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Proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) leads to a clinical decline in the quality of life (QOL). Therefore, new treatment options are needed. We performed a multicenter, randomized, parallel-group exploratory trial to determine the efficacy of hangeshashinto (HST) in patients with PPI-refractory GERD. We enrolled 78 patients with PPI-refractory GERD for standard PPI regimens for at least 4 weeks and randomly assigned patients to receive either a combination of usual dose of rabeprazole (10 mg/day) + HST (7.5 g/day; HST group) or a double dose of rabeprazole (20 mg/day; double-dose PPI group). The primary end points were the extent of improvement in FSSG (Frequency Scale for the Symptoms of GERD) score and the change over time in FSSG score. There was no significant difference in terms of the improvement degree of the FSSG score between the two groups. Although the total FSSG score and reflux syndrome score decreased significantly for both groups over time (p

Background/Aims: Diagnostic miss rate and time consumption are the two challenging limitations of small-bowel capsule endoscopy (SBCE). In this study, we aimed to know whether using of the blue mode (BM) combined with QuickView (QV) at a high reviewing speed could influence SBCE interpretation and accuracy. Materials and Methods: Seventy CE procedures were totally reviewed in four different ways; (1) using the conventional white light, (2) using the BM, [on a viewing speed at 10 frames per second (fps)], (3) using white light, and (4) using the BM (on a viewing speed at 20 fps). In study A, the results of (1) were compared with those of (2), and in study B, the results of (3) and (4) were separately compared with those of (1). Results: In study A, the total number of the vascular (P < 0.001) and the inflammatory lesions (P = 0.005) detected by BM was significantly higher than that detected by the white light. No lesion was found using the white light that was not detected by the BM. Moreover, the BM highly improved the image quality of all the vascular lesions and the erythematous ones from the nonvascular lesions. In study B, the total number of only the vascular lesions, detected by the BM on a rapid speed of viewing at 20 fps was significantly higher than that detected by the white light (P = 0.035). However, the true miss rate for the BM was 4%. Conclusion: BM imaging is a new method that improved the detection and visualization of the vascular and erythematous nonvascular lesions of SB as compared with the conventional white light imaging. Using of the BM at a slow viewing speed, markedly reduced the diagnostic miss rate of CE.

Objective The calcineurin inhibitor tacrolimus has been shown to be safe and effective as salvage therapy for steroid-refractory ulcerative colitis (UC). Since differences in the onset of action between various agents are thought to influence the achievement and maintenance of disease remission, top-down or accelerated step-up therapy with tacrolimus may be useful. However, the efficacy of tacrolimus in moderate to severe UC patients not receiving concomitant steroids remains unknown. Methods Ten patients (11 attacks) with active, moderate to severe UC were treated with oral tacrolimus at a dose of 0.1 mg/kg body weight daily. The dosages were adapted to maintain trough whole-blood levels of 10 to 15 ng/mL to induce remission and 5 to 10 ng/mL to maintain remission. Lichtiger scores, the incidence of adverse effects (serum creatinine and glucose) and long-term outcomes were assessed. Results At four weeks after the initiation of tacrolimus therapy, clinical remissions were observed for eight attacks (72.7%) and clinical responses were demonstrated for three attacks. At 12 weeks after the initiation of tacrolimus treatment, clinical remissions were achieved for nine attacks (90%). After a mean follow-up of 10.4 months, clinical remissions were maintained for eight of 11 attacks. During the tacrolimus treatment, the serum creatinine and glucose levels were not significantly elevated. Conclusion Oral tacrolimus is a safe and effective therapy for the treatment of moderate to severe UC in patients not receiving concomitant treatment with systemic steroids. Although further studies are required to establish the efficacy and safety of oral tacrolimus therapy in patients with UC, oral tacrolimus may represent a top-down or accelerated step-up treatment option for patients with moderate to severe UC.

Background and Aim: Endoscopic submucosal dissection (ESD) is reported to be a safe and reliable procedure for the elderly, but these reports could have already had a bias at the time ESD was performed. However, the reports have not clearly stated the criteria of indications. In the present study, we retrospectively elucidated the usefulness and problems of ESD for early gastric cancer in elderly patients (≥ 65 years) in comparison with non-elderly patients. Methods: The subjects were selected from 412 consecutive patients with early gastric cancer (515 lesions) for which ESD was performed between June 2002 and February 2010. The following were used for analysis between groups: pre- and postoperative performance status (PS) of subjects, prevalence rates of pre-existing comorbidities, characteristics of lesions, treatment outcomes, durations of hospitalization, operating times, incidence rates of complications and durations of hospitalization, and postoperative hemorrhage rates, and duration of hospitalization in patients with anticoagulant therapy. Results: Of the lesions in the elderly, four patients (1.0%) were elderly with a PS of 3. The PS increased to six patients (1.6%) after the procedure. None of the non-elderly had a PS of 3 before or after the procedure. The ratio of patients with a pre-existing comorbidity was higher in the elderly than in the non-elderly. There were no differences between the two groups in the characteristics of the lesions, their duration of hospitalization, their operating times, or the incidence rates of complications. However, the elderly with perforations had a significantly longer hospitalization than the comparable non-elderly. The percentage of the patients taking anticoagulant drugs was significantly higher among the elderly. Of the patients on anticoagulant therapy, the duration of hospitalization tended to be longer in the elderly but no significant difference was found. None of the non-elderly with postoperative hemorrhage had received anticoagulant therapy. In the elderly with postoperative hemorrhage, 15.8% of the lesions were in those who had received anticoagulant therapy, indicating a significantly higher percentage of such lesions in the elderly group. Conclusion: We conclude that ESD is useful in elderly patients because there is a similar risk as for the non-elderly if the approach is individualized, and the following are taken into consideration when making the final decision of performing ESD in an elderly patient: patients should have a PS of 0, 1, or 2; determine whether or not anticoagulant therapy can be discontinued and whether or not treatment can be performed reliably without complications.

Yersinia enterocolitica (YE) infection is a rare cause of intestinal intussusception, especially in adults. We herein, report a case of adult intussusception due to YE enterocolitis. A 24-year-old woman was admitted because of severe abdominal pain. She was clinically diagnosed with ileocolic intussusception on the basis of the findings of computed tomography (CT) and a gastrografin enema. Manual surgical reduction was sufficient to alleviate the intussusception. A histological examination of the lymph nodes around the ileocecum excluded lymphoma. Serological testing revealed that the cause of the intussusception was a YE infection. The patient's postoperative course was good and no recurrence was seen during the follow-up.

Intestinal deformity and stenosis are induced by fibrosis during the process healing of intestinal chronic inflammation in inflammatory bowel disease (IBD). Potent anti-inflammatory treatment of patients with Crohn's disease (CD) may induce fibrous stenosis, and this is often difficult to treat in clinical practice. Therefore, it is necessary to develop a treatment strategy that concomitantly exhibits repair/regenerative and anti-fibrotic effects, in addition to the current anti-inflammatory effect, for the treatment of inflammatory bowel diseases. However, the relationship between the course of inflammatory activity and the healing process and fibrogenesis has not been elucidated; although the complex involvement of various factors in the mechanism of biological fibrosis has been investigated. Simvastatin (SIMV), an HMG-CoA reductase inhibitor, exhibits anti-inflammatory and anti-fibrotic effects. The current study established a model of the regeneration/healing process from TNBS-induced colitis and investigated the anti-inflammatory and anti-fibrotic effects of SIMV.Four groups of TNBS-induced colitis model were prepared using male SJL/J mice: A: Normal control group, B: control group, and C and D: treatment groups. The mucosal healing process was classified into three phases (an early phase: inflammation period, a mid-phase: regeneration promoting period, and a late phase: regeneration-converging period), and inflammation, the expression of fibrosis-related growth factors, and induction of apoptosis of fibrosis-related cells were compared in each period.(1) The clinical findings showed that SIMV showed anti-inflammatory effects with body weight gain and improvement of epithelial injury in the late phase. Histological (macroscopic/microscopic) improvement was noted in the mid- and late phases. The inflammatory cytokine (TNF-α) level significantly decreased in the mid- and late phases in the high-dose treatment group. (2) SIMV also had anti-fibrotic effects characterized by a dose-dependent decrease in the level of a fibrosis-related growth factor (CTGF) in the early and mid-phases, irrespective of inflammation or changes in the TGF-β(1) level. Dose-dependent induction of apoptosis was noted in both fibroblasts and myofibroblasts from a relatively early stage.The results suggested that SIMV induces anti-fibrotic activity that is not directly involved in the anti-inflammatory effect from a relatively early stage the healing process of TNBS-induced colitis.

Endoscopic submucosal dissection has made it possible to resect large lesions during a single operation. The present study was undertaken to compare the time taken for recovery from artificial ulcers after endoscopic submucosal dissection between an H(2) Receptor Antagonist treatment group and a Proton Pump Inhibitor treatment group, focusing on analysis of the time course of reduction rate in ulcer area. The powerful acid suppression by Proton Pump Inhibitor may not be needed to treat Japanese post-endoscopic submucosal dissection ulcer which usually develops after early gastric carcinoma in the mucosa of low acid secretory capacity. The study involved 60 patients with 69 artificial ulcers following endoscopic submucosal dissection for the treatment of tumors remaining in the gastric mucosa. Of all lesions, 36 were allocated to the H(2) Receptor Antagonist group and 33 to the Proton Pump Inhibitor group. Patients in both groups underwent endoscopy at 4 and 8 weeks after the start of administration. There were no significant differences between two groups and ulcer healing rates were similar in the two groups. The efficacy of H(2) Receptor Antagonists in curing this type of ulcer can thus be expected to be comparable to that of Proton Pump Inhibitors.

Background and Aims: Various etiologies and diseases may be related to erosive and/or small ulcerative lesions without gross appearance in the colon during colonoscopy. However, few investigators report on differential diagnosis of colonic inflammatory diseases. Thus, we investigated the clinical significance of these lesions and the value of colonoscopy in the differential diagnosis of colitis. Methods: In 110 patients with erosive and/or small ulcerative lesions (

Background and Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most significant causative factors of gastroduodenal ulcers. Recent reports have demonstrated that NSAIDs can also frequently induce ulceration and erosions of the small intestine. The aim of this study was to examine whether or not roxatidine (an H2 receptor antagonist), which is known to increase gastric mucus in addition to inhibiting gastric acid, might suppress indomethacin-induced small intestinal mucosal injury, through an increase in mucus in rats. Methods: Rats were given two p.o. doses of roxatidine, famotidine or cimetidine before and after the s.c. indomethacin injection. The injured area of the small intestine was analyzed. To examine effects of drugs on small intestinal mucus, rats were also given two p.o. doses of roxatidine, famotidine or cimetidine, and the ratio of the periodic acid Schiff (PAS)-positive area to the area of the mucosa in the small intestine was analyzed. In addition, we evaluated the involvement of nitric oxide (NO) and prostaglandins (PG) in the effect of roxatidine on small intestinal mucus. Results: Roxatidine significantly ameliorated indomethacin-induced small intestinal injury and increased the PAS-stained areas in the small intestinal mucosa, while cimetidine and famotidine had no significant effect. Pretreatment with N-nitro-L-arginine methyl ester but not with indomethacin, suppressed the effect of roxatidine on small intestinal mucus, suggesting that the effect is mediated by endogenous NO but not by PG. Conclusion: Roxatidine suppressed indomethacin-induced small intestinal injury in rats. One possible mechanism is an increase of small intestinal mucus, mediated by NO.

Background and Aim: Capsule endoscopy (CE) is widely used for diagnosing small intestinal diseases. In some cases, however, observation of target sites is very poor during CE because of residues etc. Herein we report the usefulness of a preparation comprised of polyethylene glycol solution (PEG) for CE. Methods: This was a prospective, randomized, and single-blind study. Forty subjects, fasted for 12 h before CE, were randomized into two groups: 20 subjects in Group A were fasted only, whereas 20 in Group B received 1 liter (L) PEG with 200 mg dimethylpolysiloxane 3 h before CE. For evaluation, the observation period of the small intestine was divided into first and second halves. Subsequently, four investigators, blinded as to which group received the preparation, assessed the condition of the intestine using four rating scales in terms of ‘residue’ and ‘intraluminal gas bubbles’. The effects of the preparation were statistically compared. Results: CE images were better in Group B than in Group A with respect to ‘intraluminal gas bubbles’ (P = 0.0038) in the first half of the observation period, as well as residue (P = 0.0087) and intraluminal gas bubbles (P = 0.0011) in the second half. Conclusion: Bowel preparation using 1 L PEG with dimethylpolysiloxane 3 h before CE significantly reduced residue and intraluminal gas bubbles, and was considered to be a useful method for CE.

There is limited data about the mucosal lesions of portal hypertensive enteropathy (PHE) detected by capsule endoscopy, and there is no scoring system to evaluate their severity. Our aim is to create a reliable scoring system for PHE, and to explore the possible usefulness of using transient elastograhy (TE) in that field. We compared the medical records of 31 patients with liver cirrhosis and portal hypertension with 29 control patients. We found that the mucosal lesions compatible with PHE were significantly more common in cirrhotic patients than in control patients (67.7% vs 6.9%, p

The side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) include gastrointestinal damage not only in the stomach but also in the small intestine. Chymase converts promatrix metalloproteinase-9 to matrix metalloproteinase (MMP)-9, which plays an important role in NSAID-induced gastric damage, but it has been unclear whether chymase-dependent MMP-9 activation is involved in the NSAID-induced small intestinal damage. To clarify the involvement of chymase-dependent MMP-9 activation on NSAID-induced small intestinal damage, the effect of a chymase inhibitor, 2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl] thiazole-4-carboxylic acid (TY-51469), on indomethacin-induced small intestinal damage in rats was evaluated. Until 6 h after oral administration of indomethacin in rats, intestinal MMP-9 activity was unchanged compared with normal rats, but significant increases in MMP-9 activity were observed 12 and 24 h after indomethacin administration. Significant increases in the small intestinal damage score were also observed 12 and 24 h after indomethacin administration. In the extract from the small intestine 24 h after indomethacin administration, the MMP-9 activation was significantly attenuated by TY-51469. Intraperitoneal injection of TY-51469 (10 mg/kg) 3 h before indomethacin administration significantly attenuated the MMP-9 activity in the small intestine compared with placebo treatment. Myeloperoxidase activity, which indicates accumulation of neutrophils, was significantly increased in the small intestine in the placebo-treated rats, but its activity was significantly attenuated by TY-51469 treatment. The area of small intestinal damage was also significantly ameliorated by TY-51469 treatment. These findings suggest that chymase-dependent MMP-9 activation has a significant role in indomethacin-induced small intestinal damage in rats.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. The prevalence of NSAIDs-induced small intestinal injury is higher than had been expected. Recent studies show that more than 50% of patients taking NSAIDs have some mucosal damage in the small intestine. The gross appearance of NSAID-induced enteropathy varies, appearing variously as diaphragm-like strictures, ulcers, erosions, and mucosal redness. To investigate NSAID-induced enteropathy, and to rule out other specific enteropathies, other useful methods (in addition to capsule endoscopy and balloon enteroscopy) include such modalities as radiological examination of the small intestine, the permeability test, scintigraphy or the fecal excretion test using (111)Indium-labeled white blood cells, and measurement of the fecal calprotectin concentration. Diaphragm-like strictures and bleeding from mucosal breaks may be treatable with interventional enteroscopy. Misoprostol, metronidazole, and sulfasalazine are frequently used to treat NSAID-induced enteropathy, but have undesirable effects in some cases. In the experimental model, we confirmed that several existing drugs for gastroduodenal ulcers prevented indomethacin-induced small intestinal injury. Such drugs may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine. We hope to examine these drugs in future clinical studies.

Non-steroidal anti-inflammatory drugs (NSAIDs), which are used for the treatment of several inflammatory disorders including rheumatoid arthritis, are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and double-balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. Proton pump inhibitors (PPI), such as lansoprazole and omeprazole, show a potent anti-secretory effect. PPIs also have a gastroprotective effect, independent of their anti-secretory actions, which is probably mediated by inhibition of neutrophil functions as well as antioxidant actions. Administration of lansoprazole reduced the severity of the intestinal lesions in a dose-dependent manner, but omeprazole had no effect. The amount of heme oxygenase-1 (HO-1) protein in the intestinal mucosa was significantly increased by lansoprazole, but not by omeprazole. These results suggest that lansoprazole, but not omeprazole, ameliorates indomethacin-induced small intestinal ulceration through upregulation of HO-1/carbon monoxide. Therefore, lansoprazole may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine.

A case of primary NK/T-cell lymphoma of the rectum accompanied with ulcerative colitis (UC) in a 73-year-old man is reported. He had a 6-year history of repeated admission to our hospital for UC. Total colonoscopy performed 4 months after resolution of refractory UC complicated by cytomegalovirus colitis showed a markedly submucosal tumor in the rectum, which was histologically diagnosed as malignant lymphoma. The findings of computed tomography of the chest and abdomen, gallium scintigraphy, abdominal ultrasonography, and upper gastrointestinal endoscopy showed no abnormal lesions. Therefore, based on a diagnosis of localized rectal lymphoma with UC, proctocolectomy was performed. The resected specimen showed three submucosal tumors in the rectum with local nodal involvement. Histologically, the tumors were characterized by diffusely infiltrating sheets of large atypical lymphoid cells, which were negative for CD4, CD8, and CD20 but were positive for CD56, CD3, and granzyme B. The presence of Epstein-Barr virus (EBV) infection in neoplastic cells was shown by in situ hybridization for EBV-encoded early small RNA1 (EBER-1). Based on these findings, the patient was diagnosed with primary CD56+ NK/T-cell lymphoma of the rectum (stage IIE). This is the first case report of primary rectal NK/T-cell lymphoma accompanied with UC.

Background: Patients with ulcerative colitis (UC) exhibit an increased risk for the development of cancer of the colon and rectum. Cyclooxygenase (COX)-2 inhibitors are known to suppress sporadic colorectal cancer, but it is unknown whether selective COX-2 inhibitors exhibit a preventive effect in UC-associated neoplasia. This study investigated the preventive effect of nimesulide, a selective COX-2 inhibitor, on colorectal carcinogenesis in an experimental model of murine UC. Methods: Chronic colitis was induced in mice by administration of four cycles of dextran sulfate sodium (DSS) (each cycle: 5% DSS for 7 days and then distilled water for 14 days). The mice were killed 120 days after the completion of the fourth cycle. The mice were divided into the following five groups: group A served as a disease control; group B received a diet mixed with 400 p.p.m. of nimesulide during the whole period; group C received nimesulide during the four cycles of DSS administration (active phase); group D received nimesulide for 120 days from the end of the fourth cycle (remission phase); group E received no agents including DSS and served as a normal control. Results: The incidence of dysplasia and/or cancer was 28%, 15%, 11.8%, 6.7% and 0% in groups A–E, respectively. In group D, nimesulide significantly suppressed the occurrence of dysplasia and/or cancer (P

Background : We examined a technique for detecting point mutations of K- ras codon 12 in stool samples using one-step polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) analysis, in order to determine whether it could be used to screen for colorectal cancer. Methods : DNA was extracted from 200-mg stool specimens of 5 healthy controls and 31 colorectal cancer patients. A 107-base-pair fragment of exon 1 of K- ras was amplified by PCR using mismatched primers. PCR products were digested with B st NI and analyzed by gel electrophoresis followed by silver staining. Specificity of one-step PCR/RFLP was examined by using synthetic oligonucleotides. The detection limit of K- ras codon 12 mutations was determined by using SW480 and HT29 cells. Results : The K- ras gene was successfully amplified from all healthy controls and colorectal cancer patients studied. Mutations of K- ras codon 12 were not detected in any of the healthy controls, but were identified in 13 (41.9%) of the 31 patients with colorectal cancer. Mutations were detectable in all six synthetic mutant DNAs, while none were detected among the wild type. The detection limit of this method was ≥0.1%. Conclusions : PCR/RFLP analysis could be used in mass screening for colorectal cancer, because it is highly specific, has a low detection limit, and is simpler than conventional methods for detecting genetic abnormalities.

In order to investigate the mucosal injury mechanism in UC, we made dextran sulfate sodium (DSS)-induced colitis in rat and examined pathological findings, MPO activity, PGE2 level, and local mRNA expression and secretion of IL-1β, TNF-α, GRO/CINC-1 and IL-10 in DSS colitis mucosa. Moreover, we estimated the correlation between the severity of mucosal damage and changes of these local inflammatory mediators’ values. Neutrophil infiltration was marked and MPO activity was locally increased in proportion to the severity of mucosal damage. The mRNA expression and secretion of IL-1β, GRO/CINC-1 and IL-10 were increased. Especially, the secretions of IL-1β and GRO/CINC-1 were increased in proportion to the severity of mucosal damage. However, those of TNF-α were not increased in the colitis mucosa. An abnormal macrophage function and the presence of macrophage subtypes producing different cytokines would be predicted from our TNF-α data. The lesion was less severe in the colonic mucosa with higher levels of endogenous PGE2, while it was more severe in the colonic mucosa with lower levels of endogenous PGE2, implicating this compound as an inhibitory factor against the development of inflammation in the affected mucosa. Our results suggest that PGE2 might have therapeutic applicability to UC.

We previously reported that intracolonic administration of enprostil, a prostaglandin-E(2) (PGE(2)) analogue, had therapeutic effects on acute colitis induced in rodents by dextran sulfate sodium (DSS). In addition, production of growth-regulated gene product/cytokine-induced neutrophil chemoattractant-1 [GRO/CINC-1; an interleukin(IL)-8 like cytokine] was suppressed in the inflamed tissues. In the present study we used a human colon cancer cell line (HT-29) to investigate enprostil effects on the IL-8 production of intestinal epithelial cells stimulated by various stimulants. In a MTT assay, concentrations of enprostil10(-5)M had cytotoxitic effects on HT-29 cells. Furthermore, 10(-6) M enprostil suppressed IL-8 production in HT-29 cells, SW620 and CaCo2 stimulated with interleukin-1 beta (IL-1 beta) or lipopolysaccharide (LPS), but did not suppress this response when cells were stimulated with tumour necrosis factor (TNF)-alpha. These results suggest that enprostil affects a point in the pathway between the IL-1 receptor or LPS receptor and nuclear factor-kappa B(NF-kappa B), without affecting the pathway between the TNF receptor and NF-kappa B, with the latter factor being required for the IL-8 gene transcription. The therapeutic effect of exogenous enprostil on DSS colitis may involve the inhibition of IL-8 production in colonic epithelial cells stimulated by IL-1 beta or LPS.

SUMMARY Cytokines such as IL-1, tumour necrosis factor-alpha (TNF-α), IL-6 and IL-8 are increased in inflamed colonic mucosa after administration of mouse DSS. Nuclear factor κB (NF-κB) is a transcription factor which regulates the expression of these cytokine genes. The effect of intracolonically administered NF-κB (p65) antisense phosphorothioate oligonucleotide was examined in mouse DSS-induced colitis using drinking water containing 5% DSS. When antisense oligonucleotide was given on day 0, the disease activity index (DAI) representing clinical symptoms improved and the histological score decreased; furthermore, IL-1, IL-6, and TNF-α concentrations in rectal mucosa were lower compared with the control group. Clinical and histological improvement was also observed when antisense oligonucleotide was begun on day 2 but not on day 7. In addition, the distribution of antisense oligonucleotides was investigated by confocal laser microscopy. In colonic mucosa, oligonucleotides were predominantly localized to cells in the lamina propria, but also in the epithelium. Western blot analysis using homogenized rectal mucosa showed the decreased expression of NF-κB p65 in the antisense oligonucleotide-treated group, although it was increased in the colitis group. These results suggest that intracolonic administration of NF-κB antisense oligonucleotide may be effective in ulcerative colitis.

Background Proton-pump inhibitors such as omeprazole are a standard treatment to prevent non-steroidal anti-inflammatory drug-induced upper gastrointestinal mucosal injuries. However, it is unclear which drugs may protect against all NSAID-induced digestive-tract injuries. Here, we compare the efficacy of the gastromucoprotective drug irsogladine with omeprazole in preventing NSAID-induced esophagitis, peptic ulcers, and small-intestinal mucosal injury in healthy subjects. Methods Thirty-two healthy volunteers were assigned to an irsogladine group (Group I; n = 16) receiving diclofenac sodium 75 mg and irsogladine 4 mg daily for 14 days, or an omeprazole group (Group O; n = 16) receiving diclofenac sodium 75 mg and omeprazole 10 mg daily for 14 days. Esophagitis and peptic ulcers were evaluated by esophagogastroduodenoscopy and small-intestinal injuries by capsule endoscopy, fecal calprotectin, and fecal occult blood before and after treatment. Results There was no significant difference between Group I and Group O with respect to the change in lesion score in the esophagus, stomach, and duodenum before and after treatment.NSAID treatment significantly increased the number of small intestinal mucosal breaks per subject by capsule endoscopic evaluation, from a basal level of 0.1 ± 0.3 up to 1.9 ± 2.0 lesions in Group O (p = 0.0002). In contrast, there were no significant changes in the mean number of mucosal breaks before and after co-treatment in Group I (0.3 ± 0.8 to 0.5 ± 0.7, p = 0.62), and the between-group difference was significant (p = 0.0040). Fecal calprotectin concentration, when the concentration before treatment was defined as 1, was significantly increased both in Group O (from 1.0 ± 0.0 to 18.1 ± 37.1, p = 0.0002) and Group I (from 1.0 ± 0.0 to 6.0 ± 11.1, p = 0.0280); the degree of increase in Group O was significantly higher compared with that in Group I (p Conclusion Irsogladine protected against NSAID-induced mucosal injuries throughout the gastrointestinal tract, from esophagus to small intestine, significantly better than omeprazole. Trial registration This study was registered in the UMIN Clinical Trials Registry (Registry ID number; UMIN000008114)

AIM: To assess adalimumab’s efficacy with concomitant azathioprine (AZA) for induction and maintenance of clinical remission in Japanese Crohn’s disease (CD) patients. METHODS: This retrospective, observational, single-center study enrolled 28 consecutive CD patients treated with adalimumab (ADA). Mean age and mean disease duration were 38.1 ± 11.8 years and 11.8 ± 10.1 years, respectively. The baseline mean Crohn’s disease activity index (CDAI) and C-reactive protein were 177.8 ± 82.0 and 0.70 ± 0.83 mg/dL, respectively. Twelve of these patients also received a concomitant stable dose of AZA. ADA was subcutaneously administered: 160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Clinical response and remission rates were assessed via CDAI and C-reactive protein for 24 wk. RESULTS: The mean CDAI at weeks 2, 4, 8, and 24 was 124.4, 120.2, 123.6, and 135.1, respectively. The CDAI was significantly decreased at weeks 2 and 4 with ADA and was significantly suppressed at 24 wk with ADA/AZA. Overall clinical remission rates at weeks 4 and 24 were 66.7% and 63.2%, respectively. Although no statistically significant difference in C-reactive protein was demonstrated, ADA with AZA resulted in a greater statistically significant improvement in CDAI at 24 wk, compared to ADA alone. CONCLUSION: Scheduled ADA with concomitant AZA may be more effective for clinical remission achievement at 24 wk in Japanese Crohn’s disease patients.

Yersinia enterocolitica (YE) infection is a rare cause of intestinal intussusception, especially in adults. We herein, report a case of adult intussusception due to YE enterocolitis. A 24-year-old woman was admitted because of severe abdominal pain. She was clinically diagnosed with ileocolic intussusception on the basis of the findings of computed tomography (CT) and a gastrografin enema. Manual surgical reduction was sufficient to alleviate the intussusception. A histological examination of the lymph nodes around the ileocecum excluded lymphoma. Serological testing revealed that the cause of the intussusception was a YE infection. The patient's postoperative course was good and no recurrence was seen during the follow-up.

Endoscopic submucosal dissection (ESD) is reported to be a safe and reliable procedure for the elderly, but these reports could have already had a bias at the time ESD was performed. However, the reports have not clearly stated the criteria of indications. In the present study, we retrospectively elucidated the usefulness and problems of ESD for early gastric cancer in elderly patients (≥ 65 years) in comparison with non-elderly patients.The subjects were selected from 412 consecutive patients with early gastric cancer (515 lesions) for which ESD was performed between June 2002 and February 2010. The following were used for analysis between groups: pre- and postoperative performance status (PS) of subjects, prevalence rates of pre-existing comorbidities, characteristics of lesions, treatment outcomes, durations of hospitalization, operating times, incidence rates of complications and durations of hospitalization, and postoperative hemorrhage rates, and duration of hospitalization in patients with anticoagulant therapy.Of the lesions in the elderly, four patients (1.0%) were elderly with a PS of 3. The PS increased to six patients (1.6%) after the procedure. None of the non-elderly had a PS of 3 before or after the procedure. The ratio of patients with a pre-existing comorbidity was higher in the elderly than in the non-elderly. There were no differences between the two groups in the characteristics of the lesions, their duration of hospitalization, their operating times, or the incidence rates of complications. However, the elderly with perforations had a significantly longer hospitalization than the comparable non-elderly. The percentage of the patients taking anticoagulant drugs was significantly higher among the elderly. Of the patients on anticoagulant therapy, the duration of hospitalization tended to be longer in the elderly but no significant difference was found. None of the non-elderly with postoperative hemorrhage had received anticoagulant therapy. In the elderly with postoperative hemorrhage, 15.8% of the lesions were in those who had received anticoagulant therapy, indicating a significantly higher percentage of such lesions in the elderly group.We conclude that ESD is useful in elderly patients because there is a similar risk as for the non-elderly if the approach is individualized, and the following are taken into consideration when making the final decision of performing ESD in an elderly patient: patients should have a PS of 0, 1, or 2; determine whether or not anticoagulant therapy can be discontinued and whether or not treatment can be performed reliably without complications.

Collagenous colitis (CC) is a well-known cause of chronic non-bloody diarrhea, especially in elderly women. CC is characterized histopathologically by an increase in the thickness of the subepithelial collagen layer to at least 10 µm, epithelial damage, and chronic inflammation of the lamina propria. Generally, the colonic mucosa in CC is macroscopically normal, although minor, non-specific abnormalities may be found. Due to the recent advancement of endoscopic and diagnostic technologies, however, microscopic mucosal abnormalities and specific longitudinal linear lacerations of the mucosa characteristic of CC have been identified. The association of CC with non-steroidal anti-inflammatory drugs and proton pump inhibitors has also been reported. Since definitive diagnosis of CC has to rely on pathologically documented collagen bands and mononuclear infiltration, the efficiency and precision of colonic biopsy need to be improved. Of the 29 CC patients that we have encountered at our institution, it was in 15 of 29 cases that the endoscopic finding that we performed a biopsy on was apparent. Our comparison of the endoscopic and histopathological findings of CC in the 15 patients showed that the mucosa frequently appeared coarse and nodular on the surface of the mucosa, which was also significantly thicker in collagen bands, demonstrating a strong correlation between collagen band formation and CC. Also, the coarse and nodular surface of the mucosa was most frequently seen affecting the proximal colon. The results suggest that endoscopic observation and biopsy of the proximal colon, where a coarse and nodular surface of the mucosa is often found, may be useful for confirmation of the diagnosis in patients with suspected CC.

AIM: To evaluate the effectiveness of our proposed bowel preparation method for colon capsule endoscopy. METHODS: A pilot, multicenter, randomized controlled trial compared our proposed “reduced volume method” (group A) with the “conventional volume method” (group B) preparation regimens. Group A did not drink polyethylene glycol electrolyte lavage solution (PEG-ELS) the day before the capsule procedure, while group B drank 2 L. During the procedure day, groups A and B drank 2 L and 1 L of PEG-ELS, respectively, and swallowed the colon capsule (PillCam COLON® capsule). Two hours later the first booster of 100 g magnesium citrate mixed with 900 mL water was administered to both groups, and the second booster was administered six hours post capsule ingestion as long as the capsule had not been excreted by that time. Capsule videos were reviewed for grading of cleansing level. RESULTS: Sixty-four subjects were enrolled, with results from 60 analyzed. Groups A and B included 31 and 29 subjects, respectively. Twenty-nine (94%) subjects in group A and 25 (86%) subjects in group B had adequate bowel preparation (ns). Twenty-two (71%) of the 31 subjects in group A excreted the capsule within its battery life compared to 16 (55%) of the 29 subjects in group B (ns). Of the remaining 22 subjects whose capsules were not excreted within the battery life, all of the capsules reached the left side colon before they stopped functioning. A single adverse event was reported in one subject who had mild symptoms of nausea and vomiting one hour after starting to drink PEG-ELS, due to ingesting the PEG-ELS faster than recommended. CONCLUSION: Our proposed reduced volume bowel preparation method for colon capsule without PEG-ELS during the days before the procedure was as effective as the conventional volume method.

Prostaglandins play important roles in the gastric mucosal protection and gastric ulcer healing. Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin are widely used for the aged patients. Administration of the prostaglandin derivatives has been proven to be effective for both prevention and treatment of gastric ulcers associated with NSAIDs, and prostaglandin derivatives are recommended for NSAIDs-induced gastric ulcers by the Japanese guidelines. The important side effects include abdominal pain, flatulence, and diarrhea. Recent advances in diagnostic methods including video capsule endoscopy and balloon endoscopy have enabled us to examine the entire small intestine, and we recognize that prevalence of small intestinal damage in patients taking NSAIDs is high. Prostaglandin derivatives are also useful for these small intestinal damages.

Colorectal cancer is one of the most serious complications of ulcerative colitis (UC), and the risk of UC-associated neoplasia increases as the region and duration of the disease increase. Selective cyclooxygenase (COX)-2 inhibitors effectively diminish carcinogenesis in a murine UC model. However, this may exacerbate colitis. The selective COX-2 inhibitor etodolac is marketed as a racemic mixture of the R- and S-enantiomers. The biochemical and pharmacological effects of etodolac are caused by the S-enantiomer, while the R-enantiomer lacks COX-inhibitory activity. In this study, we evaluated the effect of R-etodolac on colitis-related mouse colon tumorigenesis. The mice received 1,2-dimethlhydrazine (DMH), and then chronic colitis was induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). The mice were sacrificed 28 days after the completion of both cycles. Mice were divided into the following groups: group A served as a disease control; group B received a low (2-mg/kg) dose of R-etodolac every 3 days during the entire period; group C received a high (10-mg/kg) dose of R-etodolac on the same schedule as group B; and group D served as a normal control. Administration of R-etodolac decreased the disease activity index during the DSS administration cycle. The mean number of tumors was 17.8, 15.2, 6.0, and 0 in groups A-D, respectively. In group C, R-etodolac significantly suppressed the occurrence of neoplasia (p

Various etiologies and diseases may be related to erosive and/or small ulcerative lesions without gross appearance in the colon during colonoscopy. However, few investigators report on differential diagnosis of colonic inflammatory diseases. Thus, we investigated the clinical significance of these lesions and the value of colonoscopy in the differential diagnosis of colitis.In 110 patients with erosive and/or small ulcerative lesions (5 mm) who were treated in our hospital during the past 9 years, we retrospectively investigated the relationship between endoscopic morphology and clinical diagnosis. The intestinal lesions were endoscopically classified into three groups (A, hyperemic type; B, aphthous type; and C, verrucous type).The lesions were mainly located in the rectum to the sigmoid colon in group A. In group C, the lesions were most frequently located in the transverse colon and deeper areas. Endoscopically, the etiology was unclear in 74.5% of group A and 73.8% of group B, however, in group C, most of them (81.0%) were associated with specific diseases. With respect to inflammatory bowel diseases, 71.4% of the patients with Crohn's disease and all patients with ulcerative colitis were assigned to group A or B.Erosive and/or small ulcerative lesions belonging to group A or B were mainly non-specific. However, careful follow up was required in groups A and B, which included the possibility of inflammatory bowel diseases, when the symptoms or lesions were not improved.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most significant causative factors of gastroduodenal ulcers. Recent reports have demonstrated that NSAIDs can also frequently induce ulceration and erosions of the small intestine. The aim of this study was to examine whether or not roxatidine (an H(2) receptor antagonist), which is known to increase gastric mucus in addition to inhibiting gastric acid, might suppress indomethacin-induced small intestinal mucosal injury, through an increase in mucus in rats.Rats were given two p.o. doses of roxatidine, famotidine or cimetidine before and after the s.c. indomethacin injection. The injured area of the small intestine was analyzed. To examine effects of drugs on small intestinal mucus, rats were also given two p.o. doses of roxatidine, famotidine or cimetidine, and the ratio of the periodic acid Schiff (PAS)-positive area to the area of the mucosa in the small intestine was analyzed. In addition, we evaluated the involvement of nitric oxide (NO) and prostaglandins (PG) in the effect of roxatidine on small intestinal mucus.Roxatidine significantly ameliorated indomethacin-induced small intestinal injury and increased the PAS-stained areas in the small intestinal mucosa, while cimetidine and famotidine had no significant effect. Pretreatment with N-nitro-L-arginine methyl ester but not with indomethacin, suppressed the effect of roxatidine on small intestinal mucus, suggesting that the effect is mediated by endogenous NO but not by PG.Roxatidine suppressed indomethacin-induced small intestinal injury in rats. One possible mechanism is an increase of small intestinal mucus, mediated by NO.

Background: Cytomegalovirus (CMV) infection exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies (IMT). However, the underlying UC remained active in some UC patients, despite the fact that CMV-DNA in colonic mucosa became negative after antiviral therapy. Therefore, new therapeutic strategies for UC patients concomitant with CMV infection in mucosa are required. Aims: The aim of this study was to evaluate the effect and safety of granulocyte-monocyte adsorption apheresis (GMA) in UC patients positive for CMV infection after antiviral therapy. Methods: From October 2003 to December 2008, 64 patients with UC refractory to IMT, including steroids and immunomodulators, were enrolled in this retrospective, observational, multicenter study, which was reviewed and approved by the Institutional Review Board of Kyoto University. CMV infection was investigated by 3 methods (histologic examination, CMV antigenemia, and polymerase chain reaction). We investigated the clinical outcomes of GMA and IMT after 2 weeks of treatment with ganciclovir. Results: Thirty-one (48.4%) of 64 patients with UC refractory to IMT were positive for CMV. Of the 31 patients, 4 (12.9%) underwent colectomy. Twenty-seven patients (87.1%) underwent antiviral therapy. Of those 27 patients, 7 achieved remission following antiviral therapy alone. Of the remaining 20 patients who did not achieve remission despite the disappearance of CMV-DNA, 11 and 9 patients were treated with additional GMA (GMA group) and IMT (IMT group), respectively. Of 11 patients (GMA group), 9 achieved remission and 2 underwent colectomy. Out of the remaining 9 patients (IMT group), 4 achieved remission and 5 underwent colectomy. CMV-DNA was not detected in 11 patients after GMA, but it was detected again in all 5 patients of the IMT group who underwent colectomy. The total colectomy rate in UC patients positive for CMV was 35.5% (11/31). In addition, colectomy-free survival in the CMV relapse (+) group was estimated to be 12.9% at 65 months, while that in the CMV relapse (–) group was estimated to be 100% at 60 months. Conclusion: The colectomy ratio tends to be high in refractory UC patients with recurrent CMV reactivation or infection. Therefore, GMA might be a safe and effective treatment for UC patients positive for CMV because it does not induce CMV reactivation.

Background A capsule endoscope does not allow the examiner to observe a lesion from the desired direction in real time. Objective To develop a driving system for a self-propelling capsule endoscope (SPCE) by using a magnetic field. Setting Experimental endoscopic study in a live dog model. Design and Interventions A microactuator was developed with the aim of remote-control operation. We developed a driving system for SPCE by attaching a capsule endoscope to this medical microactuator and performed the following experiments. (1) We operated this SPCE by remote control in the stomach of a dog under sedation and obtained endoscopic images using a real-time monitoring system only. (2) We placed a hemostatic clip on the gastric mucosa and recorded images of this clip with the SPCE. (3) We also placed clips at 2 other sites in the stomach and asked the SPCE operator, who was unaware of the location of the clips, to identify the site, number, and color of the clips. Main Outcome Measurements Evaluation of performance of a driving system for SPCE. Results The operator was able to obtain endoscopic images with the SPCE in the stomach of a dog in vivo, in any desired direction, by remote control. SPCE produced clear images of the clips placed in the stomach. The operator was able to easily identify the site, number, and color of the clips. Limitations Animal model. Conclusions Our trial suggests the possibility of clinical application of the driving system for an SPCE using a magnetic field.

More elderly patients now undergo gastrointestinal endoscopy following recent advances in endoscopic techniques. In this study, we conducted a high-risk survey of endoscopies in Japan, using a questionnaire administered prior to upper gastrointestinal tract endoscopy (UGITE), and identified anticholinergic agents and glucagon preparations as high-risk premedication. We also evaluated the cardiovascular effects of anticholinergic agents and glucagon through measurements of plasma levels of human atrial natriuretic peptide (hANP) and human brain natriuretic peptide (hBNP). The subjects were 1480 patients who underwent UGITE. Nurses administered a pre-endoscopy questionnaire, questioning subjects regarding heart disease, hypertension, glaucoma, and urinary difficulties as risk factors for anticholinergic agents, and Diabetes mellitus as a risk factor for glucagon preparations. Evaluation of subjects divided into under 65 and over 65 age groups revealed that in subjects aged 65 and over, risk factors for anticholinergic agents were significantly more high than those for glucagon. Analysis of the cardiovascular effects of anticholinergic agents and glucagon, in the elderly patients showed that hANP levels were significantly higher following administration of anticholinergic agents, but the change was not significant for glucagon premedication. Taking a detailed history before UGITE with the aid of a questionnaire at the same time as informed consent is obtained, is extremely useful in terms of risk management and selection of the appropriate premedication.

The aim of this research is to investigate the international and intra-observer differences in the macroscopic classification of early colorectal cancer between Japan and China.Color pictures of 9 cases of early colorectal cancer were distributed to 6 Japanese and 5 Chinese endoscopists. After reviewing the pictures, the doctors made their classificatory diagnoses independently and indicated their findings on which the diagnoses were based.There was some consistency in the classification of distinctly elevated lesions among all the Japanese and Chinese endoscopists. However, some elevated lesions classified as type II in Japan might be diagnosed as type I by Chinese endoscopists. For superficial lesions consisting of elevation plus central depression, IIa+IIc or IIc+IIa, were classified according to the ratio of elevation and depression. Although international difference is not significant, inter-observer differences still exist in classifying these lesions. In addition, the differences in laterally spreading tumor were mainly due to terminology.Japanese and Chinese doctors share a lot of similarities in the classification of flat elevated lesions; however, both international and inter-observer differences still exist in the macroscopic classification for early CRC.

Matrix metalloproteinase (MMP)-9 plays an important role in the pathogenesis of colitis. Recent studies have demonstrated that chymase is involved in the conversion of promatrix metalloproteinase (proMMP)-9 to MMP-9. However, whether chymase contributes to the activation of proMMP-9 in colitis has remained unclear. In this study, we administered 5% dextran sodium sulfate (DSS) solution to mice for 7 days. At 7 days after starting administration, both chymase activity and MMP-9 activity were significantly increased. In extract from colitis in DSS-treated mice, MMP-9 activity was significantly increased after 8 h of incubation, but increased activity was almost completely suppressed in the presence of a chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl] acetamide (NK3201). At 7 days after starting administration, intestinal length was significantly shorter in DSS-treated mice than in normal mice, but these changes were significantly prevented by NK3201 (10 mg/kg per day i.p.). Disease activity index and histological damage score were also significantly reduced by NK3201. The filtrated neutrophil number was significantly decreased by NK3201. Furthermore, NK3201 significantly attenuated not only chymase activity but also MMP-9 activity in DSS-treated mice. These findings suggest that chymase plays an important role in the development of colitis via MMP-9 activation.

Patients with ulcerative colitis (UC) exhibit an increased risk for the development of cancer of the colon and rectum. This association is widely attributed to colonic inflammation. However, the severity of colonic inflammation necessary for the development of dysplasia and/or cancer remains unknown. In this study, we investigated the pattern of cell proliferation in colorectal carcinogenesis in an experimental murine model of UC. Chronic colitis was induced by administration of four cycles of dextran sulfate sodium (DSS) (each cycle: 5% or 2% DSS for 7 days and then distilled water for 14 days). Mice were sacrificed after every cycle and at 120 days following the completion of the fourth cycle. Colonic cell proliferation was immunohistochemically evaluated using the thymidine analogue bromodeoxyuridine and the labeling index (LI) was determined. The incidence of dysplasia and/or cancer was 28%, 6.7%, and 0% in the 5% DSS, 2% DSS, and normal control groups respectively. All gross lesions were present in the middle to distal colon. Disease activity index and total LI after four cycles of DSS were significantly higher in the 5% DSS group compared to the 2% DSS group. In the 5% DSS group, the LI was significantly higher in the middle colon than in the proximal colon. Simple repeated administration of the non-genotoxic colon carcinogen DSS induced dysplasia and/or cancer. In addition, we have demonstrated the presence of regional differences in proliferation pattern between the middle and the proximal colon during carcinogenesis in experimental murine UC. These findings may provide insight into the development of colorectal cancer in humans with long-standing UC.

Helicobacter pylori (HP) infection is reported to be involved in gastric carcinogenesis. However, only a small percentage of HP-infected patients actually develop gastric cancer. In the present study, we assessed HLA antigen polymorphism and investigated its relationship with the development of gastric epithelial tumors in patients who had HP infection.Among patients with serologically proven HP infection, 80 cases who underwent endoscopic mucosectomy for gastric epithelial tumors (24 adenomas and 56 carcinomas) were recruited in the study (the tumor group), and 20 cases without tumors were also included as controls (the nontumor group). HLA status (HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1) was determined by HLA-DNA typing.HLA-B*05401, HLA-DQB1*0601 and HLA-DRB1*1502 genes showed a significantly higher frequency in the control group than in the tumor group (0.225 vs. 0.088, P=0.015; 0.3 vs. 0.163, P = 0.047; 0.175 vs. 0.069, P = 0.036, respectively).It suggests that HLA-B*5401, HLA-DQB1*0601 and HLA-DRB1*1502 may contribute to the inhibition of gastric carcinogenesis. Thus, HP-infected patients without these genotypes should undergo HP eradication therapy and close follow-up.

AIM: To investigate the histopathological and genetic differences between polypoid growth (PG) and non-polypoid growth (NPG) submucosal invasive colorectal carcinoma (CRC). METHODS: A total of 96 cases of submucosal CRC were divided into two groups according to their growth type; 60 cases of PG and 36 cases of NPG. The size, histological degree of dysplasia, depth of submucosal invasion and lymph node metastasis were compared between the two groups. Furthermore, expression of p53 was detected by immunohistochemical staining, and K-ras gene mutation was examined by polymerase chain reaction based single-strand conformation polymorphism (SSCP). RESULTS: The average size of the lesions in the NPG group was significantly smaller than those in the PG group (7.5 mm vs 13.8 mm, P < 0.001). The histological degree of dysplasia tended to be more severe in NPG group, while the incidence of submucosal massive invasion and the lymph node metastasis were both significantly higher in the NPG type than in the PG group (64.3% vs 43.3%, P = 0.004; 43% vs 7%, P = 0.008, respectively). In addition, K-ras gene mutations were detected in 67% of lesions in the PG group, but none in the NPG group, while no difference in p53 immunohistochemical expression was found between the two groups. CONCLUSION: Compared with PG submucosal CRC, NPG type demonstrates more frequent submucosal massive invasion, more lymph node metastasis and a higher degree dysplasia. Genetically, NPG type shows much less frequent K-ras mutation.

AIM: To evaluate the effect of pyrrolidine dithio-carbamate (PDTC; an NF-κB inhibitor) administered at low (50 mg/kg) and high (100 mg/kg) doses in suppressing colitis in mice with dextran sodium sulfate (DSS)-induced colitis. METHODS: Mice were divided into a DSS-untreated group (normal group), DSS-treated control group, DSS+PDTC-treated groupI(low-dose group), and DSS+PDTC-treated groupII (high-dose group). In each group, the disease activity index score (DAI score), intestinal length, histological score, and the levels of activated NF-κB and inflammatory cytokines (IL-1β and TNF-α) in tissue were measured. RESULTS: The DSS+PDTC-treated groupII exhibited suppression of shortening of intestinal length and reduction of DAI score. Activated NF-κB level and IL-1β and TNF-α levels were significantly lower in DSS+PDTC-treated groupII. CONCLUSION: These findings suggest that PDTC is useful for the treatment of ulcerative colitis.

AIM: To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis (UC) patients. METHODS: This was a prospective, multicenter, observational study. Between May 2010 and August 2012, 49 steroid-refractory UC patients (55 flare-ups) were consecutively enrolled. All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1 mg/kg per day. The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/mL for the first 2 wk. Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger’s clinical activity index (CAI). RESULTS: The mean CAI was 12.6 ± 3.6 at onset. Within the first 7 d, 93.5% of patients maintained high trough levels (10-15 ng/mL). The CAI significantly decreased beginning 2 d after treatment initiation. At 2 wk, 73.1% of patients experienced clinical responses. After tacrolimus initiation, 31.4% and 75.6% of patients achieved clinical remission at 2 and 4 wk, respectively. Treatment was well tolerated. CONCLUSION: Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation. Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.

Various hepato-biliary complications are an increased incidence in patients with inflammatory bowel disease, and portal bacteremia is well documented in patients with ulcerative colitis (UC). However, few reports mention UC in association with liver abscesses. Recently, there are several reports describing cytomegalovirus (CMV) infection in association with disease exacerbation and steroid refractoriness in patients with UC. Here we present a case of refractory UC accompanied with multiple liver abscesses and CMV colitis. The patient, a 72-year-old male, with a five-year history of repeated admissions to our hospital for UC, presented with an exacerbation of his UC. Sigmoidoscopy performed on admission suggested that his UC was exacerbated, then he was given prednisolone and mesalazine orally, and betamethasone enemas. However, he had exacerbated symptoms. Repeat sigmoidoscopy revealed multiple longitudinal ulcers and pseudopolyps in the rectosigmoid colon. Although immunohistochemical staining of biopsy specimens and the serum testing for antigenemia were negative on admission and after the repeat sigmoidoscopy, they became histologically positive for CMV. Nonetheless, the patient developed spiking fevers, soon after ganciclovir was administered. Laboratory studies revealed an increased white cell count with left shift, and Enterococcus fecalis grew in blood cultures. An abdominal computed tomography (CT) scan was obtained and the diagnosis of liver abscesses associated with UC was made, based on CT results. The hepatic abscesses were successfully treated with intravenous meropenem for 6 wk, without further percutaneous drainage. To our knowledge, this is the first reported case of multiple liver abscesses that develop during UC exacerbation complicated by CMV colitis.