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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.

Although antiplatelet agents are widely used for the treatment and prevention of thrombotic diseases, only a few studies have reported the validity of the cessation period prior to endoscopic procedures. In 2002, the American Society for Gastrointestinal Endoscopy (ASGE) published a reference on the management of anticoagulation and antiplatelet therapy for endoscopic procedures, but it should be confirmed as appropriate for use in Asian patients. To evaluate the optimal cessation period of antiplatelet agents prior to endoscopic procedures for Japanese, we have studied: (i) the current clinically adopted cessation period of antiplatelet agents prior to invasive endoscopic procedures in Japan; (ii) the relationship between the cessation period of antiplatelet agents and complications around the invasive endoscopic procedures; (iii) colonic mucosal bleeding time after aspirin ingestion; and (iv) the time course of primary hemostasis after cessation of antiplatelet agents. We conclude that 3 days cessation period for aspirin, 5 days cessation for ticlopidine and 7 days cessation for aspirin + ticlopidine administration should be sufficient for Japanese.

To clarify the protective role of transforming growth factor (TGF)-beta for the intestinal epithelial injury in vivo, the effect of antibodies against TGF-beta on epithelial destruction and apoptosis was assessed in dextran sulfate sodium (DSS)-induced colitis by histological analysis of colonic sections, account of apoptotic epithelial cells. To evaluate the pathways of epithelial apoptosis, we analyzed the activities of caspases, the level of Fas and cellular FLICE-inhibitory protein (cFLIP) expression in epithelial cells. Apoptotic epithelial cells were increased prior to the onset of ulceration in DSS-induced colitis, and the neutralization of TGF-beta exacerbated epithelial apoptosis and histological damage score. The up-regulation of caspase-8 activity and Fas expression and reduced cFLIP expression were observed in intestinal epithelial cells from anti-TGF-beta antibody-treated mice. The present study revealed that suppression of TGF-beta deteriorated epithelial apoptosis, and the increase of apoptotic epithelial cells may amplify the inflammation in gut mucosa.

有茎性大腸ポリープのポリペクトミーにともなう後出血のリスクは, 栄養動脈径に相関することが予想される. 研究の目的は, 有茎性大腸ポリープの形状変数と栄養動脈径の相関を調べ, 出血のリスクファクターを決定することである. 大腸癌手術標本に見られた有茎性ポリープ47病変 (腺腫40例, 腺腫内癌4例, 過形成ポリープ3例) を用いた. ポリープ頭部の横径5.9±2.8mm, 縦径4.8±1.9mmであった. ポリープ茎部の長さ5.8±3.2mm, 直径は2.0±0.5mmであった. 茎部における動脈の最大径は95.7±33.0μmであった. 動脈数は1.4±0.5本であった. 動脈の直径は茎部直径と正相関 (r=0.36, p 0.05). 有茎性大腸ポリープは, 茎が太くなると栄養血管も太くなることが予測され, ポリペクトミー後の出血のリスクファクターの要因のひとつと考えられた.

Background and Aim: Genetic silencing by promoter methylation has attracted attention in the carcinogenesis of colorectal cancer. Methylation of the p16 INK4a gene has been found in primary colorectal cancer. Although the p15 INK4b gene displays high homology to the p16 INK4a gene in the amino acid sequence, methylation of p15 INK4b has not been fully studied. We investigated p15 INK4b methylation status in patients with colorectal cancer to verify the association between the methylation of p15 INK4b and clinicopathological features compared with p16 INK4a . Methods: DNA samples from the tissues of primary colorectal cancer and corresponding adjacent normal colon mucosa were obtained from surgical resections of 88 patients (47 males and 41 females, aged 29-83 years). Methylation-specific polymerase chain reaction was used to analyze p15 INK4b and p16 INK4a methylation status after bisulfite modification. Cumulative survival rates (mean follow-up period: 53.2 months) were calculated by the Kaplan-Meier analysis. Results: Methylations of p15 INK4b and p16 INK4a genes were detected in 23 (26.1%) and 20 (22.7%) colorectal cancers, respectively. Methylation of p15 INK4b was not associated with any clinicopathological features. Compared with normal mucosa, the methylation of p15 INK4b was more prominent in tumor tissue (P < 0.001). Reverse transcription-polymerase chain reaction (RT-PCR) revealed that p15 INK4b methylaton decreased mRNA expression. Kaplan-Meier analysis showed that patients with stage I-II had a significant difference in survival rate between those with and without methylated p15 INK4b (P = 0.018). Conclusions: Our results suggest that methylation of the p15 INK4b gene contributes to the process of carcinogenesis in colorectal cancer as well as p16 INK4a and is useful as a prognostic factor in the early stage.

Leukocytapheresis (LCAP) is a method of therapeutic apheresis that removes peripheral leukocytes. Previous studies showed that in patients with ulcerative colitis (UC), LCAP was more effective than high-dose steroid therapy, and it had few adverse effects. We investigated LCAP in a multicenter study using active and sham devices in a double-blind study in order to elucidate the placebo effect of extracorporeal treatment including anticoagulant medication.Twenty-five patients with active UC of severe or moderately severe grade were enrolled and assigned to the active group or the sham group. Six patients were excluded from the study and 19 (10 in the active group and nine in the sham group) were evaluated. LCAP (treatment using an active device or a sham device) was performed once a week for 5 wk, followed by two additional sessions during the next 4 wk at 2-wk intervals. Steroids and other medications were continued at the same dosage for 4 wk, which included a 2-wk pre-observation period and the first 2 wk after the start of the LCAP treatment. New medications or increase in the dosage of previous medication were prohibited until evaluation was conducted.The clinical activity index (CAI) value of UC, indicated that the active group showed a significantly greater improvement (80%, 8/10) than the sham group (33%, 3/9; p0.05). Adverse effects were observed in five patients (one in the active group and four in the sham group). None of these effects was severe and none of the sessions was terminated as a consequence of the adverse effects.The results confirmed that LCAP is a safe and effective therapeutic option for patients with active UC.

Aims Lansoprazole is a substrate of CYP2C19 and CYP3A. The aim of this study was to compare the inhibitory effects of clarithromycin, an inhibitor of CYP3A on the metabolism of lansoprazole between CYP2C19 genotypes. Methods A two-way randomized double-blind, placebo-controlled crossover study was performed. Eighteen volunteers, of whom six were homozygous extensive metabolizers (EMs), six were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6-day courses of either clarithromycin 800 mg or placebo daily in a randomized fashion with a single oral dose of lansoprazole 60 mg on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5-hydroxylansoprazole and lansoprazole sulphone were monitored up to 24 h after dosing. Results During placebo administration, the mean AUC(0, ∞) of lansoprazole in homozygous EMs, heterozygous EMs and PMs were 4652 (95% CI, 2294, 7009) ng ml−1 h, 8299 (4784, 11814) ng ml−1 h and 25293 (17643, 32943) ng ml−1 h (P

Infection with Helicobacter pylori has been associated with chronic idiopathic urticaria (CIU). The aim of this study was to investigate the efficacy of H. pylori eradication in the treatment of patients with CIU.Fifty patients with CIU (16 men and 34 women; age 25-75 years) and 100 sex- and age-matched control subjects were enrolled in the study. Presence of IgG antibody to H. pylori was examined by serology. H. pylori-seropositive patients with CIU received endoscopy to confirm H. pylori infection. Patients infected with H. pylori received eradication therapy comprising lansoprazole, amoxicillin, and either clarithromycin or metronidazole. At least 2 months after finishing the eradication therapy, a (13)C-urea breath test was performed, and the effect of eradication therapy on the CIU was scored, using a three-point scale, as complete remission, partial remission, or no improvement.In the 50 patients with CIU, 26 (52%) were H. pylori-seropositive, while 48% (48/100) of the control subjects were seropositive (statistically not significant). Nineteen out of the 26 patients with CIU infected with H. pylori received eradication therapy, and eradication was successful in 17 patients. In the 17 H. pylori-eradicated patients, 6 (35%) had complete remission and 11 (65%) had complete remission or partial remission. On the other hand, in the 9 patients without H. pylori eradication, only 2 (22%) showed partial remission and 7 (78%) had no improvement.Eradication of H. pylori would be a valid choice for patients with CIU, although the prevalence of H. pylori infection is not higher in patients with CIU than it is in controls.

The degree of mucosal redness can be quantified as an index of hemoglobin (IHB) that changes with photographic conditions. The first aim of the present study was to stress the exclusion of γ correction as a critical procedure for reliable measurements of IHB. The second aim was to characterize Matts grade by pictorial parameters in the gray scale picture of IHB and to establish a computer-aided grading system of endoscopic severity in ulcerative colitis. A total of 130 digital endoscopic pictures of 55 patients with ulcerative colitis (30 Matts 1, 70 Matts 2, 20 Matts 3 and 10 Matts 4) were used. The pictures without γ correction were processed for the mean IHB, SD of IHB, kurtosis of IHB and contrast feature. A computer-aided grading system was constructed on the basis of Bayes decision theory. Significant increase in the mean IHB was seen when comparing Matts 1 to Matts 2. The SD of IHB or contrast feature significantly increased from Matts 2 to Matts 3 or from Matts 3 to Matts 4. Kurtosis of IHB was significantly larger in Matts 3 than in Matts 1 or Matts 4. Sensitivity and specificity when discriminating Matts 1 from Matts 2, Matts 2 from Matts 3 and Matts 3 from Matts 4 by the grading system were found to be 84 and 96%, 94 and 70%, and 100 and 85%, respectively. The computer-aided grading system may permit quantitative evaluation of effects of treatments in ulcerative colitis with minimal interobserver variation.

A 64-year-old Japanese man was diagnosed with a tumor of the stomach. From the findings of an upper gastrointestinal endoscopy, computed tomography scan and endoscopic ultrasonography, the tumor was suggestive of a gastric lipoma. He was successfully treated by an endoscopic unroofing technique. There remained residual tumor just after unroofing, but it disappeared a month later. There remained only a scar and there has been no recurrence.

OBJECTIVE: To investigate the in vitro effect of Tripterygium glycosides (TG) on cytokine production by splenocytes in oxazolone (OXZ)-induced colitis in mice. METHODS: Oxazolone (6 mg in 50% ethanol) was administered to male SJL/J mice intrarectally to induce colitis and the mice were killed 3 days later. Isolated splenocytes were cultured for 24 h in the presence of phorbol myristate acetate and ionomycin. A preparation of Tripterygium glycosides at a concentration of either 0.1 mg/mL or 0.01 mg/mL was added to the culture medium of splenocytes. Production of interferon gamma (IFN-γ) and interleukin-4 (IL-4) in the supernatant were measured by ELISA. RESULTS: Production of IFN-γ in the normal control group was suppressed by TG at both concentrations (0.01 and 0.1 mg/mL; 1.24 ± 0.13 pg/mL (samples without TG) 0.97 ± 0.26 pg/mL (0.01 mg/mL TG) 0.87 ± 0.18 pg/mL (0.1 mg/mL TG); P

The mutations of the SCN5A gene have been implicated to play a pathogenetic role in Brugada syndrome, which causes ventricular fibrillation. To determine the Brugada-associated mutations in Japanese patients, facilitate pre-symptomatic diagnosis, and allow genotype-phenotype studies, we screened unrelated patients with Brugada syndrome for mutations. DNAs from 6 Japanese patients were obtained and the sequence in the translated region of SCN5A was determined. We could not find the mutations reported previously, but found 17 sites of nucleotide change, consisting of 7 synonymous and 10 non-synonymous nucleotide changes in our patients. Among them, two non-synonymous nucleotide changes (G1663A and G5227A) are specific to our patients and these changes were not found in 53 healthy controls. In 4 patients out of 6, no specific nucleotide change for Brugada syndrome could be detected. Our findings demonstrating no patient-specific change in the translated region of the SCN5A gene among two thirds of the small number of patients examined here imply that another gene other than the SCN5A may be associated with this disease, supporting previous investigations in Japan and other countries.

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.

For addressing, and eventually being able to predict and prevent, both disease-related complications and changes in social status in long-term acute leukemia survivors, the follow-up is the most important factor after treatment. To this end, we assessed the complications following the attainment of complete remission in adult acute leukemia patients and the changes in social status of patients surviving more than 5 years after disease onset. In our study population of 42 survivors, 24 (57.1%) suffered from various combinations of 18 types of identified complications including posttransfusion hepatitis, diabetes mellitus, and idiopathic osteonecrosis. Regarding fertility, 9 live births were recorded in this cohort, from 2 female patients and the partner of a male patient. Of these 42 long-term survivors, at the time of this report 48.5% were working full- or part-time, 9.0% were unemployed, 30.3% were homemakers, and 12.2% were retired.

OBJECTIVE Cyclooxygenase-2 (COX-2) expression is increased in gastric cancer. We examined COX-2 expression in early stage gastric cancer and background mucosa to elucidate the role of COX-2 in gastric carcinogenesis. METHODS Thirty-three early gastric cancers obtained from 30 patients infected with Helicobacter pylori were studied. Twenty-three patients had an intestinal, four patients had a diffuse, and three patients had both an intestinal and a diffuse type cancer. Expression of COX-2 protein was detected by immunohistochemistry by counting the number of positive staining cells per 100 cells. RESULTS Mean COX-2 expression was 84.1 (SD 11.4) in 26 intestinal type cancers and was significantly higher than that in seven diffuse type cancers (23.1 +/- 9.7) (P < 0.001). In three patients who had both the intestinal and the diffuse type cancer, COX-2 expression was 92, 90 and 83 in the intestinal type cancer and only 25, 24 and 7 in the corresponding diffuse type cancer. In 18 patients who had intestinal metaplasia (15 had incomplete metaplasia), COX-2 expression was 60.2 (24.2) in the crypts with metaplasia while it was only 16.8 (10.7) in the crypts without metaplasia (P < 0.001). CONCLUSIONS COX-2 expression may be associated with the carcinogenesis of the intestinal type gastric cancer and, speculatively, inhibition of COX-2 might have preventative effects on the intestinal type gastric cancer.

It was reported that in only 19 (11%) of 173 patients was the common channel at the junction of the pancreatic and bile ducts found to be 6 mm or longer. Pancreaticobiliary maljunction (PBM) is defined as an anomaly with a markedly long common channel with the junction located outside the duodenal wall, so the action of the sphincter of Oddi does not functionally affect the junction. We defined high confluence of pancreaticobiliary ducts (HCPBD) as a length of the common channelor = 6 mm, in which the communication between the pancreatic and bile ducts was occluded when the sphincter was contracted. This study aims at investigating the clinical significance of HCPBD.2,980 consecutive cases with an adequate endoscopic retrograde cholangiopancreatography were reviewed. PBM and HCPBD were diagnosed according to the above definitions. PBM was divided into two groups: with or without biliary dilatation.PBM and HCPBD were detected in 63 (2.1%) and 50 (1.7%) cases, respectively. Biliary dilatation was detected in 30 cases having PBM. The incidences of gallbladder carcinoma associated with PBM with or without biliary dilatation and HCPBD were 13, 67, and 12%, being significantly higher than in controls (p0.05, p0.01, and p0.05). Pancreatic ductal reflux was detected in 11 (85%) of 13 patients with HCPBD in whom postoperative T tube cholangiograms were performed, and acute pancreatitis occurred in 14 (24%) of the 50 patients with HCPBD.HCPBD may be an intermediate variant of PBM. It is necessary to pay attention to an associated gallbladder carcinoma in patients with HCPBD as well as in those with PBM.

This study set out to evaluate the effects of dietary fiber on cancer development in the large bowel under in vivo experimental conditions as similar as possible to those under which this cancer develops in vivo in humans. Forty-eight Sprague-Dawley rats were divided into three groups that were fed either a nonfiber diet or a 3 g or 10 g/100 g cellulose diet in this experiment, and all groups received doses of a mild carcinogen, 1,2-dimethylhydrazine (5 mg/kg body weight) for 50 weeks. Following endoscopic observation of the large bowel, we found that the induction rates of tumor in the cellulose groups were significantly lower than that in the nonfiber diet group, both endoscopically and histologically. No differences were seen between the 3% and 10% cellulose groups in suppressing carcinogenesis. It is likely that the inhibitory effect of 3% cellulose could be confirmed only by a long-term experiment on carcinogenesis following the administration of a low dose of carcinogen.

Background and Aim: Colorectal Paneth cell metaplasia (PCM) is known to be a sign of idiopathic inflammatory bowel disease (IBD), although its distribution and histogenesis are not fully understood. Objectives of this research were to investigate the spatial distribution of PCM in IBD and other forms of colitis (non-IBD), and to find stimuli causing PCM. Methods: We studied multiple biopsy specimens from 181 patients with ulcerative colitis (UC), 159 with Crohn's disease (CD), 448 with non-IBD, and 78 normal controls. Paneth cell metaplasia frequency, at each colorectal site, was evaluated to find possible differences among diseases, phases of activity, and extents of disease. Results: In non-IBD and controls, PCM was rarely (0–1.9%) seen at distal sites, but frequently (up to 48.7%) found at the ascending colon and cecum (P < 0.001). Paneth cell metaplasia frequency was significantly higher in IBD than in non-IBD patients and controls at distal sites (P < 0.001), but did not differ significantly between UC and CD, or among active, resolving, and quiescent phases. In UC, proctitis and left-sided colitis rarely displayed PCM at unaffected sites. Multiple logistic regression analysis revealed that PCM was positively associated with crypt distortion and mononuclear cell infiltration (P < 0.005), but negatively or not significantly associated with crypt atrophy, mucin depletion, acute inflammation, or phase of activity. Conclusions: Paneth cell metaplasia is a non-specific phenomenon in the proximal colon, but distal PCM, which occurs exclusively in affected mucosa, is a useful marker indicating IBD, even in the inactive phase. Regression analysis suggests that repair and regeneration may be the most potent stimuli causing PCM.

Gut lavage fluid, collected by the oral administration of an electrolyte lavage solution, was found to be an excellent and easily collectible source of abundant mucin. Furthermore, the biochemical features of mucin from patients with ulcerative colitis (UC) and Crohn's disease (CD) were investigated. The mucin was separated into four fractions by Sepharose CL-4B, Sepharose CL-2B, and DEAE Sephacel chromatography. Compared to healthy subjects, the total yields of mucin from ulcerative colitis patients were low due to a deficiency of neutral mucin, whereas those from Crohn's disease patients were high, mainly due to high-molecular-weight mucin. Fucose and sulfate content was low in ulcerative colitis, but only the former was low in Crohn's disease. The different biochemical features of mucin obtained from gut lavage fluid appear to reflect the mucosal pathological changes associated with inflammatory bowel disease.

The abnormal expression of several genes is involved in the development of colorectal tumors. The aim of this study was to examine the expression of KAI1, CAR, and Smad4, which has been associated with the progression of other cancers. Methods. We examined 12 adenomas, 38 primary carcinomas, 10 liver metastases, and 7 adenocarcinoma cell lines, by fluorescent multiplex reverse transcription-polymerase chain reaction (RT-PCR). Results.KAI1 expression was higher in adenomas (2.55 ± 0.61; P < 0.05) and primary carcinomas (3.30 ± 0.42; P < 0.005) than in normal mucosa, but it was not correlated with tumor stage. CAR expression was lower in Dukes' B (1.28 ± 0.53) than in Dukes' A (2.38 ± 0.48) (P < 0.05), but increased with tumor progression; Dukes' C (1.45 ± 0.25), Dukes' D (1.53 ± 0.14), and metastases (2.09 ± 0.39) (P < 0.05). Smad4 expression increased in adenomas (2.30 ± 0.46; P < 0.05), but decreased with tumor progression; Dukes' A (2.14 ± 0.37), Dukes' B (1.65 ± 0.41), Dukes' C (1.57 ± 0.25), Dukes' D (1.08 ± 0.18), and metastases (0.82 ± 0.21) (P < 0.05). Conclusions. These results suggest that the upregulation of CAR and down-regulation of Smad4 are associated with the progression of colorectal tumors, while the upregulation of these genes and of KAI1 seems to be involved in the early stage.

OBJECTIVES Lipopolysaccharides of Helicobacter pylori have an antigenic structure that mimics Lewis X occurring in gastric mucosa. The pathogenic role of antigenic mimicry in H. pylori-induced gastritis has been of recent interest. The aim of this study was to examine the relevance of anti-Lewis X antibody in the development of atrophic gastritis in H. pylori infection. METHODS A total of 72 patients were studied. Serum samples were collected to measure IgG antibodies to H. pylori, CagA, VacA and Lewis X. Biopsy specimens were obtained from the antrum and the corpus to examine the grade and the type of atrophic gastritis. RESULTS Mean anti-Lewis X antibody titres were higher in 38 VacA-seropositive patients than in 13 seronegative patients (P < 0.05). The difference was not significant between patients with diffuse-type atrophic gastritis and those with multi-focal type. No significant correlation was observed between the titre of anti-Lewis X antibody and the grade of glandular atrophy, whereas CagA seropositivity was associated with glandular atrophy. CONCLUSIONS Anti-Lewis X antibody may play a role in persistent gastric inflammation, particularly in VacA-seropositive H. pylori infection. However, anti-Lewis X antibody does not seem itself to be associated with atrophic gastritis in patients with H. pylori infection.

COLO 201, human colon adenocarcinoma cells were incubated with artificial primers, p-nitrophenyl-glycoside derivatives at 1.0 mmol (mM) in the medium containing 10% fetal bovine serum to detect sugar chain elongation. However, when p-nitrophenyl-beta-N-acetylglucosamine (beta-GlcNAc-PNP) was added, the medium changed color to yellow and the cells were dead. To explain this finding, the cells were incubated with 1.0 mM each of beta-GlcNAc-PNP and 4-methylumbelliferyl-beta-N-acetylglucosamine, then the number of living cells was measured in a time course. In beta-GlcNAc-PNP, the living cells were decreased at 24 hours. The cells were survived with N-acetylglucosamine, whereas in the presence of p-nitrophenol (PNP) the living cells were decreased. It was suggested that PNP released from beta-GlcNAc-PNP induced the cell death. Activity of beta-D-N-acetylglucosaminidase was detected in fetal bovine serum. It was shown that PNP induced the cell death in time-and-dose dependent manner. Genomic DNA from COLO 201 analyzed by agarose gel electrophoresis was fragmentated. PNP analogues were tested for toxicity, and the results suggested that the phenolic OH-group linked to benzene ring and nitro-group linked to the structure in para-form (PNP) was the most effective.

Background and Objectives: γδT cell populations are well-known for their unique distribution (e.g. intra-epithelial lymphocytes). Though their ligands play a major role in the immune response they have remained largely obscure. To shed light on this issue, we have analyzed in this study the complementarity determining region (CDR) 3 of the T cell receptor (TCR) Vδ2 chains. This provides an insight into the antigenic immune response in the intestinal mucosa in sickness and health. Methodology: Total RNA was extracted from surgically resected intestinal mucosa of patients with Crohn’s disease (CD) and controls. TCR Vδ2 cDNA was PCR-amplified using Vδ2 sense primer and Cδ antisense primer. The PCR products were then subcloned in pUC18 plasmid. From each sample, 20 subclones were randomly selected and subjected to nucleotide sequence analysis. Results: Sequence analysis revealed that the CDR3 sequences of the TCR Vδ2 chains were unique to each individual. The evidence also showed a significant restriction of the junctional diversity of the TCR Vδ2 chains while no such restriction was found for CD. Conclusions: The marked complexity of the TCR Vδ2 junctional sequences and the oligoclonality of the TCR Vδ2 genes in the control subjects are indicative of a positive selection and expansion of specific T cells in the normal, healthy condition. In CD patients, however, the expression of distinct, non-overlapping TCR Vδ2 clonotypes can be found, suggesting polyclonal activation of γδT cells in the diseased colon of CD patients. These findings have led us to conclude that accumulation of multiple γδT cell clonotypes may be involved in the pathogenesis of CD.

The γδT cells have been known to play an important role in the regulation of the mucosal immune system, but the relationship between these cells and the pathogenesis of Crohn's disease (CD) has remained obscure. We now demonstrate the T-cell receptor (TCR) Vδ2 gene transcripts characterize antigenic immune response in the intestinal mucosa from patients with CD. TCR Vδ2 gene transcripts of six patients with CD and six controls were subcloned and 20 randomly selected clones from each sample were subjected to nucleotide sequencing. Sequence analysis demonstrated that the different clones in the intestinal mucosa of CD were significantly increased (11.833 ± 0.946) compared to controls (7.167 ± 1.470) (P = 0.0374). The presence of intraindividual dominance and oligoclonality of TCR Vδ2 gene transcripts in normal controls appears reflect positive selection and expansion of specific γδ T cells in normal controls. By contrast TCR Vδ2 gene transcripts in the intestinal mucosa of CD can express different clonotypes. We conclude that accumulation of multiple Vδ2+ γδ T-cell clonotypes are involved in the pathogenesis of CD.

Changes in intraluminal pressure in rat colon with aging and with the effects of dietary fiber were measured. A pressure sensor was inserted into the rat large intestine under endoscopic guidance. The intraluminal pressure curve in the colon was recorded, and the motility index was calculated by this curve. The rats were divided into three groups with a fiber-free diet, a cellulose diet (10% w/w), or a pectin diet (10% w/w). Intraluminal pressure was measured in the proximal, middle, and distal colon at 2, 4, 8, 12, and 16 months after birth. Intraluminal pressure in three sites increased with age and decreased in the latter half of the study. The motility index was lower during the course in the fiber groups, especially the pectin group more than the nonfiber group. This result suggests that long-term ingestion of dietary fiber might have a prophylactic effect on the development of diverticula.

Background: Topical pharyngeal anesthesia is generally used as a pretreatment for upper endoscopy. However its efficacy has not been established. Methods: A randomized double—blind placebo-controlled study was undertaken. Subjects were 201 patients who underwent upper endoscopy and gave informed consent. Relative risks (RR) of patient discomfort were calculated for pharyngeal anesthesia, anxiety, and other potential confounding factors by using logistic regression analyses. Results: The RR of patient discomfort on intubation was 0.56 for the anesthesia versus the placebo group (95% CI, 0.31-1.01). RR was higher in patients aged 39 or younger than in those 40 or over (RR = 2.22, 95% CI, 1.04-4.74). With subgroup analysis in those examinees less than 40 years old, the RR of patient discomfort was 0.21 for the topical anesthesia (95% CI, 0.04-0.99) versus the placebo group and 4.93 for patients undergoing upper endoscopy for the first time (95% CI, 1.13-21.60). In the first-time patients, the RR was lower in the topical anesthesia than in the placebo group (RR = 0.20; 95% CI, 0.04-0.93); it was higher in patients with a trait-anxiety score higher by 10 points than in those with a lower score (RR = 3.35, 95% CI, 1.01-11.15). With the Bonferroni correction for multiple testing of data, statistical significance is indicated by a CI of 97.5% in the subgroup analyses. Conclusions: Topical pharyngeal anesthesia appears to be effective in patients less than 40 years old and in those undergoing the procedure for the first time. A high trait-anxiety score could be a predictor of discomfort in first-time examinees. (Gastrointest Endosc 2001;53:14-8.)

Cap polyposis (CP) is a rare disease that was first described by Williams et al.1 in 1985. It is characterized by multiple polyps with a mucoid and fibrinopurulent cap. Although the pathogenesis is unknown, the characteristic histological appearance is similar to that of mucosal prolapse syndrome (MPS). Endoscopically, it is difficult to distinguish the polyps of CP from inflammatory polyps and neoplasms. True neoplasms can be differentiated from non-neoplastic lesions by magnifying colonoscopy, but the changes in the mucosal surface of CP have not been investigated in detail. A case of CP that was treated successfully with conservative therapy, is described, as well as the findings obtained by magnifying colonoscopy.

Background and Aims: Infection with Helicobacter pylori is associated with an increased risk of gastric adenocarcinoma. However, most patients with H. pylori infection will not develop gastric cancer. The aims of the present study were to examine which histological features, including H. pylori infection, would increase the risk of gastric cancer using a case-control study. Methods: Three gastric biopsy specimens were taken from 72 patients with early gastric cancer and 72 age- and sex-matched control subjects. The grade of gastritis was examined according to the updated Sydney System. The presence of H. pylori infection was determined by serology and histology. Odds ratio (OR) of developing gastric cancer was calculated for H. pylori positivity and histological features using conditional logistic regression. For patients with H. pylori infection, histological features in cancer patients and control subjects were compared. Results: The OR of the presence of mononuclear cell infiltration in the corpus and intestinal metaplasia in the angulus were significantly elevated. The grade of mononuclear cell infiltration in the corpus and antrum was significantly higher in both types of cancer patients than controls. Glandular atrophy and intestinal metaplasia were increased in patients with intestinal-type cancer in the angulus and antrum. Bacterial density in the corpus and polymorphonuclear cell infiltration in the antrum were increased in patients with diffuse-type cancer. Conclusions: Severe chronic gastritis induced by H. pylori infection seems to be associated with diffuse-type gastric cancer. Glandular atrophy and intestinal metaplasia, which occur in gastric mucosa with chronic inflammation, are significantly associated with intestinal-type cancer.

Background—Infection with a virulent Helicobacter pylori strain is associated with gastric mucosal damage and the increased risk of gastric cancer. Aims—To examine the characteristics of host gastric mucosal responses in patients with gastric cancer, histological grade of gastritis, gastric epithelial apoptosis, and proliferation were studied. Methods—Thirty two patients with early gastric cancer and 32 sex and age matched controls were studied. All subjects were infected with a virulent H pylori strain (vacA s1/m1, cagA positive genotype). Biopsy specimens were taken from the antrum and the corpus of the stomach. The grade of gastritis was assessed according to the updated Sydney system. Apoptotic cells were detected using terminal uridine deoxynucleotidyl nick end labelling, and epithelial cell proliferation was determined by means of the Ki-67 labelling index. Results—In patients with gastric cancer, significantly higher grades were observed when glandular atrophy (p < 0.05) and intestinal metaplasia (p < 0.01) were present in the antrum, and when mononuclear cell infiltration was present in the corpus (p < 0.05). The numbers of apoptotic cells were increased in patients with cancer (p < 0.05) and the apoptotic index correlated significantly with the grade of glandular atrophy. Epithelial cell proliferation was more likely to be increased in mucosa where intestinal metaplasia was present. Conclusions—Infection with H pylori causes increased gastric epithelial apoptosis, resulting in more severe glandular atrophy in patients with gastric cancer. Increased damage of gastric epithelial DNA and the presence of more severe atrophic gastritis might contribute to the development of gastric cancer. Key Words: gastric cancer • cell proliferation • apoptosis • gastritis • Helicobacter pylori

症例は39歳,男性.血便のため平成10年11月17日当科受診し,諸検査にて左側大腸炎型の潰瘍性大腸炎と診断した.入院治療を行いステロイド投与により寛解が得られたため平成11年3月24日に退院したが,4月初旬より右悸肋部痛が出現したため再入院し,上腹部スクリーニングにて急性胆嚢炎を指摘した.胆道造影では胆管系に異常所見はなく胆嚢内にも結石を指摘できなかった.保存的治療のあと当院外科にて5月17日に胆摘術を施行したが,摘出標本では胆嚢内に結石はなく胆嚢壁のびらん,出血,肥厚を伴う慢性胆嚢炎の所見であった.潰瘍性大腸炎には様々な合併症があり,胆道系疾患合併も稀ではない.しかし無石胆嚢炎合併の報告は極めて稀なので報告した.

A novel Helicobacter pylori gene, iceA, has two allelic variants, and the iceA1 strain is associated with peptic ulcer disease. The aims of this study were to evaluate whether the possession of iceA1 gene is associated with gastric cancer or the severity of gastritis.Ninety-seven subjects (46 patients with early gastric cancer and 51 control subjects) infected with H. pylori were studied. DNA was extracted from isolated H. pylori strains, and the presence of the iceA1 gene was examined by polymerase chain reaction. The features of gastritis were graded in accordance with the updated Sydney System, using gastric biopsy specimens.iceA1 was found in 61% of patients with gastric cancer and 53% of control subjects (NS). The grade of gastritis in iceA1-positive and -negative gastric mucosa was compared. Higher polymorphonuclear cell infiltration was observed in iceA1-positive subjects (P0.05). However, no significant difference was observed in the grades of mononuclear cell infiltration, glandular atrophy, and H. pylori density.Our results suggest that the iceA1 gene is not associated with the development of gastric cancer in Japan, whereas the iceA1-positive strain may induce more enhanced active gastric inflammation in cagA-positive and vacA s1/m1 strains.

Background: The non-lifting sign is considered a contraindication to endoscopic resection. Our objective was to investigate whether lifting or nonlifting of a lesion is determined by the volume of normal submucosal tissue. Methods: We measured the thickness of the submucosa and examined the relation between submucosal invasion and lesion elevation induced by submucosal injection in 60 patients with colorectal cancer with evidence of submucosal invasion. Extent of tumor elevation was classified into two groups: A, lifting; B, non-lifting. Submucosal invasion was classified as sm1, sm2, or sm3. The distance between the carcinoma and the line of resection and that between the carcinoma and the muscularis propria were measured. Results: Of 31 sm1 lesions, 29 (93.5%) were group A. All 6 sm3 lesions were group B. All lesions in group A had a value for the distance between carcinoma and muscularis propria of more than 1000 μm. Group B lesions with sm3 invasion had distances of only 105 to 750 μm. Conclusion: Lesions classified as sm3 do not elevate in response to submucosal injection, and lesions that become elevated on injection can be resected endoscopically because they are sm1 or sm2 and have a thickness of normal submucosa of more than 1000 μm. (Gastrointest Endosc 1999;50:329-33.)

A 19–year-old woman visited our hospital complaining of fever and epigastral-gia. Upper gastrointestinal endoscopy showed minute discrete erosions surrounded by elevated mucosa about one millimeter in diameter in the esophagus and aphthoid erosions in the stomach. Biopsy samples obtained from the esophagus showed non-caseating epitheloid granulomas, suggesting Crohn's disease. Colonoscopy showed a small erosion in the cecum adjacent to the vermiform appendix and biopsy showed non-caseating epitheloid granulomas and Crohn's disease was diagnosed. In hospital, she was treated with elemental diet and 5–aminosalicyclic acid. Clinical symptoms disappeared rapidly and laboratory data became normal. We thus report a rare case of early-stage Crohn's disease initially indicated by biopsy of minute esophageal erosions. (Dig Endosc 1999; 11: 255–258)

72 congenital or acquired bleeding disorder patients who all showed prolonged BT (more than 15 minutes).

We determined the levels of 15 elements in drinking water from 34 water treatment plants in Aomori Prefecture and studied how element levels relate to colorectal cancer incidence by district. Colorectal cancer incidence was calculated from the data of Aomori Colorectal Cancer Registry. Multiple regression analysis was performed by using age-adjusted incidences of rectal cancer and colon cancer by gender as object variables and each element level as an explanatory variable. The standardized partial regression coefficient was significant in gold (p

BACKGROUND/AIMS: Infection with Helicobacter pylori strains possessing the cagA gene is associated with increased risk of gastric cancer of the intestinal type. The aims of this study were to investigate whether CagA seropositivity is associated with increasing risk of gastric cancer in a Japanese population that has a much higher incidence of gastric cancer than western populations. METHODS: Eighty one gastric cancer patients and 81 sex and age matched endoscopically evaluated controls were studied. Histologically, 62 cancers were of the intestinal type and 76 were early gastric cancer. Serum CagA IgG antibodies were assayed by enzyme linked immunosorbent assay (ELISA) using purified recombinant CagA protein as antigen. Polymerase chain reaction (PCR) analysis for cagA in H pylori isolates (n = 80) showed that the CagA ELISA had a sensitivity of 83.3% (controls) and 72.5% (cancers). RESULTS: CagA seropositivity was 60% (49 of 81) in cancer patients and 44% (36 of 81) in controls. The odds ratio for the risk of cancer if CagA seropositive was 1.93 (95% confidence interval (CI) 1.01 to 3.68; p < 0.05). In the 57 H pylori positive cancer patients and their matched H pylori positive controls, the odds ratio for the risk of cancer if CagA seropositive was 2.2 (95% CI 1.04 to 4.65; p < 0.05). CONCLUSIONS: These results suggest that CagA seropositivity is associated with increased risk of gastric cancer in Japanese populations.

A 46-year-old woman with systemic lupus erythematosus (SLE) was admitted owing to a sudden severe back pain. She had been receiving corticosteroids throughout the course of long-standing nephritis, and had a family history of dissecting aortic aneurysm. Computed tomography (CT) and magnetic resonance imaging (MRI) examinations of the chest with intravenous contrast revealed a dissecting aortic aneurysm. Surgical replacement of the aortic arch was performed. The histological findings in the thoracic aorta were compatible with cystic medial necrosis. We report this rare case, and review the literature relating to this complication.

phangiomas before surgery. EUS revealed the characteristics of the intracystic space, such as the epithelial papillary-like growth features that were not detected with CT. A sagittal section of the resected specimen showed features consistent with the preoperative EUS findings. These findings suggest that EUS is a useful method for diagnosis of appendiceal mucocele. In conclusion, we diagnosed a case of vermiform appendiceal mucocele at colonoscopy with the use of an EUS probe. The endoscopic and EUS images were highly suggestive of an appendiceal mucocele. If findings at routine colonoscopy suggest the presence of an appendiceal mucocele, EUS with a miniprobe should be performed for accurate preoperative diagnosis. Although the lesion in the present case was benign, we believe that EUS would also reveal the irregular thickness or the disruption of the cyst wall that are likely to occur with invasion into the stroma. Therefore, in the future, EUS may be able to distinguish the more benign lesions from the more malignant types. REFERENCES

Cold snare excision (CSE) has proved to be an effective method for the destruction of diminutive polyps of the colon and rectum. We investigated the correlation between polyp size and bleeding time at the resected end after CSE, and also an appropriate measuring method using CSE. Eighty patients with single polyps were examined. Each polyp was identified as being 5 mm in diameter or smaller using the open-biopsy forceps technique (OBFT). The size of the polyp was calculated using our measuring system (SMS). Of the polyps identified as being 5 mm in diameter or less using OBFT, 15% were 6 mm or more using the SMS. CSE was performed for each polyp, and the time taken for the hemostasis (bleeding time of the CSE; BTCSE) was determined. In seventy-seven polyps that were 6 mm or smaller in SMS, a correlation was noted between SMS and BTCSE. In three polyps that were 7 mm or more by SMS, hemostasis took 10 min or more after CSE, and required electrocoagulation. These results suggest that CSE is a safe method for the removal of polyps determined to be 6 mm in diameter or smaller using the SMS.

Background: Several studies have shown that infection of Helicobacter pylori strains possessing cagA is associated with atrophic gastritis and gastric cancers. Method: In 58 pairs of early gastric cancer patients and sex- and age-matched controls, isolated H. pylori strains were tested for possession of cagA. The presence of atrophic gastritis was also examined. Results: Proportions of cagA-positive strains were 100% in cancer patients and 92.3% in controls. Atrophic gastritis was seen in 96.7% and 95.8% of cancer and control patients in whom cag4-positive strains (NS) were detected. However, it was seen in only 20% of H. pylori-negative control patients (P < 0.01). Conclusions: The present results do not suggest any specific association between cagA -positive strains and gastric cancer. However, frequent prevalence of cagA-positive strains might be associated with the high incidence of atrophic gastritis in Japanese populations.

BACKGROUND In recent years, the mortality rate for colorectal carcinoma in Japan has rapidly been increasing, and there are indications that it may surpass that of gastric carcinoma, with colorectal carcinoma fast becoming one of the main targets of cancer treatment in Japan. METHODS Eight thousand three hundred and eighty-six case records of colorectal carcinoma (4479 males and 3907 females; 4691 colon carcinoma cases and 3695 rectal carcinoma cases), diagnosed over 18 years from 1974 to 1991 in Aomori Prefecture, were analyzed. RESULTS Age-adjusted incidence for colorectal carcinoma per 100,000 population were 12.6 and 8.7 for males and females, respectively, in 1974. The corresponding rates were 20 and 13.6, respectively, in 1980, and 42.5 and 25.6, respectively, in 1991. Among patients with colon carcinoma, a higher proportion have sigmoid colon carcinoma. The degree of increase in the incidence of sigmoid colon carcinoma was almost the same as that of right-sided colon carcinoma. By birth cohort analysis, among those born in 1934 or earlier, the incidence at the same age was higher in the younger population. CONCLUSION It is possible that the age-adjusted incidence of colorectal carcinoma in Japan will soon resemble that of the white population in the United States, in a manner similar to that of Japanese-Americans. Cancer 1996;78:1187-94.

We evaluated the preventive effects of wheat bran (40%, weight percent of diet) on the development of large bowel carcinoma induced by weekly intraperitoneal administration of 25 mg/kg (body weight) of 1,2-dimethylhydrazine over 19 weeks in the rat. Feces number and volume per pellet in wheat bran diet group were significantly greater than those in basal diet group, and the induction rates of tumor in the wheat bran diet group was found to be significantly lower than that in the basal diet group. These results suggested that wheat bran was effective in inhibiting large bowel carcinogenesis, and that the increased fecal weight and volume from wheat bran may be involved in such an inhibitory effect.

In this report, we attempt to propose a recommended level of dietary fiber (DF) for the Japanese from several epidemiological reports. The authors previously investigated the daily DF intake in 50 patients with colon polyp, 33 patients with colon diverticulosis, 45 patients with colorectal cancer, and two groups 84 and 45 control subjects; the values obtained were 18.2, 17.4, 14.9, and 21.1 and 19.9 g, respectively. In another study, of the 5 regions in Japan, in only one, Aomori, where the rate of the colon diverticulosis detection was the lowest, did the DF intake exceed 20 g. Furthermore, in Japan the incidence of colorectal cancer showed a marked increase after 1955. It was assumed that the period between the diagnosis of colorectal cancer and death was 15 years, and that the DF intakes at this time (before 1940) to had contributed to the development of the disease. However unfortunately daily DF intake before 1940 in Japan were unknown, and we have only data 25.0 g in 1946. Thus, it is proposed that the recommended level for daily DF intake in Japanese be set at about 20–25 g, i.e. 10 g per 1,000 kcal.

Polymerase chain reaction (PCR) is a useful method of detecting H. pylori from gastric juice, which can be obtained more safely and easily than gastric biopsies. We investigated the applicability of PCR assays of gastric juice aspirates to evaluate cure of H. pylori infection. Fifteen H. pylori positive patients with gastric ulcer or gastritis received anti H. pylori therapy. Four weeks after the cessation of treatment, endoscopy and the 13C-urea breath test (13C-UBT) were performed to evaluate the status of H. pylori infection. Gastric juice samples were collected and one biopsy specimen each was taken from the antrum and the body of the stomach. Results obtained from PCR of gastric juice aspirates were compared with those from PCR of gastric mucosae and 13C-UBT. Fourteen of the 15 showed identical results. However, PCR assays of gastric juice aspirates were positive in one patient with negative results on the other two examinations. Restriction fragment length polymorphism of PCR products suggested that this discrepancy was due to detection of another strain passing through the stomach into the duodenum. Despite the detection of transient strains in gastric juice aspirates being infrequent, the results suggest the possibility of oral transmission of this organism.

Epidemiological and experimental studies have shown that dietary fiber may prevent colon cancer. Resistant starch, like dietary fiber, is not subject to digestion in the small intestine. However, it is unknown whether resistant starch inhibits colonic carcinogenesis. In vitro studies have shown that butyrate slows the growth of cultured colon cancer cells. The effect of resistant starch diet on 1,2-dimethylhydrazine-induced colonic carcinogenesis in rats was evaluated, and the colonic butyrate concentration was measured.Sprague-Dawley rats were randomly divided into five groups that were fed diets containing no fiber, 3% cellulose, 10% cellulose, 3% resistant starch, or 10% resistant starch. Colonic carcinogenesis and butyrate concentration of colonic contents and feces in each diet group were compared.Total cancer volume per rat in the 10% cellulose group was significantly lower than that in the basal group (109 +/- 54 mm3 and 247 +/- 83 mm3; P0.05), but the other groups showed no significant differences. The butyrate concentration in colonic content and in feces were higher in the resistant starch groups than in the cellulose groups.The resistant starch diet increased butyrate concentration but did not inhibit colonic carcinogenesis. It remains doubtful whether butyrate inhibits the proliferation of colon cancer cells.

It is clinically important to distinguish idiopathic inflammatory bowel disease (IBD) from other colitides, and ulcerative colitis (UC) from Crohn's disease (CD); however only a few histological criteria based on colonic biopsies have been established. We investigated 209 consecutive series of biopsies taken from 38 patients with UC, 12 with CD, and 105 with other colitides, to evaluate whether combinations of histological features, selected on the basis of our experience, and listed below, could be useful criteria for the differential diagnosis of IBD, and, more specifically, of UC: (A) chronic inflammation with a predominant increase of plasma cells, (B) crypt distortion, (C) crypt atrophy, (D) diffuse chronic inflammation within a biopsy and between biopsies, and (E) diffuse mucin depletion within a biopsy and between biopsies. Findings that fulfilled all or two of A-C distinguished IBD from the other colitides with high sensitivity (94.3%) and specificity (95.8%). When the findings fulfilled the additional criteria of D and/or E, UC was differentiated from CD or the other colitides with high sensitivity (86.4%) and specificity (99.3%).