Tomotaka Shindo

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.

Migration of eosinophils and CCR2-/CD68-double positive cells into the duodenal mucosa of patients with postinfectious functional dyspepsia.

OBJECTIVES:Recent studies have shown that postinfectious functional dyspepsia (FD) symptoms may persist after elimination of gastrointestinal (GI) infection as well as postinfectious irritable bowel syndrome accompanying colonic inflammation. However, it is unclear whether intestinal chronic inflammation can contribute to clinical symptoms of certain FD patients such as postinfectious FD. To determine the relationship between local inflammation of the duodenum and clinical symptoms, we evaluated the infiltration of several phenotypes of duodenal inflammatory cells as well as gastric motility using 13C urea breath test in postinfectious FD patients.METHODS:We enrolled 136 consecutive patients diagnosed with FD according to Rome III criteria, and 20 healthy controls, after upper GI endoscopy. Gastric motility was evaluated by gastric emptying time (T-max) using the 13C-acetate breath test. Upper abdominal symptoms including epigastric pain, epigastric burning, postprandial fullness, abdominal distension, and early satiety were assessed by questionnaire scores. We obtained biopsy specimens from the stomach and duodenum during upper GI endoscopy. Histological gastritis and duodenitis were assessed as mild, moderate, or severe according to previously described criteria. Characteristics of inflammatory cells and neuroendocrine cells were determined immunohistochemically with antibodies to CD3, CD68, CCR2, Vdelta1 TCR, and serotonin.RESULTS:Endoscopic duodenitis was observed in only 5.7% of postinfectious FD patients. However, the rates of histological duodenitis in duodenal biopsies of postinfectious FD patients were 17% for mild, 26% for moderate, and 57% for severe grades of duodenitis. The degree of histological duodenitis of postinfectious FD patients was significantly greater than that of healthy volunteers. There was a significant correlation between epigastric burning and the degree of duodenitis in postinfectious FD patients. There was no significant difference in histological duodenitis and T-max value in the postinfectious FD patients with or without Helicobacter pylori infection. In addition, CD68-positive cell number in postinfectious FD patients was significantly increased compared with the numbers in subjects with epigastric pain syndrome or postprandial distress syndrome and in healthy volunteers. CCR2-/CD68-double positive cell number in postinfectious FD patients was significantly (P=0.009) increased compared with those in healthy volunteers.CONCLUSIONS:Migration of inflammatory cells, in particular, duodenal CCR2-positive macrophages, may have an important function in the pathophysiology of postinfectious FD patients.

Nizatidine improves clinical symptoms and gastric emptying in patients with functional dyspepsia accompanied by impaired gastric emptying.

Background/Aims: In this crossover study, we investigated whether nizatidine, a H2-receptor antagonist, can alleviate clinical symptoms and gastric emptying in patients with Rome III-based functional dyspepsia (FD) with or without impaired gastric emptying. Methods: We enrolled 30 patients presenting with FD symptoms (epigastric pain syndrome, n = 6; postprandial distress syndrome, n = 24). Rome III-based FD patients were treated with nizatidine (300 mg/day) or placebo for 4 weeks in a crossover trial. Gastric motility was mainly evaluated with the Tmax value using the 13C-acetate breath test. Meal-related symptoms were defined as postprandial fullness and early satiation. Gastroesophageal symptom was defined as a burning feeling rising from the stomach or lower chest up toward the neck. Acylated- and desacylated ghrelin levels were evaluated by the ELISA method. Clinical symptoms, gastric emptying and ghrelin levels were evaluated at three different points during the study (pretreatment, after 4 weeks former treatment and after 4 weeks later treatment). The primary end point of this study was to determine whether nizatidine would improve clinical symptoms and gastric emptying in FD patients with or without impaired gastric emptying via affecting ghrelin levels. Results: Meal-related symptoms of the patients treated with nizatidine improved significantly (21/30; 70%) compared to those treated with placebo (3/30; 10%). In addition, nizatidine treatment also significantly improved gastroesophageal symptoms (16/30; 53%) compared to those treated with placebo (0/30; 0%). Nizatidine treatment in patients with FD accompanied by impaired gastric emptying significantly improved clinical symptoms and Tmax value as a marker of gastric emptying (10/11, 91%; 9/11, 82%) compared to placebo therapy, respectively. There were no significant differences in ghrelin levels between nizatidine treatment and placebo therapy. Conclusion: Nizatidine administration significantly improved both gastric emptying and clinical symptoms in FD patients with impaired gastric emptying.

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.

G-protein β3 subunit 825CC genotype is associated with postprandial distress syndrome with impaired gastric emptying and with the feeling of hunger in Japanese.

Background  G‐protein dysfunction related alteration of intracellular signal transduction might be linked to various abnormalities of functional gastrointestinal (GI) disorders. Serotonin (5‐hydroxytryptamine; 5‐HT) as well as G‐protein is also key signaling molecule sensorimotor functions in the GI tract. Thus, this study aims to evaluate the correlation between gastric emptying and GNβ3 and 5‐HTs polymorphisms in functional dyspepsia (FD) as defined by Rome III classification.

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.

Expression of apurinic/apyrimidinic endonuclease-1 (APE-1) in H. pylori-associated gastritis, gastric adenoma, and gastric cancer.

Background and Aim:  Apurinic/apyrimidinic endonuclease‐1 (APE‐1) is a key enzyme in DNA base excision repair (BER), linked to cancer chemosensitivity. However, little is known about the localization of APE‐1 in Helicobacter pylori‐infected gastric mucosa or its role in the development of gastric cancer. To investigate the role of APE‐1 in the development of gastric cancer, we examined APE‐1 expression and localization in cultured cells and gastric biopsies from patients with H. pylori‐infected gastritis or gastric adenoma, and from surgically resected gastric cancer.

Impact of sleep disorders in Japanese patients with functional dyspepsia (FD): Nizatidine improves clinical symptoms, gastric emptying and sleep disorders in FD patients

The association between functional dyspepsia (FD) and sleep disorders has yet to be studied in detail. The aim of this study is to evaluate the risk factors associated with sleep disorders and the clinical response to nizatidine therapy for sleep disorders in Rome III‐based FD patients.

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.