Stearoyl-CoA Desaturase-1 (SCD1) Augments Saturated Fatty Acid-Induced Lipid Accumulation and Inhibits Apoptosis in Cardiac Myocytes

Mismatch between the uptake and utilization of long-chain fatty acids in the myocardium leads to abnormally high intracellular fatty acid concentration, which ultimately induces myocardial dysfunction. Stearoyl-Coenzyme A desaturase-1 (SCD1) is a rate-limiting enzyme that converts saturated fatty acids (SFAs) to monounsaturated fatty acids. Previous studies have shown that SCD1-deficinent mice are protected from insulin resistance and diet-induced obesity; however, the role of SCD1 in the heart remains to be determined. We examined the expression of SCD1 in obese rat hearts induced by a sucrose-rich diet for 3 months. We also examined the effect of SCD1 on myocardial energy metabolism and apoptotic cell death in neonatal rat cardiac myocytes in the presence of SFAs. Here we showed that the expression of SCD1 increases 3.6-fold without measurable change in the expression of lipogenic genes in the heart of rats fed a high-sucrose diet. Forced SCD1 expression augmented palmitic acid-induced lipid accumulation, but attenuated excess fatty acid oxidation and restored reduced glucose oxidation. Of importance, SCD1 substantially inhibited SFA-induced caspase 3 activation, ceramide synthesis, diacylglycerol synthesis, apoptotic cell death, and mitochondrial reactive oxygen species (ROS) generation. Experiments using SCD1 siRNA confirmed these observations. Furthermore, we showed that exposure of cardiac myocytes to glucose and insulin induced SCD1 expression. Our results indicate that SCD1 is highly regulated by a metabolic syndrome component in the heart, and such induction of SCD1 serves to alleviate SFA-induced adverse fatty acid catabolism, and eventually to prevent SFAs-induced apoptosis

Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes

BACKGROUND: Diabetes mellitus (DM) is associated with an increased risk of ischemic heart disease and of adverse outcomes following myocardial infarction (MI). Here we assessed the role of endoplasmic reticulum (ER) stress in ventricular dysfunction and outcomes after MI in type 2 DM (T2DM). METHODOLOGY AND PRINCIPAL FINDINGS: In hearts of OLETF, a rat model of T2DM, at 25∼30 weeks of age, GRP78 and GRP94, markers of ER stress, were increased and sarcoplasmic reticulum calcium ATPase (SERCA)2a protein was reduced by 35% compared with those in LETO, a non-diabetic control. SERCA2a mRNA levels were similar, but SERCA2a protein was more ubiquitinated in OLETF than in LETO. Left ventricular (LV) end-diastolic elastance (Eed) was higher in OLETF than in LETO (53.9±5.2 vs. 20.2±5.6 mmHg/µl), whereas LV end-systolic elastance and positive inotropic responses to β-adrenergic stimulation were similar in OLETF and LETO. 4-Phenylbutyric acid (4-PBA), an ER stress modulator, suppressed both GRP up-regulation and SERCA2a ubiquitination and normalized SERCA2a protein level and Eed in OLETF. Sodium tauroursodeoxycholic acid, a structurally different ER stress modulator, also restored SERCA2a protein level in OLETF. Though LV dysfunction was modest, mortality within 48 h after coronary occlusion was markedly higher in OLETF than in LETO (61.3% vs. 7.7%). Telemetric recording showed that rapid progression of heart failure was responsible for the high mortality rate in OLETF. ER stress modulators failed to reduce the mortality rate after MI in OLETF. CONCLUSIONS: ER stress reduces SERCA2a protein via its augmented ubiquitination and degradation, leading to LV diastolic dysfunction in T2DM. Even at a stage without systolic LV dysfunction, susceptibility to lethal heart failure after infarction is markedly increased, which cannot be explained by ER stress or change in myocardial response to sympathetic nerve activation

Phase II trial of aflibercept with FOLFIRI as a second‐line treatment for Japanese patients with metastatic colorectal cancer

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second‐line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression‐free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5‐fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%‐15.3%), and the disease control rate (DCR) was 80.0% (69.9%‐90.1%). The median progression‐free survival was 5.42 months (4.14‐6.70 months) and the median overall survival was 15.59 months (11.20‐19.81 months). No treatment‐related deaths were observed, and no significant drug‐drug interactions were found. The most common treatment‐emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5‐fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5‐fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well‐tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868

Heterogeneity and Temporal Stability of Residential Water Use Responsiveness to Price Change

Many papers estimate the price elasticity of water demand. However, heterogeneity and temporal variation of price elasticity of residential water use are still unclear. We analyze these issues by applying the latent class analysis and t-test using disaggregated data of approximately 30,000 households recorded over five years: Two years before and three years after a tariff revision. As a result, the households are divided into three (heterogeneous) groups: About 5% of them responded to the price change sensitively, 40–60% slightly, and 35–55% not at all. Households with high water use prior to the revision had higher price elasticity. In addition, the price elasticity in the first and third years after the revision was the same

Characteristics of Cyclist Crashes Using Polytomous Latent Class Analysis and Bias-Reduced Logistic Regression

Although the number of cyclist crashes is decreasing in Japan, the fatality rate is not. Thus, reducing their severity is a major challenge. We used a polytomous latent class analysis to understand their characteristics and bias-reduced logistic regression to analyze their severity. Specifically, 90,696 combinations and 139,955 cyclist accidents were divided into 17 classes. The variable contributing the most to the classification was the crash location. Common fatality risks included older age groups and rural areas, whereas other factors differed among crash locations. Median strips, stop signs, and boundaries between the sidewalk and roadway affected the severity of crashes at intersections. Moreover, the existence of a median strip, collision partner, and time period affected the severity of crashes between intersections. On the sidewalks, the fatality risk was higher when the front part of the bicycle was subjected to the collision

Impact analysis of road infrastructure and traffic control on severity of pedestrian–vehicle crashes at intersections and non-intersections using bias-reduced logistic regression

Pedestrian safety is essential to realize a walkable city. This study analyzed the impact of road infrastructure and traffic control on severity of pedestrian–vehicle crashes at intersections and non-intersections. We applied a bias-reduced logistic regression analysis using 86,406 pedestrian–vehicle crashes data including 2636 fatal accidents in Japan. The results of the study indicate that medians increased the severity of crashes at intersections; on the other hand, they decreased the severity at non-intersections. In addition, flashing traffic signals increase the severity while stop signs decrease the severity at intersections

The bending technique of a scoring balloon Aperta NSE leading to successful crossing into stents

Abstract A new scoring balloon Aperta NSE has 3 longitudinal nylon elements mounted on the non‐compliant balloon surface. Although a high‐pressure balloon is usually used as a post‐dilation balloon in an implanted stent, it is difficult to pass into the stents because a balloon gets caught in stents in some cases. Aperta NSE has some grooves at elements; therefore, this balloon is bendable and shaped in an arc. The bent scoring balloon could eliminate interference between the balloon and the stents or lesions. Moreover, the point where the tip of the balloon contacts could change. As a result, it helps to improve crossability of this balloon. The bending technique of a scoring balloon Aperta NSE could lead to successful crossing into stents or complex lesions