Suvorexant (Belsomra(®)), a first-in-class, orally active dual orexin-1 receptor and orexin-2 receptor antagonist, has been developed by Merck for the treatment of insomnia. Variations in the levels ...of the neuropeptides orexin A and orexin B have been linked to circadian rhythms and wakefulness. Orexin-producing neurons in the lateral hypothalamus regulate wakefulness by signalling through orexin receptors. Blockade of orexin receptors is known to promote sleep. Suvorexant was approved in the US in August 2014 for the treatment of adults with sleep onset and/or sleep maintenance insomnia. The drug is also preregistration in Japan, with approval submissions planned for other countries worldwide for this indication. This article summarizes the milestones in the development of suvorexant leading to this first approval for insomnia.
Schizophrenia is a severe mental disorder that affects 0.5-1% of the population worldwide. Current diagnostic methods are based on psychiatric interviews, which are subjective in nature. The lack of ...disease biomarkers to support objective laboratory tests has been a long-standing bottleneck in the clinical diagnosis and evaluation of schizophrenia. Here we report a global metabolic profiling study involving 112 schizophrenic patients and 110 healthy subjects, who were divided into a training set and a test set, designed to identify metabolite markers. A panel of serum markers consisting of glycerate, eicosenoic acid, β-hydroxybutyrate, pyruvate and cystine was identified as an effective diagnostic tool, achieving an area under the receiver operating characteristic curve (AUC) of 0.945 in the training samples (62 patients and 62 controls) and 0.895 in the test samples (50 patients and 48 controls). Furthermore, a composite panel by the addition of urine β-hydroxybutyrate to the serum panel achieved a more satisfactory accuracy, which reached an AUC of 1 in both the training set and the test set. Multiple fatty acids and ketone bodies were found significantly (P<0.01) elevated in both the serum and urine of patients, suggesting an upregulated fatty acid catabolism, presumably resulting from an insufficiency of glucose supply in the brains of schizophrenia patients.
In this paper, on-axis tensile behavior of a coated 2D-C/SiC composite at elevated temperatures was studied experimentally and theoretically. The measured data reveals that the tensile modulus and ...strength increase continuously with increasing temperature till 1273K. Contrarily, the failure strains decrease sharply at high temperatures than the counterpart at room temperature, manifesting the significant influence of thermal residual stresses (TRS) on mechanical behavior of C/SiC composites. Simulation of stress-strain response is based on a two-scale analytical model, in which the plain-weave element is idealized as a cross-ply laminate and its macroscopic mechanical parameters are evaluated by shear-lag approach. The primary calculation was concentrated on TRS of the composite. And, a new crack evolution model was introduced to describe the stochastic cracking process. The total strain response including residual strain and elastic strain from the loading-unloading-reloading conception was finally formulated through micromechanical analysis involving the influence of TRS on matrix cracking and interface debonding. Additionally, a strength model was developed for plain-weave structures by using shear-lag theory, statistical theory and rule of mixture. Both of the proposed constitutive and strength models can give accurate predictions for 2D-C/SiC composites at elevated temperatures.
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight ...risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
The Tubridge flow diverter is a novel device developed in China and aimed at reconstructing the parent artery and occluding the aneurysm. We conducted this study to evaluate its feasibility, safety, ...and efficacy for the treatment of large or giant internal carotid artery aneurysms, which are still challenging with conventional therapy.
The clinical and angiographic data of 28 patients with 28 large or giant internal carotid artery aneurysms treated with Tubridge flow diverters were prospectively collected and analyzed.
Thirty-three Tubridge flow diverters were successfully implanted except for 1 poor midstent opening; the result was a technical success rate of 97.0% (32/33). Follow-up angiographies were available for 25 aneurysms; the mean follow-up was 9.9 months (5-24 months). Of the 25 aneurysms, 18 (72.0%) were completely occluded, 6 (24.0%) were improved, and 1 (4.0%) was unchanged. All of the visible covered branches and parent arteries were patent, with no stenosis or obliteration. During a follow-up of 6-30 months (mean, 19 months), symptoms were resolved in 13 patients, improved in 6 patients, and unchanged in 4 patients. Five patients experienced transient clinical deterioration due to a postoperative increased mass effect. Procedure-related morbidity and mortality were both zero.
Our preliminary experience shows that the Tubridge flow diverter is a safe and effective tool for treating large and giant internal carotid artery aneurysms. However, multicenter randomized trials and studies involving a long-term follow-up are necessary.
The associations between long-term risk of hepatocellular carcinoma (HCC) and spontaneous seroclearance of HBV e antigen (HBeAg), HBV DNA and HBV surface antigen (HBsAg) have never been examined by a ...prospective study using serially measured seromarkers. This study aimed to assess the importance of spontaneous HBeAg, HBV DNA and HBsAg seroclearance in the prediction of HCC risk.
This study included 2946 HBsAg seropositive individuals who were seronegative for antibodies against HCV and free of liver cirrhosis. Serial serum samples collected at study entry and follow-up health examinations were tested for HBeAg, HBV DNA and HBsAg. Cox proportional hazards models were used to calculate the HRs of developing HCC after seroclearance of HBV markers.
The HR (95% CI) of developing HCC after seroclearance of HBeAg, HBV DNA and HBsAg during follow-up was 0.63 (0.38 to 1.05), 0.24 (0.11 to 0.57) and 0.18 (0.09 to 0.38), respectively, after adjustment for age, gender and serum level of alanine aminotransferase at study entry. High HBV DNA levels at the seroclearance of HBeAg (mean±SD, 4.35±1.64 log10 IU/mL) may explain the non-significant association between HBeAg seroclearance and HCC risk. Among HBeAg seronegative participants with detectable serum HBV DNA at study entry, the lifetime (30-75-years-old) cumulative incidence of HCC was 4.0%, 6.6% and 14.2%, respectively, for those with seroclearance of both HBV DNA and HBsAg, seroclearance of HBV DNA only, and seroclearance of neither.
Spontaneous seroclearance of HBV DNA and HBsAg are important predictors of reduced HCC risk.
A relation among invariants of filtered velocity gradients with two different filter sizes is derived. Based on this relation and physical reasoning, it is shown analytically that strain ...self-amplification contributes more to energy transfer than vortex stretching in homogeneous turbulence, as observed in recent numerical investigations of homogeneous isotropic turbulence. We note that the invariant relation studied and hence the inequality between strain self-amplification and vortex stretching apply to all homogeneous flows, not restricted to isotropic turbulence.
BACKGROUND AND AIMS Stress may be an important factor in exacerbating inflammatory bowel disease but the underlying mechanism is unclear. Defective epithelial barrier function may allow uptake of ...luminal antigens that stimulate an immune/inflammatory response. Here, we examined the effect of chronic stress on colonic permeability and the participation of mast cells in this response. METHODS Mast cell deficient Ws/Ws rats and +/+ littermate controls were submitted to water avoidance stress or sham stress (one hour/day) for five days. Colonic epithelial permeability to a model macromolecular antigen, horseradish peroxidase, was measured in Ussing chambers. Epithelial and mast cell morphology was studied by light and electron microscopy. RESULTS Chronic stress significantly increased macromolecular flux and caused epithelial mitochondrial swelling in +/+ rats, but not in Ws/Ws rats, compared with non-stressed controls. Stress increased the number of mucosal mast cells and the proportion of cells showing signs of activation in +/+ rats. No mast cells or ultrastructural abnormalities of the epithelium were present in Ws/Ws rats. Increased permeability in +/+ rats persisted for 72 hours after stress cessation. CONCLUSIONS Chronic stress causes an epithelial barrier defect and epithelial mitochondrial damage, in parallel with mucosal mast cell hyperplasia and activation. The study provides further support for an important role for mast cells in stress induced colonic mucosal pathophysiology.
•Tree ring data are used as a proxy for transpiration in the calibration data set.•Transpiration data (T) is vital for simulation of efficiency of freshwater releases.•Tree ring records provide ...accessible, complimentary information to hydraulic heads.•The riparian water use efficiency of ecological freshwater releases is assessed.•To fully use data captured in tree rings more data relating growth to T is required.
The interactions between surface water, the vadose zone, groundwater, and vegetation are governed by complex feedback mechanisms. Numerical models simulating these interactions are essential in quantifying these processes. However, the notorious lack of field observations results in highly uncertain parameterizations. We suggest a new type of observation data to be included in the calibration data set for hydrological models simulating interactions with vegetation: Tree rings as a proxy for transpiration. We use the lower Tarim River as an example site for our approach. In order to forestall the loss of riparian ecosystems from reduced flow over a 300km reach of the lower Tarim River, the Chinese government initiated periodical, ecological water releases. The water exchange processes in this region were simulated for a cross-section on the lower reaches of the Tarim River using a numerical model (Hydro-GeoSphere) calibrated against observations of water tables, as well as transpiration estimated from tree ring growth. A predictive uncertainty analysis quantifying the worth of different components of the observation dataset in reducing the uncertainty of model predictions was carried out. The flow of information from elements of the calibration dataset to the different parameters employed by the model was also evaluated. The flow of information and the uncertainty analysis demonstrate that tree ring records can significantly improve confidence in modeling ecosystem dynamics, even if these transpiration estimates are uncertain. To use the full potential of the historical information encapsulated in the Tarim River tree rings, however, the relationship between tree ring growth and transpiration rates has to be studied further.
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