selective removal of blood cells, and intravenous infusion of cyclosporin should be included in the therapeutic option for severe and fluminant cases.

Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, Maruyama N, Kamano T, Kamiya Y, Nakagawa Y, Fujita H, Nagasaka M, Iwata M, Takahama K, Watanabe M, Hirata I, Arisawa T. · Department of Gastroenterology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Aichi, 470-1192, Japan. · Int J Mol Med. · Pubmed #19288029 No free full text.

Abstract: Altered MDR1 expression and/or function contribute to the pathogenesis of inflammatory bowel disease (IBD). DNA methylation was shown as an important mechanism in gene silencing. We investigated DNA methylation of the MDR1 gene in ulcerative colitis (UC) and its relation to MDR1 C3435T genotypes. Eighty-three UC patients were enrolled. Methylation of MDR1 promoter was determined by methylation specific polymerase (MSP) for rectal inflammatory mucosa from all patients and normal terminal ileum from 17 patients. Promoter methylation of MDR1 gene was also quantified by digital densitographic analysis following MSP. MDR1 methylation was detected in 51 (61.4%) out of 83 patients in rectal inflammatory mucosa. Mean methylation level of MDR1 gene in rectal inflammatory mucosa was significantly higher than in normal terminal ileum (p=0.021). MDR1 methylation occurred more frequently in total colitis, and total+left side colitis, compared to rectal colitis (p=0.001, 0.013, respectively). Higher methylation levels were also associated with chronic continuous type (p=0.034) and earlier onset of disease (p=0.038). The 3435 CC+CT genotype of MDR1 was associated with more than 6-fold increased risk of MDR1 methylation, especially in UC patients with 9 years and shorter duration. Both frequency and level of MDR1 methylation were higher in UC onset at younger or in middle age with the same genotype. MDR1 methylation frequently occurred in inflammatory rectal mucosa from UC patients and was influenced by MDR1 C3435T polymorphism, especially in patients with shorter duration and younger onset.

Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, Maruyama N, Kamano T, Kamiya Y, Fujita H, Nakagawa Y, Nagasaka M, Iwata M, Takahama K, Watanabe M, Nakano H, Hirata I, Arisawa T. · Department of Gastroenterology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan, · Clin Exp Med. · Pubmed #19184329 No free full text.

Abstract: Tryptase acting at protease-activated receptor 2 (PAR2) contributes to the pathogenesis of Inflammatory bowel diseases (IBDs). DNA methylation has been shown to be an important mechanism in gene silencing. We attempted to clarify the relationship between the promoter methylation of PAR2 and ulcerative colitis (UC). 84 UC patients enrolled in the study. UC patients were classified by disease behavior, severity and extent of disease. For rectal inflammatory mucosal specimens from all the patients, and normal terminal ileum from 23 patients, promoter methylation of PAR2 gene was quantified by digital densitographic analysis following to methylation-specific polymerase chain reaction (MSP). The mean methylation levels of the PAR2 gene in all 84 subjects was 38.4 +/- 19.6%. Although mean methylation levels in rectal inflammatory mucosa, and paired normal terminal ileum did not vary, methylation levels of PAR2 gene was significantly higher in total colitis than rectal colitis (total colitis vs. rectal colitis; 42.9 +/- 19.6% vs. 34.5 +/- 18.9%, P = 0.046). The higher methylation levels were also associated with Steroid-dependent (P = 0.002) and refractory (P = 0.007) UC. Our data suggest that PAR2 methylation status in rectal mucosa correlates with more severe disease phenotypes of UC.

Tahara T, Arisawa T, Fujita H, Kamiya Y, Nagasaka M, Iwata M, Wang F, Shibata T, Nakamura M, Yoshioka D, Okubo M, Takahama K, Watanabe M, Nakano H, Hirata I. · Department of Gastroenterology, Fujita Health University School of Medicine, Japan. · Hepatogastroenterology. · Pubmed #19102345 No free full text.

Abstract: BACKGROUND/AIMS: Reactive oxygen species has been implicated in the development of ulcerative colitis (UC). NADPH oxidase, a major source of superoxide generation play a critical role in H. pylori related gastric inflammation. We aimed to clarify the effect of C242T polymorphism of p22PHOX, an essential component of NADPH oxidase on the risk of UC in a Japanese population. METHODOLOGY: 123 UC patients and 459 healthy control (HC) subjects participated in this study. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In the HC group, the p22 PHOX genotype distribution was 379C/C (82.6%), 79C/T (17.2%), and 5T/T (1.2%). Meanwhile, the p22 PHOX geno type distribution in UC group was 96C/C (78.0%), 26C/T (21.1%), and 1T/T (0.9%). No significant difference of the p22 PHOX genotype distribution was observed between HC and UC groups. (C/C vs. T/T; OR=0.80, 95% CI=0.09-6.84, C/C vs. C/T; OR=1.37, 95% CI=0.83-2.25, C/C vs. T carriers; OR=1.33, 95% CI=0.82-2.18, T/T vs. others; OR=0.74, 95% CI =0.09-6.43). No association was also found between p22PHOX gene polymorphism and different clinicopathological features of UC such as gender, age, age of onset, clinical type, extension of colitis and response to treatment. CONCLUSIONS: It appears that the C242T polymorphism of p22 PHOX is not associated with the incidence of gastric cancer in the Japanese population.

Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, Fujita H, Yoshioka D, Okubo M, Sakata M, Wang FY, Hirata I, Nakano H. · Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan. · Hepatogastroenterology. · Pubmed #18705313 No free full text.

Abstract: BACKGROUND/AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) aggravate or ameliorate clinical disease activity in patients with ulcerative colitis (UC). UC is associated with increased local production of prostanoids. This study attempted to clarify the relationship between cyclooxygenase-1 (COX1) gene polymorphisms (T-1676C and A-842G/C50T) and ulcerative colitis in a Japanese population. METHODOLOGY: The study was performed on 108 patients with UC (mean age: 39.1 years, M:F=56:52) and 293 healthy controls (mean age: 49.0 years, M:F=161:132). The PCR-SSCP method was employed to detect COX1 polymorphisms using DNA extracted from peripheral blood cells. RESULTS: No A-842G/C50T polymorphism was detected in all 401 Japanese subjects. The frequency of -1676C allele of COX1 gene in HC group and UC group was 48.8% and 48.1%, respectively. T-1676C genotypes of COX1 did not show significant association with UC risk. In addition, these genotypes were not also associated with the clinicopathological parameters of UC. CONCLUSIONS: This research suggests that COX1 promoter polymorphisms (T-1676C and A-842G/ C50T) may not be associated with the risk of developing ulcerative colitis in a Japanese population.

Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, Fujita H, Yoshioka D, Okubo M, Sakata M, Wang FY, Hirata I, Nakano H. · Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan. · Hepatogastroenterology. · Pubmed #18613373 No free full text.

Abstract: BACKGROUND/AIMS: Transcription factor Nrf2 regulates the expression of detoxifying and antioxidant genes. Three promoter polymorphisms of this gene have been identified. This study attempted to clarify the relationship between Nrf2 gene polymorphism and ulcerative colitis in a Japanese population. METHODOLOGY: The study was performed in 89 patients with ulcerative colitis (mean age: 40.2 years, M:F = 47:42) and 141 healthy volunteers (mean age: 38.7 years, M:F = 75:66). The PCR-SSCP method was employed to detect Nrf2 polymorphisms using DNA extracted from peripheral blood cells. RESULTS: Comparison of genotype frequency, -686*-684 A* G/A*G genotype was significantly lower in the UC group than those in the HC group (OR = 0.45, 95% CI:0.22-0.93, p = 0.029) and G*G carrier was higher in the UC group, especially in female subjects. Furthermore, -686*-684 G*G carrier was more closely associated with chronic continuous phenotype (OR = 2.57, 95% CI:1.01-6.60, p = 0.043). On the other hand, no association between -650 genotype and ulcerative colitis was found. CONCLUSIONS: The -686*-684 genotype of Nrf2 gene may be associated with the development of ulcerative colitis.

Wang F, Tahara T, Arisawa T, Sakata M, Takahama K, Watanabe M, Hirata I, Nakano H. · Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan. · Hepatogastroenterology. · Pubmed #18507082 No free full text.

Abstract: BACKGROUND/AIMS: Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) has been reported to be impaired in patients with ulcerative colitis (UC), and activation of PPARgamma is proved to inhibit the intestinal inflammation. As Plo12Ala polymorphism in codon 12 of the PPARgamma gene may decrease the promoter activity, we investigated the influences of PPARgamma polymorphism on the risk of UC in Japanese population. METHODOLOGY: The study recruited 118 patients with UC and 142 health controls. Plo12Ala polymorphisms of PPARgamma were detected by polymerase chain reaction based restricted fragment length polymorphism. RESULTS: The frequency of Pro/Alo heterozygotes of PPARgamma gene in UC and control group was 4.2% and 4.9%, respectively. No significant difference was found between UC and control group (P=1.00, Fisher's exact test). Plo12Ala genotype of PPARgamma did not show significant association with UC risk (OR=0.85, 95%CI=0.26-2.76). CONCLUSIONS: Our research suggests that Plo12Ala polymorphism of PPARgamma may not be associated with the risk of developing ulcerative colitis in Japanese population.

Wang FY, Arisawa T, Tahara T, Takahama K, Watanabe M, Hirata I, Nakano H. · Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan. · Hepatogastroenterology. · Pubmed #18507080 No free full text.

Abstract: BACKGROUND/AIMS: DNA methylation has been reported to correlate with the development of colitis associated cancer. We detected the promoter methylation of estrogen receptor gene (ER), TP53, p14, p16, p21 and hMLH1 in ulcerative colitis without neoplasia. METHODOLOGY: A total of 49 specimens from 36 patients, including 36 at rectal inflammatory mucosa and 13 at terminal ileum were obtained by colonoscopic biopsies. Methylation specific polymerase chain reaction were performed to detect the methylation in promoters of the above six genes. RESULTS: Methylation rate of ER promoter was significantly higher in the rectal mucosa than that in the ileum (76.3% vs. 46.2%, P=0.044). Moreover, ER methylation in rectal mucosa was significantly higher in relapse-remitting type compared to one attack only type cases (P=0.008), and also increased in cases longer than 7 years (P=0.036). Methylation rates of p14 or p16 were higher in rectal mucosa than those in the ileum, but the differences were not of statistic significance. Meanwhile, methylation in TP53 promoter was found in only one case, while p21 and hMLH1 methylation were negative in all cases. CONCLUSIONS: Methylation in promoters of ER, p14 and p16 occurs in rectal inflammatory mucosa without neoplasia. Examination of ER methylation in rectal mucosa may be useful for predicting cases at high risk of neoplasia.

Wang FY, Arisawa T, Tahara T, Nagasaka M, Fujita H, Hirata I, Nakano H. · Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake 470-1192, Japan. · J Clin Biochem Nutr. · Pubmed #18231631 links to  free full text

Abstract: Series studies suggest that enteropathogenic microorganisms play a substantial role in the clinical initiation and relapses of ulcerative colitis (UC). Mannan-binding lectin (MBL) is an important constituent of the innate immune system, and deficiency of MBL has been reported to increase the overall susceptibility of an individual to infectious disease. This study was aimed to investigate the associations between polymorphisms of the MBL gene and UC. Recruited in this study were 108 Japanese patients with UC and 144 healthy control subjects. Polymorphism at codon 54 of exon 1 of the MBL gene was investigated by polymerase chain reaction based restriction fragment length polymorphism. In general, no significant difference in MBL polymorphism was found between UC patients and health controls. However, the frequency of A carriers was significantly higher in the relapsing cases than controls (Odds ration = 2.19, 95%CI, 1.10-4.34; p = 0.023), and similar tendency was also found in A/A genotype. In conclusion, the polymorphism at codon 54 of exon 1 of the MBL gene associated with the susceptibility to the relapsing phenotype of ulcerative colitis. It suggests that codon 54 A variants of MBL gene may have an increased risk for the flare-ups of UC.

Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, Fujita H, Nakamura M, Yoshioka D, Arima Y, Okubo M, Hirata I, Nakano H. · Department of Gastroenterology, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan. · J Clin Immunol. · Pubmed #17828618 No free full text.

Abstract: We investigated the association between ulcerative colitis (UC) and polymorphisms of IL-17A (rs2275913, G-197A) and IL-17F (rs763780, 7488T/C) genes. We employed the multiplex PCR-SSCP method to detect gene polymorphisms. Both the numbers of -197A (IL-17A) and 7488T (IL-17F) alleles were significantly correlated to the development of UC. The frequencies of -197A/A and 7488T/T genotypes in the UC group were significantly higher than those in the non-UC group. An adjusted analysis revealed that -197A and 7488T alleles were independent risk factors for the developing UC. In addition, both polymorphisms were significantly associated with the pancolitis phenotype. Furthermore, -197A allele was significantly correlated to the chronic relapsing phenotype and -197A/A homozygote was more frequent in steroid-dependent cases, whereas 7488T allele was correlated with the chronic continuous phenotype. Our results provided the first evidence that -197A (IL-17A) and 7488T (IL-17F) alleles may influence the susceptibility to and pathophysiological features of UC independently.

Wang F, Tahara T, Arisawa T, Shibata T, Nakamura M, Fujita H, Iwata M, Kamiya Y, Nagasaka M, Takahama K, Watanabe M, Hirata I, Nakano H. · Department of Gastroenterology, School of Medicine, Fujita Health University, Toyoake, Japan. · J Gastroenterol Hepatol. · Pubmed #17565650 No free full text.

Abstract: BACKGROUND AND AIM: Ulcerative colitis (UC) is a multifactorial disease resulting from a complex interaction of genetic and environmental factors. Identifying genetic variants that alter the innate immune response is highly relevant to understanding the pathogenesis of UC. The aim of this study was to investigate the association between CD14 and Toll-like receptor-2 (TLR2) genetic polymorphisms and chronic UC in Japanese patients. METHODS: The study population consisted of 102 chronic UC patients and 146 healthy control subjects. Polymorphisms in the promoter at C-260T of CD14 gene were investigated by PCR restriction fragment length polymorphism, and -196 to -174 del of TLR2 was investigated by allele-specific PCR. RESULTS: The frequencies of CD14 TT and T carrier were significantly higher in UC patients than in controls (TT: OR = 3.98, 95% CI 1.82-8.71, P = 0.0005; T carrier: OR = 2.98, 95% CI 1.47-6.01, P = 0.002). In addition, TT and T carrier were more closely associated with distal colitis phenotype (TT: OR = 7.78, 95% CI 2.14-28.28, P = 0.0007; T carrier: OR = 6.30, 95% CI 2.71-14.58, P = 0.005), onset after 20 years of age (TT: OR = 5.28, 95% CI 2.18-12.79; T carrier: OR = 3.79, 95% CI 1.67-8.59), chronic continuous type (TT: OR = 4.26, 95% CI 1.56-11.64; T carrier: OR = 3.09, 95% CI 1.33-7.82), and fewer than two hospitalizations (TT: OR = 4.44, 95% CI 1.81-10.89; T carrier: OR = 3.26, 95% CI 1.43-7.27). There was no significant difference in TLR2 -196 to -174 del/del and del/ins carrier frequencies between UC patients and healthy controls. However, these frequencies were significantly higher in steroid-dependant patients than in controls (del/del: OR = 6.08, 95% CI 1.41-26.21; del carrier: OR = 3.00, 95% CI 1.13-7.98). CONCLUSION: The results suggest that existence of a mutation in the CD14 gene is associated with an increased susceptibility to developing UC, especially chronic continuous distal colitis phenotypes that develop after 20 years of age. Furthermore, polymorphism of TLR2 may be related to an increased risk of intensive types such as steroid-dependent patients.

Tahara T, Inoue N, Hisamatsu T, Kashiwagi K, Takaishi H, Kanai T, Watanabe M, Ishii H, Hibi T. · Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan. · J Gastroenterol Hepatol. · Pubmed #15853983 No free full text.

Abstract: BACKGROUND AND AIM: Although molecular mechanisms underlying ulcerative colitis (UC)-associated neoplasms have been studied for years, understanding of these mechanisms remains incomplete and no good predictable marker for development of colonic neoplasms in patients with UC has been established. The aim of this study was to assess if microsatellite instability (MSI) contributes to the development of colonic neoplasms in patients with UC. METHODS: We have examined MSI in chronic inflamed and neoplastic colonic mucosa of UC patients. We have also obtained serial biopsied colonic tissues retrospectively 2-12 years before the final diagnosis from patients with high level MSI (MSI-H+) UC-associated neoplasms, and analyzed MSI using them at different periods. RESULTS: Eight of 12 UC-associated colon cancers (67%), four of six UC-associated high grade dysplasias (67%), and two of six UC-associated low grade dysplasias (33%) revealed MSI-H+ phenotypes. In contrast, 15 of 59 lesions (25%) in inflamed UC mucosa without colonic neoplasm revealed MSI-H +. Interestingly, all four patients with MSI-H+ phenotypes at the final diagnosis of UC-associated colon cancer or dysplasia had already had MSI-H+ at the stage of chronic colitis, 2-12 years before the final diagnosis. CONCLUSION: These results support the notion that MSI contributes to the carcinogenesis of UC-associated neoplasms, and indicate that this analysis in inflamed colonic mucosa at surveillance colonoscopy is useful for identifying UC patients who have high risk for neoplastic progression.

Yoshimura K, Hirata I, Maemura K, Sugi K, Tahara T. · Department of Internal Medicine, Kodama Hospital, Takarazuka, Hyogo. · Intern Med. · Pubmed #11197790 links to  free full text

Abstract: Radiation therapy is a powerful method for the control of cancer. The utilization of abdominal or pelvic radiation has been extended, and the incidence of radiation enteritis appears to be increasing. The majority of the induced lesions is in the distal ileum, sigmoid colon, or rectum. Reported here is an unusual case of radiation enteritis which caused a severe sequelae of stricture in the transverse colon as a long-term effect of therapeutic irradiation for uterine cancer, and required a surgical resection.