Evaluation of Japanese people's perception of risk information for making decisions to receive influenza and rubella vaccinations.

BACKGROUND: Generally, vaccination uptake in Japan lags behind World Health Organization targets. OBJECTIVE: This study aimed to understand how risk information and advice affect intention to receive vaccinations. METHODS: This study had a within-subjects design. An online survey based on the Health Belief Model was sent to 2501 Japanese individuals (≧20 years) to assess the intention to be vaccinated for influenza and rubella after receiving minor and severe risk information and hypothetical advice about each vaccine. Regression analysis was used to measure changes in intentions to receive each vaccination after being provided with (1) risk information about each vaccine and (2) hypothetical encouragement and discouragement to be vaccinated. MAIN OUTCOMES: The main outcomes included changes in vaccination intentions from baseline. RESULTS: Forty-one percent (N = 1030) of those sent the survey completed it. At baseline, 43% and 65% of the respondents intended to have influenza and rubella vaccinations, respectively. Being provided with information about severe risks and susceptibility increased the intention to have the influenza vaccination among females in their 40s. Receiving inaccurate and discouraging information from one's mother significantly decreased the intention to have the rubella vaccination. Women 50 and older were more likely to intend not to have vaccination for rubella. Severe risk information decreased rubella vaccination intention in all age groups, except women in their 30s and 40s (p < .05). CONCLUSION: For both vaccinations, older individuals demonstrated vaccine hesitancy. This group requires tailored messaging to help them understand their vulnerability (to influenza) and their role in transmission (for rubella) to encourage uptake of essential vaccinations. PATIENT OR PUBLIC CONTRIBUTION: Members of the Japanese public responded to our online questionnaire on vaccination risk.

Efficacy and safety of glecaprevir and pibrentasvir combination therapy in old-aged patients with chronic hepatitis C virus infection.

Objective: Combination therapy with glecaprevir and pibrentasvir (G/P) has been shown to provide a sustained virologic response (SVR) rate of >97% in patients with chronic hepatitis C virus (HCV) infection in the first published real-world Japanese data. However, a recently published study showed that the treatment was often discontinued in patients ≥75 years old, resulting in low SVR in intention-to-treat (ITT) analysis. Thus, our aim was to evaluate real-world data for G/P therapy in patients ≥75 years of age, the population density of which is high in "rural" regions. Patients and Methods: We conducted a multicenter study to assess the efficacy and safety of G/P therapy for chronic HCV infection, in the North Kanto area in Japan. Results: Of the 308 patients enrolled, 294 (95.5%) completed the treatment according to the protocol. In ITT and per-protocol analyses, the overall SVR12 rate was 97.1% and 99.7%, respectively. The old-aged patients group consisted of 59 participants, 56 of whom (94.9%) completed the scheduled protocol. Although old-aged patients tended to have non-SVR factors such as liver cirrhosis, history of HCC, and prior DAA therapies, the SVR12 rates in old-aged patients were 98.3% and 100% in the ITT and PP analyses, respectively. Of 308 patients enrolled, adverse events were observed in 74 patients (24.0%), with grade ≥3 events in 8 patients (2.6%). There was no significant difference in any grade and grade ≥3 adverse events between the old-aged group and the rest of the study participants. Only one patient discontinued the treatment because of adverse events. Conclusion: G/P therapy is effective and safe for old-aged patients.

Effects of Metformin on Left Ventricular Size and Function in Hypertensive Patients with Type 2 Diabetes Mellitus: Results of a Randomized, Controlled, Multicenter, Phase IV Trial.

BACKGROUND: Metformin is the most widely used oral antihyperglycemic agent for patients with type 2 diabetes mellitus (T2DM). Despite the possible benefits of metformin on diabetes mellitus (DM) and heart failure (HF), acute or unstable HF remains a precaution for its use. OBJECTIVE: The aim of the present prospective randomized controlled trial was to assess whether metformin treatment has beneficial effects on patients with T2DM with hypertension without overt HF. METHODS: A total of 164 patients (92 males, 72 females; median age 66 years) were included in this study. Patients with T2DM with a history of hypertension were randomized 1:1 to treatment for 1 year with either metformin (metformin-treated group) or other hypoglycemic agents (control group). The primary endpoints were changes in brain natriuretic peptide (BNP) levels, left ventricular (LV) mass index, and indicators of LV diastolic function. We also evaluated changes in both clinical findings and blood laboratory examination data. RESULTS: We observed no significant changes between baseline and 1-year post-treatment in LV mass index, BNP levels, or E/e' (early diastolic transmitral flow velocity/early diastolic mitral annular velocity; an indicator of LV diastolic function) in either the metformin-treated (n = 83) or the control (n = 81) groups. The metformin-treated group had a significant reduction of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C), but the control group did not. We determined that renal function, including serum creatinine and estimated glomerular filtration rate, deteriorated significantly in the control group but not in the metformin-treated group. CONCLUSION: LV mass and diastolic function were not affected after 1 year of metformin treatment in patients with T2DM. However, we observed benefits in terms of reductions in both BMI and LDL-C levels and preservation of renal function. TRIAL REGISTRATION: UMIN000006504. Registered 7 October 2011.

[Determination of the Effect of Aprepitant and Fosaprepitant for Nausea in Patients with Oral Cancer Receiving Combination Chemotherapy with TPF].

The objective of this study was to determine the effect of aprepitant(from days 1 to 3, po)and fosaprepitant(day 1, iv) for nausea in patients with oral cancer receiving combination chemotherapy with docetaxel, nedaplatin, or cisplatin(divided doses for 5 days), and 5-fluorouracil(TPF).The incidence rate of nausea in the aprepitant group was 60%(6/10), and that in the fosaprepitant group was 90%(9/10).The incidence rate of continuous nausea for more than 2 days was significantly lower in the aprepitant group than in the fosaprepitant group(40%[4/10]vs 90%[9/10], p=0.02; c 2 test).In addition, the mean area under the curve of the chronological changes in the grade of nausea tended to be lower in the aprepitant group than in the fosaprepitant group.In both groups, 3 cases(30%)of vomiting were observed.However, the incidence of continued daily vomiting tended to be lower in the aprepitant group than in the fosaprepitant group.These results suggest that aprepitant is more effective than fosaprepitant for nausea induced by TPF.

Impact of vascular access intervention therapy on cardiac load in hemodialysis patients.

Vascular access intervention therapy (VAIVT) has been positioned as the first choice of treatment for stenosis lesions frequently observed in arteriovenous fistula (AVF) for hemodialysis patients in Japan. Furthermore, increased blood flow can provide a stable dialysis. In contrast, it has been reported that excess blood flow of AVF causes high-output heart failure. Although VAIVT is used to increase blood flow of AVF, the impact of VAIVT on cardiac load has been rarely reported. We examined the factors associated with cardiac load in hemodialysis patients undergoing VAIVT by measuring levels of α human atrial natriuretic polypeptide (hANP) and brain natriuretic peptide (BNP) before and after VAIVT. Data were extracted on hemodialysis patients who underwent measurements of αhANP and BNP in before and after VAIVT at our facility and related facilities between February 2014 and December 2014. Nineteeen patients (median age, 73.0 [66.5-80.5] years; male, 52.6%; 36.8% with diabetes; median duration of dialysis treatment, 50.0 [21-109] months) were enrolled in this study. Flow volume of AVF was higher after VAIVT than that before VAIVT (442.0 vs. 758.0 mL/minute, P < 0.001). Moreover, resistance index (RI) of AVF after VAIVT was lower than that before VAIVT (0.61 vs. 0.53, P < 0.01). Although αhANP did not change before and after VAIVT (55.6 vs. 54.9 pg/mL, P = 0.099), BNP after VAIVT was significantly higher than that before VAIVT (145.2 vs. 175.0 pg/mL, P < 0.05). Factors correlated with the increase in BNP were flow volume of AVF before VAIVT (r = -0.458, P = 0.049) and levels of BNP before VAIVT (r = 0.472, P = 0.041). There was no significant correlation between the increase in αhANP with flow volume of AVF before VAIVT, levels of αhANP before VAIVT. Patients with high levels of BNP and low flow volume of AVF before VAIVT were considered to have a high risk of developing heart failure after VAIVT.

Estimated Glomerular Filtration Rate Variability Independently Predicts Renal Prognosis in Advanced Chronic Kidney Disease Patients.

BACKGROUND: We often experience visit-to-visit estimated glomerular filtration rate (eGFR) variability among patients with advanced chronic kidney disease (CKD). However, the impact of eGFR variability on renal prognosis is not well understood. METHODS: The Kanagawa Valsartan Trial was a multicenter, randomized, open-label trial that compared the effect of add-on treatment with angiotensin II receptor blocker, valsartan, with that of conventional treatment on the rate of CKD progression in 293 advanced CKD patients. In this post hoc analysis, we compared the effect of high eGFR variability on end-stage renal disease (ESRD). To evaluate eGFR variability, we chose participants with ≥ 5 serial measurements of eGFR during the study period and assessed the residual coefficient of variation (CV) of eGFR (residual eGFR-CV) derived from a regression line of eGFR (eGFR slope). The primary end point was the first event of ESRD. RESULTS: Among 237 patients with ≥ 5 serial measurements of eGFR in a median follow-up of 1.47 years, there were 54 ESRD events in the higher than median residual eGFR-CV group and 36 ESRD events in the lower than median eGFR-CV group (log-rank test, p = 0.008). In multivariate Cox regression analysis, high eGFR variability was significantly associated with the primary end point as well as hypertension, high proteinuria, low baseline eGFR and steep eGFR slope (hazards ratio 2.11, 95% CI 1.33-3.33, p = 0.001). CONCLUSION: High eGFR variability predicts poor renal prognosis; therefore, further attention is warranted for ambulatory patients with large eGFR fluctuations, especially those with advanced CKD.

Genetic diversity and distribution of the ciguatera-causing dinoflagellate Gambierdiscus spp. (Dinophyceae) in coastal areas of Japan.

BACKGROUND: The marine epiphytic dinoflagellate genus Gambierdiscus produce toxins that cause ciguatera fish poisoning (CFP): one of the most significant seafood-borne illnesses associated with fish consumption worldwide. So far, occurrences of CFP incidents in Japan have been mainly reported in subtropical areas. A previous phylogeographic study of Japanese Gambierdiscus revealed the existence of two distinct phylotypes: Gambierdiscus sp. type 1 from subtropical and Gambierdiscus sp. type 2 from temperate areas. However, details of the genetic diversity and distribution for Japanese Gambierdiscus are still unclear, because a comprehensive investigation has not been conducted yet. METHODS/PRINCIPAL FINDING: A total of 248 strains were examined from samples mainly collected from western and southern coastal areas of Japan during 2006-2011. The SSU rDNA, the LSU rDNA D8-D10 and the ITS region were selected as genetic markers and phylogenetic analyses were conducted. The genetic diversity of Japanese Gambierdiscus was high since five species/phylotypes were detected: including two reported phylotypes (Gambierdiscus sp. type 1 and Gambierdiscus sp. type 2), two species of Gambierdiscus (G. australes and G. cf. yasumotoi) and a hitherto unreported phylotype Gambierdiscus sp. type 3. The distributions of type 3 and G. cf. yasumotoi were restricted to the temperate and the subtropical area, respectively. On the other hand, type 1, type 2 and G. australes occurred from the subtropical to the temperate area, with a tendency that type 1 and G. australes were dominant in the subtropical area, whereas type 2 was dominant in the temperate area. By using mouse bioassay, type 1, type 3 and G. australes exhibited mouse toxicities. CONCLUSIONS/SIGNIFICANCE: This study revealed a surprising diversity of Japanese Gambierdiscus and the distribution of five species/phylotypes displayed clear geographical patterns in Japanese coastal areas. The SSU rDNA and the LSU rDNA D8-D10 as genetic markers are recommended for further use.

Attenuation of acetic acid-induced gastric ulcer formation in rats by glucosylceramide synthase inhibitors.

INTRODUCTION: Ceramide has been suggested to play a role in apoptosis during gastric ulcerogenesis. The present study is designed to investigate whether accumulated ceramide could serve as the effector molecules of ulcer formation in a rat model of acetic acid-induced gastric ulcer. METHODS: The effect of fumonisin B1, an inhibitor of ceramide synthase, and of d,l,-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP) and N-butyldeoxynojirimycin (NB-DNJ), both inhibitors of glucosylceramide synthase, on the accumulation of ceramide and formation of gastric ulcer were examined in the rat model of acetic acid-induced gastric ulcer. RESULTS: Fumonisin B1 attenuated acetic acid-induced gastric ulcer formation, associated with a decrease in the number of apoptotic cells. Our results showed that it is neither the C18- nor the C24-ceramide itself, but the respective metabolites that were ulcerogenic, because PPMP and NB-DNJ attenuated gastric mucosal apoptosis and the consequent mucosal damage in spite of their reducing the degradation of ceramide. CONCLUSION: The ceramide pathway, in particular, the metabolites of ceramide, significantly contributes to acetic acid-induced gastric damage, possibly via enhancing apoptosis. On the other hand, PPMP and NB-DNJ treatment attenuated gastric mucosal apoptosis and ulcer formation despite increasing the ceramide accumulation, suggesting that it was not the ceramides themselves, but their metabolites that contributed to the ulcer formation in the acetic acid-induced gastric ulcer model.

Aliskiren-associated acute kidney injury in a patient with pre-existing chronic kidney disease and dilated cardiomyopathy.

We report a case of acute kidney injury (AKI) caused by a novel direct renin inhibitor, aliskiren. A 43-year-old Japanese man with dilated cardiomyopathy on cardiac resynchronization therapy with defibrillator and chronic kidney disease (CKD) was started on aliskiren in addition to enalapril, carvedilol, furosemide, and spironolactone for worsening cardiac function suggested by the elevation of serum brain natriuretic peptide. After 1 month, he noticed general malaise, loss of appetite and his serum creatinine level increased from 2.0 to 7.24 mg/dL. He had no evidence of exacerbation of hemodynamic instability (heart failure or hypotension) or post-renal cause of AKI. Although a cessation of aliskiren did not ameliorate AKI, renal function returned to baseline after withholding enalapril. Careful monitoring is necessary when aliskiren is used in patients with CKD and/or significant systolic dysfunction since it can cause normotensive ischemic AKI, especially when there is a concomitant use of other renin-angiotensin-aldosterone system inhibitors.

Phylogeography of ostreopsis along west Pacific coast, with special reference to a novel clade from Japan.

BACKGROUND: A dinoflagellate genus Ostreopsis is known as a potential producer of Palytoxin derivatives. Palytoxin is the most potent non-proteinaceous compound reported so far. There has been a growing number of reports on palytoxin-like poisonings in southern areas of Japan; however, the distribution of Ostreopsis has not been investigated so far. Morphological plasticity of Ostreopsis makes reliable microscopic identification difficult so the employment of molecular tools was desirable. METHODS/PRINCIPAL FINDING: In total 223 clones were examined from samples mainly collected from southern areas of Japan. The D8-D10 region of the nuclear large subunit rDNA (D8-D10) was selected as a genetic marker and phylogenetic analyses were conducted. Although most of the clones were unable to be identified, there potentially 8 putative species established during this study. Among them, Ostreopsis sp. 1-5 did not belong to any known clade, and each of them formed its own clade. The dominant species was Ostreopsis sp. 1, which accounted for more than half of the clones and which was highly toxic and only distributed along the Japanese coast. Comparisons between the D8-D10 and the Internal Transcribed Spacer (ITS) region of the nuclear rDNA, which has widely been used for phylogenetic/phylogeographic studies in Ostreopsis, revealed that the D8-D10 was less variable than the ITS, making consistent and reliable phylogenetic reconstruction possible. CONCLUSIONS/SIGNIFICANCE: This study unveiled a surprisingly diverse and widespread distribution of Japanese Ostreopsis. Further study will be required to better understand the phylogeography of the genus. Our results posed the urgent need for the development of the early detection/warning systems for Ostreopsis, particularly for the widely distributed and strongly toxic Ostreopsis sp. 1. The D8-D10 marker will be suitable for these purposes.

Significant role of ceramide pathway in experimental gastric ulcer formation in rats.

Ceramides have emerged as key participants in the signaling pathway of cytokines and apoptosis. We previously revealed that phorbol 12-myristate 13-acetate (PMA) induced experimental ulcers in rat gastric mucosa. In this study, we investigated the role of ceramide in ulcer formation and its relation to the activation of transcription factors and apoptosis. PMA was subserosally injected to rat glandular stomach. Fumonisin B1 (FB1), an inhibitor of ceramide synthase, was administered together with the PMA. The time course of ceramide content was quantified using thin layer chromatography and the number of apoptotic cells was determined by immunohistochemistry. The activation of transcription factor nuclear factor-kappaB (NF-kappaB) or activator protein-1 (AP-1) was evaluated using an electrophoretic mobility shift assay. The administration of FB1 attenuated PMA-induced gastric ulcer formation in a dose-dependent manner. Before the ulcers became obvious, the ceramide content (C18 and C24 ceramide) increased significantly in the gastric wall. The activation of NF-kappaB and AP-1 and an increase in the number of apoptotic cells were also observed. Both of these were significantly inhibited by the coadministration of FB1. However, NF-kappaB inhibitors attenuated gastric ulcer formation without affecting the ceramide content or the number of apoptotic cells. Ceramide formation in the stomach significantly contributes to PMA-induced tissue damage, possibly via the activation of transcription factors and an increase in apoptosis in the gastric mucosa. However, after the increase in ceramide levels, the NF-kappaB and apoptosis pathways may be separately involved in ulcer formation.

Nuclear factor-kappaB and TNF-alpha mediate gastric ulceration induced by phorbol myristate acetate.

Phorbol esters induce inflammation in rodents by activating protein kinase C. We determined whether nuclear factor-kappaB (NF-kappaB) and tumor necrosis factor-alpha (TNF-alpha) play role in the formation of gastric ulcer induced by phorbol-12-myristate-13-alphacetate (PMA) in rats. Subserosally injected PMA dose-dependently induced gastric mucosal ulcer. Activation of NF-kappaB in the gastric mucosa corresponding to the PMA injection sites was observed before the ulcers became obvious as assessed by an in situ fluorescence DNA binding assay and electrophoretic mobility shift assay. The NF-kappaB activation and subsequent ulcer formation were significantly inhibited by injection of pyrrolidine dithiocarbamate, proteasome inhibitor (MG132), or NF-kappaB decoy. Antibody against TNF-alpha significantly inhibited ulcer formation without attenuating NF-kappaB activation. These results suggest that both NF-kappaB activation followed by TNF-alpha release contribute to tissue damage in PMA-induced gastric ulcer formation.