Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

Activation of WBC leads to increased expression of GLUT1, GLUT3 and GLUT4 isoforms on their plasma membrane; this process was further augmented by insulin. During infection, these mechanisms may help to redistribute glucose as a potential source of energy away from peripheral tissues and direct it towards cells that mediate the immune response and are therefore crucial to survival.

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The small size (58 residues) and simple structure of the B domain of staphylococcal protein A (BdpA) have led to this domain being a paradigm for theoretical studies of folding. Experimental studies of the folding of BdpA have been limited by the rapidity of its folding kinetics. We report the folding kinetics of a fluorescent mutant of BdpA (G29A F13W), named F13W*, using nanosecond laser-induced temperature jump experiments. Automation of the apparatus has permitted large data sets to be acquired that provide excellent signal-to-noise ratio over a wide range of experimental conditions. By measuring the temperature and denaturant dependence of equilibrium and kinetic data for F13W*, we show that thermodynamic modeling of multidimensional equilibrium and kinetic surfaces is a robust method that allows reliable extrapolation of rate constants to regions of the folding landscape not directly accessible experimentally. The results reveal that F13W* is the fastest-folding protein of its size studied to date, with a maximum folding rate constant at 0 M guanidinium chloride and 45°C of 249,000 s ؊1 . Assuming the single-exponential kinetics represent barrier-limited folding, these data limit the value for the preexponential factor for folding of this protein to at least Ϸ2 ؋ 10 6 s ؊1 . Small single-domain proteins that fold with simple two-state kinetics have played an important role both experimentally and in theory͞simulations for delineating models for folding (1-9). While folding with two-state kinetics, this set of proteins fold over a wide range of time scales ranging from 1.2 s Ϫ1 at 37°C for the ␣͞␤ protein MerP (10) to 8,100 s Ϫ1

BackgroundCongenital coronary anomalies are uncommon with an incidence ranging from 0.17 % in autopsy cases to 1.2 % in angiographically evaluated cases. The recent development of ECG–gated multi–detector row computed tomography (MDCT) coronary angiography allows accurate and noninvasive depiction of coronary artery anomalies.MethodsThis retrospective study included 2572 patients who underwent coronary 64-slice MDCT coronary angiography from January 2008 to March 2012. Coronary angiographic scans were obtained with injection of 80 ml nonionic contrast medium. Retrospective gating technique was used to synchronize data reconstruction with the ECG signal. Maximum intensity projection, multi-planar reformatted, and volume rendering images were derived from axial scans.ResultsOf the 2572 patients, sixty (2.33 %) were diagnosed with coronary artery anomalies (CAAs), with a mean age of 53.6 ± 11.8 years (range 29–80 years). High take-off of the RCA was seen in 16 patients (0.62 %), of the left main coronary artery (LMCA) in 2 patients (0.08 %) and both of them in 2 patients (0.08 %). Separate origin of the left anterior descending artery (LAD) and left circumflex artery (LCx) from left sinus of Valsalva (LSV) was found in 15 patients (an incidence of 0.58 %). In 9 patients (0.35 %) the right coronary artery (RCA) arose from the opposite sinus of Valsalva with a separate ostium. In 6 patients (0.23 %) an abnormal origin of LCX from the right sinus of Valsalva (RSV) was found with a further posterior course within the atrioventricular groove. A single coronary artery was seen in 3 patients (0.12 %). It originated from the right sinus of Valsalva in one patient and from LSV in two patients. In two other patients (0.08 %) the left coronary trunk originated from the RSV with separate ostium from the RCA. LCA originating from the pulmonary artery was found in one patient (0.04 %). A coronary artery fistula, which is a termination anomaly, was detected in 4 patients (0.15 %).DiscussionAlthough these anomalies, which are remarkably different from the normal structure, exist as early as birth, they are incidentally encountered during selective angiography or at autopsy. The incidence in reported angiographic series ranges from 0.6 % to 1.3 %. Variations in the frequency of primary congenital coronary anomalies may possibly have a genetic background. The largest angiographic series of 126595 patients, by Yamanaka and Hobbs, reported a 1.3 % incidence of anomalous coronary artery.ConclusionThe results of this study support the use MDCT coronary angiography as a safe and effective noninvasive imaging modality for defining CAAs in an appropriate clinical setting, providing detailed three-dimensional anatomic information that may be difficult to obtain with invasive angiography.

Neural recording devices normally require one output connection for each electrode. This constrains the number of electrodes that can be accommodated by the thin shafts of implantable probes. Sharing a single output connection between multiple electrodes relaxes this constraint and permits designs of ultra-high density neural probes.Here we report the design and in vivo validation of such a device, a complementary metal-oxidesemiconductor (CMOS) scanning probe with 1344 electrodes and 12 reference electrodes along an 8.1 mm x 100 μm x 50 μm shaft; the outcome of the European research project NeuroSeeker. This technology presented new challenges for data management and visualization, and we also report new methods addressing these challenges developed within NeuroSeeker.Scanning CMOS technology allows the fabrication of much smaller, denser electrode arrays. To help design electrode configurations for future probes, several recordings from many different brain regions were made with an ultra-dense passive probe fabricated using CMOS process. All datasets are available online.

Objectives To study the analgesic effect of electroacupuncture (EA) as perioperative adjunctive therapy added to a systemic analgesic strategy (including tramadol and ketamine) for postoperative pain, opioid-related side effects and patient satisfaction. Methods In a sham-controlled participant- and observer-blinded trial, 75 patients undergoing radical prostatectomy were randomly assigned to two groups: (1) EA (n=37; tramadol+ketamine+EA) and (2) control (n=38; tramadol+ketamine). EA (100 Hz frequency) was applied at LI4 bilaterally during the closure of the abdominal walls and EA (4 Hz) was applied at ST36 and LI4 bilaterally immediately after extubation. The control group had sham acupuncture without penetration or stimulation. The following outcomes were evaluated: postoperative pain using the Numerical Rating Scale (NRS) and McGill Scale (SF_MPQ), mechanical pain thresholds using algometer application close to the wound, cortisol measurements, rescue analgesia, Spielberger State Trait Anxiety Inventory (STAI Y-6 item), patient satisfaction and opioid side effects. Results Pain scores on the NRS and SF_MPQ were significantly lower and electronic pressure algometer measurements were significantly higher in the EA group than in the control group (p<0.001) at all assessments. In the EA group a significant decrease in rescue analgesia was observed at 45 min (p<0.001) and a significant decrease in cortisol levels was also observed (p<0.05). Patients expressed satisfaction with the analgesia, especially in the EA group (p<0.01). Significant delays in the start of bowel movements were observed in the control group at 45 min (p<0.001) and 2 h (p<0.05). Conclusions Adding EA perioperatively should be considered an option as part of a multimodal analgesic strategy.

The aim of this pilot study is to evaluate sarcosine, uracil, and kynurenic acid in urine as potential biomarkers in prostate cancer detection and progression monitoring. Sarcosine, uracil, and kynurenic acid were measured in urine samples of 32 prostate cancer patients prior to radical prostatectomy, 101 patients with increased prostate-specific antigen prior to ultrasonographically-guided prostatic biopsy collected before and after prostatic massage, and 15 healthy volunteers (controls). The results were related to histopathologic data, Gleason score, and PSA (Prostate Specific Antigen). Metabolites were measured after analysis of urine samples with Ultra-High Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) instrumentation. Multivariate, nonparametric statistical tests including receiver operating characteristics analyses, one-way analysis of variance (Kruskal–Wallis test), parametric statistical analysis, and Pearson correlation, were performed to evaluate diagnostic performance. Decreased median sarcosine and kynurenic acid and increased uracil concentrations were observed for patients with prostate cancer compared to participants without malignancy. Results showed that there was no correlation between the concentration of the studied metabolites and the cancer grade (Gleason score <7 vs. ≥7) and the age of the patients. Evaluation of biomarkers by ROC (Receiving Operating Characteristics) curve analysis showed that differentiation of prostate cancer patients from participants without malignancy was not enhanced by sarcosine or uracil levels in urine. In contrast to total PSA values, kynurenic acid was found a promising biomarker for the detection of prostate cancer particularly in cases where collection of urine samples was performed after prostatic massage. Sarcosine and uracil in urine samples of patients with prostate cancer were not found as significant biomarkers for the diagnosis of prostate cancer. None of the three metabolites can be used reliably for monitoring the progress of the disease.