A Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Improves Endothelial Function and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E–Deficient Mice

ObjectivesThe aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS).BackgroundThe new class of anti–type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1.MethodsEndothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E–deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease.ResultsDFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10−4 mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001).ConclusionsA DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium

Impact of early treatment with intravenous vasodilators and blood pressure reduction in acute heart failure

Objective Although vasodilators are used in acute heart failure (AHF) management, there have been no clear supportive evidence regarding their routine use. Recent European guidelines recommend systolic blood pressure (SBP) reduction in the range of 25% during the first few hours after diagnosis. This study aimed to examine clinical and prognostic significance of early treatment with intravenous vasodilators in relation to their subsequent SBP reduction in hospitalised AHF. Methods We performed post hoc analysis of 1670 consecutive patients enrolled in the Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure. Intravenous vasodilator use within 6 hours of hospital arrival and subsequent SBP changes were analysed. Outcomes were gauged by 1-year mortality and diuretic response (DR), defined as total urine output 6 hours posthospital arrival per 40 mg furosemide-equivalent diuretic use. Results Over half of the patients (56.0%) were treated with intravenous vasodilators within the first 6 hours. In this vasodilator-treated cohort, 554 (59.3%) experienced SBP reduction 25%. In patients experiencing Conclusions Intravenous vasodilator therapy was associated with greater DR and lower mortality, provided SBP reduction was less than 25%. Our results highlight the importance in early administration of intravenous vasodilators without causing excess SBP reduction in AHF management

Discovery of a Giant Lya Emitter Near the Reionization Epoch

We report the discovery of a giant Ly{alpha} emitter (LAE) with a Spitzer/IRAC counterpart near the reionization epoch at z = 6.595. The giant LAE is found from the extensive 1 deg{sup 2} Subaru narrow-band survey for z = 6.6 LAEs in the Subaru/XMM-Newton Deep Survey (SXDS) field, and subsequently identified by deep spectroscopy of Keck/DEIMOS and Magellan/IMACS. Among our 207 LAE candidates, this LAE is not only the brightest narrow-band object with L(Ly{alpha}) = 3.9 {+-} 0.2 x 10{sup 43} erg s{sup -1} in our survey volume of 10{sup 6} Mpc{sup 3}, but also a spatially extended Ly{alpha} nebula with the largest isophotal area whose major axis is at least {approx_equal} 3-inches. This object is more likely to be a large Ly{alpha} nebula with a size of {approx}&gt; 17-kpc than to be a strongly-lensed galaxy by a foreground object. Our Keck spectrum with medium-high spectral and spatial resolutions suggests that the velocity width is v{sub FWHM} = 251 {+-} 21 km s{sup -1}, and that the line-center velocity changes by {approx_equal} 60 km s{sup -1} in a 10-kpc range. The stellar mass and star-formation rate are estimated to be 0.9-5.0 x 10{sup 10}M{sub {circle_dot}} and &gt; 34 M{sub {circle_dot}}yr{sup -1}, respectively, from the combination of deep optical to infrared images of Subaru, UKIDSS-Ultra Deep Survey, and Spitzer/IRAC. Although the nature of this object is not yet clearly understood, this could be an important object for studying cooling clouds accreting onto a massive halo, or forming-massive galaxies with significant outflows contributing to cosmic reionization and metal enrichment of inter-galactic medium

Accumulation of Pericardial Fat Correlates with Left Ventricular Diastolic Dysfunction in Patients with Normal Ejection Fraction

Background Left ventricular diastolic dysfunction (LVDD) plays an important role inheart failure with normal left ventricular ejection fraction (LVEF). Obesity is one ofthe major comorbid conditions of LVDD. Pericardial fat (PF) is an ectopic fat depotwith possible paracrine or mechanical effects on the coronary circulation and35 myocardial function.Methods We measured PF volume on 64 slice computed tomography and analyzedechocardiographic parameters to confirm LVDD in 229 consecutive patients suspectedof coronary artery disease with LVEF of more than 50% and no symptomatic heartfailure (59% men, 67±12 years). LVDD was defined as the ratio of transmitral40 Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity(E/e’) >10.Results PF volume correlated significantly with E/e’ (r=0.21, p<0.01), left ventricularmass index (r=0.23, p<0.001), and left atrial diameter (r=0.32, p<0.001). The mean PFvolume was significantly greater in patients with LVDD (184±61 cm3, n=141) than in45 those without LVDD (154±58, n=88, p<0.001). Multivariate logistic regressionanalysis indicated that PF volume correlated significantly with the presence of LVDD(odds ratio: 2.00 per 100 cm3 increase in PF volume, p=0.02) independent of age,gender, abdominal obesity, hypertension, and diabetes.Conclusions PF volumes are significantly associated with LVDD, independent of50 other factors such as hypertension or diabetes. PF may be implicated in the pathogenesis of LVDD in patients with normal LVEF

Highly strong and conductive carbon nanotube/cellulose composite paper

Carbon nanotube (CNT)/cellulose composite materials were fabricated in a paper making process optimized for a CNT network to form on the cellulose fibers. The measured electric conductivity was from 0.05-671 S/m for 0.5-16.7-wt% CNT content, higher than that for other polymer composites. The real permittivities were the highest in the microwave region. The unique CNT network structure is thought to be the reason for these high conductivity and permittivity values. Compared to other carbon materials, our carbon CNT/cellulose composite material had improved parameters without decreased mechanical strength. The near-field electromagnetic shielding effectiveness (EMI SE) measured by a microstrip line method depended on the sheet conductivity and qualitatively matched the results of electromagnetic field simulations using a finite-difference time-domain simulator. A high near-field EMI SE of 50-dB was achieved in the 5-10 GHz frequency region with 4.8-wt% composite paper. The far-field EMI SE was measured by a free space method. Fairly good agreement was obtained between the measured and calculated results. Approximately 10-wt% CNT is required to achieve composite paper with 20-dB far-field EMI SE