Akihiko Kurosawa

Oesophageal hypersensitivity in Japanese patients with non‐erosive gastro‐oesophageal reflux diseases

Background : Visceral hypersensitivity plays a major role in the pathogenesis of non‐erosive oesophageal reflux disease (NERD). Prevalence of NERD differs according to the population and geographical region. Oesophageal hypersensitivity in NERD has not been well studied, especially in Japanese patients.

Alteration of histological gastritis after cure of Helicobacter pylori infection

Background : It is still disputed whether gastric atrophy or intestinal metaplasia improves after the cure of Helicobacter pylori infection.

Addition of Metronidazole to Rabeprazole-Amoxicillin-Clarithromycin Regimen for Helicobacter pylori Infection Provides an Excellent Cure Rate with Five-Day Therapy

Background. New triple therapy for eradication of Helicobacter pylori based on a proton pump inhibitor (PPI) provides a cure rate of approximately 90% with few adverse effects. Recently, a PPI‐based quadruple therapy, which consists of a PPI plus bismuth‐based triple therapy for 7 days, has been studied, and a sufficient eradication rate has been achieved. However, a shorter duration results in improved compliance. In this study, newly developed short‐term, simple twice‐daily quadruple therapy consisting of rabeprazole, amoxicillin, clarithromycin, and metronidazole (RACM) was compared with a PPI‐based triple‐therapy regimen for eradication of H. pylori.

Increased esophageal sensitivity to acid and saline in patients with nonerosive gastro-esophageal reflux disease

Goals To investigate the features of nonerosive reflux disease (NERD). Background NERD is not considered as a milder form of erosive gastro-esophageal reflux disease (eGERD). Although the prevalence of NERD was reported to be high in our country, there have been very few studies about NERD. Study We performed upper gastrointestinal endoscopy to confirm the diagnosis of GERD. The modified acid perfusion test and saline perfusion test were performed in 7 control subjects, 14 NERD, and 11 eGERD patients. The stimulus-response function to acid and saline was quantified by the duration of typical symptom perception (minutes), total sensory intensity rating (0 to 10), and the perfusion sensory score (SS), which was defined as the product of minutes and the sensory intensity rating. Results The mean value of SS by saline was 0 in control subjects, 12.0 in NERD patients, and 1.5 in eGERD patients (P<0.01 control vs. NERD, P<0.01 NERD vs. eGERD). The mean SS with acid was 0.9 in control subjects, 52.5 in NERD patients, and 23.0 in eGERD patients (P<0.01 control vs. NERD, control vs. eGERD, P<0.05 NERD vs. eGERD). A statistically significant association was shown between the acid and saline perfusion SSs with a correlation coefficient value of r=0.57 in the NERD group (P<0.05). Conclusions Both eGERD and NERD, but especially NERD, exhibited esophageal hypersensitivity not only to acid but also saline perfusion, suggesting that hyperalgesia to acid and other factors (eg, psychologic and/or autonomic nerve disturbance) may play some roles in symptom generation in NERD.

Altered localization and expression of tight-junction proteins in a rat model with chronic acid reflux esophagitis.

BackgroundThe esophageal tight junction is responsible for the paracellular sealing of the epithelium. Alteration of the expression of tight-junction proteins plays crucial roles in the pathogenesis of some human diseases. The aim of this study was to investigate the distribution and expression pattern of tight-junction proteins in the esophageal mucosa of control rats and rats with reflux esophagitis.MethodsChronic acid reflux esophagitis was experimentally induced by operation in rats. The animals were killed on days 7 and 14 after the operation. The thickness of the mucosa and the 5-bromo-2-deoxyuridine (BrdU) labeling index were assessed. The expression pattern of the tight-junction proteins claudin 1-4 and occludin in the esophageal mucosa was investigated by immunofluorescence staining and Western blotting in the controls and esophagitis rats.ResultsIn the esophagitis model, the thickness and BrdU labeling index increased with time. In control rats, claudin-1, -3, and -4 were localized on the cellular membranes of esophageal epithelial cells, mainly in the spinous and granular layers, while claudin-2 was not detected in any layer. Occludin was seen on the cellular membranes in all esophageal mucosal layers. In the esophagitis rats, the expression of claudin-1 was increased both in the plasma membrane and in the cytoplasm around the erosion in the spinous and granular layers. The expression of claudin-4 and occludin shifted to the cytoplasm from the plasma membrane in the spinous and granular layers. In contrast, the expression of claudin-3 was decreased in the spinous and granular layers.ConclusionsThe localization and the expression patterns of tight-junction proteins were different in the controls and the rat esophagitis model. The expression of claudin-3 in the esophageal mucosa was decreased, while that of claudin-1 was increased. It is postulated that these alterations in tight-junction proteins most likely increase the permeability of the esophageal the epithelium, thereby impairing the defense mechanism of this epithelium.

Five-day proton pump inhibitor-based quadruple therapy regimen is more effective than 7-day triple therapy regimen for Helicobacter pylori infection

There have been no reports that describe whether 5‐day quadruple therapy (rabeprazole + amoxicillin + clarithromycin + metronidazole; RACM) could substitute for standard 7‐day triple therapy as a first‐line therapy for Helicobacter pylori.

Is antimicrobial susceptibility testing necessary before second-line treatment for Helicobacter pylori infection?

Background:  An antimicrobial susceptibility test for Helicobacter pylori before second‐line treatment is often performed, although whether the test is truly necessary remains unknown.

Improvement in serum pepsinogens and gastrin in long-term monitoring after eradication of Helicobacter pylori: comparison with H. pylori-negative patients

Background : A decrease in pepsinogen and gastrin levels 1–3 months after Helicobacter pylori eradication is well known. However, few data are available on the long‐term progression of these decreases beyond 1 year after eradication, and there has been no investigation into whether pepsinogen and gastrin levels return to normal levels as defined by data from H. pylori‐negative patients with dyspepsia.

Second-line treatment for Helicobacter pylori infection in Japan : proton pump inhibitor-based amoxicillin and metronidazole regimen

BackgroundRecent studies have reported that proton pump inhibitor (PPI)/amoxicillin (A) metronidazole (M) therapy for Helicobacter pylori infection provides a sufficient cure rate in Japan in patients who have failed first-line treatment with PPI/amoxicillin and clarithromycin (AC). To validate the efficacy of this regimen as second-line therapy, our experience with second-line treatment using a PPI/AM regimen was reviewed.MethodsWe analyzed data on 151 patients who had been prescribed a 10-day PPI/AM re-treatment regimen after eradication failure of 1 to 2 weeks’ first-line PPI/AC therapy. The PPI/AM regimen was given according to results of susceptibility testing (S+) in 31 patients. The group that had undergone susceptibility testing was further divided into two subgroups according to dosage: standard dose of omeprazole (O)/AM (n = 11) and double dose of lansoprazole (L)/AM (n = 20). The PPI/AM regimen was given without susceptibility testing (S−) to 120 patients. These patients were also divided into two subgroups according to whether they received omeprazole or lansoprazole: OAM (n = 61) and LAM (n = 59). Cure rates and adverse effects in each group were analyzed.ResultsThe intention-to-treat (ITT)-based cure rate with/without susceptibility testing was 93.5% (95% confidence interval [CI], 79%–99%) and 87.5% (95% CI, 80%–93%), respectively (not significant [NS]). The ITT-based cure rate in S+/S− for OAM and S+/S− for LAM was 90.9% (95% CI, 59%–100%)/82% (95% CI, 70%–91%), and 95% (95% CI, 75%–100%)/93.2% (95% CI, 84%–98%), respectively (NS). Adverse effects were seen in 26.3% and 32.5% of patients in the OAM group and the LAM group, respectively (NS).ConclusionsThe 10-day PPI/AM re-treatment regimen is safe and effective, suggesting its usefulness as second-line treatment in Japan in patients who have failed initial treatment with the PPI/AC regimen.

Inhibition of cell proliferation and induction of apoptosis by Helicobacter pylori through increased phosphorylated p53, p21 and Bax expression in endothelial cells.

Microcirculation plays a crucial role in mucosal physiological function as well as repair of gastric mucosal damage. Endothelial cell damage is known to disturb microcirculation and suppress angiogenesis. Therefore, the direct effect of Helicobacter pylori on endothelial cells in vitro was investigated with H. pylori water extract. The effect of H. pylori water extract on cell proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) was evaluated. The ratio of BrdU-positive HUVECs in both cagA/vacA-positive and -negative H. pylori water extract-treated groups was significantly lower at 24 h than that in the control group, but Escherichia coli water extract did not affect the proliferation of these endothelial cells. Apoptosis was induced by H. pylori water extracts after incubation for 24 h in a cagA/vacA-independent manner. In the mitochondrial permeability transition assay, tetramethylrhodamine methyl ester was accumulated in mitochondria of HUVECs. Western blot analysis showed no difference in the level of total p53 protein in H. pylori water extract-treated and non-treated cells, but the level of phosphorylated p53 protein was increased in the treated cells at 15 and 60 min after addition of the extract. Reverse transcription (RT)-PCR products for p21 and Bax were elevated in the H. pylori water extract-treated cells. p21 levels began to increase 0.5-1 h after addition of the extract, whereas Bax increased in the period 0.5-2 h. H. pylori induced a disturbance of cell proliferation and apoptosis in the vascular endothelial cells which may contribute to gastric mucosal injury and to delayed healing of gastric lesions.