Masahiko Gosho

Prevalence of Helicobacter pylori Infection by Birth Year and Geographic Area in Japan

Helicobacter pylori (H. pylori)‐related diseases are responsible for a tremendous amount of morbidity and mortality in Japan. We estimated the prevalence of H. pylori infection by sex, birth year, and geographic area among Japanese adults.

Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: A meta-analysis of randomized controlled trials

OBJECTIVESnVitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH.nnnMETHODSnPubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis.nnnRESULTSnAccording to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment.nnnCONCLUSIONSnVitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH.

Morningness–eveningness questionnaire score and metabolic parameters in patients with type 2 diabetes mellitus

“Morningness” and “Eveningness” represent lifestyle patterns including sleep–wake patterns. Although previous studies described a relationship between the morningness–eveningness trait and glycemic control in patients with type 2 diabetes mellitus (T2DM), the mechanism underlying this association remains unknown. The study participants comprised 725 Japanese T2DM outpatients free of history of cardiovascular diseases. Various lifestyles were analyzed using self-reported questionnaires, including morningness–eveningness questionnaire (MEQ). The relationships between morningness–eveningness trait and various biochemical parameters were investigated by linear regression analysis and logistic regression analysis. We classified the study patients into three groups, morning type (nu2009=u2009117), neither type (nu2009=u2009424) and evening type (nu2009=u2009184). Subjects of the evening type had high levels of alanine aminotransferase, triglyceride, fasting blood glucose and HbA1c and low high-density lipoprotein-cholesterol level in a model adjusted for age and gender. Furthermore, multivariate analysis showed that the evening type was associated with high HbA1c and estimated glomerular filtration rate even after adjustment for other lifestyle factors known to affect metabolic control. The results suggest that T2DM patients with eveningness trait are under inadequate metabolic control independent of other lifestyle factors. Thus, the evening trait of T2DM patients represents an important target for intervention to ensure appropriate metabolic function.

Comparison of effects of pitavastatin and atorvastatin on glucose metabolism in type 2 diabetic patients with hypercholesterolemia

The distinct effects of different statins on glycemic control have not been fully evaluated. In this open‐label, prospective, cross‐over clinical trial, we compared the effects of pitavastatin and atorvastatin on glycemic control in type 2 diabetic patients with hypercholesterolemia.

Criterion for the Selection of a Working Correlation Structure in the Generalized Estimating Equation Approach for Longitudinal Balanced Data

The generalized estimating equation is a popular method for analyzing correlated response data. It is important to determine a proper working correlation matrix at the time of applying the generalized estimating equation since an improper selection sometimes results in inefficient parameter estimates. We propose a criterion for the selection of an appropriate working correlation structure. The proposed criterion is based on a statistic to test the hypothesis that the covariance matrix equals a given matrix, and also measures the discrepancy between the covariance matrix estimator and the specified working covariance matrix. We evaluated the performance of the proposed criterion through simulation studies assuming that for each subject, the number of observations remains the same. The results revealed that when the proposed criterion was adopted, the proportion of selecting a true correlation structure was generally higher than that when other competing approaches were adopted. The proposed criterion was applied to longitudinal wheeze data, and it was suggested that the resultant correlation structure was the most accurate.

Severity of morphological lesion complexity affects fractional flow reserve in intermediate coronary stenosis

BACKGROUNDnAlthough functional ischemia identification is important when determining revascularization, angiographic assessment alone is challenging in intermediate coronary stenosis. Previous studies have reported that lesion-specific characteristics affected the fractional flow reserve (FFR). However, the relationship between morphological lesion complexity and FFR has not yet been fully evaluated. This study aimed to evaluate the impact of morphological lesion complexity on FFR in intermediate coronary stenosis.nnnMETHODSnA total of 109 consecutive patients with 136 intermediate coronary stenoses (visually estimated diameter stenosis: 40-70%) were assessed via quantitative coronary angiography, lesion-specific characteristics, and FFR. Indexed lesions were assessed according to 6 morphological lesion characteristics: eccentricity, bend, irregularity, calcification, bifurcation, and diffuse. The lesions were then classified into 3 groups according to the morphological severity count represented by the number of present characteristics (mild-complex: 0-1, moderate-complex: 2-3, and severe-complex: 4-6), and their functional severities were evaluated. Lesions with an FFR <0.80 were considered functionally significant coronary stenoses.nnnRESULTSnOf the 136 lesions, 51% were located in the left anterior descending artery (LAD) and 47% had an FFR <0.80. The FFR differed significantly among the 3 lesion complexity groups (0.84±0.10 vs. 0.79±0.10 vs. 0.73±0.07, for mild-, moderate-, and severe-complex, respectively; p<0.01). In a multivariate logistic analysis, LAD lesions, moderate- and severe-complex, and diameter stenosis were independently associated with an FFR <0.80 [odds ratio (OR): 5.65, 95% confidence interval (CI): 2.50-12.80, p<0.01; OR: 2.96, 95% CI: 1.30-6.72, p<0.01; OR: 7.11, 95% CI: 1.25-40.37, p=0.03, and OR: 2.65, 95% CI: 1.04-6.72, p=0.04, respectively].nnnCONCLUSIONSnBoth indexed vessels and the degree of diameter stenosis affected the FFR. In addition, the severity of morphological lesion complexity correlated with the degree of functional severity in intermediate coronary stenosis.

Rationale, design, and baseline characteristics of a clinical trial for prevention of atherosclerosis in patients with insulin-treated type 2 diabetes mellitus using DPP-4 inhibitor: the Sitagliptin Preventive study of Intima-media thickness Evaluation (SPIKE)

BackgroundSitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to achieve glycemic targets in patients with type 2 diabetes mellitus (T2DM). The addition of DPP-4 inhibitors to ongoing insulin therapy is expected to reduce insulin dosage, leading to a reduction in the frequency of hypoglycaemia and/or weight gain. Recent studies have demonstrated potential anti-atherosclerotic effects for DPP-4 inhibitors. The aim of the present ongoing study is to assess the effects of sitagliptin on the progression of atherosclerosis in patients with insulin-treated T2DM using carotid intima-media thickness (IMT), an established marker of cardiovascular disease.Methods and DesignThe Sitagliptin Preventive study of Intima media thickness Evaluation (SPIKE) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between February 2012 and September 2012, 282 participants who failed to achieve glycemic control despite insulin therapy were recruited at 12 clinics and randomly allocated to the sitagliptin group (n =u2009142) or the control group (n =u2009140). Primary outcomes are changes in maximum and mean IMT of the common carotid artery after 24-month treatment period measured by carotid arterial echography. Secondary outcomes include changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, occurrence of cardiovascular events and adverse events such as hypoglycaemia, and biochemical markers of vascular function.DiscussionThe present study is designed to assess the effects of sitagliptin on the progression of carotid IMT. Results will be available in the near future, and the findings are expected to provide new strategy to prevent atherosclerosis in patients with insulin-treated T2DM.Clinical Trial RegistrationUMIN000007396

Carotid intima-media thickness progression predicts cardiovascular events in Japanese patients with type 2 diabetes

AIMSnThe aim of this retrospective study was to investigate the relationship between progression of carotid intima-media thickness (cIMT) and cardiovascular events in Japanese patients with type 2 diabetes mellitus (T2DM) and free of history of cardiovascular events.nnnMETHODSnPatients with T2DM (n=342) without history of cardiovascular events whose cIMT was assessed more than twice by ultrasonography were recruited and followed up for cardiovascular events.nnnRESULTSnDuring a mean follow-up of 7.6 years, 56 (16.4%) cardiovascular events (27 coronary events and 29 cerebrovascular events) were recorded. Multivariate analysis with the Cox proportional hazard model identified cIMT progression as a significant determinant of cardiovascular events, with a hazard ratio (HR) of 2.24 (95% confidence interval; CI, 1.25-4.03, P<0.01), in addition to baseline cIMT. The Kaplan-Meier curves also showed significantly higher event rate in patients with high cIMT progression compared with those with low cIMT progression (log-rank χ(2)=6.65; P<0.01). Furthermore, the combination of high baseline cIMT and high cIMT progression was a significant predictor of cardiovascular events.nnnCONCLUSIONnOur findings suggest that cIMT progression, in addition to baseline cIMT, is a predictor of cardiovascular events in patients with T2DM without history of cardiovascular events, and that the combination of cIMT progression and baseline cIMT has a strong predictive power for such events.

Enhanced expression of WD repeat-containing protein 35 via CaMKK/AMPK activation in bupivacaine-treated Neuro2a cells.

We previously reported that bupivacaine induces reactive oxygen species (ROS) generation, p38 mitogen-activated protein kinase (MAPK) activation and nuclear factor-kappa B activation, resulting in an increase in expression of WD repeat-containing protein 35 (WDR35) in mouse neuroblastoma Neuro2a cells. However, the identity of signaling upstream of p38 MAPK pathways to WDR35 expression remains unclear. It has been shown that AMP-activated protein kinase (AMPK) can activate p38 MAPK through diverse mechanisms. In addition, several kinases acting upstream of AMPK have been identified including Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). Recent studies reported that AMPK may be involved in bupivacaine-induced cytotoxicity in Schwann cells and in human neuroblastoma SH-SY5Y cells. The present study was undertaken to test whether CaMKK and AMPK are involved in bupivacaine-induced WDR35 expression in Neuro2a cells. Our results showed that bupivacaine induced activation of AMPK and p38 MAPK in Neuro2a cells. The AMPK inhibitors, compound C and iodotubercidin, attenuated the bupivacaine-induced activation of AMPK and p38 MAPK, resulting in an inhibition of the bupivacaine-induced increase in WDR35 expression. Treatment with the CaMKK inhibitor STO-609 also attenuated the bupivacaine-induced activation of AMPK and p38 MAPK, resulting in an inhibition of the bupivacaine-induced increase in WDR35 expression. These results suggest that bupivacaine activates AMPK and p38 MAPK via CaMKK in Neuro2a cells, and that the CaMKK/AMPK/p38 MAPK pathway is involved in regulating WDR35 expression.

Inference of median difference based on the Box–Cox model in randomized clinical trials

In randomized clinical trials, many medical and biological measurements are not normally distributed and are often skewed. The Box-Cox transformation is a powerful procedure for comparing two treatment groups for skewed continuous variables in terms of a statistical test. However, it is difficult to directly estimate and interpret the location difference between the two groups on the original scale of the measurement. We propose a helpful method that infers the difference of the treatment effect on the original scale in a more easily interpretable form. We also provide statistical analysis packages that consistently include an estimate of the treatment effect, covariance adjustments, standard errors, and statistical hypothesis tests. The simulation study that focuses on randomized parallel group clinical trials with two treatment groups indicates that the performance of the proposed method is equivalent to or better than that of the existing non-parametric approaches in terms of the type-I error rate and power. We illustrate our method with cluster of differentiation 4 data in an acquired immune deficiency syndrome clinical trial.