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The relationship between symptom improvement (SI) and acceleration of gastric emptying (GE) for different drugs used in the treatment of idiopathic and diabetic gastroparesis is uncertain. In this paper we examined the study-specific correlations between SI and GE, and we performed a meta-regression analysis of the association across multiple studies.The MEDLINE database (1,946 to present) was searched, and only controlled trials or trials with an established effective comparator that compared both SI and GE were included.Studies were identified for metoclopramide (n=6), domperidone (n=6), cisapride (n=14), erythromycin (n=3), botulinum toxin (n=2), and levosulpiride (n=3). Even though most drugs concomitantly improved symptoms and accelerated GE, no study reported a significant correlation between SI and GE. Moreover, a correlation analysis over all studies using meta-regression did not show a significant relationship between SI and GE. Our findings need to be qualified by inconsistencies in study methods, which is a limitation but also suggests that our findings are robust to methodological factors.In this review, no evidence of a relationship between SI and GE was identified for different drugs used for the treatment of gastroparesis. This finding questions the use of GE measurement to direct drug development for gastroparesis.

Eradication of Helicobacter pylori should not be avoided because of complicated reflux symptoms. Previously, although H. pylori eradication in patients with GORD was considered to induce unfavourable effects that worsen reflux symptoms, recent reports indicates that it can have favourable consequences by reducing symptoms and therefore improving quality of life, especially in GORD patients without severe corpus atrophy or severe hiatal herniation.

Functional dyspepsia (FD) is a highly prevalent condition with major socioeconomic and healthcare impact. To date, no pharmacological treatment for FD has been approved. The Rome consensus proposed to subdivide FD into postprandial distress syndrome (PDS), characterized by meal-related symptoms and epigastric pain syndrome, characterized by pain and burning. Acotiamide (Z-338 or YM443) is a new drug, developed for the treatment of FD. Acotiamide enhances acetylcholine release from enteric neurons through muscarinic receptor antagonism and acetycholinesterase inhibition, thereby enhancing gastric emptying and gastric accommodation. Acotiamide was evaluated in FD in clinical studies in Europe, Japan and the USA, beneficial effects were observed for the PDS symptoms of postprandial fullness and early satiation, with a dose of 100 mg three-times a day. A 4-week placebo-controlled Phase III study in PDS patients in Japan confirmed efficacy of acotiamide in relieving postprandial fullness, early satiation and upper abdominal bloating.

Background & Aims There is controversy over the optimal management strategy for patients with branch-duct type intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs), precursors to pancreatic cancer. We aimed to identify factors associated with the presence of BD-IPMNs and changes in their diameter. Methods Two separate analyses were conducted in a cohort of patients who underwent magnetic resonance cholangiopancreatography (MRCP) in a single year (2006). MRCP findings and clinical outcomes of these patients were followed for a maximum of 6 years. We evaluated initial MRCP findings and demographics associated with the presence of BD-IPMNs at baseline and increase in BD-IPMN diameter over time. Results During the follow-up period, 154 patients developed BD-IPMN and 322 patients did not. Older age, diabetes mellitus, gallbladder adenomyomatosis, and absence of gallstones were associated with the presence of BD-IPMNs at baseline. Increases in diameter of BD-IPMNs were associated with 3 baseline factors: BD-IPMN diameter greater than 17 mm, gallbladder adenomyomatosis, and a common bile duct diameter less than 5.5 mm. Patients with BD-IPMNs could be stratified into 4 groups with varying risk for the enlargement of BD-IPMNs over time: those with 3 risk factors (hazard ratio [HR], 11.4; 95% confidence interval [CI], 3.4–37.8), 2 risk factors (HR, 4.7; 95% CI, 1.7–12.8), or 1 risk factor (HR, 3.1; 95% CI, 1.2–8.2) compared with those without risk factors. Conclusions For patients with BD-IPMNs, careful follow-up evaluation is particularly important for those with BD-IPMN >17 mm in size, common bile duct diameter

BACKGROUND & AIMS: Impaired accommodation and hypersensitivity to gastric distention are believed to be involved in the development of functional dyspepsia (FD). Buspirone, a 5-hydroxytryptamine 1A receptor agonist, relaxes the proximal stomach in healthy individuals. We studied the effects of buspirone on symptoms and mechanisms of FD. METHODS: We performed a randomized, double-blind, placebo-controlled, crossover study of 17 patients (13 women; mean age, 38.5 2.4 years). The study included 2 treatment periods of 4 weeks each, separated by a 2-week washout period. In the first period, 7 participants were given buspirone (10 mg, 3 times daily for 4 weeks) and 10 were given placebo 15 minutes before meals; patients switched groups for the second period. We assessed meal-related symptoms and severity, along with gastric sensitivity, accommodation, and emptying (by using barostat and breath tests) before and after 4 weeks of treatment. RESULTS: Buspirone significantly reduced the overall severity of symptoms of dyspepsia (7.5 1.3 vs 11.5 1.2 for placebo; P .005) and individual symptoms of postprandial fullness, early satiation, and upper abdominal bloating, whereas placebo had no significant effect (all P .05). Buspirone did not alter the rate of gastric emptying of solids or sensitivity to gastric distention, but it significantly increased gastric accommodation, compared with placebo (229 28 vs 141 32 mL, respectively; P .05), and delayed gastric emptying of liquids (half-life 64 5v s 119 24 minutes, respectively). Adverse events were similar when patients were given buspirone or placebo. CONCLUSIONS: In patients with FD, 4 weeks of administration of buspirone significantly improved symptoms and gastric accommodation, compared with placebo, whereas gastric emptying of liquids was delayed.

Ghrelin has distinct effects on gastrointestinal motility through the vagus nerve and gastric excitatory neural plexus. The objectives of this study were to investigate the dynamics of ghrelin and expression of neuromuscular markers in a newly established surgically manipulated rat model of gastric outlet obstruction (GOO), akin to the pyloric stricture associated with duodenal ulcer, advanced gastric cancer, and other conditions, in the clinical setting.The rats were divided into two groups, a control group (sham operation) and the GOO group (proximal duodenal stricture). The animals were sacrificed 2 weeks after the operation. Plasma and gastric ghrelin were measured by radioimmunoassay. mRNA expression in the stomach of neural choline acetyltransferase (ChAT), c-kit, and membrane-bound stem cell factor (SCF) were analyzed by quantitative RT-PCR. In addition, gastric mRNA expression of the aforementioned were also evaluated 60 min after intraperitoneal administration of a synthetic GHS-R1a antagonist ([D: -Lys3] GHRP-6 6.0 mg/kg).Mechanical GOO induced increases of fasting plasma ghrelin levels and hyperplasia of the gastric muscle layers, with enhanced expression of the gastric neuromuscular markers. Administration of [D: -Lys3] GHRP-6 normalized the enhanced expression of c-kit and SCF.GOO stimulates ghrelin dynamics and then enhances the mechanistic expression of gastric cellular communication network molecules between nerves and smooth muscle cells.

Background and Aim: This study was designed to investigate the efficacy of gatifloxacin (GAT)–based triple therapy as a third-line treatment for Helicobacter pylori (H. pylori) eradication, according to the assessment of the susceptibility to GAT and gyrA mutation. Methods: Fourteen patients who had eradication failure following both clarithromycin-based triple therapy and metronidazole-based triple therapy, or who were infected with H. pylori isolates that were resistant to both clarithromycin and metronidazole after failure of clarithromycin-based triple therapy, were enrolled. These patients were randomly assigned to two groups: (i) rabeprazole and amoxicillin (RA) and (ii) rabeprazole, amoxicillin, and GAT for 7 days (RAG). The minimal inhibitory concentrations were determined by the agar dilution method. The gyrA gene was examined by sequencing. Results: The eradication rate was 0% in the RA group and 75% in the RAG group. The eradication rate in the RAG group was 100% in patients infected with GAT-susceptible bacteria and/or bacteria without gyrA mutations, but was only 33.3% in those infected with GAT-resistant bacteria or bacteria with gyrA mutations. Conclusion: Although GAT may be a promising candidate for third-line therapy, its selection must be based on the results of drug susceptibility testing or gyrA analyses.

Sonic hedgehog (Shh) is a morphogen involved in the homeostasis of the gastric fundic glands. Alterations of gastric mucosal Shh expression after eradication of Helicobacter pylori were examined.Mongolian gerbils were inoculated with H. pylori at the age of 5 weeks. H. pylori eradication was then carried out at 12, 24 or 48 weeks after the inoculation, and the gerbils were examined at 10 weeks after the eradication. Gastric inflammation was evaluated by the tissue myeloperoxidase activity and the histological scoring. Immunohistochemistry and in situ hybridization were performed for determining the Shh expression.Significant decrease of the myeloperoxidase activity and scores for acute and chronic inflammation as well as atrophy were observed in the H. pylori-eradicated gerbils as compared with the findings in the non-H. pylori-eradicated gerbils. Significant increase of the horizontal length of the area positive for Shh expression was noted in the H. pylori-eradicated gerbils as compared with that in the non-H. pylori-eradicated gerbils. Earlier eradication promoted better restoration of Shh expression. 50% of the animals of the 24-week eradication group and all animals in the 48-week eradication group exhibited heterotopic proliferative glands. In the animals showing heterotopic proliferative glands, the front line of Shh regeneration was cut off at the point of development of heterotopic proliferative glands.H. pylori-associated deregulation of Shh expression that could be linked to gastric atrophy and the associated preneoplastic transformation appears to be reversible with early H. pylori eradication.

To examine the influence of long-term treatment of H. pylori-infected patients with proton pump inhibitors (PPI) on the toxic oxidant production in the stomach.Eight H. pylori-positive patients with gastric ulcer were enrolled, and tissue samples were obtained endoscopically from the antrum and corpus. The tissue contents of neutrophil myeloperoxidase (MPO) and oxygen-derived free radicals were quantified by ELISA and chemiluminescence (ChL) assay. The H. pylori density in the tissue specimens was scored by immunohistochemistry and the mucosal infiltration by neutrophils and monocytes was scored by histopathology. The effects of PPI on these parameters were evaluated by oral administration of lansoprazole (LPZ) at the dose of 30mg od for 8 weeks, followed by 15mg for 24 weeks.Eight-week treatment with LPZ significantly increased the corpus ChL by 400%, which remained unchanged at this level during the subsequent 24 weeks, but the antrum ChL decreased slightly following LPZ-treatment. No significant changes in the mucosal MPO activity or the histologically determined parameters of H. pylori density and neutrophil/monocyte infiltration were observed in either portion of the stomach.The mucosal oxidative stress level significantly increased in the corpus mucosa after long-term treatment with LPZ, which may be independent of inflammatory cell infiltration.

Immune thrombocytopenia purpura (ITP) is a bleeding disorder in which platelet-specific autoantibodies cause a loss of platelets. In a subset of patients with ITP and infected with Helicobacter pylori, the number of platelets recovers after eradication of H. pylori. To examine the role of H. pylori infection in the pathogenesis of ITP, the response of 34 ITP patients to treatment with a standard H. pylori eradication regimen, irrespective of whether they were infected with H. pylori, was evaluated. Eradication of H. pylori was achieved in all H. pylori-positive patients, and a significant increase in platelets was observed in 61% of these patients. By contrast, none of the H. pylori-negative patients showed increased platelets. At baseline, monocytes from the H. pylori-positive patients exhibited an enhanced phagocytic capacity and low levels of the inhibitory Fcgamma receptor IIB (FcgammaRIIB). One week after starting the H. pylori eradication regimen, this activated monocyte phenotype was suppressed and improvements in autoimmune and platelet kinetic parameters followed. Modulation of monocyte FcgammaR balance was also found in association with H. pylori infection in individuals who did not have ITP and in mice. Our findings strongly suggest that the recovery in platelet numbers observed in ITP patients after H. pylori eradication is mediated through a change in FcgammaR balance toward the inhibitory FcgammaRIIB.

Background and Aim: Several scoring systems have been devised to identify patients with upper gastrointestinal (UGI) bleeding who are at a high risk of adverse outcomes. We retrospectively evaluated the accuracy of the Blatchford scoring system for assessing the need for clinical intervention in cases of UGI bleeding admitted to the emergency department (ED). Methods: This was a retrospective study conducted on patients who underwent emergency GI endoscopy at the ED of our hospital. Those who needed blood transfusion, operative or endoscopic interventions to control the hemorrhage were classified into the ‘high risk’ group. Results: Of the 93 enrolled patients, 70 (75.3%) were classified into the high risk group. The Blatchford score was significantly higher in the high risk group than in the low risk group. When a cut-off value of 2 was used, the sensitivity and specificity of the Blatchford scoring system were determined to be 100% and 13%, respectively. Thus, the Blatchford scoring system was deemed to be useful for distinguishing between the high risk group and the low risk group of patients with GI hemorrhage admitted to the ED. Conclusion: The Blatchford scoring system is accurate for identifying definitively low-risk patients of GI hemorrhage, even prior to the performance of emergency UGI endoscopy at the ED.

Sonic hedgehog (Shh) is a morphogen involved in many aspects of patterning of the gut during embryogenesis and in gastric fundic gland homeostasis in the adult. Shh expression is reportedly to be reduced in Helicobacterpylori-associated gastritis. The aim of this study was to assess the restoration of Shh expression after H. pylori eradication.Twenty H. pylori-positive patients who underwent upper gastrointestinal endoscopy before and after the eradication were studied. Biopsy specimens were taken from the greater curvature of the middle third of the stomach body. The specimens were evaluated for the severity of acute and chronic inflammation and for that of mucosal atrophy, based on the updated Sydney system. Immunohistochemistry for Shh and H(+)-, K(+)-ATPase was also performed; the percentages of positively stained epithelial cells for the two molecules were expressed as the Shh index and H(+)-, K(+)-ATPase index, respectively.There was a significant decrease in the acute and chronic inflammation scores and also in the mucosal atrophy score following the eradication. The Shh and H(+)-, K(+)-ATPase index were significantly increased following the eradication.Suppressed Shh expression in the gastric mucosa by H. pylori infection was significantly restored following eradication of the infection.

It is helpful in clinical practice to predict the effects of eradication therapy on Helicobacter pylori.To develop a useful predictor of the response to metronidazole (MNZ)-containing second-line regimens by combining minimal inhibitory concentrations (MICs) of both amoxicillin (AMX) and MNZ, and the results of urea breath test (UBT) before the treatment.We enrolled 107 patients who showed eradication failure following first-line triple therapy with a proton pump inhibitor, AMX and clarithromycin. The eradication resistance index was defined as: [pre-treatment UBT result ( per thousand)] x [AMX MIC (microg/ml)] x [MNZ MIC (microg/ml)]. Second-line eradication therapy with lansoprazole, AMX and MNZ was administered for 1 week. Eradication was confirmed by the UBT.The eradication resistance index in subjects showing eradication failure and those showing successful eradication was 9.72 +/- 6.63 and 1.25 +/- 2.31, respectively (p0.001). When a cutoff value of 3 was used, the eradication resistance index predicted the response to therapy with a specificity of 93.8%, sensitivity of 81.8%, and accuracy of 92.5%.The eradication resistance index is a more useful predictor of response to MNZ-containing regimens for second-line treatment than only pretreatment UBT results or MNZ resistance.

change was determined as the ratio of the level of gene expression in treated cells to that in untreated control cells grown in parallel. Results: NES-B10T cells treated with A+B for 30 weeks were round and aggregated in clumps (columnar morphological features), whereas untreated cells were spindle-shaped and dispersed (squamous features). Treated NES-B10T cells showed increased expression of CDX2 (11-fold), SOX9 (238-fold), villin (2-fold) and Cox-2 (1,310-fold). Treated NES-B10T cells also showed increased immunofluorescence for mAb DAS-1, (P< 0.04), and also for CK8 (P< 0.02). Immunofluorescence for CK4 is decreased. In contrast to these changes observed in NES-B10T squamous cells (derived from a patient with BE), NES-G2T cells (derived from a patient who had GERD without BE) exhibited no morphological, gene expression or immunofluorescence changes after 30 weeks of A+B treatment. Conclusion: Esophageal squamous cells exposed repeatedly to acid and bile salts in vitro exhibit columnar differentiation typical of Barrett's metaplasia. This finding is novel and supports the hypothesis that BE results from reflux-induced transdifferentiation or transcommitment of native esophageal cells. The absence of these changes in similarlytreated squamous cells from a patient who had GERD without BE suggest that certain host genetic factors, in addition to acid and bile reflux, are required for the development of Barrett's metaplasia.

The patient was a 50-year-old woman who suffered from gastric discomfort. She was first diagnosed as intrahepatic cholangiocarcinoma with hepatic, paraaortic lymphnodal and bone metastasis. Initial systemic chemotherapy using gemcitabine (GEM) and 5-FU failed to control the disease activity. Then she was given GEM and cisplatin (CDDP) combination chemotherapy. The response was assessed as stable disease (SD), but grade 4 leukopenia was seen. Then systemic therapy using GEM, and hepatic arterial infusion therapy with CDDP, l-leucovorin and 5-FU were continued biweekly. Partial response (PR) was achieved six months later, and her disease status was maintained as SD. This hepatic arterial infusion chemotherapy would be safe and feasible as therapy for inoperable intrahepatic cholangiocarcinoma.

Ghrelin, a novel gastrointestinal peptide with 28 amino acids, is secreted from the A-like cells of the gastric fundus. This peptide hormone does not only promote the release of growth hormone, but also stimulates food intake, gastric motility and cardiac output. Increased plasma ghrelin level has been reported in patients with upper gastrointestinal (GI) disease or in their disease animal model, suggesting its important role in the pathogenesis of upper GI disease.

A high resistance rate (47.9%) to gatifloxacin (GAT; 8-methoxy fluoroquinolone) in Helicobacter pylori ( H. pylori ) strains from 48 Japanese patients is observed after unsuccessful H. pylori eradication. A significant association between MICs for GAT equal to or above 1 μg/ml and mutations of the gyrA gene of H. pylori was demonstrated.

Attention has been focused on apoptosis in terms of its involvement in the pathogenesis of various diseases including hepatitis, graft-versus-host disease (GVHD), and multiple sclerosis [1–3]. Some pathways are known to be implicated in cytotoxic T lymphocyte (CTL)-mediated apoptotic induction: perforin/granzyme pathway (based on granules stored in cytoplasmic azurophile granules of CTLs), Fas/Fas ligand (FasL), tumor necrosis factor (TNF)/TNF receptor (TNFR), or TNF-related apoptosis-inducing ligand (TRAIL) pathways based on type II transmembrane proteins belonging to the TNF family expressed on the cell surface. Among them, the perforin/granzyme and Fas/FasL pathways are considered the two major routes of apoptosis. The aim of this study is to investigate whether apoptosis associated with peptic ulcer formation may occur via either or both of these two pathways.

In the multitude of mechanisms involved in the development of gastric mucosal inflammation, derangement of the microcirculatory system is a common initial pathway. In response to gastric luminal antigens such as bacteria and food factors, the microvascular endothelium transduces signals to circulating cells. Helicobacter pylori colonization induces a significant level of leukocyte recruitment to the gastric mucosa as a result of the sequential pathological processes in the microcirculatory system. This bacterial infection is associated with a variety of clinical outcomes, including benign and malignant gastroduodenal diseases. After H. pylori inoculation, the bacteria colonize the surface epithelium, upon which numerous leukocytes rolling or adhering to the endothelial cells can be observed in the venules of the gastric mucosa. The adherent leukocytes migrate into the gastric mucosal parenchyma. Among the numerous proinflammatory factors, such as cytokines, free radicals, and enzymes, a monochloramine, derived from both leukocytes and H. pylori, is an important factor involved in the development of H. pylori-associated disease. Persistent H. pylori infection has recently been achieved in Mongolian gerbil models, in which the sequential microcirculatory and histopathological changes in the gastric mucosa have been shown to closely mimic the changes leading to gastric mucosal lesion formation in association with H. pylori infection in humans. Gastric mucosa infected with H. pylori exhibited significantly higher gastritis scores. Because the recently isolated growth-hormone-releasing peptide ghrelin is secreted mainly from the A-like cells in the gastric corpus, the anatomical extension of H. pyloriassociated inflammation to the gastric corpus mucosa might also affect ghrelin secretion and its associated appetite control.

It has previously been reported that human-beta defensin 2 (hBD2) has a physiological role as a proinflammatory mediator in gastric mucosal inflammation as well as an antimicrobial peptide for Helicobacter pylori (Hp). The present study was conducted to evaluate the possibility of hBD2 as a molecular marker of gastric mucosal inflammation.The subjects were 40 A1 to S2 gastric ulcer patients, with or without Hp infection. Biopsy specimens of the mucosa were obtained endoscopically before and after the administration of lansoprazole (LPZ) (15mg/day) or famotidine (FAM) (40 mg/day or 20 mg/day), consecutively, and each set of samples was divided into two groups; one group was subjected to RT-PCR to assess the expression of hBD2, and the other was subjected to immunohistochemical analysis for evaluating the expression of CD68.The expression of hBD2 was observed through the stage of gastric ulcer, from A1 to S1, regardless of the presence or absence of Hp infection, both before and after LPZ or FAM administration, and its intensity of expression decreasing as the number of CD68-positive cells decreased. The number of CD68-positive cells deceased as the severity of the ulcer increased from stage A1 to S2, regardless of the presence/absence of Hp infection. CD68-positive cells could hardly be observed in stage S2 gastric ulcers, in which hBD2 expression was also only scarcely noted.These results suggested the possibility that hBD2 may be a molecular marker of gastric mucosal inflammation, irrespective of the presence/absence of Hp infection.

We report on a case of chronic atrophic gastritis in which the serological markers of gastric diseases were strictly monitored for 2 years after successful Helicobacter pylori (H. pylori) eradication. A 31-year-old man with upper abdominal pain was diagnosed as having H. pylori infection. Laboratory examination revealed low serum levels of pepsinogen (PG) I, low PG I/II ratio, and low plasma levels of ghrelin. Upper gastrointestinal endoscopy revealed severe corpus-dominant atrophic gastritis. H. pylori eradication therapy was performed. Successful eradication was confirmed three months later by the 13C urea breath test. Decreased serum PG II levels and an increased serum PG I/II ratio were detected a week after completion of the eradication therapy. The serum anti-H. pylori IgG titer decreased to less than 75% of the baseline level by 24 weeks after completion of the eradication therapy. On the other hand, the plasma levels of total and active ghrelin showed no marked changes after successful eradication therapy. This is the first report of long-term follow-up of changes of the plasma ghrelin levels after H. pylori eradication therapy, the observations suggesting that reduction of plasma ghrelin levels cannot be achieved merely by H. pylori eradication, without resolution of the gastric atrophy.

Human beta-defensins (HBDs) recognized in the stomach include HBD1, which is the constitutional human beta-defensin (HBD), and HBD-2 and HBD-4, which are inducible HBDs. HBD-2 is an antimicrobial peptide that is involved in host defences against bacterial infections, such as Helicobacter pylori (H.pylori) in infection of the gastric mucosal epithelium. We examined the pathophysiological role of HBD-2, besides their roles as antimicrobial peptides. The materials used for the study consisted of gastric mucosal tissue specimens collected endoscopically from patients with conditions such as chronic gastritis associated with H. pylori infection, and gastric ulcers and gastritis due to non-steroidal anti-inflammatory drugs (NSAIDs) with or without H. pylori infection. We investigated the expression of HBD-2 and NF-kappaB by RT-PCR and immunoblotting, and the relation between the localization of HBD-2 and follicular dendritic cells (FDCs) by immunohistochemistry. Expression of HBD-2 was recognized in all the mucosal tissue specimens, irrespective of the presence or absence of H. pylori infection. All of the mucosal specimens expressing HBD-2 also revealed expression of NF-kappaB. In consecutive immunohisto-chemical staining, while expression of HBD-2 was observed in the gastric mucosal epithelium, FDCs were found to be localized in the lamina propria mucosae under the epithelial cell layer. These data suggested that in addition to being antimicrobial peptides, HBD-2 may also have a pathophysiological role as proinflammatory mediators, and that the HBD may act as proinflammatory mediators in concert with the dendritic cells (DC) by transmitting a signal from the mucosal surface to the lamina propria mucosae, which seems to be the original site of gastric mucosal damage.

Human beta-defensins (HBDs) recognized in the stomach include HBD1, which is the constitutional human beta-defensin (HBD), and HBD-2 and HBD-4, which are inducible HBDs. HBD-2 is an antimicrobial peptide that is involved in host defences against bacterial infections, such as Helicobacter pylori (H.pylori) in infection of the gastric mucosal epithelium. We examined the pathophysiological role of HBD-2, besides their roles as antimicrobial peptides. The materials used for the study consisted of gastric mucosal tissue specimens collected endoscopically from patients with conditions such as chronic gastritis associated with H. pylori infection, and gastric ulcers and gastritis due to non-steroidal anti-inflammatory drugs (NSAIDs) with or without H. pylori infection. We investigated the expression of HBD-2 and NF-kappaB by RT-PCR and immunoblotting, and the relation between the localization of HBD-2 and follicular dendritic cells (FDCs) by immunohistochemistry. Expression of HBD-2 was recognized in all the mucosal tissue specimens, irrespective of the presence or absence of H. pylori infection. All of the mucosal specimens expressing HBD-2 also revealed expression of NF-kappaB. In consecutive immunohisto-chemical staining, while expression of HBD-2 was observed in the gastric mucosal epithelium, FDCs were found to be localized in the lamina propria mucosae under the epithelial cell layer. These data suggested that in addition to being antimicrobial peptides, HBD-2 may also have a pathophysiological role as proinflammatory mediators, and that the HBD may act as proinflammatory mediators in concert with the dendritic cells (DC) by transmitting a signal from the mucosal surface to the lamina propria mucosae, which seems to be the original site of gastric mucosal damage.

Ghrelin, a novel growth-hormone-releasing peptide, has been reported to be localized mainly in the A-like cells in the gastric fundic mucosa. With the extension of gastric inflammation caused by H. pylori infection, gastric mucosal atrophy extends from the antrum to the corpus, which is the predominant site of localization of the ghrelin-producing A-like cells. The present study was designed to investigate the correlation between the plasma ghrelin levels and the extent of gastric mucosal atrophy in patients with chronic gastritis caused by H. pylori infection.Sixty-nine patients with dyspeptic symptoms were enrolled for the study. Of these, 41 patients were confirmed to become negative for H. pylori after therapy to eradicate the infection. The other 28 patients were diagnosed as positive for H. pylori infection. Blood samples were collected from all the patients after 12 hours of fasting, before upper gastrointestinal endoscopy was performed. The plasma levels of total and active ghrelin, as well as the serum levels of pepsinogen I (PGI) and pepsinogen II (PGII) were measured by radioimmunoassay. Based on endoscopic assessment, the atrophic changes in the gastric mucosa were classified as open-type atrophy or closed-type atrophy.There were no significant differences in the plasma total and active ghrelin levels between H. pylori-positive and H. pylori-eradicated (negative) patients. The serum levels of PGI correlated well with the plasma levels of total ghrelin (p0.01, r=0.38) and active ghrelin (p0.05, r=0.29). The ratio of serum PGI to PGII level (PG I/II ratio) also correlated well with the plasma level of total ghrelin (p0.05. r=0.31) and active ghrelin (p0.05, r=0.27). The plasma levels of total as well as active ghrelin were significantly decreased in patients with low PG levels as compared with those in patients with high PG levels (PGI70 ng/mL or PGI/II3.0). The plasma levels of total as well as active ghrelin were also significantly decreased in patients with endoscopically diagnosed open-type atrophy as compared with those in patients with endoscopically diagnosed closed-type atrophy (p0.01), especially in the H. pylori-eradicated cohorts.The plasma levels of ghrelin, which correlated well with the serum levels of PGI as well as the PGI/II ratio, decreased with increasing extent of gastric mucosal atrophy, suggesting that it could be a potentially useful non-invasive marker for chronic atrophic gastritis.

Problems after Helicobacter pylori (Hp) eradication therapy include recurrence of Hp-negative peptic ulcers. We investigated the pathophysiological characteristics of Hp-negative recurrent ulcer scars, and performed proton pump inhibitor (PPI) maintenance therapy as a new therapy for prevention of recurrence in patients with Hp-negative recurrence after Hp eradication and investigated its usefulness.The subjects were 21 patients with Hp-negative recurrent peptic ulcers after Hp eradication (gastric ulcer: 19, duodenal ulcer: 2) and 25 patients with non-recurrent ulcers (gastric ulcer: 20, duodenal ulcer: 5). The mucosa from the ulcer scar lesion was endoscopically obtained from patients, and HE staining, CD68 immunohistochemical staining, and investigation of the mucosal expression levels of TNF-alpha and IFN-gamma were performed by ELISA. Patients with recurrence after eradication were divided into two groups at the time of ulcer scar after the first treatment, and received maintenance therapy: the intermittent treatment group that received lansoprazole (LPZ), 30 mg/day, on two days on weekends (gastric ulcer: 9, duodenal ulcer: 1) and the ranitidine (RAN) 150 mg/day daily treatment group (gastric ulcer: 8, duodenal ulcer: 1).Infiltration of CD68-positive inflammatory cells was observed in the lamina propria mucosae over the epithelial layer in ulcer scars of the Hp-negative recurrent ulcer group compared with the non-recurrent ulcer group, and TNF-alpha and IFN-gamma significantly increased (27.22+/-6.23 pg/mg, 52.12+/-5.41 pg/mg vs. 4.23+/-2.14 pg/mg, 7.11+/-3.06 pg/mg, P0.001). In the RAN maintenance therapy group, the ulcer recurred within 10 months in all patients, while the ulcer recurred in only one patient in the intermittent LPZ treatment group.These results suggested that the pathophysiological characteristic of Hp-negative recurrent ulcer scar lesions after eradication was infiltration of inflammatory cells, mainly monocytes/macrophages, in the lamina propria mucosae over the epithelial layer, and this may be a key factor in ulcer recurrence. Furthermore, intermittent PPI therapy using LPZ may be a useful maintenance therapy for prevention of recurrence in these cases.

Cell proliferation and migration are important repair mechanisms in cell defect type mucosal injuries, such as peptic ulcers. To evaluate the level of cell restitution in vitro, we established a normalized assay system for analyzing the area of a tissue defect created in the center of a cultured cell layer. Although proton pump inhibitors are known to be potently effective in the treatment of peptic ulcers by inducing acid suppression, they are also effective in low-acid conditions, such as in gastric ulcers associated with severe atrophic gastritis of the corpus. The present study was designed to examine the pH-independent effect of lansoprazole (LPZ) on cell restitution in vitro. The mouse gastric mucosal cell line, GSM06, was cultured to confluence. A 4-fluoric ethylene-tipped aluminum stick was then used to produce a cell-free area in the center of the culture well. After measuring the area of the cell defect using a digital analyzer equipped with an inverted microscope, LPZ was added to each well; the area of the residual cell defect was then measured 6 and 24 hours after LPZ administration. To investigate the involvement of the p44/p42 mitogen-activated protein kinase (MAPK) and p38 MAPK in this process, PD98059 (a MEK inhibitor) or FR167653 (a p38 MAPK inhibitor) was added to the cell cultures. In a separate experiment, GSM06 cells were cultured to the subconfluent level, each test agent was added, and the cell number in each well was measured using an MTT assay 16 hours after the administration of the agents. Six hours after the addition of LPZ, a slight but significant increase in the cell restitution rate was observed in the LPZ-treated groups compared with that in the control group. After 24 hours, a further significant increase in the cell restitution rate was observed in the LPZ groups compared with that in the control group. While the addition of PD98059 significantly attenuated the cell restitution rate in the LPZ groups, the addition of FR167653 had no such effect. The total cell number in the subconfluent cell cultures was significantly increased in the LPZ-treated groups compared with that in the control group. In conclusion, LPZ promotes the healing of injured gastric mucosal cells following injury by enhancing cell proliferation and migration. Furthermore, the mechanism by which cell proliferation and migration is promoted by LPZ may involve the activation of p44/p42 MAPK.

Background and aim: Although ghrelin, a novel growth hormone releasing peptide localised mainly in the gastric fundus, is reported not only to accelerate food passage and gastrointestinal motility but also to affect appetite and weight control, regulation of gastric ghrelin secretion under the conditions of gastric Helicobacter pylori infection is unknown. The present study was designed to investigate plasma and gastric ghrelin levels in Mongolian gerbils with H pylori colonisation of the gastric mucosa. Methods: Gerbils orally inoculated with H pylori were examined after inoculation. To examine preproghrelin mRNA expression in the gastric mucosa, cDNA encoding the gerbil preproghrelin and glyceraldehyde-3-phosphate dehydrogenase homologue was isolated and a quantitative reverse transcription-polymerase chain reaction system was established. Results: In gerbils showing H pylori colonisation (H pylori group), expression of preproghrelin mRNA and total ghrelin levels were significantly decreased 17 and 23 weeks later (p

Ghrelin is a novel gastrointestinal peptide that stimulates growth hormone secretion, food intake, and body weight gain. Increased ghrelin secretion has been reported in such negative energy states as starvation and low body weight. We investigated the dynamics of ghrelin in rats with streptozotocin-induced diabetes, because they present reduced body weight and hyperphagia. The plasma ghrelin levels and gastric preproghrelin mRNA expression levels of the diabetic rats increased significantly and their gastric ghrelin levels decreased significantly. Negative energy balance may enhance preproghrelin mRNA expression and ghrelin secretion into the bloodstream.

Since Marshall's discovery before 20 years, Helicobacter pylori (H. pylori) infection is reportedly to be associated with a variety of clinical outcomes including peptic ulcer disease and gastric cancer. The first step of the H. pylori colonization might be its adhesion to the surface epithelial cells, which evokes gastric inflammatory events initiated by neutrophil recruitment from the microcirculation. Mongolian gerbil is one of the suitable animal models for H. pylori infection, which exerts gastric ulcer and cancer with its bacterial infection. In H. pylori-colonized gerbils, extensive levels of microvascular leukocyte adhesion and migration into the parenchymal side and significant levels of inflammatory cell infiltration are encountered. Bacterial urease not only neutralizes gastric luminal acid, but also plays as an adhesion factor to the surface epithelium. Recently, such an adhesion to the epithelium is reported to be important for bacterial type IV secretory system, which intermediates Cag A injection into the epithelial cells. Then, multiple chemokine and cytokine networks are activated and mucosal inflammatory lesion formation would be completed. In the long-term colonization of H. pylori, gastric mucosal cell turnover would be modified due to persistent inflammation and then such deregulation of cell turnover might link to the precancerous lesion formation.

BACKGROUND AND AIMS: Recent reports indicate the presence of low grade inflammation in functional gastrointestinal disorders (FGID), in these cases often called "post-inflammatory" FGIDs. However, suitable animal models to study these disorders are not available. The Biobreeding (BB) rat consists of a diabetes-resistant (BBDR) and a diabetes-prone (BBDP) strain. In the diabetes-prone strain, 40-60% of the animals develop diabetes and concomitant nitrergic dysfunction. Our aim was to investigate the occurrence of intestinal inflammation, nitrergic dysfunction and intestinal dysmotility in non-diabetic animals. METHODS: Jejunal inflammation (MPO assay, Hematoxylin&Eosin staining and inducible nitric oxide synthase (iNOS) mRNA expression), in vitro jejunal motility (video analysis) and myenteric neuronal numbers (immunohistochemistry) were assessed in control, normoglycaemic BBDP and diabetic BBDP rats. To study the impact of iNOS inhibition on these parameters, normoglycaemic BBDP rats were treated with aminoguanidine. RESULTS: Compared to control, significant polymorphonuclear (PMN) cell infiltration, enhanced MPO activity, increased iNOS mRNA expression and a decreased ratio of nNOS to Hu-C/D positive neurons were observed in both normoglycaemic and diabetic BBDP rats. Aminoguanidine treatment decreased PMN infiltration, iNOS mRNA expression and MPO activity. Moreover, it restored the ratio of nNOS to Hu-C/D positive nerves in the myenteric plexus and decreased the abnormal jejunal elongation and dilation observed in normoglycaemic BBDP rats. CONCLUSIONS: Aminoguanidine treatment counteracts the inflammation-induced nitrergic dysfunction and prevents dysmotility, both of which are independent of hyperglycaemia in BB rats. Nitrergic dysfunction may contribute to the pathophysiology of "low-grade inflammatory" FGIDs. Normoglycaemic BBDP rats may be considered a suitable animal model to study the pathogenesis of FGIDs.

Background. Although the pathogenesis of delayed gastric emptying, namely gastroparesis, is still unclear, diabetes mellitus is major etiology of gastroparesis. Decreased neuronal nitric oxide synthase (nNOS), which induces relaxation of gastric smooth muscle through the production of nitric oxide, is supposed to be one of the mechanisms of gastroparesis (Gastroenterology 113:1535, 1997). However, the effective treatment for gastroparesis has not been developed. While dyslipidemia is a risk factor of diabetic neuropathy, the defect of apolipoprotein E (apoE), a lipid transporter secreted from glial cell, decreased the expression of nNOS in the stomach (Dig Dis Sci. 57:1504, 2012). Furthermore, transplantion of neural stem cell into gastric antral wall was reported to improve delayed gastric emptying in nNOS knockout mouse (Gastroenterology 129:1817, 2005). The aim of the present study is to explore the role of apoE on gastric emptying and evaluate the effect of neural stem cell transplantation against the model of gastroparesis. Methods. The model of type2 diabetes, db/db mice, and apoE knockout mice, which is the model of arteriosclerosis and hyperlipidemia, were used. For measurement of gastric emptying, 0.48 mg of 13C-acetic acid with 0.15 ml liquid meal (Lacol®) was orally administered. The gastric half emptying time (t1/2) measured by 13C breath test was used for evaluation. The expression levels of nNOS, pan-neuronal marker, PGP 9.5, glial fibrillary acidic protein (GFAP), and glia derived neurotrophic factor (GDNF) were examined by immunohistochemistry andWestern blotting. Neural stem cells were isolated from ffLuc-transgenic mouse, which fluorescent protein, venus, and luciferase gene was fused (BBRC 419; 188, 2012). After tertiary neurosphere was formed, it was injected into gastric antral wall by glass needle. Results. Delayed gastric emptying was observed in 27% of db/db mice, while the levels of blood glucose and body weight were not significantly different. The expression of nNOS in gastric antrum and serum level of apoE were significantly decreased in db/db mice which presented delayed gastric emptying. In apoE knockout mice, the gastric emptying was also delayed compared with control. Although, the expression of PGP 9.5 was not changed, the expression of nNOS was significantly decreased in apoE knockout mice. Furthermore, the expression levels of GFAP and GDNF were significantly decreased in apoE knockout mice. Transplantation of neural stem cell significantly improved the delayed gastric emptying in apoE knockout mice. Conclusion. Neural stem cell transplantation restored the delayed gastric emptying in apoE knockout mice, suggesting a promising application of regenerative therapy against gastroparesis.

Background: Twenty percent of advanced gastric cancers are HER2-positive. Trastuzumab(Tmab), a monoclonal antibody that interferes with the HER2 receptor, combined with cisplatin and a fluoropyrimidine has been shown to increase survival in HER2-positive gastric cancer. Tmab induces reactive oxygen species (ROS) in lung adenocarcinoma in vitro, and may have similar effects in other cancer types as well. CD44 variant 9 (CD44v9) expression is associated with a poor prognosis in gastric adenocarcinomas. The CD44v9 isoform interacts with and stabilizes xCT, a glutamate-cystine transporter, resulting in increased intracellular levels of reduced glutathione (GSH), and increased defense against ROS. The relationship between CD44v9 expression and HER2 status in the response of gastric cancer to various treatments, including Tmab has not been reported. The present study was conducted to investigate the role of CD44v9 in the effectiveness of Tmab treatment on gastric adenocarcinomas. We hypothesize that CD44v9 causes resistance to Tmab via induction of ROS resistance, and targeting CD44v9 may increase effectiveness of Tmab therapy. Methods: NCI-N87(high HER2), a gastric cancer cell line, was used for this study. Anti-HER2 siRNA was used to knockdown HER2 expression in NCI-N87 cells. The pRc/CMV expressing plasmid encoding human CD44v9 was transfected into NCI-N87 cells (CD44v9-NCI-N87). N-acetyl cysteine (NAC) (15mM) was used as a ROS scavenger for 72h in vitro. Cells were incubated for 72h with different concentrations of Tmab (a range of doses between 0, 10, 50 μg/ml), and cell viability was determined by MTS assay. Intracellular GSH levels were measured by luminescent based assay. Intracellular ROS were measured by flow cytometry with CM-H2DCFDA. Cells were cultured for 24h with different concentrations of Tmab (a range of doses between 0, 40, 80, 120, 200 μg/ml) in this assay. Results: Tmab caused a dose-dependent decrease in cell viability in NCI-N87 cells(10μg/ml 88.2%(p=0.015), 50μg/ml 73.3%(p

Introduction: Loss of intestinal nitrergic motor control has been reported in Biobreeding diabetes-prone (BBDP) rats (Zandecki 2008). We previously demonstrated that loss of jejunal neuronal nitric oxide synthase (nNOS) mRNA expression occurs in the BBDP, which is related to transient intestinal inflammation (myeloperoxidase: MPO activity) and inducible nitric oxide synthase (iNOS) expression, and which is independent from the development of hyperglycemia (Kindt DDW 2009). Studies in enteric neuron cultures suggest that iNOS overexpression downregulates nNOS expression through oxidative stress (Zandecki 2006). Moreover, aminoguanidine an iNOS inhibitor, counteracts the inflammation-induced nitrergic dysfunction and prevents intestinal elongation and dilatation caused by a 3cm H2O pressure stimulus in normoglycemic BBDP (Masaoka DDW 2011). Aim: To investigate the pathophysiological role of oxidative stress in inflammatory nitrergic dysfunction, we designed a controlled antioxidant supplementation study. Methods: BBDP were fed chow supplemented with 2% vitamin E (α-tocopherol) and 2g/l vitamin C (ascorbic acid) in the drinking water from 21days onwards. After onset of diabetes, 1% vitamin E and 1g/l vitamin C were supplemented to compensate for polyphagia and polydypsia. All rats were sacrificed at 220days. Jejunal inflammation, spontaneous intestinal motility, nitrergic neuron number and nNOS mRNA expression were analyzed respectively by MPO measurements, organ bath (37°C) video analysis, NADPH-diaphorase staining and realtime PCR, both in antioxidant supplemented animals and in a control group of age-matched non-supplemented diabetic animals. Results: Compared with controls (n=7), MPO activity decreased significantly in the antioxidant supplemented group (n=6) (9.9±3.9 vs. 2.1±1.4 U/mg, p 0.05) of a 5-cm jejunum segment in response to intraluminal pressure rise In Vitro. Conclusion: Antioxidant supplementation improves inflammation-induced nitrergic dysfunction and partially prevents intestinal dysmotility in diabetic BBDP.

G A A b st ra ct s CCh were not affected by TS infection (Table). However, in TS-infected rats receiving ketotifen contractile responses to CCh were increased by 60%; an effect completely prevented by pre-incubation with NGF, while the peptide did not affect contractility by itself (Table). Overall, ketotiken had also a tendency to increase cholinergic responses in non-infected animals (Table). L-NNA responses were unaltered by TS infection or ketotifen. Conclusions: During TS infection a significant MMC infiltrate appears in the colon without other structural or functional (as contractility relates) alterations. Altered colonic contractile responses during ketotifen treatment and prevention by NGF suggests that MCs play a protective role normalizing altered motility, likely through a NGF-related mechanism. Overall, these observations suggest that the MMC infiltrate that characterize functional gastrointestinal disorders might represent a protective mechanism aiming the normalization of colonic motility. Contractility (g)