Ulcerative Colitis: Fukushima K

Kariya S, Fukushima K, Kataoka Y, Tominaga S, Nishizaki K. · Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho,Okayama, Japan. · J Laryngol Otol. · Pubmed #18086336 No free full text.

Abstract: OBJECTIVE: Systemic autoimmune diseases, including ulcerative colitis, may involve the inner ear. Several ulcerative colitis cases presenting with sensorineural hearing loss have been reported. We report the T2-weighted, three-dimensional, inner-ear magnetic resonance imaging findings in the inner ears of two such patients. METHODS: Case reports and a review of the literature concerning autoimmune disease and sensorineural hearing loss are presented. RESULTS: We describe two cases of ulcerative colitis with sensorineural hearing loss in which three-dimensional magnetic resonance imaging revealed obliteration of the inner ear. Those inner ears with obliteration had severe hearing loss, and responded poorly to steroid therapy. CONCLUSION: To our knowledge, there has been no previous published report of the T2-weighted, inner-ear magnetic resonance imaging findings of cases of ulcerative colitis with sensorineural hearing loss. This paper represents the first published report in the world literature of inner-ear obliteration in such patients. Three-dimensional magnetic resonance imaging is beneficial in elucidating the pathophysiology of the inner-ear involvement seen in ulcerative colitis.

Kohyama A, Funayama Y, Fukushima K, Shibata C, Miura K, Takahashi K, Ogawa H, Ueno T, Sasaki I, Hiwatashi N. · Division of Biological Regulation and Oncology, Department of Surgery, Tohoku University Postgraduate School of Medicine. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #19498314 No free full text.

Abstract: We encountered a rare operative case of hyperthyroidism followed by ulcerative colitis (UC). A 26-year-old mam was referred to our department to undergo an operation. We suspected the possible complication of adrenal insufficiency, since he suffered from severe weight loss, a high fever and palpitation on admission. We diagnosed hyperthyroidism, however, based on the presence of high serum free T3 and T4 levels and a decreased TSH level. After improving the symptoms and the thyroid function by administering thiamazole, we then performed a total proctocolectomy. Although a high rate of association of autoimmune thyroid diseases with UC has been suggested, only 9 cases of hyperthyroidism coexisting with UC have so far been reported in Japan. A common immunological process has been suggested to be implicated in the pathogenesis of this association, however, the exact mechanism needs to be elucidated in the future.

Watanabe K, Funayama Y, Fukushima K, Shibata C, Takahashi K, Sasaki I. · Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo-machi, Aoba-ku, Sendai, Japan. · Dis Colon Rectum. · Pubmed #19404068 No free full text.

Abstract: PURPOSE: This study aimed to assess the feasibility and safety of undergoing emergency subtotal colectomy with hand-assisted laparoscopic surgery in patients with severe ulcerative colitis. METHODS: We reviewed the medical records of 60 patients who underwent emergency subtotal colectomy with hand-assisted laparoscopic technique (30 cases) or open technique (30 cases) for severe ulcerative colitis. RESULTS: No intraoperative complications occurred in either group. One patient in the laparoscopic group required conversion to open surgery. The median operative time was significantly longer in the laparoscopic group (242 vs. 191 minutes; P < 0.001). The rate of early postoperative complications in the laparoscopic group was significantly less than that in the open group (37 percent vs. 63 percent; P = 0.041). In the open group, four patients required relaparotomy because of peritoneal abscess or strangulation ileus, whereas no patient required relaparotomy in the laparoscopic group (P = 0.040). In the laparoscopic group, the median duration of postoperative food prohibition was significantly shorter (4.8 vs. 5.9 days; P = 0.007), and the median length of hospital stay was significantly shorter (23.0 vs. 33.0 days; P = 0.001). CONCLUSIONS: Although the operative time was elongated in the laparoscopic group, intraoperative safety and postoperative recovery were satisfactory. For severe ulcerative colitis, hand-assisted laparoscopic surgery can be an alternative to conventional open surgery.

Kohyama A, Ogawa H, Funayama Y, Takahashi K, Benno Y, Nagasawa K, Tomita S, Sasaki I, Fukushima K. · Department of Surgery, Tohoku University, Sendai, Japan. · Surgery. · Pubmed #19303993 No free full text.

Abstract: BACKGROUND: Colonic transformation is defined by phenotypic alterations in the ileum after total proctocolectomy. Changes in microbiota of the ileal pouch and the roles of these microbes in colonic transformation, however, have not been addressed. METHODS: A total of 151 stool samples were collected from patients with ulcerative colitis patients and an ileostomy, those with an ileal pouch, and healthy control volunteers. Bacterial DNA was extracted from stool, and the diversity of complex bacteria was assessed by terminal restriction fragment length polymorphism (T-RFLP) analysis, a novel DNA-based approach that enables us to investigate the presence of nonculturable bacteria. To determine whether ileal pouch bacterial communities shift to a more colon-like distribution, the relative abundance of terminal restriction fragments that could be classified as "colonic," "ileal," or "common" was investigated. RESULTS: Cluster analysis demonstrated that most of the ileostomy samples were categorized into Cluster I or II and that less than 10% of ileostomy samples were classified into Cluster IV. In contrast, more than 90% of control samples were grouped in Cluster IV. In further analyses, the median lifetimes of pouches in Clusters I, II, III, and IV were significantly different at 11, 56, 265, and 310 days, respectively. T-RFLP patterns of the ileal pouch were characterized by a time-dependent decrease in "ileal" and increase in a part of "colonic" fragments, which represented mainly nonculturable bacteria such as the Clostridium coccoides group. CONCLUSION: T-RFLP analysis demonstrated that a time-dependent shift to a "colon-like" bacterial community, including nonculturable bacteria, in the ileal pouch after total proctocolectomy.

Funayama Y, Kumagai E, Takahashi K, Fukushima K, Sasaki I. · Department of Colorectal Surgery, Tohoku Rosai Hospital, Sendai, Japan. · Dis Colon Rectum. · Pubmed #19279428 No free full text.

Abstract: PURPOSE: To evaluate the efficacy of early diagnosis and early administration of corticosteroid for peristomal pyoderma gangrenosum, a prospective study was carried out. METHODS: In April 1998, we began studying a new treatment regimen of peristomal pyoderma gangrenosum in which prednisone at a dose of 20 to 40 mg was administered systemically immediately after diagnosis. Early-stage peristomal pyoderma gangrenosum was treated concurrently with topical cadexomer iodine, and at the granulation stage, treatment with clobetasol ointment was started. Healing of peristomal pyoderma gangrenosum was determined by complete epithelialization of ulcer without pain or exudates. Patients were assigned to group A (n = 7) before April 1998 and group B (n = 10) after April 1998, and historical comparison was done between the 2 groups. RESULTS: In group A, all patients had ulcerative colitis, and in group B, 7 patients had ulcerative colitis, 2 had Crohn's disease, and one had indeterminate colitis. In group B, significantly earlier diagnosis (P = 0.0093), earlier start of treatment (P = 0.0057), higher initial dose of corticosteroid (P = 0.0052), and earlier healing of peristomal pyoderma gangrenosum (P = 0.0023) were observed. CONCLUSIONS: Early diagnosis and early corticosteroid administration appeared to be effective for promoting healing of peristomal pyoderma gangrenosum.

Takahashi K, Funayama Y, Fukushima K, Shibata C, Ogawa H, Kumagai E, Sasaki I. · Department of Surgery, Division of Gastrointestinal and Colorectal Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. · Dig Surg. · Pubmed #18292656 No free full text.

Abstract: BACKGROUND: This study was designed to evaluate the incidence and details of stoma-related complications in patients with ulcerative colitis and Crohn's disease who underwent permanent enterostomas, and to analyze the specific problems in these diseases. METHODS: Permanent enterostomas constructed for ulcerative colitis and Crohn's disease between 1984 and 2004 in our institution were included. The incidence and details of stoma-related complications were investigated retrospectively. The cumulative probability of complications and stoma reconstruction was also estimated by the Kaplan-Meier life-table analysis. RESULTS: 43 patients with ulcerative colitis and 59 patients with Crohn's disease underwent 46 and 76 stoma constructions, respectively. Stoma-related complications, including fistula, retraction and stenosis, were significantly more frequent in patients with Crohn's disease (36.8%) than ulcerative colitis (17.4%) (p < 0.05). The cumulative risk of complications and the necessity for stoma reconstruction was significantly higher in patients with Crohn's disease (p < 0.05). Among the patients with Crohn's disease, colostomies were likely to receive revisional surgery earlier than ileostomies (p < 0.05). CONCLUSION: In the surgical therapy of inflammatory bowel disease, special attention should be paid in the high incidence of stoma-related complications in patients with Crohn's disease, which needs revisional surgery more frequently.

Fukushima K, Fujii H, Yamamura T, Sugita A, Kameoka S, Nagawa H, Futami K, Watanabe T, Hatakeyama K, Sawada T, Yoshioka K, Kusunoki M, Konishi F, Watanabe M, Takahashi K, Ogawa H, Funayama Y, Hibi T, Sasaki I, Anonymous00291. · Department of Surgery, Tohoku University, Graduate School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, Japan. · J Gastroenterol. · Pubmed #17940832 No free full text.

Abstract: "Pouchitis" is a term for nonspecific mucosal inflammation of the pouch after total proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis. Pouchitis is the most frequent complication of the pelvic pouch at the late stage. To improve the accuracy of the pouchitis diagnosis, sets of clinical symptoms and endoscopic findings (with or without histology of biopsy samples) have previously been evaluated. Endoscopic findings are central to the diagnosis, and a universal consensus of various endoscopic findings must be the initial step toward an objective diagnosis of pouchitis. Since a proper signpost for the endoscopic evaluation of pouchitis has been absent, we developed this pouchitis atlas to minimize the diagnostic variation inherent among individual endoscopists. We also propose new criteria for the diagnosis of pouchitis: the Japanese criteria for diagnosis of pouchitis. These criteria are based on clinical symptoms and endoscopic findings that are clearly categorized in the atlas, and exclude infectious enteritis, anastomotic insufficiency, pelvic infection, anal dysfunction, and Crohn's disease. Advantages of the new criteria include ease of bedside diagnosis, without the calculation of points required by the other criteria for pouchitis. This pouchitis atlas, together with our new criteria, should contribute to the establishment of a clear-cut diagnosis for pouchitis and promote better evaluation and treatment of this novel intestinal inflammation.

Shibata C, Funayama Y, Fukushima K, Takahashi K, Ogawa H, Haneda S, Watanabe K, Kudoh K, Kohyama A, Hayashi K, Sasaki I. · Division of Biological Regulation and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Sendai, Japan. · Dig Dis Sci. · Pubmed #17394081 No free full text.

Abstract: The aim of the present study was to determine if calcium polycarbophil ameliorates diarrhea after ileal J-pouch anal anastomosis for ulcerative colitis. Twenty-one randomized patients were given either bifidobacterium (3 g/day) plus calcium polycarbophil (3 g/day), in the polycarbophil group (11 patients), or bifidobacterium (3 g/day), in the control group (10 patients), p.o. for 6 months. Anal manometry was performed and bowel function (stool frequency, stool consistency, and nighttime soiling) was assessed via a questionnaire before and 1, 3, and 6 months after drug administration. Eight patients were deemed eligible in each group; five patients were excluded from the study, including two patients whose stool consistency was too firm and who experienced difficulty in defecating attributed to polycarbophil. Anal manometry and stool consistency did not change with time and did not differ between the polycarbophil and the control groups. Stool frequency decreased with time in both groups and did not differ between the groups. Nighttime soiling improved with time in the polycarbophil group but did not change in the control subjects. These results suggest that polycarbophil might be able to improve nighttime soiling without obviously affecting stool frequency and consistency after ileal J-pouch anal anastomosis for ulcerative colitis.

Watanabe K, Funayama Y, Fukushima K, Shibata C, Takahashi K, Ogawa H, Haneda S, Kudo K, Kohyama A, Sasaki I, Anonymous00097. · Department of Surgery, Division of Biological Regulation and Oncology (GI & Colorectal Surgery), Tohoku University Graduate School of Medicine, 1-1 Seiryou-machi, Aoba-ku, Sendai, 980-8574, Japan. · J Gastroenterol. · Pubmed #16933003 No free full text.

Abstract: BACKGROUND: The Inflammatory Bowel Disease Questionnaire (IBDQ) is the most widely used disease-specific health-related quality of life questionnaire for patients with inflammatory bowel disease. However, little has been reported about the validation of IBDQ for patients with ulcerative colitis after surgery. The aim of this study was to assess the validity and reliability of the Japanese version of IBDQ in patients with ulcerative colitis after total proctocolectomy and ileal pouch anal anastomosis (IPAA). METHODS: The validity and reliability of the Japanese IBDQ were assessed in patients with ulcerative colitis who had received IPAA in our hospital. We mailed them the Japanese IBDQ and a supplemental questionnaire on bowel function, which was developed at our institution. Internal consistency, discriminative validity, and factor validity were assessed. RESULTS: Of the 121 patients to whom we sent the questionnaires, 64 patients (53%) participated in this study. The Japanese IBDQ scores correlated well with Cronbach's alpha value (0.800 to 0.923) and daily life satisfaction score (Pearson's r, 0.492 to 0.700). The total IBDQ score and two subscale scores of the IBDQ, "bowel symptoms" and "systemic symptoms," correlated well with daily bowel-movement frequency (Pearson's r, -0.256 to -0.329). Factor analysis revealed a four-factor structure, and all correlations among factors were moderately positive (0.337 to 0.465). Although the factor distribution was not clearly divided into the four IBDQ subscales, these four factors showed a marked tendency to represent the IBDQ subscales independently. CONCLUSIONS: The Japanese IBDQ is a valid and reliable instrument for the assessment of Japanese patients with ulcerative colitis after IPAA.

Shibata C, Funayama Y, Fukushima K, Takahashi K, Saijo F, Nagao M, Haneda S, Watanabe K, Kudoh K, Kohyama A, Sasaki I. · Division of Biological Regulation and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. · J Gastrointest Surg. · Pubmed #16843879 No free full text.

Abstract: The aim was to study determinants of postoperative bowel function after restorative proctocolectomy for ulcerative colitis. Medical records of patients who underwent proctocolectomy with ileal J pouch-anal anastomosis (IPAA) in two- or three-stage operations and whose status of defecation was known via a questionnaire were retrospectively reviewed. Bowel function, including stool frequency, stool consistency, and degree of nighttime soiling, was correlated with age at the time of surgery, time after ileostomy closure, mean resting anal pressure, longitudinal length of ileal J pouch, and duration of fecal diversion by using univariate and multivariate analyses. Stool frequency decreased significantly with time after ileostomy closure in both univariate and multivariate analyses. Stool frequency tended to be less in patients having a long J pouch, but the correlation was not significant (P = 0.071) in univariate analysis. Nighttime soiling ameliorated with time after ileostomy closure in multivariate, but not univariate, analysis. Deterioration of nighttime soiling was seen in patients whose duration for fecal diversion was long, both in univariate (P = 0.068) and multivariate (P = 0.052) analyses. Stool consistency was related to none of the five factors investigated. These results indicate that as the time after surgery increases, stool frequency decreases and nighttime soiling ameliorates. Delaying ileostomy closure because of anticipated postoperative incontinence does not significantly alter postoperative continence.

Haneda S, Fukushima K, Funayama Y, Shibata C, Takahashi K, Ogawa H, Nagao M, Watanabe K, Sasaki I. · Department of Surgery, Tohoku University, Graduate School of Medicine, Sendai, Japan. · J Gastrointest Surg. · Pubmed #16843877 No free full text.

Abstract: Our previous studies demonstrated that sodium glucose cotransporter 1 (SGLT-1) was induced in the remnant ileum of total colectomized rats via the action of factors other than hyperaldosteronism. The aim of the present study was to clarify whether fecal stream is required for the enhancement of SGLT-1-mediated sodium transport. Twenty-seven pairs of ileal tissues were obtained from the proximal and distal side, respectively, of loop ileostomy after total proctocolectomy. Mucosae were mounted in an Ussing chamber to evaluate glucose-coupled sodium transport. Levels of SGLT-1 mRNA in proximal and distal mucosae were compared by Northern blotting. Villous height and crypt depth were measured to test for correlations between mucosal structure and SGLT-1-mediated sodium transport or mRNA expression levels. Both glucose-coupled sodium transport and expression of SGLT-1 mRNA were significantly lower in distal mucosae relative to proximal mucosae. In distal mucosae, villous height, but not crypt depth, was significantly lower than in proximal mucosae, demonstrating a positive correlation between villous height and SGLT-1 function and expression. Comparative studies of proximal and distal mucosae demonstrated that in addition to hormonal changes, fecal stream is required for full induction of the sodium transport system (which includes SGLT-1-mediated transport) in the remnant ileum following total proctocolectomy.

Jinno Y, Ohtani H, Nakamura S, Oki M, Maeda K, Fukushima K, Nagura H, Oshitani N, Matsumoto T, Arakawa T. · Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan. · Virchows Arch. · Pubmed #16435133 No free full text.

Abstract: Abnormalities in humoral immunity are implicated in the pathogenesis of ulcerative colitis. However, the detailed mechanisms of B-cell activation in the locale remain unaccounted for. We analyzed ulcerative colitis from the standpoint of lymphocytic expansion in the loco. Intestinal specimens obtained at surgery from 30 patients with ulcerative colitis treated with corticosteroids and 15 with Crohn's disease were analyzed by immunohistochemistry and flow cytometry. Ulcerative colitis was characterized by a diffuse distribution of Ki-67(+) small round cells particularly in the ulcer base (that were CD19(+) and CD20(-)), with a significant number of them also CD138(+). Immunoelectron microscopy for CD19 revealed an abundance of rough endoplasmic reticulum in the cytoplasm. These indicated that they are of immature plasma lineage cells. By contrast, plasma cells in Crohn's disease were negative for CD19, and the labeling for Ki-67 was infrequent, showing mature phenotype. Flow cytometry revealed an occurrence of CD19(+) and CD20(-) cells in ulcerative colitis but not in Crohn's disease. The labeling index of Ki-67 among CD19(+) plasma cells was positively correlated with the clinical activity of ulcerative colitis. High labeling of Ki-67 in CD19(+) plasma cells is specific for active ulcerative colitis that was resistant to medical treatment by corticosteroids.

Kitayama T, Funayama Y, Fukushima K, Shibata C, Takahashi K, Ogawa H, Ueno T, Hashimoto A, Sasaki I. · Department of Surgery, Division of Gastrointestinal and Colorectal Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan. · Surg Today. · Pubmed #15772791 No free full text.

Abstract: PURPOSE: Total proctocolectomy and ileal pouch anal anastomosis (IPAA) is now a common procedure for ulcerative colitis (UC). Moreover, it has been reported that fertility is preserved in women who undergo this procedure, many of whom can experience normal delivery. METHODS: We assessed the perinatal outcomes and changes in anal function in four women, aged from 27 to 35 years, who gave birth after undergoing IPAA for UC. Pregnancies were confirmed 15-111 months after IPAA, three women had full-term pregnancies, and one gave birth after 31 weeks' gestation. RESULTS: Cephalic delivery with a vacuum extractor was used for one patient, and another underwent cesarean section. The other two patients experienced normal delivery. None of the patients needed artificial insemination and none had any symptoms of intestinal obstruction during their pregnancy. After delivery, two patients suffered a transient increase in bowel frequency and soiling, which gradually resolved. CONCLUSIONS: Although transient anal dysfunction occurred in the puerperal period, there were no changes in anal function during pregnancy. Therefore, there are no factors directly prohibiting pregnancy and vaginal delivery in women who undergo IPAA for UC.

Fukushima K, Fiocchi C. · Div. of Gastroenterology, Univ. Hospitals of Cleveland, Case Western Reserve Univ. School of Medicine (BRB 425 10900 Euclid Ave., Cleveland, OH 44106-4952, USA. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #15068964 links to  free full text

Abstract: Ulcerative colitis (UC) is a condition characterized by chronic inflammation targeted at the epithelial layer. In addition to being involved in immune phenomena, UC epithelial cells exhibit decreased oxidation of butyrate, downregulation of oxidative pathway regulatory genes, and overexpression of mitochondrial (mt) genes. We investigated whether these events, which translate an altered energy metabolism, are associated with an abnormal pattern of mtDNA deletions. Highly purified colonocytes were isolated from surgically resected control, involved and uninvolved inflammatory bowel disease mucosa. The frequency, type, and number of mtDNA deletions were assessed by PCR amplification, Southern blot analysis, and cloning and sequencing of amplified DNA fragments. The 4977 mtDNA deletion was less frequent in UC than control and Crohn's disease (CD) epithelium, regardless of patient age. Several other deletions were detected, but all were less common in UC than control and CD cells. The frequency, variety, and number of mtDNA deletions were invariably lower in colonocytes isolated from inflamed mucosa than in autologous cells from noninflamed mucosa. In conclusion, in the absence of inflammation, UC colonocytes exhibit an mtDNA deletion pattern similar to that of control cells, indicating a normal response to physiological levels of oxidative stress. In active inflammation, when oxidative stress increases, the frequency, variety, and number of mtDNA deletions decrease. Because comparable abnormalities are absent in active CD, the mtDNA deletion pattern of active UC suggests that colonocytes respond uniquely to inflammation-associated stress in this condition.

Shibata C, Jin XL, Funayama Y, Fukushima K, Takahashi K, Hashimoto A, Nagao M, Haneda S, Watanabe K, Matsuno S, Sasaki I, Naito H. · Division of Biological Regulation and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. · Tohoku J Exp Med. · Pubmed #14738325 links to  free full text

Abstract: We report a patient with synchronous multiple liver metastases from rectal cancer associated with ulcerative colitis. Because the liver tumors were unresectable, we performed total proctocolectomy and hepatic intra-arterial cisplatin infusion with systemic oral administration of fluorouracil. A complete response was obtained. The patient is alive without sign of recurrence 5 years postoperatively. Hepatic intra-arterial administration of cisplatin should be considered in the treatment of unresectable liver metastases from colorectal cancer.

Fukushima K, Yonezawa H, Fiocchi C. · Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. · Inflamm Bowel Dis. · Pubmed #14555912 No free full text.

Abstract: Intestinal epithelial cells are actively involved in the pathogenesis of inflammatory bowel disease resulting in an altered functional phenotype. The modulation of epithelial gene expression may occur as a consequence of proliferative, metabolic, immune, inflammatory, or genetic abnormalities.Differential screening of epithelial-cell-derived cDNA libraries (from control, ulcerative colitis, and Crohn's disease epithelial cells) and differential display of mRNA were used for investigation of disease-associated gene expression and modulation. Intestinal epithelial gene expression was successfully analyzed by both approaches. Using differential screening with clones encoding mitochondrial genes, quantitative overexpression was observed in both ulcerative colitis and Crohn's disease, while a unique expression of small RNA was noticed in Crohn's disease cells using Alu-homologous clones. Differential display demonstrated that several genes were differentially displayed among control, ulcerative colitis, and Crohn's disease epithelial cells. This was confirmed by immunohistochemical staining of pleckstrin, desmoglein 2 and voltage-dependent anion channel in control and inflammatory bowel disease mucosal samples.In summary, several inflammatory bowel disease-related associations were found. Since both differential screening and display have advantages and limitations, the combination of both techniques can generate complementary information, facilitate search for novel genes, and potentially identify genes uniquely associated with inflammatory bowel disease.

Ogawa H, Fukushima K, Naito H, Funayama Y, Unno M, Takahashi K, Kitayama T, Matsuno S, Ohtani H, Takasawa S, Okamoto H, Sasaki I. · Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. · Inflamm Bowel Dis. · Pubmed #12792221 No free full text.

Abstract: Although microorganisms play a role in gut inflammation, it remains uncertain which epithelial genes are expressed in response to luminal flora and whether these molecules are also involved in pathologic mucosal inflammation. Germ-free mice were orally challenged with a bacterial suspension prepared from conventionally housed mice (bacterial reconstitution). Thereafter, the differential gene expression in gut epithelial cells was identified by differential display. The expression of the identified genes was also examined in dextran sulfate sodium (DSS)-induced colitis and human inflammatory bowel disease (IBD) epithelial cells. Regenerating gene III (Reg III) was strongly induced in gut epithelial cells following bacterial reconstitution, as well as in the colitis initiated by DSS. The mRNA expression of hepatocarcinoma-intestine-pancreas/pancreatic associated protein (HIP/PAP), a human counterpart of Reg III, was enhanced in colonic epithelial cells of patients with IBD. Reg III mRNA expression was localized in the epithelial cells including goblet cells and columnar cells in mice; on the other hand, HIP/PAP-expressing cells were correlated with Paneth cell metaplasia in human colon. Epithelial expression of Reg III or HIP/PAP was induced under mucosal inflammation initiated by exposure to commensal bacteria or DSS as well as inflamed IBD colon.

Arihiro S, Ohtani H, Suzuki M, Murata M, Ejima C, Oki M, Kinouchi Y, Fukushima K, Sasaki I, Nakamura S, Matsumoto T, Torii A, Toda G, Nagura H. · Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan. · Pathol Int. · Pubmed #12100519 No free full text.

Abstract: Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is selectively expressed in the endothelial cells of intestinal mucosa and gut-associated lymphoid tissue (GALT). Engagement of MAdCAM-1 to its ligand, integrin alpha4beta7, on lymphocytes is associated with the homing of gut-associated lymphocytes to normal gastrointestinal tract and inflammation sites. The present study was designed to elucidate differences between Crohn's disease (CrD) and ulcerative colitis (UC) from the expression patterns of MAdCAM-1. Samples were taken from 40 patients with CrD and 24 patients with UC at surgical resection. Using frozen sections, immunohistochemistry was performed for MAdCAM-1, E-selectin and CD34. MAdCAM-1+ venules were abundant in inflamed mucosa in both UC and CrD. In contrast, clear differences were noted between UC and CrD in the inflammatory area in the ulcer base, that is, MAdCAM-1+ venules were more abundant in CrD than in UC (P < 0.001), while E-selectin was expressed equally in these venules in both diseases. Furthermore, CrD was characterized by the occurrence of MAdCAM-1+ venules in deeper layers of the intestinal tissue, mainly in lymphoid aggregates. Our data indicated more extensive expression of MAdCAM-1 in CrD, which could contribute not only to mucosal inflammation, but also to transmural inflammation in CrD.

Hashimoto A, Funayama Y, Naito H, Fukushima K, Shibata C, Naitoh T, Shibuya K, Koyama K, Takahashi K, Ogawa H, Satoh S, Ueno T, Kitayama T, Matsuno S, Sasaki I. · First Department of Surgery, Tohoku University School of Medicine, Sendai, Miyagi, Japan. · Surg Today. · Pubmed #11318122 No free full text.

Abstract: To assess the advantages of a laparoscope-assisted proctocolectomy with ileal J-pouch anal anastomosis compared with conventional procedures, we retrospectively analyzed the results of the two procedures as follows: Eleven patients including five patients with familial adenomatous polyposis (FAP) and six with ulcerative colitis (UC) underwent a laparoscope-assisted proctocolectomy and hand-sewn ileal J-pouch anal anastomosis at our department from June 1997 to November 1999. This laparoscope-assisted colectomy (LAC) group was then compared with a group of 13 patients who had undergone conventional ileal pouch anal anastomosis using a standard laparotomy from 1986 to 1997. The median operative time of the LAC group was 8h 23min, which was 81 min longer than that of the standard colectomy (SC) group. The number of days during which eating was prohibited were similar in the two groups but the median postoperative hospital stay was significantly shorter in the LAC group (24.1 days). In the LAC group, the small incisions showed better cosmetic results and there was also a remarkable reduction in the degree of postoperative pain. In conclusion, a laparoscope-assisted proctocolectomy with ileal J-pouch anal anastomosis can be employed widely in patients with FAP and also in selected patients with UC.

Takahashi KI, Fukushima K, Sasano H, Sasaki I, Matsuno S, Krozowski ZS, Nagura H. · Department of Surgery, Tohoku University School of Medicine, Sendai, Japan. · Dig Dis Sci. · Pubmed #10630506 No free full text.

Abstract: Type IIbeta-hydroxysteroid dehydrogenase endows specificity on the mineralocorticoid receptor by metabolizing cortisol and regulates sodium absorption in renal and colonic epithelium. Altered expression of this enzyme may be associated with impaired sodium absorption often seen in colonic mucosa of inflammatory bowel disease. The aim of this study was to investigate possible abnormality of 11beta-hydroxysteroid dehydrogenase protein and mRNA expression in inflammatory bowel disease. In Crohn's disease, the colonic epithelium showed comparable levels of immunoreactivity and mRNA expression to those of control, except for the decreased immunoreactivity in severe inflamed lesions with deep ulcer. In contrary, a lack or decrease of immunoreactivity was relevant in ulcerative colitis regardless of the histological degree of inflammation. The mRNA expression was also significantly decreased in ulcerative colitis. This study demonstrates that abnormality of epithelial cells in ulcerative colitis includes the enzyme that regulates water and sodium absorption, which are physiologically essential.

Fukushima K, Sasaki I, Takahashi K, Naito H, Funayama Y, Matsuno S. · The First Department of Surgery, Tohoku University School of Medicine, Sendai, Japan. · Tohoku J Exp Med. · Pubmed #10458490 links to  free full text

Abstract: Because the beginning of extraction of lamina propria mononuclear cells is to obtain mucosal tissues that are exposed to luminal bacteria, the contaminated endotoxin in this step and/or the enzymes for mucosal digestion may activate mucosal macrophages and other cells. To address this issue, endotoxin levels in isolation solutions were evaluated during the extraction of lamina propria mononuclear cells from 8 control, 7 Crohn's disease and 8 ulcerative colitis specimens. Endotoxin levels were measured using Toxicolor system based on the limulus tests. Endotoxin levels were consistently below 500 pg/ml, and more importantly, these in enzyme digestion solutions were comparable among control, Crohn's disease, and ulcerative colitis. Therefore, comparative experiments using lamina propria mononuclear cells from these mucosae can be appropriately carried out, at least as far as in a comparable amount of contaminated endotoxin. However, careful consideration is required for the comparative and functional study using peripheral blood and lamina propria mononuclear cells.

Ina K, Itoh J, Fukushima K, Kusugami K, Yamaguchi T, Kyokane K, Imada A, Binion DG, Musso A, West GA, Dobrea GM, McCormick TS, Lapetina EG, Levine AD, Ottaway CA, Fiocchi C. · Division of Gastroenterology, Molecular Cardiovascular Research Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. · J Immunol. · Pubmed #10395708 links to  free full text

Abstract: Crohn's disease (CD) is a condition characterized by excessive numbers of activated T cells in the mucosa. We investigated whether a defect in apoptosis could prolong T cell survival and contribute to their accumulation in the mucosa. Apoptotic, Bcl-2+, and Bax+ cells in tissue sections were detected by the TUNEL method and immunohistochemistry. T cell apoptosis was induced by IL-2 deprivation, Fas Ag ligation, and exposure to TNF-alpha and nitric oxide. TUNEL+ leukocytes were few in control, CD, and ulcerative colitis (UC) mucosa, with occasional CD68+ and myeloperoxidase+, but no CD45RO+, apoptotic cells. Compared with control and UC, CD T cells grew remarkably more in response to IL-2 and were significantly more resistant to IL-2 deprivation-induced apoptosis. CD T cells were also more resistant to Fas- and nitric oxide-mediated apoptosis, whereas TNF-alpha failed to induce cell death in all groups. Compared with control, CD mucosa contained similar numbers of Bcl-2+, but fewer Bax+, cells, while UC mucosa contained fewer Bcl-2+, but more Bax+, cells. Hence, the Bcl-2/Bax ratio was significantly higher in CD and lower in UC. These results indicate that CD may represent a disorder where the rate of T cell proliferation exceeds that of cell death. Insufficient T cell apoptosis may interfere with clonal deletion and maintenance of tolerance, and result in inappropriate T cell accumulation contributing to chronic inflammation.

Fukushima K, Sasaki I, Takahashi K, Naito H, Matsuno S. · First Dept. of Surgery, Tohoku University, School of Medicine, Sendai, Japan. · Scand J Gastroenterol. · Pubmed #10232875 No free full text.

Abstract: BACKGROUND: Although epithelial cells in ulcerative colitis may be metabolically deficient, it remains unknown whether epithelial cells modulate energy metabolism in inflamed mucosa. The purpose of the present study is to investigate whether inflammatory mediators such as lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) alter energy metabolism in epithelial cells. METHODS: Adenosine 5'-triphosphate (ATP) levels in HT29 cells cultured with LPS, IL-1beta, IL-6, or TNF-alpha were measured with high-performance liquid chromatography, using a reversed-phase chromatography column. Cellular and mitochondrial (antimycin A-sensitive) respiration rates were determined polarographically, using a Clark-type oxygen electrode. RESULTS: When the cells were cultured with LPS, IL-6, and TNF-alpha but not IL-1beta, ATP levels increased significantly at 6 h, followed by a decrease at 24 h. Enhancement of oxygen consumption, which was completely blocked by antimycin A, was also shown at 3 h by the exposure to these substrates. CONCLUSION: LPS and proinflammatory cytokines induced cellular ATP generated by mitochondrial phosphorylation. An active energy production in epithelial cells on the exposure to inflammatory mediators may be critical for escape from chronic mucosal inflammation.

Fukushima K, Sasaki I, Ogawa H, Naito H, Funayama Y, Matsuno S. · The First Department of Surgery, Tohoku University, School of Medicine, Sendai, Japan. · J Gastroenterol. · Pubmed #10204611 No free full text.

Abstract: To investigate the pathogenesis of inflammatory bowel disease, it is critical to develop a system that uses simple and reproducible models for analyzing the "normal" mucosal defense mechanism. In the present study, germ-free mice were conventionalized by the oral administration of microorganisms prepared from the feces of genetically identical mice. Histological assessment and mucin characterization of small intestine and colon were then carried out. Histological findings in the gut were site-dependent and clearly time-dependent. Acute inflammation was most evident in the cecum. The cecal mucosa exhibited hyperplastic changes in epithelial cells, infiltration of polymorphonuclear cells, crypt abscesses, and epithelial projections on the epithelial surface 7 days after conventionalization. Some of the changes were similar to those seen in human ulcerative colitis. The histological findings in the conventionalized mice were comparable to those in specific pathogen-free mice after 28 days. Mucin histochemistry revealed that bacterial colonization altered the number of rectal goblet cells and the mucin composition in a time-dependent fashion. Although this model shares only some characteristics of human inflammatory bowel disease, it is unique in demonstrating the acquisition of mucosal defense. Understanding of this process is critical for the elucidation of inflammatory bowel disease pathogenesis.

Funayama Y, Fukushima K, Shibata C, Koyama K, Miura K, Takahashi K, Hashimoto A, Sasaki I, Kinouchi Y, Hiwatashi N, Takeda K, Matsuno S. · No affiliation provided · J Gastroenterol. · Pubmed #15235881 No free full text.

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