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Objectives/hypothesis: Our previous study demonstrated that a large amount of reactive oxygen species (ROS) is produced during the early phase of vocal fold wound healing. In the current study, we investigated the effect of astaxanthin, which is a strong antioxidant, on the regulation of oxidative stress and scarring during vocal fold wound healing., Study Design: Prospective animal experiment with control., Methods: Sprague-Dawley rats were dosed with astaxanthin (Ast-treated group, 100 mg/kg/day) or olive oil (sham-treated group) by oral gavage daily from preinjury day 1 to postinjury day 4. After vocal folds were injured under the endoscope, larynges were harvested for histological and immunohistochemical examinations on postinjury days 1, 3, 5, and 56, and quantitative real time polymerase chain reaction (PCR) on postinjury days 1 and 3., Results: The expression of 4-hydroxy-2-nonenal, which is an oxidative stress marker, was reduced significantly in the lamina propria of the Ast-treated group as compared to the sham-treated group. Histological examination showed significantly less tissue contraction with favorable deposition of hyaluronic acid in the lamina propria of the Ast-treated group compared to the sham-treated group. Real time PCR revealed significantly upregulated mRNA expression of basic fibroblast growth factor on postinjury day 1 and procollagen type I in the Ast-treated group compared to the sham-treated group., Conclusions: These findings suggest that astaxanthin has the potential to prevent vocal fold scarring by regulating oxidative stress during the early phase of vocal fold wound healing., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

A 68-year-old man with chronic hepatitis C and of a heavy drinker was admitted to our hospital because of a huge liver tumor (10cm in diameter) in segment-5 detected on CT in July 2009. One month later, the size of liver tumor was reduced to 5cm in diameter and another liver tumor of 1cm in segment-3 was detected on CT. AFP and AFP-L3 spontaneously decreased to normal range. In October, a partial hepatectomy was performed. The resected specimen demonstrated complete necrosis with thick capsule. The tumor in segment-3 became equivocal without resection. We considered this is a case of spontaneous complete necrosis of hepatocellular carcinoma.

Background and Aims: 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., Methods: 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., Results: 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., Conclusions: 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.

Radiation-induced sarcoma usually develops after an interval of more than 10 years from the completion of radiation therapy to the diagnosis of secondary sarcoma. However, the theory of radiation-induced transformation does not rule out postirradiation sarcomas with a short latency period. We experienced the case of a patient with postirradiation leiomyosarcoma of the tongue, which occurred 19 months after he had received chemoradiotherapy. Besides the short latency period, a pseudotumor stage developed between the time of radiation exposure and the development of leiomyosarcoma. In this article, we also describe an immunohistochemical approach to diagnose leiomyosarcoma and the efficacy of a gemcitabine and docetaxel regimen., (Copyright © 2011 S. Karger AG, Basel.)

This retrospective study examined the etiology and treatment results for traumatic, conductive hearing loss in 22 patients who underwent surgery between 1998 and 2008 at Osaka Red Cross Hospital. All patients underwent computed tomography (CT) of the temporal bone preoperatively. The ear surgery comprised closure of the ruptured tympanic membranes and restoration of the sound-transmitting function of the ossicular chain. Their mean age was 30.3 years, and the average delay from injury until treatment was 6.0 years. Of the injuries due to foreign-body insertion, the most common cause was ear-pick injury. Incudostapedial disarticulation was the most common finding, which was diagnosed preoperatively using CT in seven cases and identified at surgery in 15 cases. Closure of the air-bone gap to within 10 and 20 dB was observed in 50.0 and 68.2% of the patients, respectively. The hearing threshold improved by 10 dB or more in 16 (72.7%) patients. If no improvement in hearing loss follows the absorption of hemotympanium or closure of an eardrum perforation, dislocation of the ossicular bones should be suspected. Ossicular reconstruction following trauma produces more stable and better hearing results, even after delayed treatment.

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.

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.

Case1 was a 52-year-old man who had recurrence of postoperative intra-abdominal disseminations from gastrointestinal stromal tumor (GIST) of the jejunum. Case2 was a 66-year-old man who had GIST of the jejunum with multiple liver metastases. Two cases presented hemoperitoneum caused by administration of imatinib mesylate, and we conducted emergent surgery. In spite of surgically non-curative cases, it is suggested that the surgical management for GIST of high grade group with peritoneal exposure should be followed by the administration of imatinib mesylate.

Objective: Irritable bowel syndrome is characterized by abdominal discomfort and/or pain associated with altered bowel habits. The neurotransmitter serotonin and serotonin type 3 receptors that are extensively distributed on enteric neurons in the human gastrointestinal tract play a role in increasing the sensation of pain and affecting bowel habits in patients with irritable bowel syndrome. The aim of this study was to evaluate the efficacy and safety of the serotonin type 3 receptor antagonist ramosetron hydrochloride in Japanese patients with diarrhea-predominant irritable bowel syndrome., Material and Methods: In a double-blind, placebo-controlled, parallel group-comparative study with a 1-week run-in period, 539 patients with diarrhea-predominant irritable bowel syndrome meeting the Rome II diagnostic criteria received either 5 microg ramosetron hydrochloride (n=270) or placebo (n=269) once daily for 12 weeks., Results: Forty-seven percent of ramosetron hydrochloride-treated patients were monthly responders in the primary end-point, "Patient-reported global assessment of relief of irritable bowel syndrome symptoms", compared with 27% for placebos (p<0.001). The most frequently reported adverse event in the ramosetron hydrochloride-treated group compared with the placebo group was hard stool., Conclusions: Ramosetron hydrochloride 5 microg once daily is effective and well tolerated in the treatment of abdominal pain, discomfort and bowel habits in patients with diarrhea-predominant irritable bowel syndrome.

At the treatment of bile duct stones using EST, we sometimes experienced the difficult cases, even if the stones were small. For these cases, we tried endoscopic papillary balloon dilatation, and as a result knoches were made. And after the disappearance of the knoch, we could easily remove the stone. So we prospectively examined how often and at what cases, the knoches were made immediately after EST. As a result, knoches were present for 25% (13/52) of patients even after EST. Narrow distal segments of knoch-present patients were longer than that of knoch-absent patients, significantly. As a result, some function of sphincter was shown to be remained for a quarter of patients even after EST, and for these cases, the treatment of the stones may be difficult.

A 72-year-old man was given a diagnosis of Crohn's disease in 1976 at age 44, and partial resection of is ileum was performed. In November 1982, barium enema examination revealed on ileorectal fistula. As he had no complaint, conservative therapy was chosen. In August 2003, he had high fever and CT scan revealed presacral abscess. Ileocecal resection, partial resection of is small intestine and loop sigmoid colostomy were performed. In December 2004, the serum level of CEA was gradually elevated and he complained of anal mucus discharge. Endoscopic examination showed a fistula orifice in the rectum and biopsy of the fistula revealed mucinous adenocarcinoma. We performed abdominoperineal resection of the rectum with partial resection of the sacrum. We thought that careful observation helped the detection of such a rare case of carcinoma arising from a fistula tract.

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.

We report two cases of patients with hepatocellular carcinoma (HCC) that developed in cryptogenic cirrhosis suggestive of nonalcoholic steatohepatitis (NASH) as background liver disease. Case 1 was a 68-year-old woman, and case 2 was a 46-year-old man. They were admitted to our department for evaluation and treatment of HCC. The causes of the underlying liver disease were not determined from blood tests. However, histological analysis of non-tumor tissues of the liver revealed cirrhosis with few fat droplets. Both patients had undergone liver biopsy 26 years before the treatment of HCC. Histological review of the biopsy specimens revealed NASH (case 1) and fatty liver (case 2), respectively. It was suggested that these cases progressed from NASH and fatty liver, respectively, to NASH-related cirrhosis (so called burned-out NASH), eventually, developing HCC. These findings suggest that substantial number of burned-out NASH cases may be included in those with cryptogenic cirrhosis. These two patients are indicative cases that may reveal the long-term natural course of fatty liver and NASH.

Purpose: This study was designed to investigate retrospectively the efficacy and safety of endoscopic balloon dilation for intestinal strictures in Crohn's disease., Methods: 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., Results: 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., Conclusions: Using endoscopic balloon dilation, it may be possible to avoid or postpone surgery. Primary strictures seem to have increased risk of perforation.

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

We report here 3 cases of rectal varices treated with endoscopic variceal ligation and discuss the pathogenesis, treatment, and prognosis of rectal varices with referring to previous reports. Of the 3 patients, 2 had been diagnosed as liver cirrhosis and 1 as extrahepatic portal hypertension. All of the 3 patients had previously undergone treatment of esophagogastric varices. The rupture of rectal varices appeared to have some relationship with the treatment of esophageal varices. In previous reports, 73% of patients with ruptured rectal varices treated with endoscopic injection sclerotherapy or endoscopic variceal ligation had undergone treatments of esophageal varices. The endoscopic treatments resulted in a favorable prognosis in 2 patients. Although no fatality from endoscopic injection sclerotherapy or endoscopic variceal ligation has been reported, 1 of the present 3 cases died of liver failure.

The use of percutaneous endoscopic gastrostomy (PEG) has widely spread in recent years, even in Japan. In our hospital, we have performed this procedure in over 20 patients per year recently. In this study, we investigated the usefulness of PEG in home health care from the view point of cost effectiveness. We found that medical expenses decreased remarkably when patients underwent PEG because they could switch from hospital care to home health care, shortening there by the period of hospital care. The role of PEG in home health care will be more important also from cost effectiveness.

Purpose: The HLA-B gene is one of the susceptibility genes for inflammatory bowel disease. Previous association studies of HLA-B showed several associated alleles and haplotypes of HLA-B in patients with ulcerative colitis, and among the associated alleles HLA-B*52 is well known to be strongly associated with ulcerative colitis in Japanese patients. However, there are no convincing reports about HLA-B including the B*52 allele in patients with Crohn's disease. The purpose of this study was to determine if HLA-B, especially the B*52 allele, confers susceptibility to Crohn's disease or determines the disease phenotype of Crohn's disease., Methods: A total of 195 patients with Crohn's disease (49 ileitis, 106 ileocolitis, 34 colitis, 6 uncertain) and 185 healthy controls were studied in this case-controlled study. All patients and healthy controls were Japanese. Genotyping of the HLA-B gene was performed by a polymerase chain reaction, sequence-specific primer that can classify the gene into 23 allele groups. Allele frequencies were compared between patients with Crohn's disease and healthy controls with chi-squared test using a 2 x 2 contingency table. P value was corrected by the number of allele groups (n = 23) observed in the Japanese population or the number of clinical subgroups. Corrected P values of <0.05 were considered to be statistically significant., Results: Before the correction for multiple testing, B*4001 and B*44 were associated with patients with Crohn's disease, positively and negatively, respectively. However, after the correction there were no significant differences in any HLA-B alleles between patients with Crohn's disease and healthy controls. In the subgroup analysis according to clinical phenotypes (disease location, anal lesion, age at diagnosis, need for surgery), none of the HLA-B alleles except B*52 showed any disease phenotype-genotype associations. The allele frequency of B*52 in the colitis type (16.2 percent; corrected P = 0.011) was significantly higher than that in the combined group of the ileitis (7.1 percent) and ileocolitis (5.2 percent) types., Conclusions: These results demonstrated that HLA-B did not confer overall susceptibility to Crohn's disease in Japan, but the B*52 allele may affect the location of the disease.

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.

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.

Background. A major longterm risk for patients with ulcerative colitis (UC) is the development of colorectal dysplasia and cancer. Microsatellite instability (MI) has now been reported not only in colitic cancers but also in dysplasias, and even in nondysplastic inflamed mucosa. With the conventional microdissection technique, however, contamination by nonepithelial cells cannot be prevented and this could produce less reliable results than other methods. Therefore, we examined the condition of MI and loss of heterozygosity (LOH) of UC epithelium using a crypt isolation technique. Methods. One hundred and twenty-nine biopsy samples from 21 patients with UC were investigated for histology and microsatellite status, using nine microsatellite markers. A total of 1031 polymenase chain reaction (PCR) products were evaluated. Results. We found that no microsatellite markers displayed instability, but LOH at the 3p locus was detected in the nondysplastic epithelium of one patient with longstanding UC. Conclusions. Our study strongly suggests that MI does not contribute to the progression of the colitis-dysplasia sequence.

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<0.001). The patients were able to continue the trial for a longer period in the LCAP group than the h-PSL group (p=0.012). Clinical activity and endoscopic indexes showed the LCAP group had better improvements than the h-PSL group. Interpretation The results of the trial show that LCAP permits a reduction in total PSL dosage and is more effective and safer than high-dose PSL administration for intensive therapy, and LCAP may maintain remission longer than PSL.

Background: In the present study, we examined the relationships between microsatellite status and Ki-67 labeling index, a proliferative marker, in colorectal cancers in order to clarify the common biological profiles of familial and sporadic cases of MSI (microsatellite inability)-positive tumors., Patients and Methods: Seventy-eight invasive colorectal carcinomas were studied. Five microsatellite loci were analyzed by polymerase chain reaction, while Ki-67 was studied by immunohistochemistry., Results: The MSI was found in 15 (19.2%) of the 78 tumors, and the Ki-67 labeling index was significantly higher in the 15 MSI-positive tumors than that in the 15 MSI-negative ones (p = 0.0181). Moreover, the Ki-67 labeling index was significantly higher in the 7 tumors with MSI at more than 2 loci (MSI-H; high-frequency MSI) than that in the MSI-negative ones (p = 0.0082)., Conclusion: The present study demonstrates that colorectal cancers with MSI show high Ki-67 labeling index irrespective of hereditary or nonfamilial cancer types, suggesting their common biological aspects distinct from MSI-negative ones.

Aim: The aim of this study was to examine whether and relationships could be found among polymorphism of the NQO1 gene, telomere length and telomerase activity in colorectal cancers., Materials and Methods: Fifty-one invasive colorectal cancers were studied. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was undergone to detect mutation of the NQO1 gene. Telomere length was examined by Southern blot analysis. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications., Results: Of the 51 tumors, 20 (39.2%) and 9 (17.6%) were heterozygous and homozygous for the mutation, respectively. Most of the cases homozygous for the mutation (88.9%) showed short telomeres and its frequency was significantly higher than in those heterozygous (p = 0.0432). However no relationship was found between the telomerase activity and mutation in the NQO1 gene., Conclusion: Our data suggest that oxidative stress by the lack of NQO1 activity could result in telomere shortening through colorectal cancinogenesis.

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.

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.

Background: Several studies have reported that the chimeric monoclonal antibody to tumor necrosis factor (TNF)-alpha (Infliximab) is extremely valuable in the treatment of Crohn's disease. The aim of this study was to clarify the efficacy of this treatment in Japanese patients with Crohn's disease., Methods: A 12-week multicenter, open trial of Infliximab was carried out and involved 25 patients with moderate to severe Crohn's disease who were resistant to conventional treatment. Patients received a single 2-h intravenous infusion of Infliximab at a dose of 1, 3, 5 or 10 mg/kg bodyweight. Clinical evaluation of this treatment response was defined as a reduction in the index of the inflammatory bowel disease (IOIBD) and of the Crohn's disease activity index scores (CDAI), and in serum levels of C-reactive protein (CRP) at 2, 4, 8 and 12 weeks, and as an increase in serum levels of rapid turnover proteins as well as improvement of radiologic and endoscopic findings at 4 weeks., Results: The IOIBD score was reduced after 4 weeks in 66.7% of the group receiving 1 mg/kg Infliximab, 71.4% in the group receiving 3 mg/kg, 80.0% in the group receiving 5 mg/kg, and 85.7% in the group receiving 10 mg/kg. Improvement was better maintained over 12 weeks in the 5 and 10 mg/kg groups compared with the 1 and 3 mg/kg groups. Similar results were obtained for the CDAI scores. Serum levels of rapid turnover proteins significantly increased to within the normal ranges after infusion in all groups. Seven of the 11 (63.6%) patients evaluated showed improvement of radiologic and endoscopic findings., Conclusions: A single infusion of Infliximab was effective for the treatment of Japanese patients with Crohn's disease. Serum rapid turnover proteins reflected the clinical response to antibody for TNF-alpha well.

Active ulcerative colitis (UC) is characterized by activation and infiltration of granulocytes and monocytes/macrophages into the colonic mucosa. The infiltrated leukocytes can cause mucosal damage by releasing degradative proteases, reactive oxygen derivatives, and proinflammatory cytokines. The aim of this trial (conducted in 14 specialist centers) was to assess safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active UC most of whom were refractory to conventional drug therapy. We used a new adsorptive type extracorporeal column (G-1 Adacolumn) filled with cellulose acetate beads (carriers) of 2 mm in diameter, which selectively adsorb granulocytes and monocytes/macrophages. Patients (n = 53) received five apheresis sessions, each of 60 minutes duration, flow rate 30 ml per minute for 5 consecutive weeks in combination with 24.4 +/- 3.60 mg prednisolone (mean +/- SE per patient per day, baseline dose). During 60 minutes apheresis, 26% of granulocytes, 19.5% of monocytes and 2% of lymphocytes adsorbed to the carriers. At week 7, 58.5% of patients had remission or improved, the dose of prednisolone was reduced to 14.2 +/- 2.25 mg (n = 37). The apheresis treatment was fairly safe, only eight non-severe side effects (in 5 patients) were reported. Based on our results, we believe that in patients with active severe UC, patients who are refractory to conventional drugs, granulocyte and monocyte adsorption apheresis is a useful adjunct to conventional therapy. This procedure should have the potential to allow tapering the dose of corticosteroids, shorten the time to remission and delay relapse.

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-alpha 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., (Copyright 2001 S. Karger AG, Basel)

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.

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

New diagnostic criteria for Crohn's disease and a review of Japanese epidemiologic studies are presented. New diagnostic criteria for Crohn's disease were established by the Research Committee of Inflammatory Bowel Disease, set up by the Japanese Ministry of Health and Welfare. For a definite diagnosis one of the following three conditions is required: 1) longitudinal ulcer or luminal deformity induced by longitudinal ulcer or cobblestone pattern, 2) intestinal small aphthous ulcerations arranged in a longitudinal fashion for at least three months plus noncaseating granulomas, and 3) multiple small aphthous ulcerations in both the upper and lower digestive tract not necessarily with longitudinal arrangement, for at least three months, plus noncaseating granulomas. Moreover, ulcerative colitis, ischemic enterocolitis, and acute infectious enterocolitis should be excluded. Data from the Japanese Ministry of Health and Welfare, in addition to data collected from two study groups, these being the two largest studies in Japan, are reviewed with regard to epidemiology. The number of patients with Crohn's disease has increased remarkably. The prevalence and the annual incidence of patients with Crohn's disease in Japan were estimated to be approximately 2.9 and 0.6 per 10(5) population in 1986, respectively, and 13.5 and 1.2 per 10(5) population in 1998. Characteristic features of Crohn's disease in Japan are that the male-female ratio exceeds 2, and that there is no second peak of incidence in the age group of 55 to 65 years. Clinically, Crohn's disease with only multiple small aphthous ulcerations, which is the earliest stage of the disease that is diagnosable, was found in 5 percent of patients.

"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.

Aims: Serrated adenoma (SA) is a relatively newly defined entity of colorectal neoplasm. In this study, we examined the cell proliferation, DNA ploidy, and clinicopathological features of SA in order to investigate its biological features., Methods and Results: We reviewed 10,532 polypectomy specimens of the colorectum obtained from Japanese cases between 1974 and 1998 at Tohoku University Hospital. In total, 193 cases of SA were detected. We first examined clinical features of these cases by reviewing the charts, and then studied cell proliferation using immunohistochemistry of Ki-67 and topoisomeraseIIa, p53 immunoreactivity and DNA ploidy. Results were subsequently compared with those of tubular adenoma (TA) and hyperplastic polyp (HP). Mean size of SA (8.6 +/- 4.6 mm) was significantly larger than those of TA (7.3 +/- 4.6 mm) and HP (5.6 +/- 3.0 mm). More than 80% of SA were protuberant in macroscopic appearance. SA was located predominantly in the sigmoid colon and rectum. Incidences of concomitant carcinoma in HP, SA and TA were 0.4% (1 out of 263), 4.1% (8 out of 193) and 10.3% (809 out of 7838), respectively. Labeling indices for Ki-67 and topoisomeraseIIa in HP, SA and TA were as follows: Ki-67--24.2%, 30.8%, 39.5% and topoisomeraseIIa--15.3%, 16.1%, 23.9%, respectively. In SA, p53 immunoreactivity was detected in the intramucosal carcinoma co-existing with the serrated component. Two out of the ten SA cases examined demonstrated non-diploid patterns of DNA ploidy., Conclusion: SA is a distinct colorectal neoplastic lesion with the potential of malignant transformation similar to that of tubular adenoma.

Sulfasalazine and 5-aminosalicylic acid are very useful therapeutic agents for the treatment of the inflammatory bowel disease, such as ulcerative colitis or Crohn's disease. However, the mechanism of action of the aminosalicylates remains obscure. Recently, many studies about their mechanism have been performed. As a result, aminosalicylates have been identified to have several antiinflammatory pathways: (1) alterations in eicosanoid metabolism of arachidonic acid; particularly inhibition of leukotrien B4 production, (2)free radical scavengers; scavenging reactive oxygen metabolites or nitric oxide (3)immunologic suppression; inhibition of HLA-DR expression on the intestinal epithelial cells, inflammatory cytokine(IL-1 and IL-2) production, adhesion molecule expression, platelet-activating factor release, or histamine release from mast cell, and so on.

Background: It has been reported that shortening of telomeres and strong activation of telomerase occur frequently in colorectal carcinomas. In the current study, the authors examined the correlations between the telomere length of colorectal carcinomas and their clinicopathologic characteristics as well as the activity of telomerase to clarify whether telomere length might represent the biologic behavior of tumors and the mode of tumor development., Methods: Telomere length was examined by Southern blot analysis in 61 invasive colorectal carcinomas and corresponding normal mucosas. Telomerase activity was assayed by the telomeric repeat amplification protocol with minor modifications., Results: Shortening of the telomere was detected in 38 (62.3%) and elongation in 3 (4. 9%) of the 61 carcinomas. The telomere shortening occurred more frequently in nonulcerating polypoid carcinomas than in ulcerating carcinomas (P = 0.0373) and also occurred more frequently in ascending colon carcinomas than in sigmoid colon or rectal carcinomas (P = 0.0259 and P = 0.0407, respectively). However, no significant correlation was found between the activity of telomerase and the length of telomere., Conclusions: The results of this study indicate that telomere length may represent the biologic behavior of individual tumors and possibly the mode of development of colorectal carcinomas., (Copyright 1999 American Cancer Society.)

Purpose: Bacterial overgrowth sometimes complicates the clinical course of Crohn's disease and may lead to inappropriate treatment. To clarify the effect of antibiotic therapy, we monitored the hydrogen concentration in expiratory breath after fasting., Methods: We evaluated 18 patients (15 males; median age, 32.7; range, 22.3-60 years) for postoperative bacterial overgrowth symptoms and for intestinal dilation by plain abdominal x-ray. Five patients had ileitis and 13 patients had ileocolitis. Various intestinal resections were performed in all, and strictureplasties were done at the same time in 13 patients. The median postoperative period was 10.2 (range, 1.2-102) months. Nine patients, who had symptoms such as bloating, nausea, vomiting, or pain, were classified as the symptomatic group, whereas nine other patients, who had no symptoms, were classified as the symptom-free group. Sixteen patients who had undergone intestinal resections for noninflammatory bowel disease served as the control group. After overnight fasting, hydrogen concentration in end-expiration, breath was measured with gas chromatography. At the same time clinical examinations of white blood cell count, hemoglobin, total protein, serum albumin, iron, sialic acid, and C-reactive protein in the peripheral blood were performed. To assess the effect of antibacterial treatment, changes in symptoms were assessed in eight patients who received antibacterial treatment. Hydrogen concentration was measured repeatedly before and after treatment in six patients., Results: The symptomatic group had an expiratory hydrogen concentration level significantly higher (median, 40; range, 20-139 ppm) than the control group (median, 3; range, 1-6 ppm) and the symptom-free group (median, 4; range, 1-10 ppm). After the antibiotic treatment the symptoms were improved in all of the patients, and the hydrogen concentration level was significantly reduced (median, 4.5; range, 2-13 ppm)., Conclusions: Antibacterial treatment was useful in the postoperative patients whose assessments were complicated by bacterial overgrowth. Using a hydrogen breath test, bacterial overgrowth was effectively monitored and managed, effecting a change in clinical symptoms.

11Beta-Hydroxysteroid dehydrogenase type II (11betaHSD2) confers specificity on the mineralocorticoid receptor (MR) by converting biologically active glucocorticoids to inactive 11-keto metabolites. The biological significance of 11betaHSD2 activity during fetal development is currently being explored, but the temporal and spatial distributions of the enzyme and receptor have not been examined. We therefore examined their distributions during various stages of human fetal development using immunohistochemistry. Both 11betaHSD2 and MR immunoreactivity were detected in the distal convoluted and collecting tubules of the kidney from early in gestation. Fetal skin, intermediate layer of the epidermis, peridermal cells, and hair follicles were positive for both 11betaHSD2 and MR. Weak 11betaHSD2 and MR immunoreactivity was detected in the superficial ciliated epithelium of the esophagus, the deep layer of gastric epithelial cells, and the superficial epithelium of the small intestine. Columnar epithelium in the terminal bronchiolar budding component of fetal lung and tracheal and bronchial ciliated epithelium were also positive for MR and 11betaHSD2 from early gestation. Colonic epithelium and pancreatic exocrine duct cells, which demonstrated marked immunoreactivity of both MR and 11betaHSD2 in the adult, did not express MR and 11betaHSD2 until very late in gestation. These results imply that mineralocorticoid action in the upper fetal gastrointestinal tract, kidney, skin, and lung is facilitated by 11betaHSD2 and is involved in water and electrolyte transport between fetus and amniotic fluid as well as fetal urine production.

We studied the clinical courses of 70 pregnancies in 47 women with ulcerative colitis (UC) and 18 pregnancies in 12 women with Crohn's disease (CD) retrospectively. We concluded as follows. 1. Pregnancy has less influence on the course of UC. 2. The patients with UC who kept remission for more than 1 year before conception have less risk of relapse and severity during pregnancy. 3. The patients with active UC at the time of conception tend to worsen during pregnancy. The patients whose onset of UC is during pregnancy tend to worsen. 4. UC has a little influence on the course of pregnancy except severe active disease. 5. It is not obtained that pregnancy becomes a relapsing factor of CD. 6. CD during pregnancy has little influences on the course of pregnancy, if it is remitted. 7. Salazosulfapyridine and corticosteroids therapy has less influence on the fetus and the course of pregnancy.

We report herein the case of a 16-year-old boy diagnosed as having Turcot syndrome, otherwise known as glioma-polyposis syndrome. The patient was transferred from the Department of Neurosurgery where he was undergoing investigation of a brain tumor, to the Department of Medicine for investigation of gastrointestinal symptoms. The patient was diagnosed as having Turcot syndrome, and was then transferred to the Department of Surgery for treatment of an obstruction in the sigmoid colon and small intestinal invagination. A subtotal colectomy with side-to-end ileoproctostomy and release of the invaginations was carried out. Multiple polyps were found in the colon, two of which, including a large polyp that obstructed the colonic lumen, were confirmed histologically to be adenocarcinoma. The remaining polyps were adenomas. A biopsy of the brain tumor confirmed a diagnosis of astrocytoma (WHO grade II). This case report describes the characteristic features of Turcot syndrome presented by this patient.

To determine immunosuppression by leukocytapheresis, we studied the immune profiles of filter-passed lymphocytes (FPLs) in patients with ulcerative colitis. These patients were treated with a leukocytapheresis (LCAP) filter of granulocyte apheresis (GCAP) column. Cytokine profiles or FPLs and peripheral blood mononuclear cells (PBMCs) were examined using interleukin (IL)-4 and interferon-gamma (IFN-gamma) immunoassay with lectin stimulation. The IL-4 production of LCAP FPLs was significantly higher than in prefilter PBMCs and GCAP column-passed lymphocytes (median: 540 pg/ml x 10(6) cells versus 4.7 and 2.9, respectively, p = 0.001). IL-4 production in PBMCs was increased after LCAP. IFN-gamma production was not increased in the FPLs. The IL-4 immune deviation was not shown in the patients treated with GCAP. LCAP FPLs showed increased CD4+DR- cells and decreases CD4+DR+ cells in comparison to PBMCs. LCAP FPLs could produce IL-4 and may lead to bystander suppression.