Nobue Ueki

Comparison of gastric emptying and plasma ghrelin levels in patients with functional dyspepsia and non-erosive reflux disease.

Background and Aims: The symptoms of postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), the two subtypes of functional dyspepsia (FD) under the new Rome III classification, tend to overlap with those of non-erosive reflux disease (NERD). Plasma ghrelin levels have been associated with gastric motility; however, clinical studies have yet to examine this relationship among patients with PDS, EPS or NERD. Thus, this study aims to evaluate the correlation between gastric emptying and ghrelin levels as possible candidate factors for gastric motility in these diseases. Methods: One hundred and fifty-one patients presenting with typical symptoms of FD (EPS, n = 36; PDS, n = 76) or NERD (n = 39), and 20 healthy volunteers were enrolled. Gastric motility was evaluated with the Tmax value as a marker of gastric emptying using the 13C-acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms, and SRQ-D scores to determine depression status. We measured both acylated and des-acylated ghrelin levels by ELISA methods. Results: The Tmax value in PDS patients was significantly higher than in healthy volunteers. Acylated ghrelin levels were significantly lower in NERD and PDS patients than in healthy volunteers. Interestingly, there was significant correlation between the acylated ghrelin levels and Tmax value in PDS patients but not in EPS or NERD patients. Conclusion: Our results suggest that acylated ghrelin might play an important role in the pathophysiology of PDS patients through its effect on gastric emptying.

THERAPEUTIC OUTCOMES OF ENDOSCOPIC SUBMUCOSAL DISSECTION OF UNDIFFERENTIATED-TYPE INTRAMUCOSAL GASTRIC CANCER WITHOUT ULCERATION AND PREOPERATIVELY DIAGNOSED AS 20 MILLIMETRES OR LESS IN DIAMETER

Aim:  The aim of the present study was to examine therapeutic outcomes of endoscopic submucosal dissection (ESD) of undifferentiated‐type intramucosal gastric cancer and the problems of diagnosis.

Impact of quadruple regimen of clarithromycin added to metronidazole-containing triple therapy against Helicobacter pylori infection following clarithromycin-containing triple-therapy failure.

Background: The establishment of an optimal second‐line regimen for Helicobacter pylori infection is required. Although quadruple therapy should overcome resistance to either clarithromycin or metronidazole, the effects of a quadruple regimen in second‐line therapy are unknown. This study aims to evaluate the efficacy of triple therapy composed of proton pump inhibitor/amoxicillin plus metronidazole with the combined additive effects of clarithromycin as a second‐line quadruple therapy against H. pylori infection.

Monocyte chemoattractant protein 1 and CD40 ligation have a synergistic effect on vascular endothelial growth factor production through cyclooxygenase 2 upregulation in gastric cancer

BackgroundRecent studies have reported that expression of monocyte chemoattractant protein 1 (MCP-1) and its receptor (CCR2) and CD40 ligation on mesenchymal cells play important roles in tumor development. Cyclooxygenase 2 (COX-2) has also been shown to contribute to tumor angiogenesis. We examined the interaction between MCP-1 and CD40 ligation in mesenchymal cells in gastric cancer to determine the effect of these factors on vascular endothelial growth factor (VEGF) production via upregulation of COX-2 expression.MethodsCOX-2, prostaglandin E2 (PGE2), and VEGF production were evaluated in CD40 ligand (CD40L)-stimulated macrophages. CD40L and MCP-1 mRNA levels in gastric cancer tissues were evaluated by real-time polymerase chain reaction (PCR). Localizations of MCP-1, CD40L, CD34, CD40, and CCR2 in 34 gastric cancer tissue specimens were evaluated by single-or double-label immunohistochemistry.ResultsCOX-2 expression levels were significantly higher in CD40L-stimulated macrophages and correlated with increased PGE2 and VEGF production. Addition of MCP-1 to CD40L-stimulated macrophages had a synergistic effect on COX-2 expression and subsequent PGE2 and VEGF production. CD40L and MCP-1 mRNA levels were significantly higher in poorly differentiated gastric cancers than in H. pylori-infected gastritis patients. High microvessel density was significantly associated with MCP-1 and CCR2 scores and lymph node metastasis.ConclusionsMCP-1 and CD40L had a synergistic effect on COX-2 expression and subsequent VEGF production in gastric cancer.

Chemopreventive effect of celecoxib in gastric cancer.

Abstract.COX (cyclooxygenase) is one of the key enzymes involved in the synthesis of a variety of prostaglandins (PGs), some of which have been strongly linked to inflammation. One of its two well-known isoforms, COX-2, is an inducible enzyme whose induction and expression is dynamically regulated by growth factors, mitogens, and tumor promoters.Several animal and clinical studies have reported the chemopreventive effect of celecoxib, a selective COX-2 inhibitor; and in particular, a few studies have shown that celecoxib prevents the development of gastric cancer. Administration of celecoxib also showed increases in cardiovascular risk and disruption of renal physiology. Therefore, studies hoping to clarify how selective COX-2 inhibitors modulate gastric cancer must keep in mind that coxibs have also been linked to serious cardiovascular events and disruption of renal physiology.

Celecoxib Inhibits Cdx2 Expression and Prevents Gastric Cancer in Helicobacter pylori-Infected Mongolian Gerbils

Background/Aim: The aim of this study was to see whether administration of celecoxib, a selective COX-2 inhibitor, prior to the appearance of intestinal metaplasia could prevent the development of gastric cancer in Helicobacter pylori-infected Mongolian gerbils. Methods:Fifty-two Mongolian gerbilswere divided into 3 groups and given 5 biweekly doses of N-methyl-N-nitrosourea (MNU; 30 ppm). At week 12, group 2 (n = 20) and group 3 (n = 22) gerbils were then given an injection of H. pylori, while group 1 controls (n = 10) received Brucella broth alone. In addition, 7 weeks after H. pylori inoculation, at week 19, group 3 gerbils also received a 36-week administration course of celecoxib (1,500 ppm) in their diet. The incidence of gastric adenocarcinoma was determined at week 54 by histological analysis. COX-2 and Cdx2 protein expression and COX activity were evaluated for each group. The extent of intestinal metaplasia, Cdx2 and MUC2 expression, and the apoptotic index were evaluated semi-quantitatively by immunohistochemistry. Results: The incidence of gastric adenocarcinoma was: group 1, 0% (0/10); group 2, 65% (13/20), and group 3, 23% (5/22; p < 0.05). Continuous celecoxib administration significantly reduced COX activity and COX-2 protein expression, Cdx2 and MUC2 protein immunoreactivity, and the extent of Alcian blue periodic acid-Schiff-positive intestinal metaplasia in H. pylori-infected gerbils. Celecoxib also induced apoptosis in these gerbils. Significant inhibition of Cdx2 expression in group 3 gerbils was also shown by Western blot analysis. Conclusions: Prior to the first appearance of intestinal metaplasia, timely administration of celecoxib prevents gastric cancer occurrence by disrupting the progression of intestinal metaplasia into gastric carcinoma through its inhibition of Cdx2 expression in MNU-pretreated H. pylori-infected Mongolian gerbils.

COMPARISON OF THE DIAGNOSTIC UTILITY OF THE ULTRATHIN ENDOSCOPE AND THE CONVENTIONAL ENDOSCOPE IN EARLY GASTRIC CANCER SCREENING

Currently, transnasal esophagogastroduodenoscopy using an ultrathin endoscope is being widely carried out as a screening test for early gastric cancer. We compared the diagnostic utility of ultrathin esophagogastroduodenoscopy with that of conventional esophagogastroduodenoscopy in detecting 42 lesions of early gastric cancer that had a diameter of ≤20 mm. Only 27 lesions (64%) could be accurately diagnosed using ultrathin esophagogastroduodenoscopy. In nine lesions (22%), we failed to discern whether they were malignant. Six lesions (14%) could not even be detected. We found that the diagnostic utility of ultrathin esophagogastroduodenoscopy was inadequate, especially in the case of lesions that were located in the upper third region of the stomach and variegated lesions. In conclusion, the diagnostic utility of ultrathin esophagogastroduodenoscopy might be lower than that of conventional esophagogastroduodenoscopy in terms of screening for early gastric cancer. The disadvantages of ultrathin esophagogastroduodenoscopy should be taken carefully into consideration while examining lesions.

Preventive therapy for non-steroidal anti-inflammatory drug-induced ulcers in Japanese patients with rheumatoid arthritis: the current situation and a prospective controlled-study of the preventive effects of lansoprazole or famotidine

Background : There is a lack of evidence for the efficacy of preventive medications for peptic ulcers (PUs) among long‐term users of non‐steroidal anti‐inflammatory drugs (NSAIDs) in Japan.

Rebamipide reduces indomethacin-induced gastric injury in mice via down-regulation of ICAM-1 expression

Non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric mucosal injury occurs through subsequent events following free radical production derived from activated neutrophils. In this study, we hypothesized that rebamipide, a novel anti-ulcer agent, exerts a protective effect on NSAID-induced gastric injury through its antioxidant properties. The protective effect of rebamipide in a mouse model of indomethacin-induced gastric injury and mechanisms for this effect were investigated. Pre-treatment with rebamipide significantly inhibited indomethacin-induced gastric mucosal injury in mice. Gastric thiobarbituric acid reactive substances (TBARS) levels and myeloperoxidase (MPO) activity substantially increased 3 hr after indomethacin administration. These increases were significantly inhibited by pre-treatment with rebamipide. Furthermore, rebamipide pre-treatment notably decreased intercellular adhesion molecule-1 (ICAM-1) expression that was up-regulated in gastric tissue treated with indomethacin. Therefore, rebamipide may reduce indomethacin-induced gastric mucosal injuries through its antioxidant effect, which inhibits the neutrophil activation step following up-regulation of ICAM-1 expression on endothelial cells.

Proton pump inhibitors are associated with lower gastrointestinal tract bleeding in low-dose aspirin users with ischaemic heart disease

BACKGROUND Impact of acid suppressants on lower gastrointestinal bleeding remains unclear in low-dose aspirin users; we aimed to investigate this relationship. METHODS Retrospective cohort study of low-dose aspirin users who underwent coronary angiography for ischaemic heart disease in our institution between October 2005 and December 2006; patients were evaluated for upper or lower gastrointestinal bleedings within 3 years post-angiography. RESULTS 538 patients were enrolled (males, 74.4%; mean age 67.4±10.6 years). Risk for upper gastrointestinal bleeding decreased with concomitant use of statins (HR, 0.37; 95% CI, 0.15-0.89), calcium channel blockers (HR, 0.29; 95% CI, 0.10-0.85), and histamine-2 receptor antagonists (HR, 0.26; 95% CI, 0.08-0.89). Concomitant use of proton pump inhibitors tended to decrease risk of upper gastrointestinal bleeding (HR, 0.27; 95% CI, 0.06-1.18). Risk for lower gastrointestinal bleeding increased with both concomitant use of warfarin (HR, 15.68; 95% CI, 4.43-55.53) and proton pump inhibitors (HR, 6.55; 95% CI, 2.01-21.32), but not with histamine-2 receptor antagonists. Hyperuricemia lowered risk for lower gastrointestinal bleeding (HR, 0.12; 95% CI, 0.02-0.88). CONCLUSIONS In low-dose aspirin users, concomitant use of proton pump inhibitors increased lower gastrointestinal bleeding risk, independent from effects on upper gastrointestinal bleeding.