Changes of Dyspeptic Symptom after Successful Eradication in Helicobacter pylori-Associated Dyspepsia.

BACKGROUND: Helicobacter pylori (H. pylori) gastritis could cause dyspepsia, and eradication is recommended as the first-line treatment. Patients who continuously have their symptoms under control > 6 months after eradication are defined as having H. pylori-associated dyspepsia (HPD), whereas patients who do not benefit from successful eradication are defined as having functional dyspepsia. OBJECTIVES: We assessed changes in dyspeptic symptoms after successful eradication of H. pylori by using a questionnaire. METHODS: We studied H. pylori-infected dyspeptic participants with abdominal symptom scores > 4 points on the Global Overall Symptom (GOS) scoring items and received eradication therapy. We evaluated their symptoms using the GOS questionnaire before their eradications, at 1-month and at 1-year check-ups after eradication therapy. RESULTS: Thirty dyspeptic participants (mean age 59.6 ± 15.3 years) answered every questionnaire. Fourteen participants (46.7%) had HPD, whereas 16 participants (53.3%) were non-HPD patients. The questionnaire at 1 month showed sensitivity of 64.3% (9/14) and specificity of 56.3% (9/16) for HPD. Approximately 60% of H. pylori-infected dyspepsia participants were identified as having HPD or non-HPD within 1 month after their eradications. CONCLUSIONS: Approximately 60% of HPD participants improved at 1 month after eradication. The questionnaire at 1 month helped diagnose HPD in advance and guided next treatment choice.

Multicenter observational study on functional bowel disorders diagnosed using Rome III diagnostic criteria in Japan.

BACKGROUND: The Rome III diagnostic criteria had been used to diagnose functional gastrointestinal disorders (FGIDs) world wide, and functional bowel disorders (FBDs) including irritable bowel syndrome (IBS) have recently attracted the attention of Japanese physicians. However, there have been few reports on the prevalence of FBDs diagnosed by the Rome III diagnostic criteria. AIMS: The aim of this study was to determine the prevalence of FBDs diagnosed according to the diagnostic criteria of Rome III in Japan. PATIENTS AND METHODS: All patients who were booked for colonoscopy were enrolled from eight institutions in Japan. This study was a prospective observational study in the period from April 2013 to December 2013. Patients filled out FGID questionnaires of Rome III when they were waiting for colonoscopy. RESULTS: Data for 1200 patients who underwent colonoscopy were analyzed. A total of 547 patients (45.6%) were diagnosed with FBDs. Out of those patients, 9.1% had IBS. According to the Rome III diagnostic criteria, 134 patients (11.2%) had functional bloating (FB), 73 (6.1%) had functional constipation (FC), 40 (3.3%) had functional diarrhea (FD), and 191 (15.9%) had unspecified functional bowel disorder (UFBD). Patients with FBDs had significantly higher rates of almost all symptoms (abdominal pain, hard or lumpy stools, loose or watery stools, and bloating) than those in the controls. CONCLUSIONS: In Japan, the prevalence of FBDs and IBS is high, similar to that in the US. Many patients with FBDs have multiple symptoms.

Vonoprazan improves the efficacy of Helicobacter pylori eradication therapy with a regimen consisting of clarithromycin and metronidazole in patients allergic to penicillin.

BACKGROUND: Although all Helicobacter pylori (H. pylori)-positive patients should receive eradication therapy, the therapy is a challenge for patients allergic to penicillin. There have been a few reports on the efficacy of eradication therapy for such patients. OBJECTIVE: To analyze the efficacy of vonoprazan or proton pump inhibitor (PPI)-based 7-day triple therapy in patients allergic to penicillin. MATERIALS AND METHODS: A total of 88 consecutive patients allergic to penicillin who received H. pylori eradication therapy were retrospectively analyzed. Thirty-one patients had a history of failed eradication therapy. Four 7-day regimens were prescribed during the study period: clarithromycin-metronidazole-PPI (13 patients), clarithromycin-metronidazole-vonoprazan (14 patients), metronidazole-sitafloxacin-PPI (44 patients) and metronidazole-sitafloxacin-vonoprazan (17 patients). A 13 C-urea breath test was used for confirmation of eradication, and efficacy of eradication was evaluated by "intention-to-treat" analysis and "per-protocol" analysis. RESULTS: Intention-to-treat and per-protocol eradication rates were 46.2%/54.6% for patients who received clarithromycin-metronidazole-PPI, 92.9/92.9% for patients who received clarithromycin-metronidazole-vonoprazan, 100/100% for patients who received metronidazole-sitafloxacin-PPI and 88.2/93.8% for patients who received metronidazole-sitafloxacin-vonoprazan. For first eradication, vonoprazan significantly raised the intention-to-treat efficacy of the triple therapy including clarithromycin-metronidazole (vonoprazan: 92.9%, PPI: 46.2%, P=.0128). A 7-day regimen consisting of metronidazole and sitafloxacin was effective for patients allergic to penicillin with or without past failure of eradication. CONCLUSION: For first eradication in patients allergic to penicillin, a 7-day triple therapy consisting of clarithromycin, metronidazole and vonoprazan could be a candidate eradication regimen.

A prospective, multicenter survey on the validity of shorter periendoscopic cessation of antithrombotic agents in Japan.

BACKGROUND: The management of antithrombotic agents for endoscopic procedures has recently focused on preventing periprocedural thrombosis in Western countries. However, this focus on shorter cessation of antithrombotic agents needs to be examined for its implications for post-procedural bleeding, with potential risk factors for such bleeding clarified in real-world clinical settings in Japan. METHODS: A Sapporo consensus group convened and developed a consensus document on the criteria for cessation of antithrombotic agents. In the multicenter, prospective, observational study that followed to validate the criteria in a real-world clinical setting, of all patients ≥20 years of age receiving antithrombotic agents and undergoing endoscopic procedures, all consenting patients were enrolled. All participating facilities were followed up on their adherence to the criteria and clinical outcomes, such as the occurrence of post-procedural bleeding and thrombosis. RESULTS: A total of 5250 patients, who accounted for 6944 endoscopic procedures, were enrolled from 19 study sites. The consensus criteria, which proved to be nearly consistent with the JSGE criteria revised in 2012, had been adhered to in a total of 6531 procedures performed in 4921 patients. Bleeding and thrombosis were reported in 53 (0.76 %) and two (0.03 %) patients, respectively, among those receiving antithrombotic agents. Post-procedural bleeding was significantly associated with high-bleeding-risk procedures, a high thromboembolic risk with heparin bridging, and the presence of renal failure/dialysis. CONCLUSIONS: With the new criteria in place for cessation of antithrombotic agents focused on prevention of periprocedural thrombosis, endoscopic procedures may be safely performed without substantially increasing bleeding in clinical practice in Japan.

Multicenter randomized controlled study to assess the effect of prophylactic clipping on post-polypectomy delayed bleeding.

BACKGROUND AND AIM: Prophylactic clipping has been widely used to prevent post-procedural bleeding in colon polypctomy. However, its efficiency has not been confirmed and there is no consensus on the usefulness of prophylactic clipping. The aim of the present study was to evaluate the preventive effect of prophylactic clipping on post-polypectomy bleeding. METHODS: A multicenter randomized controlled study was conducted from January 2012 to July 2013 in Japan. Patients who had polyps <2 cm in diameter were divided into a clipping group and a non-clipping group by cluster randomization. After endoscopic polypectomy, patients allocated to the clipping group underwent prophylactic clipping, whereas the procedure was completed without clipping in patients allocated to the non-clipping group. Occurrence of post-polypectomy bleeding was compared between the two groups. RESULTS: Seven hospitals participated in this study. A total of 3365 polyps in 1499 patients were evaluated. The clipping group consisted of 1636 polyps in 752 patients, and the non-clipping group consisted of 1729 polyps in 747 patients. Post-polypectomy bleeding occurred in 1.10% (18/1636) of the cases in the clipping group, and in 0.87% (15/1729) of those in the non-clipping group. The difference was -0.22% (95% confidence interval [CI]: -0.96, 0.53). Upper limit of the 95% CI was lower than the non-inferiority margin (1.5%), and we could thus prove non-inferiority of non-clipping against clipping. CONCLUSION: Prophylactic clipping is not necessary to prevent post-polypectomy bleeding for polyps <2 cm in diameter.

Multicenter study on hemorrhagic risk of heparin bridging therapy for periendoscopic thromboprophylaxis.

BACKGROUND: For endoscopic interventions, heparin bridging therapy is recommended in patients who are at high risk from interruption of antithrombotic therapy. Although heparin bridging has been reported to be effective in preventing thrombosis, several reports have raised concerns about increased risk of bleeding. The aim of this study was to clarify complications of hepari bridging therapy in therapeutic endoscopy. METHODS: A nationwide multicenter survey using questionnaire was performed about patients undergoing therapeutic endoscopy with heparin bridging. Patients who underwent therapeutic endoscopy without heparin bridging therapy were considered as controls. Compliance scores of heparin bridging therapy guideline were employed, and association was analyzed between the score and occurrence of post-procedural bleeding. RESULTS: The incidence of post-procedural bleeding was significantly higher (13.5%, 33/245) in the heparin group compared with the control group (2.7%, 299/11102)(p < 0.001). Thrombosis occurred in 1 patient each in the two groups. In the heparin group, post-procedural bleeding was more likely to be delayed bleeding. Dose adjustment of heparin was a significant factor contributing to bleeding. The compliance score of heparin bridging therapy guideline was significantly higher in those who suffered bleeding. CONCLUSIONS: Heparin bridging therapy significantly increased the risk of post-procedural bleeding compared with the control. The bleeding risk was associated with greater adherence with guidelines for heparin bridging therapy.

Effect of mirabegron on plasma gonadotropic and steroidal hormone levels in rats after two weeks of oral administration.

The effects of mirabegron on plasma gonadotropic and steroidal hormone levels in rats were investigated, when administered orally once daily for two weeks to male and female rats at doses of 10, 30, and 100 mg/kg/day, in order to elucidate a potential mechanism for findings in the reproductive system observed in toxicity studies in rats. Significantly decreased body weight gain and food consumption were observed in males and females at 100 mg/kg/day on Days 1 to 4 of dosing. A significantly prolonged estrous interval was observed in females at 100 mg/kg/day and increased liver weights were noted in females at 30 mg/kg/day or greater. No histopathological changes were observed in the pituitary gland, adrenal glands, liver, testes, epididymides, prostate, seminal vesicle, ovaries, uterus, or vagina at any dose. In males, no treatment-related changes in levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, or dihydrotestosterone (DHT) were observed at any dose. Corticosterone levels in males increased in a dose-dependent manner at 30 mg/kg/day or greater. In females, no treatment-related changes in levels of LH, FSH, prolactin, estradiol, progesterone, or corticosterone were observed at any dose in any stage of the estrous cycle. Taken together, these results suggest that mirabegron has no effect on gonadotropic or sex steroidal hormone levels in either sex at doses up to 100 mg/kg/day. In contrast, adrenocortical hormone levels were increased in males at mirabegron doses of 30 mg/kg/day or greater.

Endoscopic diagnosis of early neoplasia of the esophagus with narrow band imaging: correlations among background coloration and iodine staining findings.

BACKGROUND AND AIM: It was previously reported that high-grade intraepithelial neoplasia of the esophagus turns pink within a few minutes after iodine staining (pink-color sign; PCS); however, iodine staining is uncomfortable. By using narrow band imaging (NBI), color change in the area between the intraepithelial papillary capillary loop (background coloration; BGC) is often observed within the brownish area. The diagnostic usefulness of BGC findings for differentiating high-grade intraepithelial neoplasia from low-grade intraepithelial neoplasia was evaluated. METHODS: In a prospective observational study from September 2010 to August 2012, 285 patients who were in a high-risk group for esophageal squamous cell carcinoma underwent endoscopic examination. Lesions with both endoscopic findings of dilated intraepithelial papillary capillary loop on NBI and iodine-unstained areas were studied, in which endoscopic biopsy or endoscopic resection was subsequently performed. The esophageal background mucosa was also evaluated on the basis of the iodine staining pattern (uniform type: Group U, scattered type: Group S). RESULTS: One hundred three esophageal lesions in 87 patients were studied. When BGC was used as the differentiation index, sensitivity was 93.8%, specificity was 88.2%, and accuracy was 91.3%. When PCS was used, sensitivity was 97.9%, specificity was 88.2%, and accuracy was 93.2% (P = 0.79). In Group U (n = 54), BGC had an accuracy of 93.8%, and PCS had an accuracy of 92.3% (P = 1.0). On the other hand, in Group S (n = 33), BGC had an accuracy of 86.8%, while PCS had an accuracy of 94.7% (P = 0.27). CONCLUSIONS: Diagnosis using BGC on NBI may substitute for diagnosis based on PCS in many patients.

Comparison of gastric relaxation and sensory functions between functional dyspepsia and healthy subjects using novel drinking-ultrasonography test.

BACKGROUND: Functional dyspepsia (FD) is a heterogeneous disease characterized by various upper abdominal symptoms. The major mechanism of FD includes impaired fundic accommodation, delayed gastric emptying and visceral hypersensitivity. We developed a novel drinking-ultrasonography test to combine a drink test with ultrasonography to assess gastric motility and sensory function of FD patients. METHOD: Subjects were 20 healthy volunteers and 26 successive FD patients according to the Rome III criteria. The subjects ingested 200 ml of water at 2-min intervals 4 times (total 800 ml) through a straw. The maximum cross section of the proximal stomach was visualized before water intake, after each water intake, and 5 and 10 min after the completion of drinking using extracorporeal ultrasonography. Abdominal symptoms were evaluated using the visual analog scale (VAS) a total of 5 times. RESULTS: The mean cross-sectional area of the fornix after 800 ml of water intake was significantly lower in the FD group compared with the control group. In the FD group, marked abdominal symptoms developed immediately after initiation of water intake, and VAS score differed significantly (p < 0.01) between the control and FD groups at each time point. CONCLUSION: We developed the novel drinking-ultrasonography test which revealed abnormalities in gastric accommodation and sensation in patients with FD compared with healthy controls. This approach can be readily performed and allows the simultaneous evaluation of gastric accommodation, emptying and sensation.

Clinicopathological analysis of early-stage gastric cancers detected after successful eradication of Helicobacter pylori.

BACKGROUND AND AIMS: The results of a randomized controlled study and meta-analysis study have recently proved that Helicobacter pylori eradication has a preventive effect against the development of metachronous and primary gastric cancer. However, gastric cancer is sometimes detected after successful eradication. There is a lack of study about gastric cancers in eradicated patients. To clarify the characteristics of gastric cancers detected after H. pylori eradication, we analyzed the clinicopathological features of these cancers. METHODS: The subjects were 18 early-stage gastric cancer specimens resected from 17 patients who had received successful eradication of H. pylori from February 1995 to March 2009. The control group consisted of 36 specimens from noneradicated patients with persistent H. pylori infection who were matched with the subjects in age, sex, and depth of invasion. Clinicopathological features and mucin phenotypes of gastric cancer were clinically and immunohistologically evaluated. RESULTS: The average diameter of gastric cancer was smaller and Ki-67 index was lower in the eradication group. The morphological distribution of depression types was significantly lower in the control group. Immunohistochemical phenotyping revealed that 72.2% of the lesions in the eradicated group were complete gastric type or gastric predominant mixed type, whereas the percentages of gastric type and intestinal type in the control group were similar. CONCLUSION: Our findings indicate that the clinicopathological characteristics of gastric cancers detected after H. pylori eradication are different from those of gastric cancers in patients with persistent H. pylori infection. H. pylori eradication may suppress intestinalization during the development of gastric cancer.

Lafutidine prevents low-dose aspirin and loxoprofen induced gastric injury: a randomized, double-blinded, placebo controlled study.

BACKGROUND AND AIM: The concomitant use of non-steroidal anti-inflammatory drugs is a risk factor for low-dose aspirin (LDA)-associated upper gastrointestinal toxicity. Lafutidine is an H2-receptor antagonist with gastroprotective activity, produced by acting on capsaicin-sensitive afferent neurons. To evaluate the preventive effect of lafutidine on gastric damage caused by LDA alone and by the combination of both LDA and loxoprofen, we conducted a clinical study using healthy volunteers. METHODS: A randomized, double-blinded, placebo-controlled, crossover study was carried out. Sixteen healthy volunteers without Helicobacter pylori infection were randomly assigned to two groups. Both groups received 81 mg of aspirin once daily for 14 days (on days 1 to 14) and 60 mg of loxoprofen three times daily for the last 7 days (on days 8 to 14). Placebo or 10 mg of lafutidine was administered twice daily for 14 days in each group. After a 2-week washout period, placebo and lafutidine were crossed over. Endoscopic findings of gastric mucosal damage were evaluated according to the modified Lanza score. RESULTS: The mean modified Lanza score was 2.19 ± 1.06 (SD) for aspirin plus placebo as compared with 0.50 ± 0.77 for aspirin plus lafutidine (P < 0.001), and 3.00 ± 1.56 for aspirin plus loxoprofen and placebo as compared with 1.25 ± 1.37 for aspirin plus loxoprofen and lafutidine (P < 0.01). CONCLUSIONS: The addition of loxoprofen to LDA increases gastric mucosal damage. Standard-dose lafutidine significantly prevents gastric mucosal damage induced by LDA alone or LDA plus loxoprofen in H. pylori-negative volunteers. Larger controlled studies are needed to strengthen these findings.

[Position of NSAIDs in causal factors of peptic ulcer].

The cause of peptic ulcer is classified into five categories; infectious, drug-induced, hyperacidic, secondary, and idiopathic. Among these factors, H. pylori infection and non-steroidal anti-inflammatory drugs including aspirin (NSAIDs) are most important for development of gastroduodenal ulcer. More than 95 percent of gastroduodenal ulcers are associated with H. pylori or NSAIDs. Therefore, the frequency of non-H. pylori non-NSAIDs ulcer is very low. NSAIDs have the effect to inhibit synthesis of cyclooxygenase-1 (COX 1) and COX-2. This inhibitory action induces analgesic and anti-inflammatory effects. On the other hand, inhibitory action for COX-1 reduces the production of prostaglandin that is related to protective effect for gastrointestinal mucosa. Its mechanism is able to induce gastroduodenal ulcer. Since the elderly population in Japan is rising, the number of patients who need NSAIDs treatment is expected to increase in near future.

Improvement in symptoms after H2-receptor antagonist-based therapy for eradication of H pylori infection.

AIM: To investigate the therapeutic effects of triple therapy combining lafutidine with clarithromycin and amoxicillin on H pylori infection and the resolution of gastroesophageal symptoms after eradication. METHODS: We conducted a randomized, multicenter, open-label controlled trial to compare the effectiveness of a triple therapy of lafutidine, clarithromycin, and amoxicillin (lafutidine group) with that of a triple therapy of lansoprazole, clarithromycin, and amoxicillin (lansoprazole group) in patients with H pylori infection. The study group comprised 22 patients with gastric ulcers and 18 patients with duodenal ulcers who had H pylori infection. RESULTS: H pylori eradication rates were similar in the lafutidine group (14/20, 70%) and the lansoprazole group (14/20, 70%). Gastroesophageal reflux and abdominal symptoms improved after eradication therapy in both groups, whereas abdominal discomfort, diarrhea, and constipation were unchanged. H pylori status had no apparent effect on improvement of gastroesophageal reflux or abdominal symptoms after treatment. Adverse events were similar in both groups. CONCLUSION: The triple therapy including lafutidine is equivalent to triple therapy including lansoprazole in terms of H pylori eradication rates and improvement in gastroesophageal reflux and abdominal symptoms. These results are attributed to the fact that lafutidine has strong, continuous antisecretory activity, unaffected by CYP2C19 polymorphisms.

[Immunological rapid urease test].

Immunological rapid urease test for detection of Helicobacter pylori infection, composed of a solid-phase tip coated with monoclonal antibody against H. pylori's urease and ion-sensitive field transistor (ISFT)-based pH sensor system, was developed. The monoclonal antibody against H. pylori's urease was useful to avoid the contamination of urease activity in other bacteria. Because ISFTT had high ability to detect pH change, the sensitivity and specificity of immunological rapid urease test was significantly improved comparing with that of conventional rapid urease test. The utility of immunological rapid urease test was evaluated in some clinical studies.

Long-term alteration of gene expression without morphological change in testis after neonatal exposure to genistein in mice: toxicogenomic analysis using cDNA microarray.

In this study, we carried out toxicogenomic analysis using in-house cDNA microarray to ascertain the long-term effects of neonatal exposure to genistein, also known as phytoestrogen, on testicular gene expression in mice. Male ICR mice, 1 day after birth, were exposed for 5 days to genistein (1000 microg/mouse/day) or diethylstilbestrol (DES) (50 microg/mouse/day), used as an example of a potent estrogen, and their testes were used when they were 12 weeks old. Since exposure to DES was been reported to induce morphological changes and alteration of gene expression in reproductive organs, DES was used as a positive control. Genistein-treated mice did not show any histological abnormalities or increased apoptotic cells in testes, but these abnormalities and increases were found in DES-treated mice. On the other hand, mRNA expression analysis using in-house cDNA microarray revealed that 2 down-regulated genes (GeneBank accession No. W49392 and AI430907) were detected in genistein-treated mouse testes. Moreover, real-time PCR analysis revealed that mRNAs of the W49392 gene, estrogen receptor alpha (ERalpha) and androgen receptor (AR), were down-regulated in the testes of both genistein-treated and DES-treated mice. In our present study using toxicogenomic analysis, long-term alteration in testicular mRNA expression, without morphological change in testes, was detected after neonatal treatment with genistein, indicating that the W49392 gene, in addition to ERalpha and AR, might be useful as a biological marker for predicting the effects of neonatal exposure to DES and genistein.

Detection of mitomycin C-induced testicular toxicity by micronucleus assay in mice.

Background, Aims and Methods: Mitomycin C is a promising cancer agent that has been shown to inhibit DNA synthesis. Our previous study showed that mitomycin C induces spermatogenic cell apoptosis in the mouse testis. By using TdT-mediated dUTP-biotin nick-end labeling in the study, we confirmed that apoptotic cell death was most commonly found in the spermatogonia and less frequently found in spermatocytes in mitomycin C-treated mice. We therefore hypothesized that the spermatogenic cell apoptosis induced by mitomycin C occurred as the result of a mechanism to eliminate male germ cells with DNA damage or chromosomal aberrations. To test our hypothesis, we used a micronucleus assay for the detection of chromosomal damage induced in the spermatogonia or spermatocyte stages. Results and Conclusions: The frequency of micronuclei was clearly increased in the mitomycin C-treated animals, and the number of micronuclei was greater at the spermatogonia or early spermatocyte stage than at the secondary spermatocyte stage. These results revealed that apoptosis and chromosomal aberration in the mouse testis after mitomycin C treatment occurred in the same cell types, that is, spermatogonia and spermatocytes. These findings indicate that chromosomal aberration of the spermatogenic cells induced by mitomycin C may have caused the spermatogenic cell apoptosis. (Reprod Med Biol 2003; 2: 69-73).