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Recently in Japan, the morbidity of colorectal polyp has been increasing. As a result, a large number of cases of colorectal polyps that are diagnosed and treated using colonoscopy has now increased, and clinical guidelines are needed for endoscopic management and surveillance after treatment. Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Ten specialists for colorectal polyp management extracted the specific clinical statements from articles published between 1983 and September 2011 obtained from PubMed and a secondary database, and developed the CQs and statements. Basically, statements were made according to the GRADE system. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid. The professional committee created 91CQs and statements for the current concept and diagnosis/treatment of various colorectal polyps including epidemiology, screening, pathophysiology, definition and classification, diagnosis, treatment/management, practical treatment, complications and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumor/carcinoma). After evaluation by the moderators, evidence-based clinical guidelines for management of colorectal polyps have been proposed for 2014.

Oral mesalazine formulations are effective in the treatment of active ulcerative colitis (UC). It is not clear what induction dose of mesalazine is optimal for treating patients with active UC. We aimed to evaluate the efficacy and safety of 4 versus 2.25 g/day for selected patients with active UC. A multicenter, randomized, double-blind, parallel-group clinical study in 39 Japanese medical institutions. A total of 123 patients with moderately active UC received 4 g/day (two divided doses) versus 2.25 g/day (three divided doses) for 8 weeks. Primary endpoint was the ulcerative colitis-disease activity index (UC-DAI) score before and after 8 weeks of treatment. The improvement of each individual UC-DAI variable, remission, and efficacy rates were secondary endpoints. Safety was determined by laboratory data, vital signs, subjective symptoms, and objective findings. Patients receiving 4 g/day achieved a change in UC-DAI score significantly superior to those receiving 2.25 g/day [−3.0 (95% confidence intervals (CI) −3.8 to −2.3) vs. −0.8 (95% CI −1.8 to 0.1), respectively]. There were significant differences in all UC-DAI variables between the groups. Remission rates were 22.0% (4 g/day) and 15.3% (2.25 g/day). The efficacy rate was significantly better with 4 versus 2.25 g/day [76.3 vs. 45.8%, respectively (95% CI 13.8–47.2); P = 0.001]. No difference was seen in adverse events or adverse drug reactions. A dose of 4 g/day was significantly superior to 2.25 g/day in terms of UC-DAI score for patients with moderately active UC. Safety profiles were similar for both doses.

Background/Aims: Several earlier studies on factors predicting the long-term outcome of ulcerative colitis only encompassed treatment failure for one severe episode, or suffered from a lack of multivariate analyses. We aimed to identify factors assessable at diagnosis or after the first induction therapy which predicted relapse or later colectomy in patients with mild to severe ulcerative colitis. Methods: Clinical parameters (age, sex, disease extent, and disease activity at diagnosis) and laboratory data (hemoglobin, albumin, C-reactive protein, and erythrocyte sedimentation rate at diagnosis and 4 weeks after the first induction therapy) were evaluated in 296 patients (median follow-up 87 months). Factors predicting relapse and later colectomy were sought using the Cox proportional hazard model. Results: The presence of moderate or severe disease at diagnosis were significant predictors of relapse [adjusted hazard ratio (95% CI) 2.07 (1.48–2.89) and 1.70 (1.06–2.72), respectively] and later colectomy [3.40 (1.09–10.54) and 6.77 (1.92–23.86)]. After the first induction therapy, hemoglobin and albumin were associated with relapse [0.87 (0.76–0.99) and 0.58 (0.41–0.83)] and later colectomy [0.60 (0.47–0.77) and 0.11 (0.06–0.22)]. Conclusion: Relapse and later colectomy were associated with (1) disease activity at diagnosis and (2) lower levels of hemoglobin and albumin after the first induction therapy.

症例は72歳男性．下痢を主訴に近医を受診し，腹部腫瘍を指摘され当院へ紹介となった．腹部CTでは膵鉤部から上腸間膜動脈を巻き込む腫瘍を認めた．CA19-9やDUPAN-2などの腫瘍マーカーの上昇は認めなかった．治療方針決定のため開腹下腫瘍生検を行い，退形成性膵管癌と診断した．S-1による化学療法を開始したが，閉塞性黄疸を併発した．経皮経肝的胆道ドレナージ術（PTBD）を施行し，黄疸の改善を認めたが，病状の進行は早く，初診より約4カ月の経過で死亡した．経過に従い白血球数の著増を認めた（93400/μl ）．血中G-CSFの上昇（312pg/ml ）を認めており，剖検にて腫瘍のG-CSF免疫染色陽性が確認され，G-CSF産生退形成性膵管癌（多形細胞型）と診断した.

Although intestinal Behcet's disease has been treated anecdotally with various therapeutic modalities, clinical evidence regarding management of intestinal Behcet's disease is lacking. The objective of this study was to develop consensus-based practice guidelines for diagnosis and treatment of intestinal Behcet's disease by using a modified Delphi approach. Three groups of Japanese gastroenterology specialists were involved in the study: moderators, an expert panel, and a professional group. Clinical statements for ratings were extracted from relevant literature, a survey of the professional group, and by discussion among the expert panel. The expert panel rated the clinical statements according to a nine point scale. After the first round of ratings, a panelist meeting was held to discuss areas of disagreement and to clarify areas of uncertainty. The list of clinical statements was revised after the panelist meeting, and a second round of rating was conducted. Thirty-two relevant articles were selected in a literature search, and 35 clinical statements were extracted. An additional 209 clinical statements were developed from the survey and discussion among gastroenterology specialists. In the first and second rounds, 56% and 60% of statements, respectively, received median scores ≥7. The range of scores decreased considerably from the first to the second round. 5-Aminosalycylic acid, corticosteroids, immunosuppressants, enteral nutrition, total parenteral nutrition, and surgical therapy were considered standard therapy for intestinal Behcet's disease. Infliximab, colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapy. Based on a two-round modified Delphi approach, practice guidelines for diagnosis and treatment of intestinal Behcet's disease were developed.

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. (Inflamm Bowel Dis 2007)

This study was designed to investigate retrospectively the efficacy and safety of endoscopic balloon dilation for intestinal strictures in Crohn’s disease. Sixteen patients with 20 strictures were treated. The stricture sites were as follows: at the ileocolonic (n = 6) or ileoileal (n = 1) anastomosis, in the colon (n = 10), ileum (n = 2), and at the ileocecal valve (n = 1). The dilations were performed with through-the-scope balloons, with diameters of 15 to 20 mm on inflation and lengths of 30 to 80 mm. In 15 of 16 patients, the strictures were successfully dilated and the symptoms caused by the strictures disappeared after the first session. The patients were followed for a median of 38.5 months. Repeat symptomatic stricture formation occurred after a mean of 19.7 months in seven patients. Four patients needed second-round dilation and three patients were treated surgically. Complications occurred in four patients who had primary strictures: bleeding in one, high fever in one, and colorectal perforation in two. One of the patients complicated with colorectal perforation was treated surgically, and the other was treated conservatively. The cumulative nonsurgical rates for the dilation strictures were 93 percent at 12 months and 65 percent at 36 months, respectively. Three patients were treated surgically because of strictures or fistulas that were not related to the procedure of dilation. As a whole, the cumulative nonsurgical rates were 81 percent at 12 months and 46 percent at 36 months. Nine patients (56.3 percent) were able to avoid surgery. Using endoscopic balloon dilation, it may be possible to avoid or postpone surgery. Primary strictures seem to have increased risk of perforation.

Ulcerative colitis (UC) is a multifactorial disorder with both genetic and environmental factors. HLA-B*52 and DRB1*1502 are reported to be strongly associated with UC in Japan. However, the actual susceptible gene has not been identified yet. In this study, to map precisely the susceptible locus for UC, we performed association mapping in the chromosome 6p using 24 microsatellite markers distributed over 16 Mb. A total of 183 patients with UC and 186 healthy controls (HC) were included in this study. In all, 15 markers around the human leukocyte antigen (HLA) region showed statistical significance in the genotypic differentiation test concerned with the allelic distribution between the UC and HC. Especially, the markers between the centromeric region of HLA class I and the telomeric region of class III showed remarkably low P-values and the allele239 of C2-4-4 in class I marker showed the strongest association (Pc=2.9 x 10(-9): OR=3.74, 95% CI=2.50-5.60). Furthermore, we found strong linkage disequilibrium (LD) between the allele239 of C2-4-4 and HLA-B*52 in haplotype analysis. These results provide evidence that, in Japanese, important determinants of disease susceptibility to UC may exist in HLA, especially between the centromeric region of class I and the telomeric region of class III, under the strong LD with HLA-B*52.

Although an elemental diet has been established as the primary treatment for patients with Crohn's disease, the influence of dietary fat on the elemental diet remains unclear. We have designed the first randomized, controlled trial for elemental diets containing different fat percentages in patients with active Crohn's disease.Each patient was randomized to receive one of three dose levels of fat in an elemental diet (Elental) for 4 weeks: 10 patients received low fat (3.06 g/day), 10 patients received medium fat (16.56 g/day) and eight patients received high fat (30.06 g/day). The additional fat was composed of long-chain fatty acids. All patients were evaluated using the International Organization of Inflammatory Bowel Disease rating, plus C-reactive protein level and erythrocyte sedimentation rate, which were measured at weekly intervals.Although the International Organization of Inflammatory Bowel Disease rating, C-reactive protein level and erythrocyte sedimentation rate in the low-fat group decreased, the values in the medium- and high-fat groups fluctuated during the study. The remission rate after 4 weeks in each group was 80%, 40% and 25% for patients in the low-, medium- and high-fat groups, respectively.When the fat consisted of long-chain triglycerides, a high amount of this fat in the elemental diet formula decreased its therapeutic effect against active Crohn's disease.

The administration of steroids is not always effective for the treatment of ulcerative colitis (UC). Their long-term use often causes adverse effects which sometimes result in their stoppage and acute exacerbation. Therefore, an alternative treatment is necessary in order to decrease steroid dosage and avoid the clinical problems associated with steroids. Methods The effectiveness and adverse effects of a leukocytapheresis (LCAP) were investigated in a controlled multicenter trial with randomized assignment of 76 active-stage UC patients in two groups. In the LCAP group (39 patients), LCAP weekly for 5 weeks as an intensive therapy was added to the on-going drug therapy, while steroids were maintained but not increased, and then LCAP was gradually reduced to once every 4 weeks as a maintenance therapy. In the high dose prednisolone (h-PSL) group (37 patients), PSL was added or increased 30 approximately 40 mg/day for moderately severe and 60 approximately 80 mg/day for severe patients and then gradually tapered. Findings The LCAP group showed a significantly higher effectiveness (74% vs. 38%; p=0.005) and lower incidence of adverse effects (24% vs. 68%; p

Objective Telomere shortening is correlated with cell turnover and aging, but it has been recently suggested to occur not only by aging but by several biochemical factors of metabolic disorders predisposing to atherosclerosis. Patients and Methods We compared telomere length of peripheral blood mononuclear cells of patients with the metabolic disorders, hypercholesterolemia (HC) and diabetes mellitus (DM), according to the presence or absence of coronary diseases. Results The results demonstrated that HC and/or DM patients with coronary diseases have significantly shorter telomere length than healthy controls (p=0.0014). Conclusion Telomere shortening may be involved in the mechanisms that promote coronary diseases under some circumstances of metabolic disorders.(Internal Medicine 42: 150-153, 2003)

Telomerase acitivity can be induced in human B lymphocytes by in vitro stimulation of their antigen receptors. To determine whether telomerase activity is induced in vivo, we analyzed telomerase activity in B lymphocytes from the mesenteric lymph nodes of patients with inflammatory bowel disease (IBD), whose lymph nodes are well known to be strongly stimulated, and from those of noninflamed controls. Seven IBD patients and 4 noninflamed controls were enrolled. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications. The mesenteric lymph nodes from patients with IBD had stronger telomerase activity than those from controls or peripheral mononuclear cells. Isolation of CD19+ B lymphocytes from these lymph nodes showed that this strong activity resides in this lymphocytes subpopulation. This study provides the evidence that telomerase activity is induced in human B lymphocytes in human inflammatory disease.

We present a rare case of multiple colonic metastases from advanced gastric cancer presenting colon depressed-type multiple early cancer (IIc)-like configuration. The case was a 74-year-old man who presented with a symptom of abdominal fullness. Colonoscopy and barium enema study revealed multiple IIc-like lesions, which were shown histologically to be metastatic deposits of signet ring cell carcinoma. He had synchronous gastric cancer, which histologically demonstrated moderate to poorly differentiated adenocarcinoma with signet ring cell differentiation. In addition, he had concomitant multiple small bowel metastatic lesions. This appears to be the first published report of multiple IIc-like colonic metastatic lesions from a gastric cancer.

Inflammatory bowel disease (IBD) is a multifactorial disease with a significant genetic background. Evidence is accumulating that molecules such as CD14, which interact with luminal bacterial constituents, are involved in the pathogenesis. It has recently been shown that the T allele of the 5'-flanking region of the CD14 gene at position -159 is related to high expression of CD14. In further exploring the genetic background of IBD, we investigated this novel polymorphism of CD14 gene in patients with ulcerative colitis or Crohn disease.DNA was obtained from 101 patients with ulcerative colitis, 82 with Crohn disease and 123 healthy controls. All were typed for the promoter polymorphism of the CD14 gene at position -159 by restriction fragment length polymorphism analysis. Serum samples were obtained from 105 healthy controls and serum sCD14 levels were measured.T allele frequencies were 57.4%, 48.2% and 44.7% in ulcerative colitis, Crohn disease and healthy controls, respectively. The T allele and T/T genotype frequencies were significantly higher in ulcerative colitis patients than in healthy controls (P = 0.0074, OR = 1.67, 95% CI = 1.15-2.42, P = 0.022, OR= 1.96 95% CI: 1.10-3.48, respectively). The sCD14 level was significantly higher in TT genotype populations than CC (P = 0.0205).The promoter polymorphism of the CD14 gene at -159T plays a significant role in regulating the CD14 expression and is positively associated with ulcerative colitis, and this polymorphism may confer a genetic predisposition to ulcerative colitis. The results also support the concept that bacterial constituents may be involved in the pathogenesis of ulcerative colitis.

Serrated adenoma (SA) is a relatively newly defined entity of colorectal neoplasm first characterized by Longacre and Fenoglio-Preiser in 1990. This lesion is characterized by a complicated serrated edge of crypts. In this study, we performed three-dimensional (3-D) reconstruction, including 3-D distribution patterns of Ki-67-positive cells and fractal dimension of SA, in order to evaluate the nature of the complicated architecture, including its possible morphogenesis. We studied nine colonoscopic polypectomy specimens including three SAs, three tubular adenomas (TAs), and three hyperplastic polyps (HPs). Sixty serial tissue sections per case were stained alternately with hematoxylin and eosin (H&E) and Ki-67 immunostain. Each serial image was then digitized for 3-D computer analysis and the distribution pattern of Ki-67-positive cells was evaluated. Ki-67-immunostained sections were also subjected to 2-D quantitative morphometric study. In addition, the fractal dimensions of images from H&E-stained sections were examined using a box-counting method. Results of the 3-D reconstruction study demonstrated that glandular budding and branching were more frequent in SA than in TA or HP. These findings were confirmed quantitatively by the results of fractal geometric analysis of these polyps (fractal dimension:1.34 +/- 0.08 for SA, 1.23 +/- 0.07 for TA, and 1.28 +/- 0.12 for HP). Ki-67-positive cells in HP were localized mainly in the bottom of crypts and those in TA were diffusely distributed, while Ki-67-positive cells in SA were mainly aggregated in the depressed sites of serrated epithelia. These findings were also confirmed quantitatively using 2-D morphometry. These distribution patterns of the proliferative zone of SA are considered to contribute to the formation of the characteristic serrated epithelia and the complicated morphological appearance of SA.

Inflammatory bowel diseases (IBD) representing both Crohn's disease and ulcerative colitis are characterized by chronic activation of macrophages. Natural resistance-associated macrophage protein 1 (NRAMP1) gene regulates macrophage activation of antimicrobial activity and has many pleiotropic effects on macrophage functions. To explore the role of the NRAMP1 gene in IBD susceptibility, we examined the promoter sequence of the NRAMP1 gene whose polymorphisms have been reported to influence the transcriptional activity of the NRAMP1 gene. One novel allele (allele 7) and two previously reported alleles (alleles 2 and 3) have been determined in a Japanese population. We investigated the association of IBD with these three alleles. The allele frequency of allele 7 was significantly higher in patients with Crohn's disease (11.1%) and ulcerative colitis (11.2%) than those in the healthy control group (4.5%) (Pc=0.015, Pc=0.018, respectively). Therefore, our findings suggest that the novel promoter polymorphism of the NRAMP1 gene may influence susceptibility to IBD in the Japanese population.

Vascular smooth muscle cells and pericytes express MMP-1, MMP-9, TIMP-1 and type I procollagen in inflammatory bowel disease Aims: Matrix metalloproteinases (MMPs) are involved in tissue remodelling, which is one of the important aspects of inflammatory disease. To assess the balance between the matrix degradation and production, we analysed the in situ expression of MMP-1, -3, -8 and -9, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, and type I procollagen (PC-I) in inflammatory bowel disease. Methods and results: Immunohistochemistry using frozen sections was performed in 17 patients with ulcerative colitis (UC) and 16 with Crohn’s disease (CD). In both UC and CD, MMPs and TIMPs were expressed by inflammatory cells as well as by fibroblastic cells most prominently in actively inflamed areas in ulcer bases, but sparsely in intact inflamed mucosa in both UC and CD. In UC, inflamed mucosa with erosions expressed these substances focally. Fibroblasts also expressed PC-I. We identified that vascular smooth muscle cells of venules in ulcer bases expressed MMP-1 and -9, TIMP-1 and PC-I. These venules also expressed E-selectin, a cell adhesion molecule to facilitate the leucocyte extravasation, and vascular endothelial growth factor (VEGF) receptor 2, consistent with their property of newly formed vessels. Conclusions: Our results suggest that MMPs are involved in the tissue remodelling, angiogenesis and promotion of leucocyte extravasation in the actively inflamed area in the ulcer base in both UC and CD. MMP-1 expression in the mucosa may be related to the initial step of ulceration in UC. Therapeutic manipulation of extracellular matrix turnover would be an effective therapy to alleviate active inflammation and accelerate ulcer healing.

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 transmit a same signal needed for growth and activation in granulocytes and macrophages, because these receptors utilize a common beta chain. Little is known about growth factors for intestinal myeloid cells in lesions of inflammatory bowel disease (IBD). Aim: To find out whether GM-CSF is produced by the intestinal cells in IBD patients and controls. Methods: We measured levels of GM-CSF, tumor necrosis factor (TNF), and IL-3 in the media of organ culture and lamina propria mononuclear cells (LPMCs) culture of colonic mucosa from the patients with IBD. Next, we have investigated GM-CSF production of colonic epithelial cell lines. Results: Spontaneous secretion of GM-CSF was increased in inflamed mucosa, while secretion of IL-3 was not detected. Release of GM-CSF was enhanced in LPMCs from inflamed mucosa. Mucosal GM-CSF production was correlated to TNF-α production. Colonic epithelial cell line and T cell produced GM-CSF with superantigen stimulation. Conclusion: We revealed pivotal production of GM-CSF but not IL-3 in intestinal lesion of IBD. Increased secretion of GM-CSF might lead to chronic gut inflammation.

The aim of the present study is to clarify in situ expression of platelet-derived growth factor (PDGF) and its receptors in different phases of inflammatory bowel disease (IBD). Tissues samples were obtained from 20 patients with ulcerative colitis (UC) and 29 with Crohn's disease (CD) at surgery. In situ hybridization and immunohistochemistry on frozen sections were performed for PDGF-A and -B and its alpha and beta receptors (alphaR and betaR). The area of active inflammation was infiltrated by abundant polymorphonuclear and mononuclear leukocytes, of which the latter expressed mRNA and proteins of PDGF-A, -B, and -alphaR and mRNA for PDGF-betaR. The area of active fibrosis, characterized by activated fibroblasts/ myofibroblasts, was juxtaposed to ulceration, which is induced as a repair process to tissue destruction. In these areas, activated fibroblasts/myofibroblasts were positive for mRNA and protein of PDGF-A, -B, -alphaR, and -betaR. The expression of PDGF-A, -B, and -alphaR declined significantly in the scar area. Our results suggest that PDGF is not only important as an inducer of fibrosis in the repair phase but also it is involved in the active inflammatory phase possibly as a chemoattractant for mononuclear inflammatory cells.

PURPOSE: Two pathways have been proposed for the development of colorectal cancers: loss of heterozygosity and replication error. Colorectal cancers arising through the replication error pathway, like most hereditary nonpolyposis colorectal cancers, show microsatellite instability. It has been also reported that telomere shortening frequently occurs in colorectal cancers and that telomerase is often activated strongly in them. The aim of this study was to examine whether any relationships can be found among microsatellite instability, telomere length, and telomerase activity in colorectal cancers. METHODS: Genomic DNA was extracted from 55 invasive cancers and corresponding normal mucosas. Five microsatellite loci were analyzed by polymerase chain reaction. Telomere length was examined by Southern blot analysis. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications. RESULTS: Microsatellite instability was found in 8 (14.5 percent) of 55 tumors, and all of them showed short telomeres. Furthermore, four high-frequency microsatellite instability tumors that showed microsatellite instability at more than two loci exhibited remarkably short telomeres. The microsatellite instability correlated significantly with frequency of telomere shortening (P=0.0183; Fisher's exact probability test), but not with strength of telomerase activity. CONCLUSION: The relationship identified by this study between microsatellite instability and telomere shortening might suggest some association between the DNA mismatch repair system and the telomere maintenance mechanism in colorectal cancers.

"Cap polyposis" is a rarely-encountered condition in which distinctive inflammatory polyps are located from the rectum to the distal descending colon. Microscopically, the polyps consist of elongated, tortuous, and distended crypts covered by a "cap" of inflammatory granulation tissue. Although the pathogenesis is unknown, mucosal prolapse has been postulated to be an important etiological factor, given certain clinical and histological similarities. We describe two cases of cap polyposis with protein-losing enteropathy. One was treated successfully by avoidance of straining at defecation. Another resolved after double-barreled transverse colostomy. Both successful treatments support a causal link of polyposis to prolapse.

In mineralocorticoid target organs, 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) confers specificity on the mineralocorticoid receptor (MR) by converting biologically active glucocorticoids to inactive metabolites. Placental 11beta-HSD2 is also thought to protect the fetus from high levels of circulating maternal glucocorticoid. In this study, we examined the immunoreactivity of 11beta-HSD2 and MR in human placenta from 5 weeks gestation to full term using immunohistochemistry, 11beta-HSD2 messenger RNA (mRNA) expression using Northern blot analysis, and MR mRNA expression using RT-PCR analysis. Marked 11beta-HSD2 immunoreactivity was detected in placental syncytiotrophoblasts at all gestational stages. MR immunoreactivity was moderately detected in syncytiotrophoblasts, some cytotrophoblasts, and interstitial cells of the villous core. Marked mRNA expression of 11beta-HSD2 was detected in placenta by Northern analysis. RT-PCR analysis of MR in placental tissues showed an amplified product consistent in length with the primers selected. These results suggest that placental 11beta-HSD2 is involved in not only regulating the passage of maternal active glucocorticoids into the fetal circulation but also in regulation of maternal-fetal electrolyte and water transport in the placenta, as in other mineralocorticoid target organs.

Background & Aims: Tumor necrosis factor (TNF) is considered to play an important role in the pathogenesis of Crohn's disease (CD). Recently, 3 polymorphisms in the 5'-flanking region of the TNF gene at positions −1031, −863, and −857, which are related to high transcriptional promoter activity, have been identified in the Japanese population. In an effort to understand potential genetic association with CD, we evaluated patients diagnosed with CD and ulcerative colitis (UC) in the presence of other novel polymorphisms. Methods: Blood samples were obtained from 103 patients with CD and 76 patients with UC. Polymorphisms in the TNF gene at their respective positions were analyzed by direct sequencing, and the allele frequencies were compared with those determined previously in a healthy Japanese population. Results: Allele frequencies of −1031C, −863A, and −857T in normal controls were 16.0%, 14.0%, and 17.7%, respectively. Polymorphic allele frequencies at positions −1031, −863, and −857 were 24.3%, 21.8%, and 27.2% in CD and 11.8%, 11.2%, and 11.8% in UC, respectively. The frequencies at all 3 positions were significantly higher in CD patients than in UC patients or healthy controls. Among the subgroups of CD, small bowel disease showed the highest frequencies. Conclusions: Although the findings need to be confirmed in other populations with larger numbers of patients, TNF gene polymorphisms −1031C, −863A, and −857T are positively associated with CD; they may influence not only the susceptibility to CD but also the disease location. GASTROENTEROLOGY 1999;117:1062-1068

症例 : 症例は23歳, 女性.14歳時に下痢にてCrohn病発症後内科的治療を行ったが, 16歳時に腸管狭窄のため結腸亜全摘, 小腸部分切除, 回腸直腸吻合術を施行した.23歳時に直腸膣瘻 (RVF) 形成, 腸管病変再燃および胆嚢結石症を認めた.術後3ヵ月後に結婚を予定して外科を受診, 術式は患者の希望を考慮して吻合部切除, 回腸直腸吻合, 胆嚢摘出およびループ式回腸瘻造設術を施行した.結婚後妊娠希望で薬物治療は行わずに病変の再燃は認めなかったが不妊が続いた.産婦人科で25歳時に排卵誘発剤投与を受けて妊娠, 26歳時に帝王切開にて正常男児 (2550g) を無事出産した.妊娠期および周産期での病変再燃, 回腸人工肛門トラブル, RVF増悪などは認めず, 出生男児は順調に成長している.結語 : RVF合併したCrohn病症例で回腸瘻造設を行い妊娠, 出産が可能であった.

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 +/- 0.36kb 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.

テロメアはヒト体細胞において一細胞分裂ごとに短縮することより,細胞分裂回数を数えるマーカーと考えられている.この特徴を利用して,潰瘍性大腸炎の発癌リスク評価を試みた.またテロメラーゼはde novoでテロメアを伸長させる酵素で,大腸癌においても9割以上で高発現を示すことより,診断マーカー,治療の標的として有望である.臨床検体を用いたテロメラーゼ活性の検出法として,従来からのTRAP法と新規に開発したhTERT遺伝子のin situ hybridization法について,その結果と特徴について記述した.

Indication for and an evaluation of enteral nutrition in Crohn's disease differ between Japan and western countries. PURPOSE: Japanese results are reported and differences are discussed. RESULTS: Enteral nutrition with an elemental diet is first-line therapy for active Crohn's disease in Japan. The remission induction rate of elemental diet therapy is approximately 80 percent, which is superior to steroids. Furthermore, elemental diet therapy induces radiographic and endoscopic remission. On the other hand, meta-analysis from randomized, controlled trials showed steroids to be more effective than enteral nutrition in western countries. The differences are considered to be the result of such differences as therapeutic duration of enteral nutrition, the composition of enteral diets used, criteria for remission, the quality of life score of a long-term fast with a nasogastric tube, medical care, and health insurance system. The main mechanism of the therapeutic effect of elemental diet is speculated to be attributable to removal of food antigens and decreases of secretion and motility (bowel rest) by very low fat. To prevent relapse and rehospitalization, home enteral nutrition is now used widely in Japan. The therapeutic effect is observed in patients with ileal involvement, and more than 1,200 kcal/day is more effective than a lower amount. CONCLUSION: Most Japanese studies were open-labeled, uncontrolled trials. We should conduct randomized, controlled trials comparing enteral nutrition with steroids during the active stage of Crohn's disease and home enteral nutrition with drugs in maintaining remission and investigate the therapeutic effect, quality of life, and costs.

Activation of T lymphocytes and monocytes/macrophages has been implicated in the pathogenesis of Crohn's disease (CD). Costimulatory molecules play important roles in optimal T-cell activation.With flow cytometric analysis we have investigated the expression of the costimulatory molecules B7-1 (CD80), B7-2 (CD86), and CD18 and the intercellular adhesion molecule-1 (ICAM-1) on peripheral blood monocytes and the expression of the activation markers HLA-DR and IL-2R (CD25) on peripheral blood T lymphocytes from 31 CD patients, 17 ulcerative colitis (UC) patients, and 10 healthy controls.In CD patients the percentage of activated T cells (CD3+ HLA-DR+ and CD3+ IL-2R+) was significantly increased compared with those of controls and UC patients (P0.05). Most monocytes from all three groups expressed B7-2, CD18, and ICAM-1 molecules (all79%), but only a few positive cells expressed B7-1 molecules (5%). No significant differences were detected in the percentage positivity of all costimulatory molecules tested among CD, UC, and controls. The mean fluorescence intensity (MFI) of B7-1 in all three groups was very weak and not significantly different. However, in CD patients there was a significantly increased MFI of B7-2, CD18, and ICAM-1 molecules compared with UC and controls (P0.05). On the other hand, both the percentage positivity and MFI of HLA-DR molecules on monocytes of UC patients were significantly lower than those of CD patients and controls (P0.05).Expression of the costimulatory molecules B7-2, CD18, and ICAM-1 on peripheral blood monocytes of CD patients is increased. In CD patients activation of peripheral T lymphocytes may correlate with increased expression of these costimulatory molecules on peripheral blood monocytes.

We report herein the cases of two patients with Crohn's disease complicated by a psoas abscess. The first patient was a 29-year-old man who underwent definitive surgery after acute inflammation had been controlled by nutritional therapy. In the second patient, a 37-year-old man, the abscess required drainage under local anesthesia prior to surgery. Both patients have been free from recurrence of any abdominal symptoms for about 2 years since undergoing surgery. Although psoas abscess is still regarded as a rare complication, with the increasing prevalence of Crohn's disease in Japan it has become one of the most important complications requiring surgical intervention.

潰瘍性大腸炎に対する内科的治療の最近の話題について解説した。5-ASAに関しては,従来から投与されてきたサラゾピリンに代わって,より副作用が少なく,局所に高濃度に放出されるような製剤が開発されてきた.本邦では5-ASAをエチルセルロースでコーティングした徐放剤であるペンタサが,サラゾピリンとの二重盲検群間比較試験で有意に有用性が認められ,現在申請中である.中等症～重症例に対してステロイドパルス療法,白血球除去療法が試みられ,いずれも有効性が報告されている.顆粒球吸着療法を含めて,今後のcontrolled trialの成績を待ちたい.欧米では腸管から吸収されにくく,初回肝循環で代謝され,レセプターとの親和性が高い新しいステロイド剤が開発され局所療法として試みられている.さらに最近の病因・病態の研究の進歩に伴い,エイコサノイド阻害剤や免疫調節剤が開発され,臨床試験が進行中である.

Phlebosclerosis of the mesenteric vein is a rare cause of ischemic colitis. The current report includes two patients with segmental ischemic colitis associated with marked calcifications of the mesenteric vessels. No evidence of systemic vasculitis, tuberculosis nor amyloidosis was observed. The patients were previously healthy and had no history of drug use of any kind. Clinical findings included abdominal pain in the right upper quadrant and diarrhea alternating with constipation, and colonic narrowing were discoverd by barium enema. An abdominal X-ray examination revealed some patchy calcifications in the right and left upper quadrants. An angiography of the superior mesenteric artery revealed sclerosis of the artery, disturbance of colonic blood flow, and calcifications of the mesenteric vessels. The patients were treated with an anticoagulant. In follow-up studies, barium enema and colonoscopy revealed a gradual progression of the disease over the last five years. Treatment with an anticoagulant may have prevented rapid advancement of the disease and thereby eliminated the need for emergency operations. These unusual venous lesions have been rarely reported, and their etiology and pathogenesis remain unknown.

The distribution abnormality of vasoactive intestinal polypeptide-containing nerves (VIP-nerves) and substance P-containing nerves (SP-nerves) was immunohistochemically investigated in the colonic mucosa with inflammatory bowel disease (IBD) in relation to colonic glands and blood vessels in the lamina propria. In active ulcerative colitis (UC), VIP- and SP-nerves decreased in severe inflammatory lesions. VIP-nerves were almost absent particularly around crypt abscesses. Even in resolving and quiescent UC, VIP-nerves still decreased, depending on the decrease of glands and blood vessels. On the other hand, both nerves increased in some hypervascular lesions. In the uninvolved mucosa of UC, they did not change their distribution. In Crohn's disease, the distribution abnormality of both nerves resembled that of UC. These results suggest that the changes in VIP- and SP-nerve distributions in the mucosa with IBD are subsequent to mucosal inflammation and damage. However, these peptides are known to be immunoregulators, and their distribution abnormalities may induce the disorder of immunoregulation in the IBD mucosa and cause the mucosal damage and/or chronicity.

It is generally considered that early lesions detected macroscopically in Crohn's disease are aphthoid ulcers. The lesions are usually found close to more advanced lesions and sometimes observed in the distal colon. However, there are a few patients who have almost only aphthoid ulcers without any typical major lesions through the alimentary tract. We studied 5 such cases (4 men and 1 woman, 15–31 years old) out of 107 patients who had not undergone any surgery at the time of their first visit. Four patients had aphthoid ulcers in both the small and large intestine as well as some lesions (ulcer, erosion and redness) in the gastroduodenal region. The remaining case had some lesions only in the large intestine. Non-caseating epitheloid cell granulomas were detected in the biopsy specimens obtained from the aphthoid ulcers of the colon in 4 cases. These cases with granulomas were considered to suffer from Crohn's disease and were treated with an elemental diet. Aphthoid ulcers showed a remarkable improvement but relapse followed the beginning of an oral diet. In 3 cases, the lesions in the small intestine developed into longitudinal ulcers 18, 27 and 37 months after the first visit, respectively. Although a female patient in whom granulomas could not be proven was not diagnosed as having Crohn's disease, she had bloody stool again 17 months later, and a barium enema revealed a cobblestone appearance in the colon so that she was diagnosed as having Crohn's disease. Consequently, aphthoid ulcers developed into longitudinal ulcers or cobblestoning, with repeated disappearance and reappearance during the follow-up period in 4 of the 5 cases. Almost only aphthoid ulcers with granulomas in non-operated cases are considered to be in the earliest stage of what can be diagnosed as being Crohn's disease.

ω-oxidation is regarded as the major pathway for the catabolism of leukotriene B4 (LTB4). To determine how LTB4 ω-hydroxylase is modulated in inflammatory bowel disease, we investigated the kinetic characteristics of this enzyme in 10 patients with Crohn's disease (CD), nine with ulcerative colitis (UC) and eight healthy control subjects. After incubating polymorphonuclear leukocytes with various concentrations of 3H-labeled LTB4, ω-oxidation products were serapated by high performance liquid chromatography (HPLC) and the radioactivity was measured by a liquid scintilation counter. The apparent Vmax values were significantly higher in both disease than in healthy control subjects, although the difference between CD and UC was insignificant. There was no difference in the apparent Km values. And the Vmax Km ratios of patients with CD were significantly higher than that of healthy control subjects. It is suggested that LTB4 metabolism is activated in inflammatory bowel disease (IBD) and that the modulation of this enzyme activity has an important role in the pathogenesis of inflammatory bowel disease.

アフタ様大腸炎は,粘液便または粘血便を主訴とし,内視鏡的には中心に白苔,周囲に紅量を伴った小隆起～陥凹, X線的には中心にバリウム斑を伴った透亮像が散在性～びまん性に多発し,生検組織所見では大腸粘膜の腫大したリンパ〓胞およびその周囲や被覆上皮に限局した炎症像を認める.病因は不明である.アフタ様潰瘍は種々の腸疾患の初期および治癒期にみられるが,特にアフタ様潰瘍のみからなるCrohn病との鑑別診断が病態解明の面からも重要である.

To investigate the role of interferony in the pathogenesis of Crohn’s disease, we examined the interferony levels of serum, supernatant of cultured peripheral blood mononuclear cells activated by phytohemagglutinin, and medium of organ culture of colonic mucosa in Crohn’s disease. Serum interferony levels in Crohn’s disease, especially in active or non-resected Crohn’s disease, were more elevated than those in normal subjects. In contrast, the production of interferony by peripheral blood mononuclear cells was reduced in Crohn’s disease. In some patients, interferony levels of organ culture medium of colonic mucosal tissue specimens were elevated. When peripheral blood mononuclear cells were preincubated for 72 hours, interferon γ production in Crohn’s disease increased from 23.8% to 62.3% in comparison to levels in healthy controls. These results indicate that elevated serum interferon γ in Crohn’s disease may originate from the intestine, and interferon γ may be related to the immune reaction and inflammation in the intestine.

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.

Two cases of eosinophilic gastroenteritis with colonic involvements and rare complications are described. Case 1. A 39-year-old male was admitted with diarrhea. He had a previous medical history of early gastric cancer two years prior to this admission. A barium enema showed a diffuse nodular granularity from the transverse colon to the rectum. A sigmoidoscopic examination demonstrated nodular granularity, spotty erythema and shallow irregular ulcers with normal intervening mucosa in the rectum and the sigmoid colon. Mucosal biopsies obtained from the rectum and the sigmoid colon revealed infiltrations of eosinophils in the lamina propria and histological reexamination of the resected stomach also revealed an infiltration of eosinophils in the subserosa. One year later the patient suffered from eosinophilic cellulitis. Case 2. A 25-year-old female was admitted for the investigation of suspected cholestasis. Based on the findings of a liver biopsy and an endoscopic retrograde cholangiography (ERC) a diagnosis of primary sclerosing cholangitis (PSC) was made. A barium enema showed moderate granularity, lack of haustration from the cecum to the splenic flexure with a rigid ileocecal valve which was open to reflux. A colonoscopic examination revealed mucosal granularity, diffuse erythema and friability in the same regions. Mucosal biopsies obtained from both the abnormal and the normalappearing mucosa showed infiltrations of eosinophils into the lamina propria. Blood peripheral eosinophilic was present in each case.

潰瘍性大腸炎重症例に対する強力静注療法の治療成績および予後について検討した.対象は,前期(1973年～80年)17例,後期(1981年～89年5月)18例である.効果判定は,強力静注療法開始後7日目まで,完全に血便が消失し五ものを有効,わずかしか見られなくなったものをやや有効,明らかな血便が持続しているものを無効とした.前期では,無効11例,やや有効3例,有効3例,後期ではそれぞれ12例,2例,4例とほぼ同様の成績であった.無効例の転帰・予後に関しては,前期の11例はすべて緊急手術を施行したが,うち3例は術後死亡した.後期の12例では緊急手術を施行したのは3例のみで,臨床症状に改善の認められた9例は強力静注療法を継続し,8例で緩解に至つた.死亡例はなかった.強力静注療法開始後7日の時点で明らかな血便が持続していても,その回数や量,他の臨床症状に改善を認めれば必ずしも手術適応とする必要はないと考えられた.