Yasuhiro Kodaka

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.

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.

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.

Impact of Sleep Disorders, Quality of Life and Gastric Emptying in Distinct Subtypes of Functional Dyspepsia in Japan

Background/Aims The association between clinical symptoms, gastric emptying, quality of life and sleep disorders in distinct functional dyspepsia (FD) patients has not been studied yet in detail. Methods We enrolled 79 FD patients (postprandial distress syndrome [PDS], n = 65; epigastric pain syndrome [EPS], n = 47; EPS-PDS overlap, n = 33) and 44 healthy volunteers. Gastric motility was evaluated. We used Rome III criteria to evaluate clinical symptoms and State-Trait Anxiety Inventory (STAI) scores to determine anxiety status. Sleep disorder was evaluated using the Pittsburgh Sleep Quality Index scores. Results There were no significant differences in age, sex and Helicobacter pylori positivity between FD subtypes and healthy volunteers. The scores of Glasgow dyspepsia severity scores (GDSS), SF-8 and Pittsburgh Sleep Quality Index (PSQI) in distinct subtypes of FD patients were significantly different from those in healthy volunteers. However, there were not significant differences in these scores, Tmax and T1/2 among 3 subtypes of FD patients. PSQI score was significantly (P = 0.027, P = 0.002 and P = 0.039, respectively) associated with GDSS among EPS, PDS and EPS-PDS overlap patients. In addition, 8-item short form health survey (SF-8; Physical Component Score and Mental Component Score) was significantly associated with global PSQI score in PDS and EPS-PDS overlap patients. In contrast, SF-8 (Mental Component Score) only was significantly linked to global PSQI score in EPS patients. Conclusions Prevalences for sleep disorders, gastric motility and quality of life in 3 subtypes of FD patients were similar levels. In PDS and EPS-PDS overlap patients, SF-8 was significantly associated with global PSQI score.

Apurinic/apyrimidinic endonuclease-1 is associated with angiogenesis and VEGF production via upregulation of COX-2 expression in esophageal cancer tissues.

Apurinic/apyrimidinic endonuclease-1 (APE-1) is a key enzyme responsible for DNA base excision repair and is also a multifunctional protein such as redox effector for several transcriptional factors. Our study was designed to investigate APE-1 expression and to study its interaction with cyclooxygenase (COX)-2 expression and VEGF production in the esophageal cancer. The expression of APE-1, COX-2, monocyte chemoattractant protein (MCP)-1, CC-chemokine receptor (CCR)2, and VEGF were evaluated by immunohistochemistry in 65 human esophageal squamous cell carcinoma (ESCC) tissues. Real-time PCR and Western blotting were performed to detect mRNA and protein expression of APE-1 and p-signal transducer and activator of transcription 3 (STAT3) expression in MCP-1-stimulated ESCC cell lines (KYSE 220 and EC-GI-10). siRNA for APE-1 was treated to determine the role of APE-1 in the regulation of COX-2 expression, VEGF production, and antiapoptotic effect against cisplatin. In human ESCC tissues, nuclear localization of APE-1 was observed in 92.3% (60/65) of all tissues. There was a significant relationship (P = 0.029, R = 0.49) between nuclear APE-1 and cytoplasmic COX-2 expression levels in the esophageal cancer tissues. In KYSE 220 and EC-GI-10 cells, MCP-1 stimulation significantly increased mRNA and protein expression of APE-1. Treatment with siRNA for APE-1 significantly inhibited p-STAT3 expression levels in MCP-1-stimulated cells. Furthermore, treatment of siRNA for APE-1 significantly reduced COX-2 expression and VEGF production in MCP-1-stimulated esophageal cancer cell lines. Treatment with APE-1 siRNA significantly increased apoptotic levels in cisplatin-incubated KYSE 220 and EC-GI-10 cells. We concluded that APE-1 is overexpressed and associated with COX-2 expression and VEGF production in esophageal cancer tissues.

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.

Improvement of meal-related symptoms and epigastric pain in patients with functional dyspepsia treated with acotiamide was associated with acylated ghrelin levels in Japan

The aim of this study is to clarify whether acotiamide and rabeprazole combination therapy can improve clinical symptoms, gastric emptying, and satisfaction with treatment in functional dyspepsia (FD) patients more effectively than acotiamide or rabeprazole monotherapy alone. We also aimed to determine whether acotiamide affects these changes via its effect on gastric emptying and appetite‐related hormones such as ghrelin.

Impact of Eating Attitude and Impairment of Physical Quality of Life Between Tertiary Clinic and Primary Clinic Functional Dyspepsia Outpatients in Japan

Background/Aims There is no available data on factors associated with healthcare-seeking behavior for functional dyspepsia (FD) symptoms at either tertiary or primary clinics in Japan. Therefore, we aimed to compare clinical symptoms and life styles such as sleep disorders and eating attitude in FD patients visiting general practitioners at primary clinics with those consulting gastroenterologists at tertiary clinics to clarify healthcare-seeking patterns in Japanese patients. Methods Fifty-one FD outpatients in a tertiary clinic (college hospital), 50 FD outpatients visiting primary clinics and 50 healthy volunteers were enrolled. Clinical symptoms, quality of life, sleep disorders, eating attitude and anxiety were estimated using the Gastrointestinal Symptom Rating Scale (GSRS), Social Functioning-8 (SF-8) test, Pittsburg Sleep Quality Index (PSQI) test and State-Trait Anxiety Inventory (STAI) for FD outpatients and healthy volunteers. Results FD outpatients exhibited higher mean scores of GSRS than healthy volunteers. The SF-8 physical component summary scores in the tertiary clinic group were significantly lower than those in the primary clinic group. GSRS scores were significantly (P < 0.001, P = 0.002) associated with global PSQI scores in FD outpatients as well as with STAI-trait scores (P = 0.006, P = 0.001) compared to healthy volunteers. The frequency of eating between meals in the primary clinic group was significantly (P < 0.05) higher than that in the tertiary clinic group. Conclusions It may be important for clarification of healthcare-seeking behavior to determine the difference in both impairment of physical quality of life and eating attitudes between tertiary clinic and primary clinic FD outpatients in Japan.

Leu72Met408 Polymorphism of the Ghrelin Gene Is Associated With Early Phase of Gastric Emptying in the Patients With Functional Dyspepsia in Japan

Background/Aims There are no available data about the relationship between ghrelin gene genotypes and early phase of gastric emptying in functional dyspepsia (FD) as defined by Rome III classification. Methods We enrolled 74 patients presenting with typical symptoms of FD and 64 healthy volunteers. Gastric motility was evaluated using the 13C-acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms and self-rating questionnaires for depression (SRQ-D) scores to determine status of depression. The Arg51Gln (346G>A), preproghrelin (3056T>C), Leu72Met (408C>A), Gln90Leu (3412T>A) and G-protein β3 (825C>T) polymorphisms were analyzed in the DNA from blood samples of enrolled subjects. Genotyping was performed by polymerase chain reaction. Results There was a significant relationship between the Gln90Leu3412 genotype and SRQ-D score in FD patients (P = 0.009). Area under the curve at 15 minutes (AUC15) value was significantly associated with the Leu72Met408 genotype (P = 0.015) but not with entire gastric emptying. Conclusions The Leu72Met (408C>A) single nucleotide polymorphism was significantly associated with early phase of gastric emptying in FD patients. Further studies will be necessary to clarify the association between ghrelin gene single nucleotide polymorphisms and early phase of gastric emptying in FD patients.

Apurinic/apyrimidinic endonuclease-1 (APE-1) is overexpressed via the activation of NF-κB-p65 in MCP-1-positive esophageal squamous cell carcinoma tissue

Apurinic/apyrimidinic endonuclease-1 (APE-1), a key enzyme responsible for DNA base excision repair (BER), has been linked to cancer chemoradiosensitivity. The phosphorylation of p65 plays a role in the activation of this pathway. In this study, we investigated APE-1 expression and its interaction with p65 in esophageal squamous cell carcinoma (ESCC) tissue. The expression of APE-1, p65, p65 nuclear localization sequence (p65-NLS), and monocyte chemoattractant protein-1 (MCP-1) was assessed by immunohistochemical analysis in 67 human ESCC tissue samples. Real-time PCR and western blotting were also performed. p65 siRNA was evaluated to determine the role of p65 in the regulation of APE-1 expression. We found nuclear localization of APE-1 in 89.6% (60/67) of ESCC tissue samples. We also observed the colocalization of p65-NLS and APE-1 in esophageal cancer tissue. In KYSE220 cells, pretreatment of MG-132 significantly abrogated upregulation of p65 and APE-1 levels induced by MCP-1, and treatment with 10 and 20 nM p65 siRNA significantly inhibited APE-1 mRNA expression. siRNA for p65 treatment significantly increased the apoptotic index in 5-FU-treated KYSE220 cells. We conclude that APE-1 is overexpressed and mainly localized in the nuclear compartment of cancer cells, and partly regulated by p65 in the NF-κB pathway in ESCC tissue.