Relationship between hemoglobin A1c and cardiovascular disease in mild-to-moderate hypercholesterolemic Japanese individuals: subanalysis of a large-scale randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Although the ADA/EASD/IDF International Expert Committee recommends using hemoglobin A1c (HbA1c) to define diabetes, the relation between HbA1c and cardiovascular disease (CVD) has not been thoroughly investigated. We analyzed this relation using clinical data on Japanese individuals with hypercholesterolemia.</p> <p>Methods</p> <p>In the large-scale MEGA Study 7832 patients aged 40 to 70 years old with mild-to-moderate hypercholesterolemia without CVD were randomized to diet alone or diet plus pravastatin and followed for >5 years. In the present subanalysis of that study a total of 4002 patients with baseline and follow-up HbA1c data were stratified according to having an average HbA1c during the first year of follow-up <6.0%, 6.0%-<6.5%, or ≥6.5% and their subsequent 5-year incidence rates of CVD compared according to sex, low-density lipoprotein cholesterol (LDL-C), and treatment arm.</p> <p>Results</p> <p>Overall, risk of CVD was significantly 2.4 times higher in individuals with HbA1c ≥6.5% versus <6.0%. A similar relation was noted in men and women (hazard ratio [HR], 2.1; p <0.01 and HR, 3.0; p <0.01, respectively) and was regardless of treatment arm (diet alone group: HR, 2.2; p <0.001; diet plus pravastatin group: HR, 1.8; p = 0.02). Spline curves showed a continuous risk increase according to HbA1c level in all subpopulations studied.</p> <p>Conclusions</p> <p>In hypercholesterolemic individuals the risk of CVD increases linearly with HbA1c level. This significant contribution by elevated HbA1c to increased CVD is independent of pravastatin therapy, and thus requires appropriate HbA1c management in addition to lipids reduction.</p

Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets

Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets. GKA-induced Fbln5 upregulation in the islets was blunted by a glucokinase inhibitor, KATP channel opener, Ca2+ channel blocker and calcineurin inhibitor, while it was augmented by harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1 A inhibitor. Although deletion of Fbln5 in mice had no significant effects on the glucose tolerance or β-cell functions, adenovirus-mediated Fbln5 overexpression increased glucose-stimulated insulin secretion in INS-1 rat insulinoma cells. Since the islet Fbln5 expression is regulated through a glucokinase/KATP channel/calcineurin/nuclear factor of activated T cells (NFAT) pathway crucial for the maintenance of β-cell functions, further investigation of Fbln5 functions in the islets is warranted

DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid

Additional file 3: Figure S2. Liver and epididymal fat weights in db/+ mice and db/db mice. The experiments were performed in db/+ or db/db mice fed an SL diet, SO diet, SL containing DPP-4 inhibitor (0.4% des-fluoro-sitagliptin) diet, or SO containing DPP-4 inhibitor diet for 8 weeks. (left) Liver weights as a proportion of body weight (n = 5). (right) Epididymal fat weights as a proportion of body weight (n = 5)

A Case of a Combination of Wearing-Off-Like Symptoms and Autonomic Hyperreflexia Following Spinal Anesthesia for a Patient with Parkinson’s Disease Who is Treated by Deep Brain Stimulation

Deep brain stimulator (DBS) has been widely performed for various medically refractory movement disorders. We report a 70’s male patients with Parkinson’s disease (PD) treated by DBS in addition to anti-parkinsonian drugs who underwent transurethral lithotomy under spinal anesthesia twice. We canceled his usual medications for PD, therefore, his blood pressure was higher than usual. His DBS was turned off in the operation room before induction of anesthesia. Both anesthesia techniques for TUL surgeries were completed by spinal anesthesia used by 0.5% hyperbaric bupivacine. Immediately after spinal anesthesia in both surgeries, severe rigidity, airway obstruction and conscious change emerged. These complications were suspected wearing-off-likes symptoms of PD, which were proved because of spinal anesthesia itself and/or DBS off effects. Autonomic hyperreflexia with severe hypertension, abnormal sweating and excessive oral secretion was gradually appeared after infusion of normal saline to obtain surgical fields of view, however, these symptoms disappeared after the end of infusion. It was suspected that the adverse events were due to low effects of spinal anesthesia on autonomic nervous system degenerated by Parkinson’s disease. We turned on DBS immediately after the completion of surgeries, and resumed his oral medications on the next day of surgeries. There were no events in his courses. As there is little information and no standard anesthetic guidelines available on patients with DBS implant who are present for surgery, a careful management is needed to avoid complications.本稿の要旨は日本麻酔科学会　中国・四国支部第55回学術集会（松山市，2018年）で発表した

Decreased serum pyridoxal levels in schizophrenia : meta-analysis and Mendelian randomization analysis

Background: Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. Methods: We first conducted a case–control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort (n = 1276). Subsequently, we conducted a meta-analysis of association studies (n = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population (n = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. Results: Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference –0.48, 95% confidence interval [CI] –0.57 to –0.39, p = 9.8 × 10–24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65–1.51, p = 0.96). Limitations: Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. Conclusion: We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach

Ehrlichia chaffeensis Infection of Sika Deer, Japan

To determine whether Ehrlichia chaffeensis exists in Japan, we used PCR to examine blood from sika deer in Nara, Japan. Of 117 deer, 36 (31%) were infected with E. chaffeensis. The E. chaffeensis 16S rRNA base and GroEL amino acid sequences from Japan were most closely related to those of E. chaffeensis Arkansas

Stable isotopic investigation of the feeding ecology of wild Bornean orangutans

Objectives We applied stable carbon and nitrogen isotope analyses to wild Bornean orangutans (Pongo pygmaeus morio) to investigate the feeding ecology of wild orangutans. Compared with African great ape species, orangutans are adapted to environments with chronic lower nutrition. But the usefulness of stable isotope analysis in the study of wild orangutan feeding ecology has not been fully explored. Methods The study site was a primary lowland dipterocarp forest in the Danum Valley, Sabah, Malaysia. A total of 164 plant and 94 fecal samples collected across 18 months were analyzed. Results Carbon and nitrogen stable isotope ratios of plant food samples do not systematically vary by plant parts (i.e., bark, fruits, and leaves). Elemental composition and stable isotope ratios of orangutan feces do not systematically vary by orangutans' sex and age classes, although fecal stable isotope ratios showed seasonal fluctuations. No isotopic contribution of breast milk was found in fecal samples collected from individuals at 2.7–6.5 years of age. Conclusions This study revealed key characteristics of the stable isotope ecology of wild orangutans living in a primary lowland forest. Although there was little isotopic variation among plant foods and orangutan individuals, seasonal fluctuations in baseline isotope ratios or orangutans' diet were found in Danum valley