A new method for insertion of long intestinal tube for small bowel obstruction: Nonendoscopic over-the-wire method via short nasogastric tube.

It is often difficult to insert a long intestinal tube (LT) in patients with small bowel obstruction (SBO). We developed a novel technique for inserting an LT without endoscopy called nonendoscopic over-the-wire method via short nasogastric tube (NEWSt). We evaluated the efficacy and safety of NEWSt.We performed a retrospective study of patients who underwent LT insertion for SBO without any indications of strangulation with either NEWSt (n = 16) or endoscopy (n = 17) between November 2011 and February 2015 at our hospital. Univariate analysis was used to assess the success rate of LT placement beyond the duodenojejunal flexure, time required for the procedure, clinical outcomes, and adverse events.The success rate was 100% in both groups. Procedure time was numerically, but not statistically, shorter in the NEWSt group compared with the endoscopy group (24 ±â€Š13 vs 30 ±â€Š13 min; P = 0.174). There were no statistically significant differences between the 2 groups in terms of surgery rate (31% vs 12%; P = 0.225), fasting period (11.3 ±â€Š6.3 vs 9.9 ±â€Š4.5 days; P = 0.482), hospital stay (26.4 ±â€Š22.1 vs 18.7 ±â€Š7.0 days; P = 0.194), and recurrence rate (19% vs 24%; P = 1.0). No serious adverse event was observed in the NEWSt group, whereas serious aspiration pneumonia was observed in 2 patients after LT insertion in the endoscopy group.Without endoscopy, NEWSt enabled the high success rate and the short procedure time for the LT insertion. Prospective, randomized controlled trials are needed.

Sitafloxacin resistance in Helicobacter pylori isolates and sitafloxacin-based triple therapy as a third-line regimen in Japan.

The third-line treatment regimen for Helicobacter pylori after failure of clarithromycin- and metronidazole-based therapies is not yet established. Sitafloxacin (STX) is a quinolone that possesses potent in vitro activity against H. pylori. In this study, the susceptibility of H. pylori isolates to STX was examined and the efficacy of STX-based triple therapy as a third-line regimen was evaluated. STX showed minimum inhibitory concentrations (MICs) of ≤1 µg/mL against all 100 H. pylori isolates, and the MIC(90) (MIC for 90% of the organisms) of STX was 5 log(2) dilutions lower than that of levofloxacin (LVX). The MIC(50) (MIC for 50% of the organisms) of STX against gyrA mutants was 0.12 µg/mL and was significantly lower than that of LVX (8 µg/mL). The activity of STX at pH 5.5 was significantly less than that at pH 7.0. In the clinical trial, 28 patients with two eradication failures were treated with STX-based triple therapy [rabeprazole 10 mg twice daily (b.i.d.), amoxicillin 750 mg b.i.d. and STX 100mg b.i.d. for 7 days]. The eradication rate was 75% using intention-to-treat analysis and 80% using per-protocol analysis. Two gyrA mutant strains were eradicated. Amongst participants, a low pepsinogen I/II ratio was associated with successful eradication. These results suggest that STX could be active against most clinical H. pylori isolates and that STX-based triple therapy is a promising and safe third-line therapy.

Endoscopic submucosal dissection is an effective and safe therapy for early gastric neoplasms: a multicenter feasible study.

BACKGROUND AND AIM: The technique of endoscopic submucosal dissection (ESD) was introduced to obtain en bloc specimens of large early gastrointestinal neoplasms. The drawback of ESD is its technical difficulty and, consequently, its higher rate of complication. In this multicenter study, we investigated the therapeutic outcomes of ESD in consecutive patients. METHODS: From January 2002 to December 2008, 485 early gastric neoplasms in 418 patients were consecutively treated by using ESD procedure performed by 6 endoscopists in 4 institutions in Tokyo. Demorgraphics, tumor location, therapeutic outcomes, and complication rates were analyzed. RESULTS: The rates of en bloc resection, complete en bloc resection, submucosal invasion, and piecemeal resection were 93.6%, 85.4%, 10.9%, and 5.4%, respectively. In multivariate analysis, the en bloc resection rate was independently lower in lesions in upper portion than in lower portion (P<0.01), lower in larger lesions (>30 mm, P<0.05; 20 to 30 mm, P<0.05), and lower in lesions with a scar (P<0.01). Delayed bleeding occurrence was independently high in larger lesions (>30 mm, P<0.01; 20 to 29 mm, P<0.01) than in small lesions (<20 mm). Institution and endoscopists were not risk factors of en bloc resection and complications CONCLUSIONS: ESD is an effective and safe therapy in the management of early gastric neoplasms when performed by well-trained endoscopists. Endoscopists should recognize the difficulty to perform ESD for en bloc resection of upper lesion, and the risk of delayed bleeding in cases of lesions >2 cm in size.

Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure. C-jun N-terminal kinase (JNK) is thought to play a central role in APAP-induced liver injury, although its upstream activator has not yet been identified. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase family and is important for stress-induced JNK activation. We tested the hypothesis that ASK1 was involved in APAP-induced JNK activation and liver injury. METHODS: ASK1-deficient (ASK1(-/-)) mice and wild-type (WT) mice were given 300 mg/kg of APAP. Serum alanine aminotransferase levels and liver histology were assessed. To investigate the involvement of ASK1 in direct hepatocellular damage and the subsequent inflammatory response, we used primary hepatocytes and splenocytes from WT and ASK1(-/-) mice. RESULTS: In ASK1(-/-) mouse liver, APAP toxicity was attenuated significantly and the prolonged activation of JNK was inhibited. In addition, thioredoxin, a direct ASK1 inhibitor, dissociated from ASK1 after APAP overdose with concomitant ASK1 activation. Although the prolonged activation of p38 also was attenuated in ASK1(-/-) mice, the p38 signaling pathway was not likely to be involved in APAP-induced liver injury. Primary hepatocyte culture also revealed that ASK1 and JNK, but not p38, contributed to direct APAP-induced cellular damage. CONCLUSIONS: Our data suggest that ASK1 is activated by APAP overdose, most likely via a mechanism involving thioredoxin-ASK1 dissociation, and that it plays a role in APAP-induced liver injury through JNK activation.

The effect of Helicobacter pylori eradication on reducing the incidence of gastric cancer.

Epidemiologically, the association between chronic Helicobacter pylori infection and development of gastric cancer is well established. Although the possibility of preventing gastric cancer by eradicating H. pylori infection was recently investigated by several research groups, the results remain controversial. The aim of this study was to determine whether the eradication of H. pylori infection would reduce the incidence of gastric cancer. In total, 304 patients with persistent H. pylori infection and 404 patients with H. pylori infection eradicated were examined annually for gastric cancer by endoscopy. Over an average of 3.1 years for the first group and 3.2 years for the second group, 13 and 6 patients, respectively, were diagnosed as having new gastric cancer. The cumulative incidence of gastric cancer was statistically different between the groups (P=0.019; log-rank test). The hazard ratio of H. pylori eradication was 0.335 by Cox proportional hazards model (P=0.047). Differentiated gastric cancer was found in 11 patients in the persistent infection group and 3 patients in the eradicated group. The incidence of differentiated cancer was significantly different (P=0.017) between the groups, but not for undifferentiated cancer (P=0.847). The results of the current study suggest that the eradication of H. pylori infection reduces the incidence of gastric cancer.

Activation of IkappaB kinase and NF-kappaB is essential for Helicobacter pylori-induced chronic gastritis in Mongolian gerbils.

The Mongolian gerbil model of Helicobacter pylori infection resembles human gastritis. In this study, we investigated the role of NF-kappaB activation in H. pylori-infected gerbils. Activated macrophages were significantly increased in H. pylori-infected gastric mucosa and were identified as being important cells with potent activation of NF-kappaB, which plays an important part in producing proinflammatory cytokines. Macrophage depletion by the administration of clodronate resulted in milder inflammation in gerbils infected with H. pylori. In macrophages, the inhibition of IkappaB kinase beta (IKKbeta), which is a critical kinase for NF-kappaB activation, resulted in lower proinflammatory cytokine expression caused by heat-killed H. pylori cells. Furthermore, treatment with IKKbeta inhibitor resulted in milder inflammation in gerbils with H. pylori gastritis. Collectively, our data suggest that H. pylori-mediated gastric inflammation critically depends on the efficient recruitment and activation of macrophages, with sufficient NF-kappaB activation.

[A patient with recurrent sigmoid colon cancer in whom pleural effusion and ascites resolved after FOLFOX 4 therapy].

We performed combination therapy with oxaliplatin/l-LV/5-FU (FOLFOX 4) in a patient with recurrent colorectal cancer (a 58-year-old man) who had pleural effusion and ascites. This resulted in disappearance of the pleural effusion and ascites, as well as negative tumor markers. Surgery was performed for sigmoid colon cancer on September 29, 2004. In February 2006, abdominal swelling was observed, and CEA increased to 15 ng/mL with multiple intraabdominal tumor nodules. The patient was diagnosed as having peritonitis carcinomatosis associated with recurrent sigmoid colon cancer, and was treated with FOLFOX 4. CEA was 134.9 ng/mL before treatment, but became negative after six courses, while his pleural effusion and ascites disappeared after 10 courses of treatment. This treatment also appeared to be useful for recurrent colorectal cancer with peritoneal dissemination.

Clinical relevance of Helicobacter pylori sabA genotype in Japanese clinical isolates.

BACKGROUND AND AIM: The clinical outcome of Helicobacter pylori infection is strongly affected by the bacterial genotype. The aim of this study was to assess the relationship between the status of H. pylori sialic acid-binding adhesin (sabA) and the severity of gastric inflammation and diseases. METHODS: Clinical isolates from 108 patients with duodenal ulcer, gastric ulcer, gastric cancer, or chronic gastritis were analyzed by sequencing and PCR assay. The degree of neutrophil infiltration in the antral region was evaluated by histopathological examination. The extent of atrophic change was evaluated using serum pepsinogen levels and the pepsinogen I/II ratio. RESULTS: Functional sabA was present in 88 (81%) of the 108 patients. Although there was no correlation between the sabA status and gastric diseases, severe neutrophil infiltration and atrophy were associated with functional sabA. CONCLUSIONS: The results show a high prevalence of functional sabA in Japanese clinical isolates. The status of sabA may be an important virulence factor in inducing chronic gastric inflammation.

Efficacy and safety of faropenem in eradication therapy of Helicobacter pylori.

AIMS: While triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin is the standard therapy for Helicobacter pylori eradication, it is ineffective against clarithromycin-resistant strains. To seek a better regimen for eradication therapy, we assessed the sensitivity of clinical strains seen in Japan to faropenem and then evaluated the efficacy and safety of eradication therapy containing this antibiotic. METHODS: Minimum inhibitory concentrations (MICs) of faropenem were determined in 78 Japanese clinical H. pylori isolates using the agar dilution method. H. pylori-positive patients were consecutively assigned to a 7-day eradication therapy protocol with LAF (lansoprazole 60 mg/day, amoxicillin 2000 mg/day, and faropenem 600 mg/day), and then to a 14-day protocol. The outcomes of the therapies were assessed by (13)C-urea breath tests. RESULTS: All 78 strains showed MICs of faropenem that were equal to or less than 0.2 microg/mL. The eradication rates according to intention-to-treat analyses were 46.5% with the 7-day therapy (n = 43) and 62.5% with the 14-day therapy (n = 32). No special measures were required to treat the adverse events observed in approximately one-third of the patients. CONCLUSIONS: Faropenem was found to have good antimicrobial action against H. pylori in vitro. The 14-day LAF therapy successfully eradicated H. pylori in about two-thirds of the patients although the incidence of adverse events was high.

Cutting edge: The IkappaB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks inflammatory injury in murine colitis.

Inflammatory mediators such as TNF-alpha, IL-6, and IL-1 are important in the pathogenesis of inflammatory bowel diseases and are regulated by the activation of NF-kappaB. The aim of the present study was to investigate whether the NF-kappaB essential modulator (NEMO)-binding domain (NBD) peptide, which has been shown to block the association of NEMO with the IkappaB kinasebeta subunit (IKKbeta) and inhibit NF-kappaB activity, reduces inflammatory injury in mice with colitis. Two colitis models were established by the following: 1) inclusion of dextran sulfate sodium salt (DSS) in the drinking water of the mice; and 2) a trinitrobenzene sulfonic acid enema. Marked NF-kappaB activation and expression of proinflammatory cytokines were observed in colonic tissues. The NBD peptide ameliorated colonic inflammatory injury through the down-regulation of proinflammatory cytokines mediated by NF-kappaB inhibition in both models. These results indicate that an IKKbeta-targeted NF-kappaB blockade using the NBD peptide could be an attractive therapeutic approach for inflammatory bowel disease.

Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer.

High-mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as a proinflammatory cytokine. We measured the HMGB1 concentration in the sera of mice with chemically induced colitis (DSS; dextran sulfate sodium salt) and found a marked increase. Inhibition of HMGB1 by neutralizing anti-HMGB1 antibody resulted in reduced inflammation in DSS-treated colons. In macrophages, HMGB1 induces several proinflammatory cytokines, such as IL-6, which are regulated by NF-kappaB activation. Two putative sources of HMGB1 were explored: in one, bacterial factors induce HMGB1 secretion from macrophages and in the other, necrotic epithelial cells directly release HMGB1. LPS induced a small amount of HMGB1 in macrophages, but macrophages incubated with supernatant prepared from necrotic cells and containing large amounts of HMGB1 activated NF-kappaB and induced IL-6. Using the colitis-associated cancer model, we demonstrated that neutralizing anti-HMGB1 antibody decreases tumor incidence and size. These observations suggest that HMGB1 is a potentially useful target for IBD treatment and the prevention of colitis-associated cancer.

MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells.

Helicobacter pylori induces NF-kappaB activation, leading to mucosal inflammation via cag pathogenicity island. Although recent studies have implicated several candidate proteins of both H. pylori and host, the molecular mechanism by which H. pylori activates NF-kappaB remains unclear. The aim of this study was to analyze the mechanism of cag pathogenicity island-mediated NF-kappaB activation in epithelial cells. The responses of human cell lines and mouse embryonic fibroblasts to infection with wild-type H. pylori or cagE mutant were investigated. The effect of small interfering RNAs (siRNAs) for several NF-kappaB signaling intermediate molecules was evaluated in H. pylori-induced IkappaBalpha phosphorylation and IL-8 production. Protein interactions of exogenously expressed TNFR-associated factor 6 (TRAF6) and MyD88 or receptor-interacting protein 2 and nucleotide-binding oligomerization domain 1 or those of endogenous IkappaB kinase, TGF-beta-activated kinase 1 (TAK1), and TRAF6 were assessed by immunoprecipitation. Cag pathogenicity island-dependent NF-kappaB activation was observed in human cell lines, but not in mouse fibroblasts. In human epithelial cells, H. pylori-induced IkappaBalpha phosphorylation and IL-8 production were severely inhibited by siRNAs directed against TAK1, TRAF6, and MyD88. In contrast, siRNAs for TRAF2, IL-1R-associated kinases 1 and 4, and cell surface receptor proteins did not affect these responses. H. pylori infection greatly enhanced MyD88 and TRAF6 complex formation in a cag-dependent manner, but did not enhance Nod1 and receptor-interacting protein 2 complex formation. H. pylori also induced TAK1 and TRAF6 complexes. These results suggest that the cag pathogenicity island of H. pylori is a cell type-specific NF-kappaB activator. TAK1, TRAF6, and MyD88 are important signal transducers in H. pylori-infected human epithelial cells.

Helicobacter pylori induces IkappaB kinase alpha nuclear translocation and chemokine production in gastric epithelial cells.

NF-kappaB is an important transcriptional factor that is involved in multiple cellular responses, such as inflammation and antiapoptosis. IkappaB kinase alpha (IKKalpha) and IKKbeta, which are critical regulators of NF-kappaB activity, possess various mechanisms for NF-kappaB activation. This variability in NF-kappaB signaling may be associated with distinct inflammatory responses in specific cell types. The gastric pathogen Helicobacter pylori is known to activate NF-kappaB. However, the role of IKK in H. pylori infection remains unclear. In this report, we show that H. pylori activates both IKKalpha and IKKbeta in gastric cancer cells and enhances NF-kappaB signaling in distinct manners. We found that IKKbeta acted as an IkappaBalpha kinase during H. pylori infection, whereas IKKalpha did not. H. pylori induced IKKalpha nuclear translocation in time-, multiplicity of infection-, and cag pathogenicity island-dependent manners. In contrast, p100 processing, which is a known IKKalpha activity induced by several cytokines, was not induced by H. pylori. Both IKKs were responsible for chemokine secretion by infected cells. However, the antiapoptotic effect of H. pylori was merely transduced by IKKbeta. Microarray analysis and real-time PCR indicated that both IKKs were involved in the transcriptional activation of genes associated with inflammation, antiapoptosis, and signal transduction. Our results indicate that H. pylori activates NF-kappaB via both IKKalpha and IKKbeta using distinct mechanisms. IKKalpha nuclear translocation induced by H. pylori is indispensable for appropriate inflammatory responses but not for antiapoptosis, which suggests a critical role for IKKalpha in gastritis development.

NF-kappaB and ERK-signaling pathways contribute to the gene expression induced by cag PAI-positive-Helicobacter pylori infection.

AIM: To elucidate the sequential gene expression profile in AGS cells co-cultured with wild-type Helicobacter pylori (H pylori) as a model of H pylori-infected gastric epithelium, and to further examine the contribution of cag-pathogenicity islands (cagPAI)-coding type IV secretion system and the two pathways, nuclear factor kappa B (NF-kappaB) and extracellular signal-regulated kinases (ERK) on wild-type H pylori-induced gene expression. METHODS: Gene expression profiles induced by H pylori were evaluated in AGS gastric epithelial cells using cDNA microarray, which were present in the 4 600 independent clones picked up from the human gastric tissue. We also analyzed the contribution of NF-kappaB and ERK signaling on H pylori-induced gene expression by using inhibitors of specific signal pathways. The isogenic mutant with disrupted cagE (Delta cagE) was used to elucidate the role of cagPAI-encoding type IV secretion system in the gene expression profile. RESULTS: According to the expression profile, the genes were classified into four clusters. Among them, the clusters characterized by continuous upregulation were most conspicuous, and it contained many signal transducer activity-associated genes. The role of cagPAI on cultured cells was also investigated using isogenic mutant cagE, which carries non-functional cagPAI. Then the upregulation of more than 80% of the induced genes (476/566) was found to depend on cagPAI. Signal transducer pathway through NF-kappaB or ERK are the major pathways which are known to be activated by cagPAI-positive H pylori. The role of these pathways in the whole signal activation by cagPAI-positive H pylori was analyzed. The specific inhibitors against NF-kappaB or ERK pathway blocked the activation of gene expression in 65% (367/566) or 76% (429/566) of the genes whose activation appealed to depend on cagPAI. CONCLUSION: These results suggest that more than half of the genes induced by cagPAI-positive H pylori depend on NF-kappaB and ERK signaling activation, and these pathways may play a role in the gene expression induced by host-bacterial interaction which may associate with H pylori-related gastro-duodenal diseases.

Helicobacter pylori activates NF-kappaB via the alternative pathway in B lymphocytes.

Helicobacter pylori causes various gastroduodenal diseases including gastric MALT lymphoma, but the mechanism underlying H. pylori-induced carcinogenesis is not known. The alternative pathway for NF-kappaB activation, which involves the processing of NF-kappaB2/p100 to p52, has been implicated in lymphocyte survival, attenuated apoptosis, and secondary lymphoid tissue development. In this study, we investigated H. pylori-induced activation of NF-kappaB through the alternative pathway in B lymphocytes. In immunoblot and EMSA, H. pylori induced NF-kappaB2/p100 processing to p52 and subsequent nuclear accumulation in IM-9 (human B cell line) cells and human peripheral blood B cells, but not in AGS (human gastric cancer cell line) cells. The activation of the alternative pathway was LPS-dependent but not cag pathogenicity island-dependent. Alternative pathway activation by H. pylori was associated with attenuated apoptosis. The expression levels of B lymphocyte chemoattractant, EBI-1 ligand chemokine, and stromal cell-derived factor-1alpha mRNAs were up-regulated in cocultured human B cells and in infected human gastric mucosa. In the infected mucosa, NF-kappaB2/p100 and p52 were detected immunohistochemically in the cytoplasm and nuclear compartments of lymphocytes, but not in epithelial cells. In summary, H. pylori activates the alternative NF-kappaB pathway in B lymphocytes. The effects on chemokine production and antiapoptosis mediated by H. pylori-induced processing of NF-kappaB2/p100 to p52 may drive lymphocytes to acquire malignant potential.

[Significance of shunt efficacy decision of SPECT on idiopathic normal pressure hydrocephalus].

PURPOSE: The purpose of this study was to investigate the significance of the shunt-effect evaluation of SPECT in idiopathic normal pressure hydrocephalus (iNPH). SUBJECTS AND METHODS: The subjects were 15 patients with possible iNPH, aged 62-83 (mean 75.3, the ratio of males to females to 6:9), who were treated at our department during the period from June to September, 2004. All patients received the lumbar tap test (LTT) at the outpatient section before surgery. An L-P shunt was conducted on patients whose the LTT positive or negative with cerebrospinal fluid outflow resistance value (Ro) was 10 mmHg/ml/min. or higher patients. As for SPECT, a 3D-SSP Z-score, as well as an mCBF, was conducted before and after the LTT and within one month after surgery. Comparisons were made for (1) the shunt effect, (2) mCBF before and after the LTT and after surgery, (3) mean cerebral blood flow increase rate (mIR) after the LTT, and (4) 3D-SSP before and after surgery. RESULTS: (1) The shunt was effective for all the patients. (2) The mCBF levels was 30.8 +/- 4.02 ml/100 g/min. before the LTT, 37.1 +/- 100 g/min. after the LTT, and 38.6 +/- 3.4 ml/100 g/min. after surgery. A significant increase in mCBF was observed both after the LTT and after surgery (p < 0.05). (3) The mean mIR after the LTT was 21.2 +/- 8.01%, with all the patients showing 10% or higher. (4) The ischemic patterns in the SD-SSP Z-score before surgery were the frontal type (F: 10 cases, 66.7%), the occipitotemporal type (OT: 3 cases, 20%), and the mixed type (M: 2 cases, 13.3%), but not the parietal localized type. The post-operative course showed no-change in 4 cases, disappearance-reduction in 9 cases, and shift to OT in 2 cases. CONCLUSION: The evaluation factors in the measurement of the cerebral blood flow for evaluation of the shunt effect were the following two items. (1) The mIR of mCBF after the LIT was 10% or higher. (2) As for the preoperative cerebral ischemic patterns, there were many F cases and no parietial localized types found.