title stringlengths 0 901 | abstract stringlengths 3 9.89k | PMID int64 22 25.3M | embedding listlengths 768 768 |
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Diffusing-wave spectroscopy in an inhomogeneous object: local viscoelastic spectra from ultrasound-assisted measurement of correlation decay arising from the ultrasound focal volume. | We demonstrate diffusing-wave spectroscopy (DWS) in a localized region of a viscoelastically inhomogeneous object by measurement of the intensity autocorrelation [g(2)(τ)] that captures only the decay introduced by the temperature-induced Brownian motion in the region. The region is roughly specified by the focal volume of an ultrasound transducer which introduces region specific mechanical vibration owing to insonification. Essential characteristics of the localized non-Markovian dynamics are contained in the decay of the modulation depth [M(τ)], introduced by the ultrasound forcing in the focal volume selected, on g(2)(τ). The modulation depth M(τ(i)) at any delay time τ(i) can be measured by short-time Fourier transform of g(2)(τ) and measurement of the magnitude of the spectrum at the ultrasound drive frequency. By following the established theoretical framework of DWS, we are able to connect the decay in M(τ) to the mean-squared displacement (MSD) of scattering centers and the MSD to G*(ω), the complex viscoelastic spectrum. A two-region composite polyvinyl alcohol phantom with different viscoelastic properties is selected for demonstrating local DWS-based recovery of G*(ω) corresponding to these regions from the measured region specific M(τ(i))vsτ(i). The ultrasound-assisted measurement of MSD is verified by simulating, using a generalized Langevin equation (GLE), the dynamics of the particles in the region selected as well as by the usual DWS experiment without the ultrasound. It is shown that whereas the MSD obtained by solving the GLE without the ultrasound forcing agreed with its experimental counterpart covering small and large values of τ, the match was good only in the initial transients in regard to experimental measurements with ultrasound. | 25,122,299 | [
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Self-similarity and scaling of thermal shock fractures. | The problem of crack pattern formation due to thermal shock loading at the surface of half space is solved numerically using the two-dimensional boundary element method. The results of numerical simulations with 100-200 random simultaneously growing and interacting cracks are used to obtain scaling relations for crack length and spacing. The numerical results predict that such a process of pattern formation with quasistatic crack growth is not stable and at some point the excess energy leads to unstable propagation of one of the longest cracks. This single-crack scenario should be understood in a local sense. There could be other unstable cracks far away that together can form a new pattern. The onset of instability has also been determined from numerical results. | 25,122,311 | [
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Healing of polymer interfaces: Interfacial dynamics, entanglements, and strength. | Self-healing of polymer films often takes place as the molecules diffuse across a damaged region, above their melting temperature. Using molecular dynamics simulations we probe the healing of polymer films and compare the results with those obtained for thermal welding of homopolymer slabs. These two processes differ from each other in their interfacial structure since damage leads to increased polydispersity and more short chains. A polymer sample was cut into two separate films that were then held together in the melt state. The recovery of the damaged film was followed as time elapsed and polymer molecules diffused across the interface. The mass uptake and formation of entanglements, as obtained from primitive path analysis, are extracted and correlated with the interfacial strength obtained from shear simulations. We find that the diffusion across the interface is significantly faster in the damaged film compared to welding because of the presence of short chains. Though interfacial entanglements increase more rapidly for the damaged films, a large fraction of these entanglements are near chain ends. As a result, the interfacial strength of the healing film increases more slowly than for welding. For both healing and welding, the interfacial strength saturates as the bulk entanglement density is recovered across the interface. However, the saturation strength of the damaged film is below the bulk strength for the polymer sample. At saturation, cut chains remain near the healing interface. They are less entangled and as a result they mechanically weaken the interface. Chain stiffness increases the density of entanglements, which increases the strength of the interface. Our results show that a few entanglements across the interface are sufficient to resist interfacial chain pullout and enhance the mechanical strength. | 25,122,327 | [
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Hidden scaling patterns and universality in written communication. | The temporal statistics exhibited by written correspondence appear to be media dependent, with features which have so far proven difficult to characterize. We explain the origin of these difficulties by disentangling the role of spontaneous activity from decision-based prioritizing processes in human dynamics, clocking all waiting times through each agent's "proper time" measured by activity. This unveils the same fundamental patterns in written communication across all media (letters, email, sms), with response times displaying truncated power-law behavior and average exponents near -3/2. When standard time is used, the response time probabilities are theoretically predicted to exhibit a bimodal character, which is empirically borne out by our newly collected years-long data on email. These perspectives on the temporal dynamics of human correspondence should aid in the analysis of interaction phenomena in general, including resource management, optimal pricing and routing, information sharing, and emergency handling. | 25,122,352 | [
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Nonequilibrium shock-heated nitrogen flows using a rovibrational state-to-state method. | A rovibrational collisional model is developed to study the internal energy excitation and dissociation processes behind a strong shock wave in a nitrogen flow. The reaction rate coefficients are obtained from the ab initio database of the NASA Ames Research Center. The master equation is coupled with a one-dimensional flow solver to study the nonequilibrium phenomena encountered in the gas during a hyperbolic reentry into Earth's atmosphere. The analysis of the populations of the rovibrational levels demonstrates how rotational and vibrational relaxation proceed at the same rate. This contrasts with the common misconception that translational and rotational relaxation occur concurrently. A significant part of the relaxation process occurs in non-quasi-steady-state conditions. Exchange processes are found to have a significant impact on the relaxation of the gas, while predissociation has a negligible effect. The results obtained by means of the full rovibrational collisional model are used to assess the validity of reduced order models (vibrational collisional and multitemperature) which are based on the same kinetic database. It is found that thermalization and dissociation are drastically overestimated by the reduced order models. The reasons of the failure differ in the two cases. In the vibrational collisional model the overestimation of the dissociation is a consequence of the assumption of equilibrium between the rotational energy and the translational energy. The multitemperature model fails to predict the correct thermochemical relaxation due to the failure of the quasi-steady-state assumption, used to derive the phenomenological rate coefficient for dissociation. | 25,122,371 | [
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Extension of the dielectric breakdown model for simulation of viscous fingering at finite viscosity ratios. | Immiscible displacement of viscous oil by water in a petroleum reservoir is often hydrodynamically unstable. Due to similarities between the physics of dielectric breakdown and immiscible flow in porous media, we extend the existing dielectric breakdown model to simulate viscous fingering patterns for a wide range of viscosity ratios (μ(r)). At low values of power-law index η, the system behaves like a stable Eden growth model and as the value of η is increased to unity, diffusion limited aggregation-like fractals appear. This model is compared with our two-dimensional (2D) experiments to develop a correlation between the viscosity ratio and the power index, i.e., η = 10(-5)μ(r)(0.8775). The 2D and three-dimensional (3D) simulation data appear scalable. The fingering pattern in 3D simulations at finite viscosity ratios appear qualitatively similar to the few experimental results published in the literature. | 25,122,390 | [
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Three-dimensional coherent structures of electrokinetic instability. | A direct numerical simulation of the three-dimensional elektrokinetic instability near a charge-selective surface (electric membrane, electrode, or system of micro- or nanochannels) has been carried out and analyzed. A special finite-difference method has been used for the space discretization along with a semi-implicit 31/3-step Runge-Kutta scheme for the integration in time. The calculations employ parallel computing. Three characteristic patterns, which correspond to the overlimiting currents, are observed: (a) two-dimensional electroconvective rolls, (b) three-dimensional regular hexagonal structures, and (c) three-dimensional structures of spatiotemporal chaos, which are a combination of unsteady hexagons, quadrangles, and triangles. The transition from (b) to (c) is accompanied by the generation of interacting two-dimensional solitary pulses. | 25,122,393 | [
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Role of viscous friction in the reverse rotation of a disk. | The mechanical response of a circularly driven disk in a dissipative medium is considered. We focus on the role played by viscous friction in the spinning motion of the disk, especially on the effect called reverse rotation, where the intrinsic and orbital rotations are antiparallel. Contrary to what happens in the frictionless case, where steady reverse rotations are possible, we find that this dynamical behavior may exist only as a transient when dissipation is considered. Whether or not reverse rotations in fact occur depends on the initial conditions and on two parameters, one related to dragging, inertia, and driving, the other associated with the geometric configuration of the system. The critical value of this geometric parameter (separating the regions where reverse rotation is possible from those where it is forbidden) as a function of viscosity is well adjusted by a q-exponential function. | 25,122,402 | [
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Theory of ion transport with fast acid-base equilibrations in bioelectrochemical systems. | Bioelectrochemical systems recover valuable components and energy in the form of hydrogen or electricity from aqueous organic streams. We derive a one-dimensional steady-state model for ion transport in a bioelectrochemical system, with the ions subject to diffusional and electrical forces. Since most of the ionic species can undergo acid-base reactions, ion transport is combined in our model with infinitely fast ion acid-base equilibrations. The model describes the current-induced ammonia evaporation and recovery at the cathode side of a bioelectrochemical system that runs on an organic stream containing ammonium ions. We identify that the rate of ammonia evaporation depends not only on the current but also on the flow rate of gas in the cathode chamber, the diffusion of ammonia from the cathode back into the anode chamber, through the ion exchange membrane placed in between, and the membrane charge density. | 25,122,405 | [
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Multiscale dynamics of semiflexible polymers from a universal coarse-graining procedure. | Simulating the dynamics of a semiflexible polymer across time and length scales that bridge the rigid and flexible regimes requires a physically sound method for generating coarse-grained representations of the polymer. Here, we study the dynamic behavior of the discrete stretchable, shearable wormlike chain model, which can be used to coarse-grain a continuous semi-elastic chain at an arbitrary discretization. We show that the dynamics of this universal model match those of the wormlike chain at length scales above the discretization length. The evolution of the stress correlation, as probed through Brownian dynamics simulations, is found to reproduce the predicted behavior in both the rigid and flexible regimes, spanning over six orders of magnitude in time scales. The coarse-graining approach employed here thus enables dynamic simulation of semiflexible polymers at lengths and times that were previously inaccessible with conventional methods. | 25,122,407 | [
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Generalized modification in the lattice Bhatnagar-Gross-Krook model for incompressible Navier-Stokes equations and convection-diffusion equations. | In this paper, two modified lattice Boltzmann Bhatnagar-Gross-Krook (LBGK) models for incompressible Navier-Stokes equations and convection-diffusion equations are proposed via the addition of correction terms in the evolution equations. Utilizing this modification, the value of the dimensionless relaxation time in the LBGK model can be kept in a proper range, and thus the stability of the LBGK model can be improved. Although some gradient operators are included in the correction terms, they can be computed efficiently using local computational schemes such that the present LBGK models still retain the intrinsic parallelism characteristic of the lattice Boltzmann method. Numerical studies of the steady Poiseuille flow and unsteady Womersley flow show that the modified LBGK model has a second-order convergence rate in space, and the compressibility effect in the common LBGK model can be eliminated. In addition, to test the stability of the present models, we also performed some simulations of the natural convection in a square cavity, and we found that the results agree well with those reported in the previous work, even at a very high Rayleigh number (Ra = 10(12)). | 25,122,412 | [
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RET mutation and expression in small-cell lung cancer. | There is growing interest in defining the somatic mutations associated with small-cell lung cancer (SCLC). Unfortunately, a serious blockade to genomic analyses of this disease is a limited access to tumors because surgery is rarely performed. We used our clinical/pathologic database of SCLC patients to determine the availability of biopsy specimens that could be used for genomic studies and to identify tumors for initial oncogene analysis. DNA was extracted from six tumors, three primary and three metastatic, and analyzed by SEQUENOM platform technology. Primary-resected tumor tissue represents less than 3% of all diagnostic specimens in this disease, highlighting the limited access to tissue sufficient for comprehensive genomic analyses. We identified an activating M918T RET somatic mutation in a metastatic SCLC tumor specimen. Bioinformatic search identified RET mutations in other SCLC studies. Stable overexpression of both mutant M918T and wild-type RET in two SCLC cell lines, H1048 and SW1271, activated ERK signaling, MYC expression, and increased cell proliferation, particularly by mutant RET. Stable cells became sensitized to the RET tyrosine kinase inhibitors, vandetanib and ponatinib. Further analysis of RET mRNA expression in SCLC revealed wide variability in both cells and tumors, and SCLC cells demonstrated significantly higher RET expression compared with adenocarcinoma lung cells. Our data suggest that a subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. Coupled with the presence of RET fusion proteins in non-small-cell lung cancer, our data indicate an emerging role for RET in SCLC. | 25,122,427 | [
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Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis. | The information regarding therapeutically relevant genomic alterations in small cell lung cancer (SCLC) is not well developed. We analyzed the SCLC genome using an integrative approach to stratify the targetable alterations. We performed whole exon sequencing (n = 51) and copy number analysis (n =47) on surgically resected tumors and matched normal tissue samples from treatment-naive Japanese SCLC patients. The demographics of the 51 patients included in this study were as follows: median age, 67 years (range, 42-86 years); female, 9 (18%); history of smoking, 50 (98%); and pathological stage I/II/III/IV, 28/13/9/1, respectively. The average number of nonsynonymous mutations was 209 (range, 41-639; standard deviation, 130). We repeatedly confirmed the high prevalence of inactivating mutations in TP53 and RB1, and the amplification of MYC family members. In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 36% of the tumors: PIK3CA, 6%; PTEN, 4%; AKT2, 9%; AKT3, 4%; RICTOR, 9%; and mTOR, 4%. Furthermore, the individual changes in this pathway were mutually exclusive. Importantly, the SCLC cells harboring active PIK3CA mutations were potentially targetable with currently available PI3K inhibitors. The PI3K/AKT/mTOR pathway is distinguishable in SCLC genomic alterations. Therefore, a sequencing-based comprehensive analysis could stratify SCLC patients by potential therapeutic targets. | 25,122,428 | [
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Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. | In the phase IV, open-label, single-arm study NCT01203917, first-line gefitinib 250 mg/d was effective and well tolerated in Caucasian patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (previously published). Here, we report EGFR mutation analyses of plasma-derived, circulating-free tumor DNA. Mandatory tumor and duplicate plasma (1 and 2) baseline samples were collected (all screened patients; n = 1060). Preplanned, exploratory analyses included EGFR mutation (and subtype) status of tumor versus plasma and between plasma samples. Post hoc, exploratory analyses included efficacy by tumor and plasma EGFR mutation (and subtype) status. Available baseline tumor samples were 1033 of 1060 (118 positive of 859 mutation status known; mutation frequency, 13.7%). Available plasma 1 samples were 803 of 1060 (82 positive of 784 mutation status known; mutation frequency, 10.5%). Mutation status concordance between 652 matched tumor and plasma 1 samples was 94.3% (95% confidence interval [CI], 92.3-96.0) (comparable for mutation subtypes); test sensitivity was 65.7% (95% CI, 55.8-74.7); and test specificity was 99.8% (95% CI, 99.0-100.0). Twelve patients of unknown tumor mutation status were subsequently identified as plasma mutation-positive. Available plasma 2 samples were 803 of 1060 (65 positive of 224 mutation status-evaluable and -known). Mutation status concordance between 224 matched duplicate plasma 1 and 2 samples was 96.9% (95% CI, 93.7-98.7). Objective response rates are as follows: mutation-positive tumor, 70% (95% CI, 60.5-77.7); mutation-positive tumor and plasma 1, 76.9% (95% CI, 65.4-85.5); and mutation-positive tumor and mutation-negative plasma 1, 59.5% (95% CI, 43.5-73.7). Median progression-free survival (months) was 9.7 (95% CI, 8.5-11.0; 61 events) for mutation-positive tumor and 10.2 (95% CI, 8.5-12.5; 36 events) for mutation-positive tumor and plasma 1. The high concordance, specificity, and sensitivity demonstrate that EGFR mutation status can be accurately assessed using circulating-free tumor DNA. Although encouraging and suggesting that plasma is a suitable substitute for mutation analysis, tumor tissue should remain the preferred sample type when available. | 25,122,430 | [
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Re-evaluating the optimal radiation dose for definitive chemoradiotherapy for esophageal squamous cell carcinoma. | The optimal radiation dose for treating esophageal squamous cell carcinoma (ESCC) has long been debated. We evaluated if doses greater than 50.4 Gy delivered with modern techniques are beneficial in terms of tumor control, survival, and toxicity. We included 193 consecutive patients with ESCC treated with definitive concurrent chemoradiotherapy from 1998 to 2012. Patients were treated to a dose of ≤50.4 Gy (low-dose, n = 137) or greater than 50.4 Gy (high-dose, n = 56). Tumor response, local-regional control, survival, and treatment toxicity were compared between groups. High-dose group had a significantly lower local failure rate (17.9% versus 34.3%, p = 0.024) and a marginal better 5-year local-regional failure-free survival (68.7% versus 55.9%, p = 0.052) than the low-dose group. No significant differences were found between high- and low-dose groups in tumor complete response rate (p = 0.975), regional failure rate (p = 0.336), distant metastasis rate (p = 0.390), or 5-year overall survival (p = 0.617). No difference in the incidence of toxic effects was observed between the two groups except for grade 3 skin reaction (12.5% [high] versus 2.2% [low], p < 0.001) and grade greater than or equal to 3 esophageal stricture (32.1% [high] versus 18.2% [low], p = 0.037). Local tumor control might be improved by higher dose of greater than 50.4 Gy, when delivered with modern techniques and concurrent chemotherapy, at the consequence of increased toxicity without impact on overall survival. | 25,122,435 | [
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Effects of aging on osteogenic response and heterotopic ossification following burn injury in mice. | Heterotopic ossification (HO) is a common and debilitating complication of burns, traumatic brain injuries, and musculoskeletal trauma and surgery. Although the exact mechanism of ectopic bone formation is unknown, mesenchymal stem cells (MSCs) capable of osteogenic differentiation are known to play an essential role. Interestingly, the prevalence of HO in the elderly population is low despite the high overall occurrence of musculoskeletal injury and orthopedic procedures. We hypothesized that a lower osteogenicity of MSCs would be associated with blunted HO formation in old compared with young mice. In vitro osteogenic differentiation of adipose-derived MSCs from old (18-20 months) and young (6-8 weeks) C57/BL6 mice was assessed, with or without preceding burn injury. In vivo studies were then performed using an Achilles tenotomy with concurrent burn injury HO model. HO formation was quantified using μCT scans, Raman spectroscopy, and histology. MSCs from young mice had more in vitro bone formation, upregulation of bone formation pathways, and higher activation of Smad and nuclear factor kappa B (NF-κB) signaling following burn injury. This effect was absent or blunted in cells from old mice. In young mice, burn injury significantly increased HO formation, NF-κB activation, and osteoclast activity at the tenotomy site. This blunted, reactive osteogenic response in old mice follows trends seen clinically and may be related to differences in the ability to mount acute inflammatory responses. This unique characterization of HO and MSC osteogenic differentiation following inflammatory insult establishes differences between age populations and suggests potential pathways that could be targeted in the future with therapeutics. | 25,122,460 | [
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Surface physicochemistry and ionic strength affects eDNA's role in bacterial adhesion to abiotic surfaces. | Extracellular DNA (eDNA) is an important structural component of biofilms formed by many bacteria, but few reports have focused on its role in initial cell adhesion. The aim of this study was to investigate the role of eDNA in bacterial adhesion to abiotic surfaces, and determine to which extent eDNA-mediated adhesion depends on the physicochemical properties of the surface and surrounding liquid. We investigated eDNA alteration of cell surface hydrophobicity and zeta potential, and subsequently quantified the effect of eDNA on the adhesion of Staphylococcus xylosus to glass surfaces functionalised with different chemistries resulting in variable hydrophobicity and charge. Cell adhesion experiments were carried out at three different ionic strengths. Removal of eDNA from S. xylosus cells by DNase treatment did not alter the zeta potential, but rendered the cells more hydrophilic. DNase treatment impaired adhesion of cells to glass surfaces, but the adhesive properties of S. xylosus were regained within 30 minutes if DNase was not continuously present, implying a continuous release of eDNA in the culture. Removal of eDNA lowered the adhesion of S. xylosus to all surfaces chemistries tested, but not at all ionic strengths. No effect was seen on glass surfaces and carboxyl-functionalised surfaces at high ionic strength, and a reverse effect occurred on amine-functionalised surfaces at low ionic strength. However, eDNA promoted adhesion of cells to hydrophobic surfaces irrespective of the ionic strength. The adhesive properties of eDNA in mediating initial adhesion of S. xylosus is thus highly versatile, but also dependent on the physicochemical properties of the surface and ionic strength of the surrounding medium. | 25,122,477 | [
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A review of the Fukushima nuclear reactor accident: radiation effects on the thyroid and strategies for prevention. | This is a summary of the nuclear accident at the Tokyo Electric Power Company Fukushima Daiichi Nuclear Power Stations (FDNPS) on 11 March 2011 to be used as a review of the radiation effects to the thyroid and strategies of prevention. The amount of radioiodine released to the environment following the Fukushima accident was 120 Peta Becquerel, which is approximately one-tenth of that in the Chernobyl accident. Residents near the FDNPS were evacuated within a few days and foodstuffs were controlled within 1 or 2 weeks. Therefore, thyroid radiation doses were less than 100 mSv (intervention levels for stable iodine administration) in the majority of children, including less than 1 year olds, living in the evacuation areas. Because the incidence of childhood thyroid cancer increased in those residing near the site following the Chernobyl accident, thyroid screening of all children (0-18 years old) in the Fukushima Prefecture was started. To date, screening of more than 280 000 children has resulted in the diagnosis of thyroid cancer in 90 children (approximate incidence, 313 per million). Thus, although the dose of radiation was much lower, the incidence of thyroid cancer appears to be much higher than that following the Chernobyl accident. A comparison of the thyroidal consequences following the Fukushima and Chernobyl nuclear reactor accidents is discussed. We also summarize the recent increased incidence in thyroid cancer in the Fukushima area following the accident in relation to increased thyroid ultrasound screening and the use of advanced ultrasound techniques. http://links.lww.com/COE/A8. | 25,122,492 | [
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A maladaptive role for EP4 receptors in mouse mesangial cells. | Roles of the prostaglandin E2 E-prostanoid 4 receptor (EP4) on extracellular matrix (ECM) accumulation induced by TGF-β1 in mouse glomerular mesangial cells (GMCs) remain unknown. Previously, we have identified that TGF-β1 stimulates the expression of FN and Col I in mouse GMCs. Here we asked whether stimulation of EP4 receptors would exacerbate renal fibrosis associated with enhanced glomerular ECM accumulation. We generated EP4(Flox/Flox) and EP4(+/-) mice, cultured primary WT, EP4(Flox/Flox) and EP4(+/-) GMCs, AD-EP4 transfected WT GMCs (EP4 overexpression) and AD-Cre transfected EP4(Flox/Flox) GMCs (EP4 deleted). We found that TGF-β1-induced cAMP and PGE2 synthesis decreased in EP4 deleted GMCs and increased in EP4 overexpressed GMCs. Elevated EP4 expression in GMCs augmented the coupling of TGF-β1 to FN, Col I expression and COX2/PGE2 signaling, while TGF-β1 induced FN, Col I expression and COX2/PGE2 signaling were down-regulated in EP4 deficiency GMCs. 8 weeks after 5/6 nephrectomy (Nx), WT and EP4(+/-) mice exhibited markedly increased accumulation of ECM compared with sham-operated controls. Albuminuria, blood urea nitrogen and creatinine (BUN and Cr) concentrations were significantly increased in WT mice as compared to those of EP4(+/-) mice. Urine osmotic pressure was dramatically decreased after 5/6 Nx surgery in WT mice as compared to EP4(+/-) mice. The pathological changes in kidney of EP4(+/-) mice was markedly alleviated compared with WT mice. Immunohistochemical analysis showed significant reductions of Col I and FN in the kidney of EP4(+/-) mice compared with WT mice. Collectively, this investigation established EP4 as a potent mediator of the pro-TGF-β1 activities elicited by COX2/PGE2 in mice GMCs. Our findings suggested that prostaglandin E2, acting via EP4 receptors contributed to accumulation of ECM in GMCs and promoted renal fibrosis. | 25,122,504 | [
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Steered quantum dynamics for energy minimization. | We introduce a quantum optimal control algorithm for energy minimization that combines the diffeomorphic modulation under observable response preserving homotopy (D-MORPH) gradient and the Broyden Fletcher Goldfarb Shanno (BFGS) iterative scheme for nonlinear optimization. An extended set of controls defining the time-dependent mass, dipole moment, and external perturbational field are optimized to find an effective Hamiltonian that steers the dynamics of the system into the global minimum without getting trapped into local minima. The algorithm is illustrated as applied to energy minimization on rugged surfaces and golf potentials comparable to those previously explored for testing quantum annealing methodologies. | 25,122,515 | [
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Infrageneric phylogeny and temporal divergence of Sorghum (Andropogoneae, Poaceae) based on low-copy nuclear and plastid sequences. | The infrageneric phylogeny and temporal divergence of Sorghum were explored in the present study. Sequence data of two low-copy nuclear (LCN) genes, phosphoenolpyruvate carboxylase 4 (Pepc4) and granule-bound starch synthase I (GBSSI), from 79 accessions of Sorghum plus Cleistachne sorghoides together with those from outgroups were used for maximum likelihood (ML) and Bayesian inference (BI) analyses. Bayesian dating based on three plastid DNA markers (ndhA intron, rpl32-trnL, and rps16 intron) was used to estimate the ages of major diversification events in Sorghum. The monophyly of Sorghum plus Cleistachne sorghoides (with the latter nested within Sorghum) was strongly supported by the Pepc4 data using BI analysis, and the monophyly of Sorghum was strongly supported by GBSSI data using both ML and BI analyses. Sorghum was divided into three clades in the Pepc4, GBSSI, and plastid phylograms: the subg. Sorghum lineage; the subg. Parasorghum and Stiposorghum lineage; and the subg. Chaetosorghum and Heterosorghum lineage. Two LCN homoeologous loci of Cleistachne sorghoides were first discovered in the same accession. Sorghum arundinaceum, S. bicolor, S. x drummondii, S. propinquum, and S. virgatum were closely related to S. x almum in the Pepc4, GBSSI, and plastid phylograms, suggesting that they may be potential genome donors to S. almum. Multiple LCN and plastid allelic variants have been identified in S. halepense of subg. Sorghum. The crown ages of Sorghum plus Cleistachne sorghoides and subg. Sorghum are estimated to be 12.7 million years ago (Mya) and 8.6 Mya, respectively. Molecular results support the recognition of three distinct subgenera in Sorghum: subg. Chaetosorghum with two sections, each with a single species, subg. Parasorghum with 17 species, and subg. Sorghum with nine species and we also provide a new nomenclatural combination, Sorghum sorghoides. | 25,122,516 | [
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"The Castle of Remembrance": New insights from a cognitive training programme for autobiographical memory in Alzheimer's disease. | Autobiographical memory deficits are prominent from the early stages of Alzheimer's disease (AD) and result in a loss of personal identity. Nevertheless, standardised methods of autobiographical memory stimulation for the neuropsychological rehabilitation of patients with AD remain underdeveloped. Our aim was to evaluate the impact of a new cognitive training programme for autobiographical memory (REMau) on both the episodic and semantic components of autobiographical memory performance across lifetime periods, as well as on mood. Pre/post evaluations were conducted on two groups of patients with early to moderate AD, assigned to one of two different training activities: either the REMau or a cognitive training programme focused on collective semantic memory. Statistical comparisons showed significant improvement of episodic and semantic autobiographical memory performance in the REMau group, which was more pronounced for the semantic component, as well as improved mood. By contrast, deleterious pre/post differences were observed in the other group. Most interestingly, this study showed that the REMau programme boosted autobiographical memory from the reminiscence bump period, which is considered crucial for the construction and maintenance of personal identity. We discuss the theoretical and practical implications of these results for the reduction of autobiographical memory deficits in AD. | 25,122,521 | [
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Preparation of microcrystals in lipidic cubic phase for serial femtosecond crystallography. | We have recently established a procedure for serial femtosecond crystallography (SFX) in lipidic cubic phase (LCP) for protein structure determination at X-ray free-electron lasers (XFELs). LCP-SFX uses the gel-like LCP as a matrix for growth and delivery of membrane protein microcrystals for crystallographic data collection. LCP is a liquid-crystalline mesophase composed of lipids and water. It provides a membrane-mimicking environment that stabilizes membrane proteins and supports their crystallization. Here we describe detailed procedures for the preparation and characterization of microcrystals for LCP-SFX applications. The advantages of LCP-SFX over traditional crystallographic methods include the capability of collecting room-temperature high-resolution data with minimal effects of radiation damage from sub-10-μm crystals of membrane and soluble proteins that are difficult to crystallize, while eliminating the need for crystal harvesting and cryo-cooling. Compared with SFX methods for microcrystals in solution using liquid injectors, LCP-SFX reduces protein consumption by 2-3 orders of magnitude for data collection at currently available XFELs. The whole procedure typically takes 3-5 d, including the time required for the crystals to grow. | 25,122,522 | [
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Addition of exogenous α-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous α-synuclein to Lewy body and Lewy neurite-like aggregates. | This protocol describes a primary neuronal model of formation of α-synuclein (α-syn) aggregates that recapitulate features of the Lewy bodies and Lewy neurites found in Parkinson's disease brains and other synucleinopathies. This model allows investigation of aggregate formation, their impact on neuron function, and development of therapeutics. Addition of preformed fibrils (PFFs) synthesized from recombinant α-syn to neurons seeds the recruitment of endogenous α-syn into aggregates characterized by detergent insolubility and hyperphosphorylation. Aggregate formation follows a lag phase of 2-3 d, followed by formation in axons by days 4-7, spread to somatodendritic compartments by days 7-10 and neuron death ~14 d after PFF addition. Here we provide methods and highlight the crucial steps for PFF formation, PFF addition to cultured hippocampal neurons and confirmation of aggregate formation. Neurons derived from various brain regions from nontransgenic and genetically engineered mice and rats can be used, allowing interrogation of the effect of specific genes on aggregate formation. | 25,122,523 | [
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Comb-push ultrasound shear elastography (CUSE) for evaluation of thyroid nodules: preliminary in vivo results. | In clinical practice, an overwhelming majority of biopsied thyroid nodules are benign. Therefore, there is a need for a complementary and noninvasive imaging tool to provide clinically relevant diagnostic information about thyroid nodules to reduce the rate of unnecessary biopsies. The goal of this study was to evaluate the feasibility of utilizing comb-push ultrasound shear elastography (CUSE) to measure the mechanical properties (i.e., stiffness) of thyroid nodules and use this information to help classify nodules as benign or malignant. CUSE is a fast and robust 2-D shear elastography technique in which multiple laterally distributed acoustic radiation force beams are utilized simultaneously to produce shear waves. Unlike other shear elasticity imaging modalities, CUSE does not suffer from limited field of view (FOV) due to shear wave attenuation and can provide a large FOV at high frame rates. To evaluate the utility of CUSE in thyroid imaging, a preliminary study was performed on a group of five healthy volunteers and 10 patients with ultrasound-detected thyroid nodules prior to fine needle aspiration biopsy. The measured shear wave speeds in normal thyroid tissue and thyroid nodules were converted to Young's modulus (E), indicating a measure of tissue stiffness. Our results indicate an increase in E for thyroid nodules compared to normal thyroid tissue. This increase was significantly higher in malignant nodules compared to benign. The Young's modulus in normal thyroid tissue, benign and malignant nodules were found to be 23.2 ±8.29 kPa, 91.2±34.8 kPa, and 173.0±17.1 kPa, respectively. Results of this study suggest the utility of CUSE in differentiating between benign and malignant thyroid nodules. | 25,122,532 | [
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Italy between drinking culture and control policies for alcoholic beverages. | This paper focuses on whether the on-going dramatic decrease in alcohol consumption in Italy, especially of wine, during 1961-2008, was associated with which parallel sociodemographic and economic changes and with alcohol control policies. The study, using both time series (TS) and artificial neural network (ANN)-based analyses documents that its selected sociodemographic and economic factors, and particularly urbanization, had a definite connection with wine consumption decrease, spirits decrease, and the increase in beer consumption over time. On the other hand, control policies showed no effect on the decline in alcohol consumption, since no alcohol control policy existed in Italy between 1960 and 1987. A few policies introduced since 1988 (BAC and sale restrictions during mass events) may have contributed to reducing or to maintaining the on-going reduction. Study limitations are noted and future needed research is suggested. | 25,122,545 | [
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DEB: definite error bounded tangent estimator for digital curves. | We propose a simple and fast method for tangent estimation of digital curves. This geometric-based method uses a small local region for tangent estimation and has a definite upper bound error for continuous as well as digital conics, i.e., circles, ellipses, parabolas, and hyperbolas. Explicit expressions of the upper bounds for continuous and digitized curves are derived, which can also be applied to nonconic curves. Our approach is benchmarked against 72 contemporary tangent estimation methods and demonstrates good performance for conic, nonconic, and noisy curves. In addition, we demonstrate a good multigrid and isotropic performance and low computational complexity of O(1) and better performance than most methods in terms of maximum and average errors in tangent computation for a large variety of digital curves. | 25,122,569 | [
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VSI: a visual saliency-induced index for perceptual image quality assessment. | Perceptual image quality assessment (IQA) aims to use computational models to measure the image quality in consistent with subjective evaluations. Visual saliency (VS) has been widely studied by psychologists, neurobiologists, and computer scientists during the last decade to investigate, which areas of an image will attract the most attention of the human visual system. Intuitively, VS is closely related to IQA in that suprathreshold distortions can largely affect VS maps of images. With this consideration, we propose a simple but very effective full reference IQA method using VS. In our proposed IQA model, the role of VS is twofold. First, VS is used as a feature when computing the local quality map of the distorted image. Second, when pooling the quality score, VS is employed as a weighting function to reflect the importance of a local region. The proposed IQA index is called visual saliency-based index (VSI). Several prominent computational VS models have been investigated in the context of IQA and the best one is chosen for VSI. Extensive experiments performed on four large-scale benchmark databases demonstrate that the proposed IQA index VSI works better in terms of the prediction accuracy than all state-of-the-art IQA indices we can find while maintaining a moderate computational complexity. The MATLAB source code of VSI and the evaluation results are publicly available online at http://sse.tongji.edu.cn/linzhang/IQA/VSI/VSI.htm. | 25,122,572 | [
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Intratympanic steroid injection for Bell's palsy: preliminary randomized controlled study. | To investigate adjuvant effect and safety of intratympanic steroid for the treatment of Bell's palsy. Prospective, investigator blinded, randomized study. Tertiary referral center. Patients who received treatment for Bell's palsy from December 2007 to March 2011 were randomly divided into two groups. The control group (n = 17) was treated with systemic steroid plus antiviral agent, and intratympanic steroid injection group (IT group, n = 14) received intratympanic steroid injection combined with medications. Facial functions were evaluated on a regular basis up to 6 months. Intratympanic steroid injection. Facial nerve functions of initial presentation and follow-up were evaluated with House-Brackmann (H-B) system. Primary outcome was complete recovery rate of 6 months. Secondary outcomes included improvement of H-B grade within 3 weeks, time of first improvement in facial function, and cumulative recovery rate. In addition, subgroup analysis of H-B grade over than IV was performed. Complete recovery rate was not different between groups. Time of first improvement was shorter in IT group (p = 0.043). And IT group had a better cumulative recovery rate (p = 0.041) and showed the significant improvement in H-B grade within 3 weeks compared with control group (p = 0.045). In severe facial palsy, complete recovery rate of IT group and control group were 80% and 50% (p = 0.16), and IT groups showed the significant facial improvement within 3 weeks (p = 0.025). And there were no major adverse effects of intratympanic injection. Intratympanic steroid injection might be a safe and useful adjuvant treatment modality for Bell's palsy. | 25,122,597 | [
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Long-term results of 185 consecutive osseointegrated hearing device implantations: a comparison among children, adults, and elderly. | To determine the occurrence and type of perioperative and postoperative complications in patients implanted with an osseointegrated hearing device (OHD) (also known as BAHA/BAHS) and compare results in children, adults, and elderly and for different surgical techniques. Retrospective case file review. Tertiary referral center. Patients implanted with an OHD between 2004 and 2012, with more than 6 months of follow-up. OHD implantation. Implant loss, adverse skin reactions (Holgers' score, ≥2), skin overgrowth, and discomfort resulting in abutment and/or implant removal. One hundred eighty-five implantations in 176 patients were reviewed. Overall, 3.8% of the implants were lost spontaneously after a mean of 2.5 years. Implant loss in children was 18% versus 2.5% in adults and 3.8% in elderly. Adverse skin reactions occurred in 14% of observations overall; in 10% in children compared with 16% in adults and 9% in elderly. Partial or total skin overgrowth was seen in 4% and 6% of the observations in children and adults, respectively, whereas none of the elderly experienced this problem. The abutment was removed because of discomfort and/or no benefit in 10% overall, in 13% of adults, and in 6% of the elderly; none of the children opted for removal. Linear incision technique showed fewest complications. OHD implantation is a procedure with few major complications. Adverse skin reaction is the most common complication. Children lose the implant more frequently than adults. Elderly patients have less adverse skin reactions/skin overgrowth. Discomfort leading to abutment removal is a concern especially among adults. | 25,122,598 | [
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Sensorimotor adaptation: multiple forms of plasticity in motor circuits. | One of the most striking properties of the adult central nervous system is its ability to undergo changes in function and/or structure. In mammals, learning is a major inducer of adaptive plasticity. Sensorimotor adaptation is a type of procedural--motor--learning that allows maintaining accurate movements in the presence of environmental or internal perturbations by adjusting motor output. In this work, we will review experimental evidence gathered from rodents and human and nonhuman primates pointing to possible sites of adaptation-related plasticity at different levels of organization of the nervous system. | 25,122,611 | [
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Male smoker and non-smoker responses to television advertisements on the harms of secondhand smoke in China, India and Russia. | Mass media campaigns can play an important role in strengthening support for smoke-free policies and reducing exposure to secondhand smoke (SHS). Identifying anti-SHS advertisements that are effective in diverse cultural contexts may allow for resource sharing in low- and middle-income countries. A convenience sample of 481 male cigarette smokers and non-smokers in three high tobacco burden and culturally dissimilar countries (India, China and Russia) viewed and rated five anti-SHS ads. Multivariate logistic regression analyses were conducted for 'Message Acceptance', 'Negative Emotion', 'Perceived Effectiveness' and 'Behavioral Intentions'. Smokers and non-smokers in all countries consistently rated the strong graphic, health harm ads as the most effective, and the 'informational' ad as the least effective overall: the graphic ad 'Baby Alive' was at least 1.8 times more likely than the informational ad 'Smoke-free works' to receive positive ratings on all four outcomes (all P < 0.001). Graphic, health harm messages about SHS exposure have the greatest universal appeal and are the most effective in motivating changes in behavioral intentions. Similarity in reactions between smokers and non-smokers, and across countries, suggests that resource sharing and the use of a single graphic ad targeted at smokers and non-smokers would be cost-efficient strategies. | 25,122,618 | [
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Strategies to Promote Cultural Competence in Distance Education. | Cultural competence is a mainstay in health care and nursing education. With the expansion in the number of distance-based nursing programs across the country, innovative teaching methods for distance learning faculty are required to instill cultural competence in students. Faculty must be deliberate when planning distance-based learning activities that incorporate cultural experiences. This article describes several such strategies including the creative use of blogging, recorded lectures, the online synchronous classroom, social media, and cultural immersion projects. These methods capitalize on existing information technologies and offer distance-based students the opportunity to connect with one another, as well as develop the awareness, sensitivity, and respect that is required when providing culturally competent care. These teaching methods are modifiable to meet the teaching and learning needs of the faculty and the students, thereby allowing educators to support the integration of cultural competence into patient care for distance students. | 25,122,626 | [
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Stability study of carboplatin infusion solutions in 0.9% sodium chloride in polyvinyl chloride bags. | Carboplatin is a platinum-containing compound with efficacy against various malignancies. The physico-chemical stability of carboplatin in dextrose 5% water (D5W) has been thoroughly studied; however, there is a paucity of stability data in clinically relevant 0.9% sodium chloride infusion solutions. The manufacturer's limited stability data in sodium chloride solutions hampers the flexibility of carboplatin usage in oncology patients. Hence, the purpose of this study is to determine the physical and chemical stability of carboplatin-sodium chloride intravenous solutions under different storage conditions. The physico-chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL carboplatin-sodium chloride solutions prepared in polyvinyl chloride bags was determined following storage at room temperature under ambient fluorescent light and under refrigeration in the dark. Concentrations of carboplatin were measured at predetermined time points up to seven days using a stability-indicating high-performance liquid chromatography method. All tested solutions were found physically stable for at least seven days. The greatest chemical stability was observed under refrigerated storage conditions. At 4℃, all tested solutions were found chemically stable for at least seven days, with nominal losses of ≤6%. Following storage at room temperature exposed to normal fluorescent light, the chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL solutions was three days, five days, and seven days, respectively. The extended physico-chemical stability of carboplatin prepared in sodium chloride reported herein permits advance preparation of these admixtures, facilitating pharmacy utility and operations. Since no antibacterial preservative is contained within these carboplatin solutions, we recommend storage, when prepared under specified aseptic conditions, no greater than 24 h at room temperature or three days under refrigeration. | 25,122,633 | [
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Glycine stimulates protein synthesis and inhibits oxidative stress in pig small intestinal epithelial cells. | Glycine has recently been classified as a nutritionally essential amino acid for maximal growth in young pigs. Currently, little is known about the metabolism or function of glycine in the neonatal intestine. This work was conducted to test the hypothesis that glycine has a protective effect against oxidative stress in intestinal epithelial cells. Jejunal enterocytes isolated from newborn pigs were cultured in the presence of 0.0-2 mmol/L glycine for measurements of glycine metabolism, cell proliferation, protein turnover, apoptosis, and antioxidative response. Compared with 0.0-0.5 mmol/L glycine, 1.0 mmol/L glycine enhanced (P < 0.05) cell growth (by 8-24% on day 2 and by 34-224% on day 4, respectively) and protein synthesis (by 36-419%) while reducing (P < 0.05) protein degradation (by 7-28%). This effect of glycine was associated with activation of the mammalian target of rapamycin signaling pathway in enterocytes. By using a model of oxidative stress induced by 30 μmol/L 4-hydroxynonenal (4-HNE), which was assessed by flow cytometry analysis, 1.0 mmol/L glycine inhibited (P < 0.05) activation of caspase 3 by 25% and attenuated (P < 0.05) 4-HNE-induced apoptosis by 38% in intestinal porcine epithelial cell line 1 cells through promotion of reduced glutathione synthesis and expression of glycine transporter 1 while reducing the activation of extracellular signal-regulated kinases, c-Jun amino-terminal kinases, and p38 protein in the mitogen-activated protein kinase signaling pathway. These novel findings provide a biochemical mechanism for the use of dietary glycine to improve intestinal health in neonates under conditions of oxidative stress and glycine deficiency. | 25,122,646 | [
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Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy. | Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease due to a CAG triplet-repeat expansion in the androgen receptor (AR) gene, which is translated into an elongated polyglutamine (polyQ) tract in AR protein (ARpolyQ). ARpolyQ toxicity is activated by the AR ligand testosterone (or dihydrotestosterone), and the polyQ triggers ARpolyQ misfolding and aggregation in spinal cord motoneurons and muscle cells. In motoneurons, testosterone triggers nuclear toxicity by inducing AR nuclear translocation. Thus, (i) prevention of ARpolyQ nuclear localization, combined with (ii) an increased ARpolyQ cytoplasmic clearance, should reduce its detrimental activity. Using the antiandrogen Bicalutamide (Casodex(®)), which slows down AR activation and nuclear translocation, and the disaccharide trehalose, an autophagy activator, we found that, in motoneurons, the two compounds together reduced ARpolyQ insoluble forms with higher efficiency than that obtained with single treatments. The ARpolyQ clearance was mediated by trehalose-induced autophagy combined with the longer cytoplasmic retention of ARpolyQ bound to Bicalutamide. This allows an increased recognition of misfolded species by the autophagic system prior to their migration into the nucleus. Interestingly, the combinatory use of trehalose and Bicalutamide was also efficient in the removal of insoluble species of AR with a very long polyQ (Q112) tract, which typically aggregates into the cell nuclei. Collectively, these data suggest that the combinatory use of Bicalutamide and trehalose is a novel approach to facilitate ARpolyQ clearance that has to be tested in other cell types target of SBMA (i.e. muscle cells) and in vivo in animal models of SBMA. | 25,122,660 | [
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Association of lower extremity performance with cardiovascular and all-cause mortality in patients with peripheral artery disease: a systematic review and meta-analysis. | Peripheral artery disease (PAD) is associated with impaired mobility and a high rate of mortality. The aim of this systematic review was to investigate whether reduced lower extremity performance was associated with an increased incidence of cardiovascular and all-cause mortality in people with PAD. A systematic search of the MEDLINE, EMBASE, SCOPUS, Web of Science, and Cochrane Library databases was conducted. Studies assessing the association between measures of lower extremity performance and cardiovascular or all-cause mortality in PAD patients were included. A meta-analysis was conducted combining data from commonly assessed performance tests. The 10 identified studies assessed lower extremity performance by strength tests, treadmill walking performance, 6-minute walk, walking velocity, and walking impairment questionnaire (WIQ). A meta-analysis revealed that shorter maximum walking distance was associated with increased 5-year cardiovascular (unadjusted RR=2.54, 95% CI 1.86 to 3.47, P<10(-5), n=1577, fixed effects) and all-cause mortality (unadjusted RR=2.23 95% CI 1.85 to 2.69, P<10(-5), n=1710, fixed effects). Slower 4-metre walking velocity, a lower WIQ stair-climbing score, and poor hip extension, knee flexion, and plantar flexion strength were also associated with increased mortality. No significant associations were found for hip flexion strength, WIQ distance score, or WIQ speed score with mortality. A number of lower extremity performance measures are prognostic markers for mortality in PAD and may be useful clinical tools for identifying patients at higher risk of death. Further studies are needed to determine whether interventions that improve measures of lower extremity performance reduce mortality. | 25,122,666 | [
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Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy. | Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments. | 25,122,679 | [
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Type of homogenization and fat loss during continuous infusion of human milk. | Substantial fat loss may occur during continuous feeding of human milk (HM). A decrease of fat loss has been described following homogenization. Well-established methods of homogenization of HM for routine use in the neonatal intensive care unit (NICU) would be desirable. We compared the loss of fat based on the use of 3 different methods for homogenizing thawed HM during continuous feeding. Sixteen frozen donor HM samples were thawed, homogenized with ultrasound and separated into 3 aliquots ("baseline agitation," "hourly agitation," and "ultrasound"), and then frozen for 48 hours. Aliquots were thawed again and a baseline agitation was applied. Subsequently, aliquots baseline agitation and hourly agitation were drawn into a syringe, while ultrasound was applied to aliquot ultrasound before it was drawn into a syringe. The syringes were loaded into a pump (2 mL/h; 4 hours). At hourly intervals the hourly agitation infusion was stopped, the syringe was disconnected and gently shaken. During infusion, samples from the 3 groups were collected hourly for analysis of fat and caloric content. The 3 groups of homogenization showed similar fat content at the beginning of the infusion. For fat, mean (SD) hourly changes of -0.03 (0.01), -0.09 (0.01), and -0.09 (0.01) g/dL were observed for the hourly agitation, baseline agitation, and ultrasound groups, respectively. The decrease was smaller for the hourly agitation group (P < .001). When thawed HM is continuously infused, a smaller fat loss is observed when syringes are agitated hourly versus when ultrasound or a baseline homogenization is used. | 25,122,692 | [
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Predictive impact on medium-term mortality of hematological parameters in Acute Coronary Syndromes: added value on top of GRACE risk score. | Red Cell Distribution Width (RDW) prognostic value in patients with Acute Coronary Syndrome (ACS) has been well validated whereas that of Platelet Distribution Width (PDW) is less well known. Investigate the incremental prognostic value, on top of GRACE risk score, of a new variable resulting from the combination of RDW and PDW. Consecutive patients with ACS. Complete blood count, with RDW and PDW, was obtained. Primary endpoint was one-year all-cause mortality and Cox regression models were used to measure the influence of RDW and PDW on patients' survival time. A new combination categorical variable (RDW/PDW) was created with both discretized RDW and PDW and logistic regression models were used. Predictive value and discriminative ability of the model with GRACE risk score alone and of the model with inclusion of RDW/PDW was assessed. We included 787 patients. Hospital and one-year mortality rates were 5.1% and 7.8%, respectively. Both continuous RDW and PDW were independent predictors of death. The best cut-off for RDW was 13.9%, and 14.5% for PDW. Inclusion of RDW/PDW in a model with GRACE risk score improved the AUC from 0.81 (95% CI 0.75-0.86) to 0.84 (95% CI 0.79-0.90) (p=0.024) with an improvement in total NRI (56%) and IDI (0.048). Simple markers such as RDW and PDW can be useful in risk stratification of death after ACS. Combining both markers with GRACE risk score improved the predictive value for all-cause mortality and reduced the estimated risk of those who did not die. | 25,122,727 | [
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Monte Carlo non-local means: random sampling for large-scale image filtering. | We propose a randomized version of the nonlocal means (NLM) algorithm for large-scale image filtering. The new algorithm, called Monte Carlo nonlocal means (MCNLM), speeds up the classical NLM by computing a small subset of image patch distances, which are randomly selected according to a designed sampling pattern. We make two contributions. First, we analyze the performance of the MCNLM algorithm and show that, for large images or large external image databases, the random outcomes of MCNLM are tightly concentrated around the deterministic full NLM result. In particular, our error probability bounds show that, at any given sampling ratio, the probability for MCNLM to have a large deviation from the original NLM solution decays exponentially as the size of the image or database grows. Second, we derive explicit formulas for optimal sampling patterns that minimize the error probability bound by exploiting partial knowledge of the pairwise similarity weights. Numerical experiments show that MCNLM is competitive with other state-of-the-art fast NLM algorithms for single-image denoising. When applied to denoising images using an external database containing ten billion patches, MCNLM returns a randomized solution that is within 0.2 dB of the full NLM solution while reducing the runtime by three orders of magnitude. | 25,122,743 | [
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Probing the elastic limit of DNA bending. | Sharp bending of double-stranded DNA (dsDNA) plays an essential role in genome structure and function. However, the elastic limit of dsDNA bending remains controversial. Here, we measured the opening rates of small dsDNA loops with contour lengths ranging between 40 and 200 bp using single-molecule Fluorescence Resonance Energy Transfer. The relationship of loop lifetime to loop size revealed a critical transition in bending stress. Above the critical loop size, the loop lifetime changed with loop size in a manner consistent with elastic bending stress, but below it, became less sensitive to loop size, indicative of softened dsDNA. The critical loop size increased from ∼ 60 bp to ∼ 100 bp with the addition of 5 mM magnesium. We show that our result is in quantitative agreement with the kinkable worm-like chain model, and furthermore, can reproduce previously reported looping probabilities of dsDNA over the range between 50 and 200 bp. Our findings shed new light on the energetics of sharply bent dsDNA. | 25,122,748 | [
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Inhibition of neuronal cell mitochondrial complex I with rotenone increases lipid β-oxidation, supporting acetyl-coenzyme A levels. | Rotenone is a naturally occurring mitochondrial complex I inhibitor with a known association with parkinsonian phenotypes in both human populations and rodent models. Despite these findings, a clear mechanistic link between rotenone exposure and neuronal damage remains to be determined. Here, we report alterations to lipid metabolism in SH-SY5Y neuroblastoma cells exposed to rotenone. The absolute levels of acetyl-CoA were found to be maintained despite a significant decrease in glucose-derived acetyl-CoA. Furthermore, palmitoyl-CoA levels were maintained, whereas the levels of many of the medium-chain acyl-CoA species were significantly reduced. Additionally, using isotopologue analysis, we found that β-oxidation of fatty acids with varying chain lengths helped maintain acetyl-CoA levels. Rotenone also induced increased glutamine utilization for lipogenesis, in part through reductive carboxylation, as has been found previously in other cell types. Finally, palmitoylcarnitine levels were increased in response to rotenone, indicating an increase in fatty acid import. Taken together, these findings show that alterations to lipid and glutamine metabolism play an important compensatory role in response to complex I inhibition by rotenone. | 25,122,772 | [
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Type I interferon protects mice from fatal neurotropic infection with Langat virus by systemic and local antiviral responses. | Vector-borne flaviviruses, such as tick-borne encephalitis virus (TBEV), West Nile virus, and dengue virus, cause millions of infections in humans. TBEV causes a broad range of pathological symptoms, ranging from meningitis to severe encephalitis or even hemorrhagic fever, with high mortality. Despite the availability of an effective vaccine, the incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuroinflammation in LGTV-infected mice, characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor deletions, we show that coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis. The type I interferon (IFN) system is important to control viral infections; however, the interactions between tick-borne encephalitis virus (TBEV) and the type I IFN system are poorly characterized. TBEV causes severe infections in humans that are characterized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available. An improved understanding of antiviral innate immune responses is pivotal for the development of effective therapeutics. We show that type I IFN, an effector molecule of the innate immune system, is responsible for the extended survival of TBEV and Langat virus (LGTV), an attenuated member of the TBE serogroup. IFN production and signaling appeared to be essential in two different phases during infection. The first phase is in the periphery, by reducing systemic LGTV replication and spreading into the central nervous system (CNS). In the second phase, the local IFN response in the CNS prevents virus-induced inflammation and the development of encephalitis. | 25,122,777 | [
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Modulation of hepatitis C virus genome replication by glycosphingolipids and four-phosphate adaptor protein 2. | Hepatitis C virus (HCV) assembles its replication complex on cytosolic membrane vesicles often clustered in a membranous web (MW). During infection, HCV NS5A protein activates PI4KIIIα enzyme, causing massive production and redistribution of phosphatidylinositol 4-phosphate (PI4P) lipid to the replication complex. However, the role of PI4P in the HCV life cycle is not well understood. We postulated that PI4P recruits host effectors to modulate HCV genome replication or virus particle production. To test this hypothesis, we generated cell lines for doxycycline-inducible expression of short hairpin RNAs (shRNAs) targeting the PI4P effector, four-phosphate adaptor protein 2 (FAPP2). FAPP2 depletion attenuated HCV infectivity and impeded HCV RNA synthesis. Indeed, FAPP2 has two functional lipid-binding domains specific for PI4P and glycosphingolipids. While expression of the PI4P-binding mutant protein was expected to inhibit HCV replication, a marked drop in replication efficiency was observed unexpectedly with the glycosphingolipid-binding mutant protein. These data suggest that both domains are crucial for the role of FAPP2 in HCV genome replication. We also found that HCV significantly increases the level of some glycosphingolipids, whereas adding these lipids to FAPP2-depleted cells partially rescued replication, further arguing for the importance of glycosphingolipids in HCV RNA synthesis. Interestingly, FAPP2 is redistributed to the replication complex (RC) characterized by HCV NS5A, NS4B, or double-stranded RNA (dsRNA) foci. Additionally, FAPP2 depletion disrupts the RC and alters the colocalization of HCV replicase proteins. Altogether, our study implies that HCV coopts FAPP2 for virus genome replication via PI4P binding and glycosphingolipid transport to the HCV RC. Like most viruses with a positive-sense RNA genome, HCV replicates its RNA on remodeled host membranes composed of lipids hijacked from various internal membrane compartments. During infection, HCV induces massive production and retargeting of the PI4P lipid to its replication complex. However, the role of PI4P in HCV replication is not well understood. In this study, we have shown that FAPP2, a PI4P effector and glycosphingolipid-binding protein, is recruited to the HCV replication complex and is required for HCV genome replication and replication complex formation. More importantly, this study demonstrates, for the first time, the crucial role of glycosphingolipids in the HCV life cycle and suggests a link between PI4P and glycosphingolipids in HCV genome replication. | 25,122,779 | [
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Emergence of broadly neutralizing antibodies and viral coevolution in two subjects during the early stages of infection with human immunodeficiency virus type 1. | Delineating the key early events that lead to the development of broadly neutralizing anti-HIV-1 antibodies during natural infection may help guide the development of immunogens and vaccine regimens to prevent HIV-1 infection. In this study, we monitored two HIV-1-positive subjects, VC20013 and VC10014, over the course of infection from before they developed broadly neutralizing antibody (bNAb) activity until several years after neutralizing breadth was detected in plasma. Both subjects developed bNAb activity after approximately 1 year postinfection, which ultimately mapped to the membrane-proximal external region (MPER) in VC20013 and an epitope that overlaps the CD4 receptor binding site in VC10014. In subject VC20013, we were able to identify anti-MPER activity in the earliest plasma sample that exhibited no bNAb activity, indicating that this epitope specificity was acquired very early on, but that it was initially not able to mediate neutralization. Escape mutations within the bNAb epitopes did not arise in the circulating envelopes until bNAb activity was detectable in plasma, indicating that this early response was not sufficient to drive viral escape. As bNAb activity began to emerge in both subjects, we observed a simultaneous increase in autologous antienvelope antibody binding affinity, indicating that antibody maturation was occurring as breadth was developing. Our findings illustrate one potential mechanism by which bNAbs develop during natural infection in which an epitope target is acquired very early on during the course of infection but require time and maturation to develop into broadly neutralizing activity. One major goal of HIV-1 vaccine research is the development of a vaccine that can elicit broadly neutralizing antibodies (bNAbs). Although no such vaccine exists, bNAbs develop in approximately 20% of HIV-1-infected subjects, providing a prototype of the bNAbs that must be reelicited by vaccine. Thus, there is significant interest in understanding the mechanisms by which bNAbs develop during the course of infection. We studied the timing, epitope specificity, and evolution of the bNAb responses in two HIV-1-positive patients who developed bNAb activity within the first several years after infection. In one subject, antibodies to a broadly neutralizing epitope developed very early but were nonneutralizing. After several months, neutralizing activity developed, and the virus mutated to escape their activity. Our study highlights one mechanism for the development of bNAbs where early epitope acquisition followed by sufficient time for antibody maturation drives the epitope-specific antibody response toward broadly neutralizing activity. | 25,122,781 | [
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The N terminus of the influenza B virus nucleoprotein is essential for virus viability, nuclear localization, and optimal transcription and replication of the viral genome. | The nucleoprotein (NP) of influenza viruses is a multifunctional protein with essential roles throughout viral replication. Despite influenza A and B viruses belonging to separate genera of the Orthomyxoviridae family, their NP proteins share a relatively high level of sequence conservation. However, NP of influenza B viruses (BNP) contains an evolutionarily conserved N-terminal 50-amino-acid extension that is absent from NP of influenza A viruses. There is conflicting evidence as to the functions of the BNP N-terminal extension; however, this has never been assessed in the context of viral infection. We have used reverse genetics to assess the significance of this region on the functions of BNP and virus viability. The truncation of more than three amino acids prevented virus recovery, suggesting that the N-terminal extension is essential for virus viability. Mutational analysis indicated that multiple regions of the protein are involved in the nuclear localization of BNP, with the entire N-terminal extension required for this to function efficiently. Viruses containing mutations in the first 10 residues of BNP demonstrated few differences in nuclear localization; however, the viruses exhibited significant reductions in viral mRNA transcription and genome replication, resulting in significantly attenuated phenotypes. Mutations introduced to ablate a previously reported nuclear localization signal also resulted in a significant decrease in mRNA production during early stages of viral replication. Overall, our results demonstrate that the N-terminal extension of BNP is essential to virus viability not only for directing nuclear localization of BNP but also for regulating viral mRNA transcription and genome replication. The multifunctional NP of influenza viruses has roles throughout the viral replication cycle; therefore, it is essential for virus viability. Despite high levels of homology between the NP of influenza A and B viruses, the NP of influenza B virus contains an evolutionarily conserved 50-amino-acid N-terminal extension that is absent from the NP of influenza A viruses. In this study, we show that this N-terminal extension is essential for virus viability, and we confirm and expand upon recent findings that this region of BNP is required for nuclear localization of the protein. Furthermore, we demonstrate for the first time that the N terminus of BNP is involved in regulating viral mRNA transcription and replication of the viral genome. As the NP of influenza A virus lacks this N-terminal extension, these viruses may have evolved separate mechanisms to regulate these processes. | 25,122,787 | [
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The VP4 peptide of hepatitis A virus ruptures membranes through formation of discrete pores. | Membrane-active peptides, components of capsid structural proteins, assist viruses in overcoming the host membrane barrier in the initial stages of infection. Several such peptides have been identified, and their roles in membrane fusion or disruption have been characterized through biophysical studies. In several members of the Picornaviridae family, the role of the VP4 structural peptide in cellular-membrane penetration is well established. However, there is not much information on the membrane-penetrating capsid components of hepatitis A virus (HAV), an unusual member of this family. The VP4 peptide of HAV differs from its analogues in other picornaviruses in being significantly shorter in length and in lacking a signal for myristoylation, thought to be a critical requisite for VP4-mediated membrane penetration. Here we report, for the first time, that the atypical VP4 in HAV contains significant membrane-penetrating activity. Using a combination of biophysical assays and molecular dynamics simulation studies, we show that VP4 integrates into membrane vesicles through its N-terminal region to finally form discrete pores of 5- to 9-nm diameter, which induces leakage in the vesicles without altering their overall size or shape. We further demonstrate that the membrane activity of VP4 is specific toward vesicles mimicking the lipid content of late endosomes at acidic pH. Taken together, our data indicate that VP4 might be essential for the penetration of host endosomal membranes and release of the viral genome during HAV entry. Hepatitis A virus causes acute hepatitis in humans through the fecal-oral route and is particularly prevalent in underdeveloped regions with poor hygienic conditions. Although a vaccine for HAV exists, its high cost makes it unsuitable for universal application in developing countries. Studies on host-virus interaction for HAV have been hampered due to a lack of starting material, since the virus is extremely slow growing in culture. Among the unknown aspects of the HAV life cycle is its manner of host membrane penetration, which is one of the most important initial steps in viral infection. Here, we present data to suggest that a small peptide, VP4, a component of the HAV structural polyprotein, might be essential in helping the viral genome cross cell membranes during entry. It is hoped that this work might help in elucidating the manner of initial host cell interaction by HAV. | 25,122,794 | [
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Global asymptotic stabilization using adaptive fuzzy PD control. | It is well-known that standard adaptive fuzzy control (AFC) can only guarantee uniformly ultimately bounded stability due to inherent fuzzy approximation errors (FAEs). This paper proves that standard AFC with proportional-derivative (PD) control can guarantee global asymptotic stabilization even in the presence of FAEs for a class of uncertain affine nonlinear systems. Variable-gain PD control is designed to globally stabilize the plant. An optimal FAE is shown to be bounded by the norm of the plant state vector multiplied by a globally invertible and nondecreasing function, which provides a pivotal property for stability analysis. Without discontinuous control compensation, the closed-loop system achieves global and partially asymptotic stability in the sense that all plant states converge to zero. Compared with previous adaptive approximation-based global/asymptotic stabilization approaches, the major advantage of our approach is that global stability and asymptotic stabilization are achieved concurrently by a much simpler control law. Illustrative examples have further verified the theoretical results. | 25,122,847 | [
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Evaluation of the nanosphere Verigene BC-GN assay for direct identification of gram-negative bacilli and antibiotic resistance markers from positive blood cultures and potential impact for more-rapid antibiotic interventions. | The Verigene BC-GN assay correctly identified all 51 Gram-negative bacilli (GNB) from positive blood cultures and all 14 carbapenemase enzymes tested. The assay gave organism identification (ID) results an average of 24 h faster compared to conventional identifications. Medical management could have been modified for 31.8% of patients an average 33 h sooner. In conclusion, the BC-GN assay is a very accurate, rapid assay which would allow for more-immediate medical management decisions in patients with bacteremia from GNB. | 25,122,857 | [
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Two cases of bacteriemia caused by nontoxigenic, non-O1, non-O139 Vibrio cholerae isolates in Ho Chi Minh City, Vietnam. | The toxigenic bacterium Vibrio cholerae belonging to the O1 and O139 serogroups is commonly associated with epidemic diarrhea in tropical settings; other diseases caused by this environmental pathogen are seldom identified. Here we report two unassociated cases of nonfatal, nontoxigenic V. cholerae non-O1, non-O139 bacteremia in patients with comorbidities in Ho Chi Minh City, Vietnam, that occurred within a 4-week period. | 25,122,858 | [
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Chemogenetic silencing of neurons in retrosplenial cortex disrupts sensory preconditioning. | An essential aspect of episodic memory is the formation of associations between neutral sensory cues in the environment. In light of recent evidence that this critical aspect of learning does not require the hippocampus, we tested the involvement of the retrosplenial cortex (RSC) in this process using a chemogenetic approach that allowed us to temporarily silence neurons along the entire rostrocaudal extent of the RSC. A viral vector containing the gene for a synthetic inhibitory G-protein-coupled receptor (hM4Di) was infused into RSC. When the receptor was later activated by systemic injection of clozapine-N-oxide, neural activity in RSC was transiently silenced (confirmed using a patch-clamp procedure). Rats expressing hM4Di and control rats were trained in a sensory preconditioning procedure in which a tone and light were paired on some trials and a white noise stimulus was presented alone on the other trials during the Preconditioning phase. Thus, rats were given the opportunity to form an association between a tone and a light in the absence of reinforcement. Later, the light was paired with food. During the test phase when the auditory cues were presented alone, controls exhibited more conditioned responding during presentation of the tone compared with the white noise reflecting the prior formation of a tone-light association. Silencing RSC neurons during the Preconditioning phase prevented the formation of an association between the tone and light and eliminated the sensory preconditioning effect. These findings indicate that RSC may contribute to episodic memory formation by linking essential sensory stimuli during learning. | 25,122,898 | [
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The essential role of primate orbitofrontal cortex in conflict-induced executive control adjustment. | Conflict in information processing evokes trial-by-trial behavioral modulations. Influential models suggest that adaptive tuning of executive control, mediated by mid-dorsal lateral prefrontal cortex (mdlPFC) and anterior cingulate cortex (ACC), underlies these modulations. However, mdlPFC and ACC are parts of distributed brain networks including orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), and superior-dorsal lateral prefrontal cortex (sdlPFC). Contributions of these latter areas in adaptive tuning of executive control are unknown. We trained monkeys to perform a matching task in which they had to resolve the conflict between two behavior-guiding rules. Here, we report that bilateral lesions in OFC, but not in PCC or sdlPFC, impaired selection between these competing rules. In addition, the behavioral adaptation that is normally induced by experiencing conflict disappeared in OFC-lesioned, but remained normal in PCC-lesioned or sdlPFC-lesioned monkeys. Exploring underlying neuronal processes, we found that the activity of neurons in OFC represented the conflict between behavioral options independent from the other aspects of the task. Responses of OFC neurons to rewards also conveyed information of the conflict level that the monkey had experienced along the course to obtain the reward. Our findings indicate dissociable functions for five closely interconnected cortical areas suggesting that OFC and mdlPFC, but not PCC or sdlPFC or ACC, play indispensable roles in conflict-dependent executive control of on-going behavior. Both mdlPFC and OFC support detection of conflict and its integration with the task goal, but in contrast to mdlPFC, OFC does not retain the necessary information for conflict-induced modulation of future decisions. | 25,122,901 | [
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Concentrations of mobile source air pollutants in urban microenvironments. | Human exposures to criteria and hazardous air pollutants (HAPs) in urban areas vary greatly due to temporal-spatial variations in emissions, changing meteorology, varying proximity to sources, as well as due to building, vehicle, and other environmental characteristics that influence the amounts of ambient pollutants that penetrate or infiltrate into these microenvironments. Consequently, the exposure estimates derived from central-site ambient measurements are uncertain and tend to underestimate actual exposures. The Exposure Classification Project (ECP) was conducted to measure pollutant concentrations for common urban microenvironments (MEs) for use in evaluating the results of regulatory human exposure models. Nearly 500 sets of measurements were made in three Los Angeles County communities during fall 2008, winter 2009, and summer 2009. MEs included in-vehicle, near-road, outdoor and indoor locations accessible to the general public. Contemporaneous 1- to 15-min average personal breathing zone concentrations of carbon monoxide (CO), carbon dioxide (CO2), volatile organic compounds (VOCs), nitric oxide (NO), nitrogen oxides (NO(x)), particulate matter (< 2.5 microm diameter; PM2.5) mass, ultrafine particle (UFP; < 100 nm diameter) number black carbon (BC), speciated HAPs (e.g, benzene, toluene, ethylbenzene, xylenes [BTEX], 1,3-butadiene), and ozone (O3) were measured continuously. In-vehicle and inside/outside measurements were made in various passenger vehicle types and in public buildings to estimate penetration or infiltration factors. A large fraction of the observed pollutant concentrations for on-road MEs, especially near diesel trucks, was unrelated to ambient measurements at nearby monitors. Comparisons of ME concentrations estimated using the median ME/ambient ratio versus regression slopes and intercepts indicate that the regression approach may be more accurate for on-road MEs. Ranges in the ME/ambient ratios among ME categories were generally greater than differences among the three communities for the same ME category, suggesting that the ME proximity factors may be more broadly applicable to urban MEs. Implications: Estimates of population exposure to air pollutants extrapolated from ambient measurements at ambient fixed site monitors or exposure surrogates are prone to uncertainty. This study measured concentrations of mobile source air toxics (MSAT) and related criteria pollutants within in-vehicle, outdoor near-road, and indoor urban MEs to provide multipollutant ME measurements that can be used to calibrate regulatory exposure models. | 25,122,949 | [
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Role of sodium ions in the vitrification process: glass matrix modification, slag structure depolymerization, and influence of metal immobilization. | This study investigates the role of Na ions, a common flux, in the vitrification process. Artificial glass systems composed of Al2O3, CaO, and SiO2 with various Na concentrations were melted at 1450 degrees C. The specimens were cooled by air cooling and water quenching and the metal mobility was evaluated using a sequential extraction procedure. The X-ray diffraction analysis and scanning electron microscopy observations showed that Na ions governed the air-cooled slag's structure. Na ions initially depolymerized CaSiO3-linked chains into CaSiO3 chains, and further cut them into shorter and nonuniform ones, making the slag structure amorphous. With even more Na ions, CaSiO3 chains were divided into single SiO4 tetrahedrons and formed Na-related crystals (Na2Ca3Si2O8 and NaAlSiO4). The phase distributions of Al, Cr, Cu Mn, and Ni showed that Na has a positive effect on the immobilization of heavy metals at suitable concentrations, but a negative effect when in excess amounts. Implications: Vitrification has been widely used to treat hazardous materials. The Na-bearing additives were often used as a flux to improve the melting process. This study described the role of Na played in the vitrification process. The Na ions acted as glass modifier and depolymerize the chain structure of slag. With adequate addition amount of Na ions, the immobilization of heavy metals was improved. The results provided much information about the crystalline phase variation, metal mobility, and surface characteristics while Na serves as a flux. | 25,122,951 | [
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Clinical supervision in the 21st century: revisiting pressing needs and impressing possibilities. | What are some of the most pressing needs currently confronting clinical supervision? In this paper, I give attention to that question. Drawing on two 1990 reviews for comparative purposes, I examine where supervision is now relative to four areas: (a) supervision training and practice; (b) measurement; (c) difference and diversity; and (d) research. Lines of advance, pressing needs, and potential remedies are considered across each area. Effort is made to accentuate the "robustly international" nature of clinical supervision and its increasing globalization. | 25,122,988 | [
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Is starting with the feet out of the water faster in backstroke swimming? | This study aimed to determine if starting with the feet above the water (FAW) in male backstroke swimming resulted in faster start times (15-m time) than when the feet were underwater (FUW). It was hypothesised that setting higher on the wall would generate increased horizontal force and velocity, resulting in quicker starts. Twelve high-level male backstrokers performed three trials of the FAW and FUW techniques. A biomechanical swimming testing system comprising one force plate (1,000 Hz), four lateral-view (100Hz), and five overhead (50Hz) video cameras captured the swimmers' performance. Data for each participant's fastest trial for each technique were collated, grouped, and statistically analysed. Analysis included Wilcoxon, Spearman Rho correlation, and regression analysis. Wilcoxon results revealed a significantly faster start time for the FAW technique (p < 0.01). Peak horizontal force was significantly smaller for FAW (p = 0.02), while take-off horizontal velocity was significantly greater (p = 0.01). Regression analysis indicated take-off horizontal velocity to be a good predictor of start time for both techniques, and the horizontal displacement of the centre of mass for the FAW start. | 25,123,000 | [
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Patency of vascular accesses for Thai hemodialysis patients. | Vascular access for hemodialysis is the mode of renal replacement therapy for chronic renal failure patients. The present study reports patency rates of arteriovenous fistula (AVF) and graft (AVG). Between July 2008 and June 2011, 336 vascular accesses were performed in 293 patients in Department of Surgery, Faculty of Medicine, Khon Kaen University. The patient was follow until June 2012. A retrospective review was conduct to analyze patency rate. Two hundred ninety three patients underwent 286 AVFs and 50 AVGs. Patency rate was analyzed with the Kaplan-Meier method. Primary patency rate of AVF at one, two, and three-year was 78.69%, 70.43%, and 60.72%, respectively Assisted primary patency of AVF at one, two, and three-year was 88.24%, 75.63%, and 40.34%, respectively. Secondary patency rate of AVF at one and two-year was 71.46% and 71.46%, respectively. Primary patency rate of AVG at one, two, and three-year was 63.94%, 43.93%, and 36.60%, respectively. Assisted primary patency of AVG at one-year was 100%. Secondary patency rate of AVG at one-year was 46.30%. Graft infection was the major complication ofAVG (12%). The authors' results of vascular access surgery were comparable to results from a review of literature. | 25,123,011 | [
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A specialized post anaesthetic care unit improves fast-track management in cardiac surgery: a prospective randomized trial. | Fast-track treatment in cardiac surgery has become the global standard of care. We compared the efficacy and safety of a specialised post-anaesthetic care unit (PACU) to a conventional intensive care unit (ICU) in achieving defined fast-track end-points in adult patients after elective cardiac surgery. In a prospective, single blinded, randomized study, 200 adult patients undergoing elective cardiac surgery (coronary artery bypass graft (CABG), valve surgery or combined CABG and valve surgery), were selected to receive their postoperative treatment either in the ICU (n = 100), or in the PACU (n = 100). Patients who, at the time of surgery, were in cardiogenic shock, required renal dialysis, or had an additive EuroSCORE of more than 10 were excluded from the study. The primary end points were: time to extubation (ET), and length of stay in the PACU or ICU (PACU/ICU LOS respectively). Secondary end points analysed were the incidences of: surgical re-exploration, development of haemothorax, new onset cardiac arrhythmia, low cardiac output syndrome, need for cardio-pulmonary resuscitation, stroke, acute renal failure, and death. Median time to extubation was 90 [50; 140] min in the PACU vs. 478 [305; 643] min in the ICU group (P < 0.001). Median length of stay in PACU was 3.3 [2.7; 4.0] hours vs. 17.9 [10.3; 24.9] hours in the ICU (P < 0.001). Of the adverse events examined, only the incidence of new onset cardiac arrhythmia (25 in PACU vs. 41 in ICU, P = 0.02) was statistically different between groups. Treatment in a specialised PACU rather than an ICU, after elective cardiac surgery leads to earlier extubation and quicker discharge to a step down unit, without compromising patient safety. ISRCTN71768341. Registered 11 March 2014. | 25,123,092 | [
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An eight-year epidemiologic study based on baculovirus-expressed type-specific spike proteins for the differentiation of type I and II feline coronavirus infections. | Feline infectious peritonitis (FIP) is a fatal disease caused by feline coronavirus (FCoV). FCoVs are divided into two serotypes with markedly different infection rates among cat populations around the world. A baculovirus-expressed type-specific domain of the spike proteins of FCoV was used to survey the infection of the two viruses over the past eight years in Taiwan. An immunofluorescence assay based on cells infected with the recombinant viruses that was capable of distinguishing between the two types of viral infection was established. A total of 833 cases from a teaching hospital was surveyed for prevalence of different FCoV infections. Infection of the type I FCoV was dominant, with a seropositive rate of 70.4%, whereas 3.5% of cats were infected with the type II FCoV. In most cases, results derived from serotyping and genotyping were highly agreeable. However, 16.7% (4/24) FIP cats and 9.8% (6/61) clinically healthy cats were found to possess antibodies against both viruses. Moreover, most of the cats (84.6%, 22/26) infected with a genotypic untypable virus bearing a type I FCoV antibody. A relatively simple serotyping method to distinguish between two types of FCoV infection was developed. Based on this method, two types of FCoV infection in Taiwan was first carried out. Type I FCoV was found to be predominant compared with type II virus. Results derived from serotyping and genotyping support our current understanding of evolution of disease-related FCoV and transmission of FIP. | 25,123,112 | [
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Predictors of long-term effect from education and exercise in patients with knee and hip pain. | Education and exercise are poorly implemented in osteoarthritis care. The purpose of the present study was to identify predictors of effectiveness at one year from education and exercise in patients with knee or hip pain in clinical practice. Good Life with Arthritis in Denmark is an implementation initiative consisting of education and 12 sessions of neuromuscular exercise delivered by trained physiotherapists. Pain (visual analogue scale 0-100) and quality of life (EQ-5D) were assessed at baseline and after three and 12 months. Changes in outcome from baseline to one year were dependent variables in regression analyses, while changes from baseline to 3 months and absolute results at three months in physical performance (30-second chair stand test) and self-efficacy were predictor variables. A total of 79/82 patients completed the one-year follow-up. Improvements in pain and EQ-5D at three months were maintained at one year (p < 0.006). Change in self-efficacy from baseline to three months (Beta = -0.369) and 30-second chair stand test (Beta = -0.251) and self-efficacy at three months (Beta = -0.492) were predictors of one-year improvement in pain (p < 0.05). Furthermore, self-efficacy at three months (Beta = 0.304) was a predictor of one-year improvement in EQ-5D (p = 0.01). The identified predictors highlight the importance of combining education and exercise. This study indicates that good long-term treatment results are achievable in clinical practice. | 25,123,117 | [
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Improvement in health-related quality of life following Roux-en-Y gastric bypass. | This study explored whether health-related quality of life (HRQOL) changes following Roux-en-Y gastric bypass surgery were associated with identifiable socio-demographic or clinical characteristics, and it examined the impact on health outcomes of changes in the Danish criteria for bariatric surgery. Participants (n = 55) completed the Short Form Health Survey v2 (SF-36) before and 22 ± 4.2 months after surgery. Information on socio-demographics, body mass index (BMI), co-morbidity and satisfaction with surgery were collected through patient questionnaires and hospital records. There was overall improvement on all SF-36 subscales and in the mean physical score (PCS) and mean mental score (MCS) (p = 0.001). A total of five patients had lower PCS and 13 patients had lower MCS after surgery, but we identified no particular characteristics associated with this poorer outcome. Co-morbidity and preoperative PCS/MCS showed a strong correlation with change in PCS/MCS score. Gastric bypass had a positive overall effect on HRQOL, but further investigation of individual variations is needed. We found no significant differences in HRQOL outcome between those patients who would be accepted for bariatric surgery under the current Danish criteria for bariatric surgery and those patients who only fulfilled the criteria for bariatric surgery before 2011. not relevant. ClinicalTrials.gov: NCT02032199. | 25,123,120 | [
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The biomechanics of biodegradable versus titanium interference screw fixation for anterior cruciate ligament augmentation and reconstruction. | The ligament augmentation and reconstruction system (LARS) is one of the options available for anterior cruciate ligament (ACL) reconstruction. To date, however, there are no published data regarding the biomechanical properties of LARS fixation for ACL reconstruction. The aim of this study was to investigate the biomechanical properties of various LARS interference-screw fixations. A total of 100 LARS ligaments were fixed in porcine femurs with five different interference screws (four biodegradable screws and one titanium interference screw) introduced from inside-out or extra-articularly outside-in. Each group consisted of ten specimens. The constructs were cyclically stretched and subsequently loaded until failure. We evaluated the maximum load before failure, elongation during cyclic loading, stiffness, and failure mode. Elongation during cyclical loading for all devices tested was significantly larger between the first and 20th cycles than between the 20th and 500th cycles (p < 0.05). Maximum failure load was not significantly lower for the biodegradable screws than for the titanium screws (p > 0.05). All specimens failed because of ligament pull-out from the bony tunnel. Our findings suggest that biomechanical secure fixation of the LARS for ACL reconstruction can be achieved using either biodegradable or titanium interference screws. The stability of fixation is independent of the approach, type of investigation, and type of fixation (extra-articular outside-in or intra-articular inside-out). | 25,123,129 | [
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Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status. | The tumor suppressor p53 is the most frequently mutated gene in human cancers, mutated in 25-30% of breast cancers. However, mutation rates differ according to breast cancer subtype, being more prevalent in aggressive estrogen receptor-negative tumors and basal-like and HER2-amplified subtypes. This heterogeneity suggests that p53 may function differently across breast cancer subtypes. We used RNAi-mediated p53 knockdown (KD) and antagomir-mediated KD of microRNAs to study how gene expression and cellular response to p53 loss differ in luminal versus basal-like breast cancer. As expected, p53 loss caused downregulation of established p53 targets (e.g. p21 and miR-34 family) and increased proliferation in both luminal and basal-like cell lines. However, some p53-dependent changes were subtype specific, including expression of miR-134, miR-146a and miR-181b. To study the cellular response to miR-146a upregulation in p53-impaired basal-like lines, antagomir KD of miR-146a was performed. KD of miR-146a caused decreased proliferation and increased apoptosis, effectively ablating the effects of p53 loss. Furthermore, we found that miR-146a upregulation decreased NF-κB expression and downregulated the NF-κB-dependent extrinsic apoptotic pathway (including tumor necrosis factor, FADD and TRADD) and antagomir-mediated miR-146a KD restored expression of these components, suggesting a plausible mechanism for miR-146a-dependent cellular responses. These findings are relevant to human basal-like tumor progression in vivo, since miR-146a is highly expressed in p53 mutant basal-like breast cancers. These findings suggest that targeting miR-146a expression may have value for altering the aggressiveness of p53 mutant basal-like tumors. | 25,123,132 | [
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Defective RAGE activity in embryonal rhabdomyosarcoma cells results in high PAX7 levels that sustain migration and invasiveness. | Rhabdomyosarcoma is a muscle-derived malignant tumor mainly affecting children. The most frequent variant, embryonal rhabdomyosarcoma (ERMS) is characterized by overexpression of the transcription factor, PAX7 which prevents ERMS cells from exiting the cell cycle and terminally differentiating. However, a role for PAX7 in the invasive properties of ERMS cells has not been investigated in detail thus far. Here we show that ectopic expression of receptor for advanced glycation end-products (RAGE) in human ERMS cells results in the activation of a RAGE/myogenin axis which downregulates PAX7 by transcriptional and post-translational mechanisms, as in normal myoblasts, and reduces metastasis formation. High PAX7 sustains migration and invasiveness in ERMS cells by upregulating EPHA3 and EFNA1 and downregulating NCAM1 thus decreasing the neural cell adhesion molecule (NCAM)/polysialylated-NCAM ratio. Microarray gene expression analysis shows that compared with the RAGE(-ve) TE671/WT cells and similarly to primary human myoblasts, TE671/RAGE cells show upregulation of genes involved in muscle differentiation and cell adhesion, and downregulation of cell migration related and major histocompatibility complex class I genes. Our data reveal a link between PAX7 and metastasis occurrence in ERMSs, and support a role for the RAGE/myogenin axis in metastasis suppression. Thus, low RAGE expression in ERMS primary tumors may be predictive of metastatic behavior. | 25,123,133 | [
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[Viral safety of biological medicinal products]. | Viral safety of blood donations, plasma products, viral vaccines and gene therapy medicinal products, biotechnical-derived products and tissue and cell therapy products is a particular challenge. These products are manufactured using a variety of human or animal-derived starting materials and reagents; therefore, extensive testing of donors and of cell banks established for production is required. Furthermore, the viral safety of reagents, such as bovine sera, porcine trypsin and human transferrin or albumin needs to be considered. Whenever possible, manufacturing steps for inactivation or removal of viruses should be introduced; however, sometimes it is not possible to introduce such steps for tissues or cell-based medicinal products as the activity and viability of cells will be compromised. It might be possible to implement steps for inactivation or removal of potential contaminating enveloped viruses only for production of small and stable non-enveloped viral gene vectors. | 25,123,140 | [
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Elevated APOBEC3B correlates with poor outcomes for estrogen-receptor-positive breast cancers. | Recent observations connected DNA cytosine deaminase APOBEC3B to the genetic evolution of breast cancer. We addressed whether APOBEC3B is associated with breast cancer clinical outcomes. APOBEC3B messenger RNA (mRNA) levels were related in 1,491 primary breast cancers to disease-free (DFS), metastasis-free (MFS), and overall survival (OS). For independent validation, APOBEC3B mRNA expression was associated with patient outcome data in five additional cohorts (over 3,500 breast cancer cases). In univariate Cox regression analysis, increasing APOBEC3B expression as a continuous variable was associated with worse DFS, MFS, and OS (hazard ratio [HR] = 1.20, 1.21, and 1.24, respectively; all P < .001). Also, in untreated ER-positive (ER+), but not in ER-, lymph-node-negative patients, high APOBEC3B levels were associated with a poor DFS (continuous variable: HR = 1.29, P = .001; dichotomized at the median level, HR = 1.66, P = .0002). This implies that APOBEC3B is a marker of pure prognosis in ER + disease. These findings were confirmed in the analyses of five independent patient sets. In these analyses, APOBEC3B expression dichotomized at the median level was associated with adverse outcomes (METABRIC discovery and validation, 788 and 706 ER + cases, disease-specific survival (DSS), HR = 1.77 and HR = 1.77, respectively, both P < .001; Affymetrix dataset, 754 ER + cases, DFS, HR = 1.57, P = 2.46E-04; NKI295, 181 ER + cases, DFS, HR = 1.72, P = .054; and BIG 1-98, 1,219 ER + cases, breast-cancer-free interval (BCFI), HR = 1.42, P = 0.0079). APOBEC3B is a marker of pure prognosis and poor outcomes for ER + breast cancer, which strongly suggests that genetic aberrations induced by APOBEC3B contribute to breast cancer progression. | 25,123,150 | [
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Immunohistochemical panel for the diagnosis of Hirschsprung's disease using antibodies to MAP2, calretinin, GLUT1 and S100. | The diagnosis of Hirschsprung's disease is currently based on the identification of aganglionosis and the presence of an increase in acetylcholinesterase-positive hypertrophic nerve fibres in the large bowel submucosa. However, acetylcholinesterase staining is laborious and requires a skilled technician. The aim of this study was to identify a method for diagnosing Hirschsprung's disease reliably using an immunohistochemical panel of recently proposed markers. Sixty-nine specimens from 37 patients were evaluated. MAP2 and calretinin antibodies were shown to stain ganglia reliably in the submucosal and myenteric plexuses of normal tissue. By contrast, reduced staining of ganglia was observed in patients with Hirschsprung's disease. Staining for GLUT1 and S100 was used to evaluate the number and thickness of nerve fibres. Gain of GLUT1 and S100 expression was in contrast to the loss of calretinin and MAP2. Hypertrophic submucosal nerve fibres in Hirschsprung's disease develop a perineurium with a ring-like GLUT1 staining pattern similar in size and intensity to that observed in deeper subserosal tissue. The diagnosis of Hirschsprung's disease using immunohistochemical panels could be as accurate as with conventional frozen section techniques. In particular, the use of a combination of markers for ganglia and hypertrophic nerve fibres highlighting a prominent perineurium in Hirschsprung's disease could be an alternative method. | 25,123,159 | [
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Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5). | The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) showed no benefit in the reduction of major neonatal mortality/morbidity or neurodevelopment at 2 and 5 years of age. Using the data from the randomized controlled trial and its follow-up, the aim of this study was to evaluate the association between gestational ages at birth in children exposed to single versus multiple courses of antenatal corticosteroid (ACS) therapy in utero and outcomes at 5 years of age. A total of 1719 children, with the breakdown into groupings of <30, 30-36, and ≥ 37 weeks gestation at birth, contributed to the primary outcome: death or survival with a disability in one of the following domains: neuromotor, neurosensory, and neurobehavioral/emotional disability and were included in this analysis. Gestational age at birth was strongly associated with the primary outcome, p < 0.001. Overall, the interaction between ACS groups and gestational age at birth was not significant, p = 0.064. Specifically, in the 2 preterm categories, there was no difference in the primary outcome between single vs. multiple ACS therapy. However, for infants born ≥37 weeks gestation, there was a statistically significant increase in the risk of the primary outcome in multiple ACS therapy, 48/213 (22.5%) compared to 38/249 (15.3%) in the single ACS therapy; OR = 1.69 [95% CI: 1.04, 2.77]; p = 0.037. Preterm birth (<37 weeks gestation) remained the primary factor contributing to an adverse outcome regardless of the number of courses of ACS therapy. Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an increased risk of neurodevelopmental/neurosensory impairment by 5 years of age. To optimize outcomes for infants/children, efforts in reducing the incidence of preterm birth should remain the primary focus in perinatal research. This study has been registered at (identifier NCT00187382). | 25,123,162 | [
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The pathologic correlation between liver and portal vein invasion in perihilar cholangiocarcinoma: evaluating the oncologic rationale for the American Joint Committee on Cancer definitions of T2 and T3 tumors. | The American Joint Committee on Cancer (AJCC) has recommended that cancers with liver involvement be graded T2b and those with portal vein involvement be graded T3, although the value of staging as prognostic factors remains unclear. We evaluated the current definition of the T2/3 tumors for perihilar cholangiocarcinoma. A total of 202 patients with perihilar cholangiocarcinoma who underwent hepatectomy without vascular resection were enrolled. Clinicopathologic data about invasion of the liver and the unilateral portal vein were evaluated. The liver and the unilateral portal vein were involved in 100 (49.5 %) and 38 (18.8 %) patients, respectively. The survival rates were not significantly different between patients with and without liver invasion (48.6 vs. 52.2 %, respectively, at 5 years, P = 0.157) and between patients with or without unilateral portal vein invasion (43.2 vs. 52.1 %, respectively, at 5 years, P = 0.363). The survival rate of patients with tumors staged pT2b was not significantly different from the rate of patients with pT2a (63.4 vs. 55.6 % at 5 years, P = 0.912), and the pT2b tumor patient survival rate was better than the rate of patients with pT3 (34.9 % at 5 years, P = 0.011). Using multivariate analysis, nodal metastasis (P = 0.003), positive surgical margin (P = 0.010), and Bismuth type IV tumor (P = 0.039) were identified as independent prognostic factors. The liver and the unilateral portal vein are frequently involved in perihilar cholangiocarcinoma. The determinants of the current AJCC T2/3 tumor classifications are rational; however, subdivision of T2 tumors may be of less clinical value. | 25,123,177 | [
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Tryptophan as a probe to study the anticancer mechanism of action and specificity of α-helical anticancer peptides. | In the present study, a single tryptophan, as a fluorescence probe, was shifted from the N-terminus to the middle and to the C-terminus of a 26-residue α-helical anticancer peptide sequence to study the mechanism of action and specificity. The hydrophobicity of peptides, as well as peptide helicity and self-associating ability, were slightly influenced by the position change of tryptophan in the peptide sequence, while the hemolytic activity and anticancer activity of the peptide analogs remained the same. The tryptophan fluorescence experiment demonstrated that peptide analogs were more selective against LUVs mimicking cancer cell membranes than LUVs mimicking normal cell membranes. During the interaction with target membranes, the N-terminus of an anticancer peptide may be inserted vertically or tilted into the hydrophobic components of the phospholipid bilayer first. The thermodynamic parameters of the peptides PNW and PCW, when interacting with zwitterionic DMPC or negatively charged DMPS, were determined by ITC. DSC experiments showed that peptide analogs significantly altered the phase transition profiles of DMPC, but did not dramatically modify the phase transition of DMPS. It is demonstrated that hydrophobic interactions are the main driving force for peptides interacting with normal cell membranes, whilst, electrostatic interactions dominate the interactions between peptides and cancer cell membranes. Utilizing tryptophan as a fluorescence probe molecule appears to be a practicable approach to determine the interaction of peptides with phospholipid bilayers. | 25,123,187 | [
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Acute kidney injury after snakebite accident treated in a Brazilian tertiary care centre. | Acute kidney injury (AKI) is one of the main causes of morbidity and mortality in cases of envenomation by venomous snakes. The present study was carried out to investigate the clinical and laboratory manifestations in accidents with venomous snakes and the risk factors associated with AKI in these accidents. A retrospective study was carried out with patients victims of snakebite admitted to a reference centre. AKI was defined according to the RIFLE and AKIN criteria. A total of 276 patients were included, of which 230 (83.7%) were males. AKI was observed in 42 cases (15.2%). The mean genus involved in the accidents was Bothrops (82.2%). Mean age of patients with AKI was higher than in patients without AKI (43 ± 20 vs. 34 ± 21 years, P = 0.015). The time elapsed between the accident and medical care was higher in the AKI group (25 ± 28 vs. 14 ± 16h, P = 0.034), as well as the time elapsed between the accident and the administration of antivenom (30.7 ± 27 vs. 15 ± 16 h, P = 0.01). Haemodialysis was required in 30% of cases and complete renal function recovery was observed in 54.8% of cases at hospital discharge. There were four deaths, none of which had AKI. Factors associated with AKI were haemorrhagic abnormalities (P = 0.036, OR = 6.718, 95% CI: 1.067-25.661) and longer length of hospital stay (P = 0.004, OR = 1.69, 95% CI 1.165-2.088). Acute kidney injury is an important complication of snakebite accidents, showing low mortality, but high morbidity, which can lead to partial renal function recovery. | 25,123,203 | [
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Effects of childhood abuse on adult obesity: a systematic review and meta-analysis. | Controversy exists surrounding the role of childhood abuse in obesity development. This is a meta-analysis of observational studies on the role of childhood abuse in adult obesity. Systematic searches of PubMed, PsycInfo, Medline and CINAHL resulted in 23 cohort studies (4 prospective, 19 retrospective) with n=112,708 participants, containing four abuse types (physical, emotional, sexual, general). Four studies reported dose-response effects. A random effects model was used to quantify effect sizes, meta-regression/subgroup analysis for identifying potential moderating variables and Egger's test for publication bias. Adults who reported childhood abuse were significantly more likely to be obese (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.24-1.45, P<0.001). All four types of abuse were significantly associated with adult obesity: physical (OR: 1.28, 95% CI: 1.13-1.46), emotional (OR: 1.36, 95% CI: 1.08-1.71), sexual (OR: 1.31, 95% CI: 1.13-1.53) and general abuse (OR: 1.45, 95% CI: 1.25-1.69). Severe abuse (OR: 1.50, 95% CI: 1.27-1.77) was significantly more associated with adult obesity (P=0.043) compared with light/moderate abuse (OR: 1.13, 95% CI: 0.91-1.41). We found no significant effects of study design (prospective vs. retrospective, P=0.07), age (P=0.96) or gender (P=0.92). Publication bias was evident (Egger's test P=0.007), but effect sizes remained statistically significant in sensitivity analyses. Childhood abuse was clearly associated with being obese as an adult, including a positive dose-response association. This suggests that adverse life experiences during childhood plays a major role in obesity development, potentially by inducing mental and emotional perturbations, maladaptive coping responses, stress, inflammation and metabolic disturbances. | 25,123,205 | [
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Low levels of low-density lipoprotein-C associated with proprotein convertase subtilisin kexin 9 inhibition do not increase the risk of hemorrhagic transformation. | Low levels of low-density lipoprotein-cholesterol (LDL-C) are suspected to be associated with a risk of hemorrhagic transformation after ischemic stroke. We assessed the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice with low levels of LDL-C resulting from proprotein convertase subtilisin kexin 9 (PCSK9) deficiency. PCSK9-/- and PCSK9+/+ mice were fed with a high-fat/high-cholesterol (21%/0.15%) diet for 1 month. Plasma lipids were measured using colorimetric assays. PCSK9-/- and PCSK9+/+ mice (n=15 per group) were subjected to a 4-hour intraluminal occlusion of the middle cerebral artery followed by 20 hours of reperfusion. Spontaneous hemorrhagic transformation was assessed by quantification of hemoglobin in ischemic tissue. In vitro, a cell model of blood-brain barrier was used to test endothelial barrier integrity in response to decreasing concentrations of LDL-C from 1 to 0.25g/L in ischemia/reperfusion conditions. PCSK9-/- mice had lower LDL-C, high-density lipoprotein-cholesterol, and total cholesterol levels than PCSK9+/+ mice before and after 1 month on the high-fat/high-cholesterol diet. Hemoglobin concentration in ischemic cerebral tissue was not different between PCSK9-/- and PCSK9+/+ mice (31.5 [18.9-60.1] and 32.8 [14.7-69.9] ng/mg protein, respectively; P=0.81). Infarct volume was also similar in both groups (P=0.66). Incubation of human cerebral endothelial cells with decreasing concentrations of LDL-C under ischemia/reperfusion conditions did not alter blood-brain barrier permeability. Low levels of LDL-C did not increase the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice. Our observations suggest that PCSK9 inhibition, leading to LDL-C lowering, should not increase hemorrhagic complications after acute ischemic stroke. | 25,123,222 | [
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0.1242748,
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A pilot prospective study to evaluate whether the bladder morphology in cystography and/or urodynamic may help predict the response to botulinum toxin a injection in neurogenic bladder refractory to anticholinergics. | We have observed different clinical responses to botulinum toxin A (BTX-A) in patients who had similar urodynamic parameters before the procedure. Furthermore, some bladders evaluated by cystography and cystoscopy during the procedure had different characteristics that could influence the outcome of the treatment. The aim of this study was to assess whether cystography and urodynamic parameters could help predict which patients with neurogenic detrusor overactivity (NDO) refractory to anticholinergics respond better to treatment with injection of BTX-A. In total, 34 patients with spinal cord injury were prospectively evaluated. All patients emptied their bladder by clean intermittent catheterization (CIC) and had incontinence and NDO, despite using 40 mg or more of intravesical oxybutynin and undergoing detrusor injection of BTX-A (300 IU). Pretreatment evaluation included urodynamic, and cystography. Follow-up consisted of urodynamic and ambulatory visits four months after treatment. The cystography parameters used were bladder shape, capacity and presence of diverticula. Urodynamic parameters used for assessment were maximum cystometric capacity (MCC), maximum detrusor pressure (MDP), compliance and reflex volume (RV). After injection of BTX-A, 70% of the patients had success, with 4 months or more of continence. Before the treatment, there were significant differences in most urodynamic parameters between those who responded successfully compared to those who did not. Patients who responded successfully had greater MCC (p = 0.019), higher RV (p = 0.041), and greater compliance (p = 0.043). There was no significant difference in the MDP (0.691). The cystography parameters were not significantly different between these groups bladder shape (p = 0.271), capacity (p > 0.720) and presence of diverticula (p > 0.999). Statistical analyses were performed using SPSS (version 20.0) and included Student's t-test for two paired samples and Fisher's exact test, with a significance threshold of 0.05. This study suggests that the cystography parameters evaluated cannot be used to help predict the response to injection of BTX-A in the treatment of refractory NDO. However, the urodynamic parameters were significantly different in patients who responded to the treatment, with the exception of the MDP. | 25,123,234 | [
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Vitamin E supplementation in chemical colorectal carcinogenesis: a two-edged knife. | This work investigated the effects of Vitamin E (VE) on aberrant crypt foci (ACF) incidence, oxidative stress parameters (serum and hepatic VE concentration, and homocysteine, glutathione (GSH), and malondialdehyde (MDA) levels), and expression of both cyclooxygenase-2 (COX2) and proliferating cellular nuclear antigen (PCNA) in experimental colorectal carcinogenesis. Male Wistar rats received subcutaneous injections of 1,2-dimethylhydrazine (DMH) twice a week, for two weeks (40 mg/kg), except for the Control group. Animals were separated into groups that received different amounts of VE in the diet: 0 IU (0×), 75 IU (recommended daily intake, RDI), 225 IU (3× RDI), or 1500 IU (20× RDI), during (dDMH) or after (aDMH) administration of carcinogen. The 0×dDMH and 3×dDMH groups showed decreased serum VE levels. Hepatic VE concentration was higher in 3×aDMH as compared with the other groups. All the groups, except the Control and the 0×aDMH groups, had reduced GSH levels. The 0×dDMH, 0×aDMH, and 20×aDMH groups exhibited increased MDA levels. The aDMH groups had higher ACF incidence and PCNA expression. The 0×aDMH group presented higher ACF rate, followed by 20×aDMH. Moreover, the 3×aDMH group displayed reduced ACF incidence and COX2 expression. Multivariate analysis revealed that GSH modulated homocysteine levels and COX2. These results suggested that 1500 IU of VE is hazardous, whereas 225 IU of VE has beneficial effects on chemical colorectal carcinogenesis. | 25,123,248 | [
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A significant inhibitory effect on advanced glycation end product formation by catechin as the major metabolite of lotus seedpod oligomeric procyanidins. | Several lines of evidence suggested that B-type procyanidin oligomers from lotus seedpod (LSOPC) may effectively modulate the formation of advanced glycation end products (AGEs). In vivo, LSOPC is metabolized by intestinal flora to become various kinds of phenolic compounds that possess potent antioxidant activities. However, few reports of the absorption and metabolism of LSOPC have been revealed. In the present study, rats were orally administered with LSOPC at a dose of 300 mg/kg body weight. The metabolites of LSOPC in urine were elucidated by HPLC-MS/MS analysis 24 h post-administration. Eight major metabolites were significantly increased by the administration of 300 mg/kg of LSOPC (p < 0.01). The anti-glycative activity of LSOPC and its metabolites were investigated. The results showed that LSOPC and catechin had greater anti-glycative activities than other metabolites, which were positively correlated to their carbonyl scavenging activities and antioxidant capacities. | 25,123,249 | [
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Matrix metalloproteinase-7 mRNA and protein expression in gastric carcinoma: a meta-analysis. | Messenger RNA (mRNA) acts as template for protein synthesis. The matrix metalloproteinase-7 (MMP-7) protein and its mRNA expression have been suggested to be involved in the development of various diseases and cancers. We aimed to study associations between the MMP-7 protein and mRNA expression in gastric carcinoma (GC) patients. We searched in the Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, Current Contents Index, and several Chinese databases. Studies were pooled and odds ratios and their corresponding 95 % confidence intervals were calculated. Subgroup analyses and publication bias detection were also conducted. Statistical analysis was performed via Version 12.0 STATA software. An updated meta-analysis based on 16 independent cohort studies was performed to investigate this association. The study suggests that significant differences in MMP-7 protein levels were observed in tumor-node-metastasis (TNM) I-II vs. III-IV (odds radio (OR) =3.19, 95 % confidence interval (95%CI) =1.59 ∼ 6.41, P=0.001), in T1-2 vs. T3-4 invasive grade (OR=1.82, 95%CI=1.07 ∼ 3.12, P=0.028), and in distant metastasis-positive vs. metastasis-negative samples (OR=3.14, 95%CI=1.05 ∼ 9.35, P=0.040). Increased MMP-7 mRNA levels were found to be significantly correlated with invasive grade (T3-4 vs. T1-2: OR=5.61, 95%CI=2.64 ∼ 11.95, P<0.001) and in the lymph node (LN) metastasis (positive vs. negative: OR=7.08, 95%CI=4.20 ∼ 11.93, P<0.001) group. Country subgroup analysis yielded significantly different estimates in the protein expression of MMP-7 of all experimental groups. MMP-7 mRNA levels were increased in LN metastasis-positive GC in contrast to metastasis-negative in China and Korea (all P<0.05); this was not shown in Japan (P>0.05). Higher protein and mRNA levels of MMP-7 were statistically associated with aggressive LN metastasis, advanced TNM stage, and invasion in GC patients; MMP-7 can thus potentially serve as a useful biomarker in determining GC progression and prognosis. | 25,123,263 | [
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Transcriptional and epigenetic networks of helper T and innate lymphoid cells. | The discovery of the specification of CD4(+) helper T cells to discrete effector 'lineages' represented a watershed event in conceptualizing mechanisms of host defense and immunoregulation. However, our appreciation for the actual complexity of helper T-cell subsets continues unabated. Just as the Sami language of Scandinavia has 1000 different words for reindeer, immunologists recognize the range of fates available for a CD4(+) T cell is numerous and may be underestimated. Added to the crowded scene for helper T-cell subsets is the continuously growing family of innate lymphoid cells (ILCs), endowed with common effector responses and the previously defined 'master regulators' for CD4(+) helper T-cell subsets are also shared by ILC subsets. Within the context of this extraordinary complexity are concomitant advances in the understanding of transcriptomes and epigenomes. So what do terms like 'lineage commitment' and helper T-cell 'specification' mean in the early 21st century? How do we put all of this together in a coherent conceptual framework? It would be arrogant to assume that we have a sophisticated enough understanding to seriously answer these questions. Instead, we review the current status of the flexibility of helper T-cell responses in relation to their genetic regulatory networks and epigenetic landscapes. Recent data have provided major surprises as to what master regulators can or cannot do, how they interact with other transcription factors and impact global genome-wide changes, and how all these factors come together to influence helper cell function. | 25,123,275 | [
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Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network. | Bach2 is a basic region-leucine zipper (bZip) transcription factor that forms heterodimers with small Maf oncoproteins and binds to target genes, thus repressing their expression. Bach2 is required for class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes in activated B cells. Bach2 represses the expression of Prdm1 encoding Blimp-1 repressor and thereby inhibits terminal differentiation of B cells to plasma cells. This causes a delay in the induction of Prdm1, thereby securing a time window for the expression of Aicda encoding activation-induced cytidine deaminase (AID) required for both CSR and SHM. Based on the characteristics of a gene regulatory network (GRN) involving Bach2 and Prdm1 and its dynamics, a 'delay-driven diversity' model was introduced to explain the responses of activated B cells. Bach2 is also required for the proper differentiation and function of peripheral T cells. In the absence of Bach2, CD4(+) T cells show increased differentiation to effector cells producing higher levels of Th2-related cytokines, such as IL-4 and IL-10, and a reduction in the generation of regulatory T cells. Bach2 represses many genes in T cells, including Prdm1, suggesting that the Bach2-Prdm1 pathway is also important in maintaining the homeostasis of T cells. Furthermore, Bach2 is essential for the function of alveolar macrophages. Therefore, Bach2 orchestrates both acquired and innate immunity at multiple points. Its connection with disease is also reviewed in this report. | 25,123,280 | [
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A search for the most accurate formula for sonographic weight estimation by fetal sex - a retrospective cohort study. | The aim of this study was to assess the effect of fetal sex on the accuracy of multiple formulas for sonographic estimation fetal weight (SEFW). The cohort included all singleton live births recorded at a single medical center from January 2004 to September 2011. The accuracy of SEFW was compared between male and female fetuses using 6575 SEFW performed within 3 days prior to delivery. Fetal weight was estimated using 27 models. The accuracy of different formulas in predicting birth weight of male and female fetuses was found to be significantly different in almost every accuracy index that was compared (P < 0.05). The model by Sabbagha et al. was found to be the most accurate in assessing female fetuses. The most accurate model for male fetuses was a sex-specific formula by Melamed et al. We also found that a combination of the most accurate formula for each sex to one combined sex-specific model increased SEFW accuracy significantly. The accuracy of SEFW is significantly related to fetal sex. The combination of the formulas by Melamed et al. and Sabbagha et al. for male and female fetuses accordingly allowed more accurate SEFW in our research population. | 25,123,290 | [
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A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone. | Pemphigus vulgaris (PV) is a blistering disease and tumour necrosis factor-α has a role in its pathogenesis. To evaluate the safety of infliximab (IFX) with prednisone compared with prednisone alone in the treatment of PV. In addition, treatment response was assessed and mechanistic studies were performed. Subjects with PV who had ongoing disease activity while being maintained on prednisone were randomized to receive either IFX or placebo in addition to prednisone. Response status and immunoglobulin (Ig) G anti-desmoglein (Dsg)1 and Dsg3 antibodies were assessed at 18 and 26 weeks. Ten subjects were randomized to each group. There were no safety signals during the course of the study. At week 18, one subject in each group had responded. At week 26, three IFX-treated subjects vs. none in the placebo group had responded (P = 0·21). At weeks 18 and 26, the median IgG anti-Dsg1 and anti-Dsg3 levels were lower in the IFX-treated patients [IgG anti-Dsg-1 (week 18, P = 0·035; week 26, P = 0·022); IgG anti-Dsg3 (week 18, P = 0·035; week, 26 P = 0·05)]. This study is limited by the relatively small sample size. There was no significant difference between study arms in the proportion of subjects with treatment-related adverse events > grade 3. IFX therapy was not shown to be effective for the treatment of patients with PV in this randomized, placebo-controlled trial, although IFX treatment may be associated with a decrease in anti-Dsg1 and Dsg3 antibodies. | 25,123,295 | [
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Separate microcircuit modules of distinct v2a interneurons and motoneurons control the speed of locomotion. | Spinal circuits generate locomotion with variable speed as circumstances demand. These circuits have been assumed to convey equal and uniform excitation to all motoneurons whose input resistance dictates their activation sequence. However, the precise connectivity pattern between excitatory premotor circuits and the different motoneuron types has remained unclear. Here, we generate a connectivity map in adult zebrafish between the V2a excitatory interneurons and slow, intermediate, and fast motoneurons. We show that the locomotor network does not consist of a uniform circuit as previously assumed. Instead, it can be deconstructed into three separate microcircuit modules with distinct V2a interneuron subclasses driving slow, intermediate, or fast motoneurons. This modular design enables the increase of locomotor speed by sequentially adding microcircuit layers from slow to intermediate and fast. Thus, this principle of organization of vertebrate spinal circuits represents an intrinsic mechanism to increase the locomotor speed by incrementally engaging different motor units. | 25,123,308 | [
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Amygdala-dependent fear memory consolidation via miR-34a and Notch signaling. | Using an array-based approach after auditory fear conditioning and microRNA (miRNA) sponge-mediated inhibition, we identified a role for miR-34a within the basolateral amygdala (BLA) in fear memory consolidation. Luciferase assays and bioinformatics suggested the Notch pathway as a target of miR-34a. mRNA and protein levels of Notch receptors and ligands are downregulated in a time- and learning-specific manner after fear conditioning in the amygdala. Systemic and stereotaxic manipulations of the Notch pathway indicated that Notch signaling in the BLA suppresses fear memory consolidation. Impairment of fear memory consolidation after inhibition of miR-34a within the BLA is rescued by inhibiting Notch signaling. Together, these data suggest that within the BLA, a transient decrease in Notch signaling, via miR-34a regulation, is important for the consolidation of fear memory. This work expands the idea that developmental molecules have roles in adult behavior and that existing interventions targeting them hold promise for treating neuropsychiatric disorders. | 25,123,309 | [
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Network structure within the cerebellar input layer enables lossless sparse encoding. | The synaptic connectivity within neuronal networks is thought to determine the information processing they perform, yet network structure-function relationships remain poorly understood. By combining quantitative anatomy of the cerebellar input layer and information theoretic analysis of network models, we investigated how synaptic connectivity affects information transmission and processing. Simplified binary models revealed that the synaptic connectivity within feedforward networks determines the trade-off between information transmission and sparse encoding. Networks with few synaptic connections per neuron and network-activity-dependent threshold were optimal for lossless sparse encoding over the widest range of input activities. Biologically detailed spiking network models with experimentally constrained synaptic conductances and inhibition confirmed our analytical predictions. Our results establish that the synaptic connectivity within the cerebellar input layer enables efficient lossless sparse encoding. Moreover, they provide a functional explanation for why granule cells have approximately four dendrites, a feature that has been evolutionarily conserved since the appearance of fish. | 25,123,311 | [
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The Drosophila IR20a clade of ionotropic receptors are candidate taste and pheromone receptors. | Insects use taste to evaluate food, hosts, and mates. Drosophila has many "orphan" taste neurons that express no known taste receptors. The Ionotropic Receptor (IR) superfamily is best known for its role in olfaction, but virtually nothing is known about a clade of ∼35 members, the IR20a clade. Here, a comprehensive analysis of this clade reveals expression in all taste organs of the fly. Some members are expressed in orphan taste neurons, whereas others are coexpressed with bitter- or sugar-sensing Gustatory receptor (Gr) genes. Analysis of the closely related IR52c and IR52d genes reveals signatures of adaptive evolution, roles in male mating behavior, and sexually dimorphic expression in neurons of the male foreleg, which contacts females during courtship. These neurons are activated by conspecific females and contact a neural circuit for sexual behavior. Together, these results greatly expand the repertoire of candidate taste and pheromone receptors in the fly. | 25,123,314 | [
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Increasing the sensitivity of endocervical curettings by performing ThinPrep® Pap on transport container fluid: is diagnostic material going down the drain? | The sensitivity of endocervical curettage (ECC) can be suboptimal because of limited epithelial tissue. The false-negative rate for ECC in patients with cervical intraepithelial neoplasia involving the endocervical canal has been reported to be 45%. ECC samples are transported to pathology in formalin- or saline-filled containers; this fluid is discarded after the specimen has been submitted. We evaluated the utility of performing liquid-based cytological preparations from ECC transport container fluid as a way to increase the sensitivity of ECC specimens. Consecutive ECC specimens received at one of the two participating institutions were selected prospectively. A surgical pathology mesh bag was placed over a ThinPrep(®) CytoLyt(®) solution container, and the specimen was filtered through the bag, collecting the transport fluid in the container. The CytoLyt(®) was processed to obtain a container fluid ThinPrep(®) (CF-TP) liquid-based Papanicolaou (Pap) slide. The CF-TP slides were reviewed and the findings were compared with those from the ECC and follow-up specimens. The cohort included 53 patients. Discrepancies between CF-TP and ECC were seen in 14 of the 53 patients (26%); a more significant lesion was identified in CF-TP relative to ECC in 13 of these cases. CF-TP diagnosis was confirmed in eight of 11 cases with histological follow-up. A positive CF-TP result was confirmed by histology in six of nine cases with negative ECC. Combining the pathological evaluation of ECC specimens with liquid-based cytology performed on the transport container fluid can increase the diagnostic sensitivity of the ECC procedure for the detection of cervical lesions. | 25,123,326 | [
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Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir. | Sofosbuvir (Sovaldi, SOF) is a nucleotide analog prodrug that targets the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase and inhibits viral replication. High sustained virological response rates are achieved when SOF is used in combination with ribavirin with or without pegylated interferon in subjects with chronic HCV infection. Potential mechanisms of HCV resistance to SOF and other nucleos(t)ide analog NS5B polymerase inhibitors are not well understood. SOF was the first U.S. Food and Drug Administration (FDA)-approved antiviral drug for which genotypic resistance analyses were based almost entirely on next-generation sequencing (NGS), an emerging technology that lacks a standard data analysis pipeline. The FDA Division of Antiviral Products developed an NGS analysis pipeline and performed independent analyses of NGS data from five SOF clinical trials. Additionally, structural bioinformatics approaches were used to characterize potential resistance-associated substitutions. Using protocols we developed, independent analyses of the NGS data reproduced results that were comparable to those reported by Gilead Sciences, Inc. Low-frequency, treatment-emergent substitutions occurring at conserved NS5B amino acid positions in subjects who experienced virological failure were also noted and further evaluated. The NS5B substitutions, L159F (sometimes in combination with L320F or C316N) and V321A, emerged in 2.2%-4.4% of subjects who failed SOF treatment across clinical trials. Moreover, baseline polymorphisms at position 316 were potentially associated with reduced response rates in HCV genotype 1b subjects. Analyses of these variants modeled in NS5B crystal structures indicated that all four substitutions could feasibly affect SOF anti-HCV activity. SOF has a high barrier to resistance; however, low-frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic HCV infection. | 25,123,381 | [
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A comparison of airway dimensions, measured by acoustic reflectometry and ultrasound before and after general anaesthesia. | Changes in airway dimensions can occur during general anaesthesia and surgery for a variety of reasons. This study explored factors associated with postoperative changes in airway dimensions. Patient airway volume was measured by acoustic reflectometory and neck muscle diameter by ultrasound echography in the pre- and post-anaesthetic periods in a total of 281 patients. Neck circumference was also assessed during these periods. A significant decrease in median (IQR [range]) total airway volume (from 63.8 (51.8-75.7 [14.7-103]) ml to 45.9 (33.5-57.2 [6.4-96.3]) ml, p < 0.0001), and a significant increase in muscle diameter (from 4.3 (3.3-5.6 [2.2-9.0]) mm to 5.8 (4.7-7.3 [2.8-1.3]) mm, p < 0.0001) and neck circumference (from 34.0 (32.5-37.0 [29.5-49.0]) cm to 35.0 (33.5-38.0 [30.5-50.5]) cm, p < 0.0001) were observed. It may be possible that changes in airway volume and neck circumference were influenced by surgical duration or peri-operative fluid management (ρ) = -0.31 (95% CI -0.24 to -0.01), p = 0.0301, -0.17 (-0.23 to -0.06), p = 0.0038, 0.23 (0.12-0.34), p < 0.0001, and 0.16 (0.05-0.27), p = 0.0062, respectively). The intra-oral space can significantly decrease and neck thickness increase after general anaesthesia, and might increase the risk of difficult laryngoscopy and intubation if airway management is required after extubation following general anaesthesia. | 25,123,382 | [
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0.04815408,
0.04771453,
-0.2806808,
0.1736749,
-0.03799437,
-0.4736003,
0.3436077,
-0.00719054,
0.1520176,
... |
A national study on adherence to a basal cell carcinoma guideline; development of a tool to assess guideline adherence. | Clinical practice guideline implementation may be at variance with actual daily practice, as guideline adherence is a complex process depending on many actors and factors. Feedback regarding adherence is essential to monitor the effect that a guideline has in clinical practice and whether or not the quality of care is raised by implementation. Developing a tool for obtaining and giving nationwide feedback regarding adherence. From February 2010 to June 2013, a 32-item questionnaire was used as an audit tool during committee visits to assess adherence across 37 dermatological centres in The Netherlands. The questions were derived from the recommendations by the Dutch Dermatological and Venereological Society (NVDV) in the Dutch Basal Cell Carcinoma (BCC) guideline. Five selected medical records per dermatologist were audited and the results were discussed with the audited centre. Data were pooled to calculate the compliance with each recommendation across all participating centres. Adherence to recommended actions varied considerably (20·2-100%) across the domains of prevention, diagnostics, treatments and aftercare. Using and reporting surgical margins, giving patient advice, restricting the use of cryosurgery for certain BCCs and reporting on prognostic factors all failed to reach a threshold of 80%. Nonadherence to recommended actions proved to be related to whether or not a dermatologist was directly involved. The findings emphasize the importance of direct feedback to practitioners regarding adherence. Furthermore, together with existing frameworks, the method described could be used by developers in a guideline update to identify and anticipate barriers to successful implementation. | 25,123,410 | [
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0.... |
Cytotoxic effects of escin on human castration-resistant prostate cancer cells through the induction of apoptosis and G2/M cell cycle arrest. | To evaluate the in vitro and in vivo effects of escin on human castration-resistant prostate cancer (CRPC) cells, PC-3 and DU-145. The inhibition of cell proliferation and its mechanism were assessed through a cytotoxicity assay, flow cytometry, and Western blot. The in vivo efficacy of escin in CRPC cells was assessed using a xenograft tumor model subcutaneously established in BALB/c nude mice. The treatment with escin significantly reduced cell viability of CRPC cells in a dose- and time-dependent manner. Escin induced apoptosis in a time-dependent manner, which was accompanied by increases in pro-apoptotic (BCL-2 associated X protein, cleaved-caspase3, and cleaved-poly [adenosine diphosphate-ribose] polymerase) proteins and decreases in antiapoptotic (X-linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis protein-1, cellular inhibitor of apoptosis protein-2B-cell leukemia/lymphoma-2, and B-cell lymphoma-extra large) proteins. Escin induced G2/M-phase cell cycle arrest and thus led to a significant decrease in the expression of cyclinB1 and its activating partner cyclin-dependent kinase 1, with the concomitant induction of p21. In addition, escin significantly inhibited the growth of CRPC cells in xenograft models. The results show that escin induced cytotoxic effects on CRPC cells through the induction of apoptosis and G2/M cell cycle arrest, indicating it may be a novel therapeutic agent for CRPC. | 25,123,426 | [
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0.1795716,
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MiR-7b directly targets DC-STAMP causing suppression of NFATc1 and c-Fos signaling during osteoclast fusion and differentiation. | DC-STAMP is a key regulating molecule of osteoclastogenesis and osteoclast precursor (OCP) fusion. Emerging lines of evidence showed that microRNAs play crucial roles in bone metabolism and osteoclast differentiation, but no microRNA has yet been reported to be directly related to OCPs fusion. Through a microarray, we found that the expression of miR-7b in RAW264.7 cells was significantly decreased after induction with M-CSF and RANKL. The overexpression of miR-7b in RAW264.7 cells attenuated the number of TRAP-positive cells number and the formation of multinucleated cells, whereas the inhibition of miR-7b enhanced osteoclastogenesis. Through a dual luciferase reporter assay, we confirmed that miR-7b directly targets DC-STAMP. Other fusogenic molecules, such as CD47, ATP6v0d2, and OC-STAMP, were detected to be down-regulated in accordance with the inhibition of DC-STAMP. Because DC-STAMP also participates in osteoclast differentiation through the ITAM-ITIM network, multiple osteoclast-specific genes in the ITAM-ITIM network were detected to identify how DC-STAMP is involved in this process. The results showed that molecules associated with the ITAM-ITIM network, such as NFATc1 and OSCAR, which are crucial in osteoclastogenesis, were consistently altered due to DC-STAMP inhibition. These findings suggest that miR-7b inhibits osteoclastogenesis and cell-cell fusion by directly targeting DC-STAMP. In addition, the inhibition of DC-STAMP and its downstream signals changed the expression of other fusogenic genes and key regulating genes, such as Nfatc1, c-fos, Akt, Irf8, Mapk1, and Traf6. In conclusion, our findings indicate that miR-7b may be a potential therapeutic target for the treatment of osteoclast-related bone disorders. | 25,123,438 | [
-0.2664229,
0.5382724,
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0.2590939,
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The free-exploratory paradigm as a model of trait anxiety in female rats: test-retest reliability. | The free-exploratory paradigm has been proposed as a model of trait anxiety and as such has been proven stable over time, which is a sine qua non condition for any model proposing to evaluate a personality trait. However this stability has only been shown for male rats. Considering that anxiety disorders are most prevalent in women, it's crucial that females are tested in animal models. With this in mind, the stability over time of female rats in the free-exploratory paradigm was evaluated using a test-retest procedure. The behaviour of drug-naive, adult, female, Wistar rats was measured in the free-exploratory apparatus on two occasions two months apart. The following parameters were evaluated: percentage of distance travelled in the novel compartment; number of attempts to enter the novel compartment; percentage of time spent in the novel compartment; and percentage of time rearing in the novel compartment. Subsequently, the intraclass correlation coefficient (ICC) and the kappa index (κ) were calculated for each of these parameters. The "percentage of time spent in the novel compartment" (ICC=0.727; κ=0.457), the "percentage of distance travelled in the novel compartment" (ICC=0.680; κ=0.370), and the "percentage of time rearing in the novel compartment" (ICC=0.648; κ=0.309) were found to be stable over time. Analysis of these parameters indicated fair to substantial reliability over time in two-month inter-trial interval. Therefore, our results support the idea of the free-exploratory paradigm as an animal model of trait anxiety for female rats. | 25,123,445 | [
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0.1287763,... |
The re-organization of functional brain networks in pharmaco-resistant epileptic patients who respond to VNS. | Vagal nerve stimulation (VNS) is a therapeutic add-on treatment for patients with pharmaco-resistant epilepsy. The mechanism of action is still largely unknown. Previous studies have shown that brain network topology during the inter-ictal period in epileptic patients deviates from normal configuration. In the present paper, we investigate the relationship between clinical improvement induced by VNS and alterations in brain network topology. We hypothesize that, as a consequence of the VNS add-on treatment, functional brain network architecture shifts back toward a more efficient configuration in patients responding to VNS. Electroencephalographic (EEG) recordings from ten patients affected by pharmaco-resistant epilepsy were analyzed in the classical EEG frequency bands. The phase lag index (PLI) was used to estimate functional connectivity between EEG channels and the minimum spanning tree (MST) was computed in order to characterize VNS-induced alterations in network topology in a bias-free way. Our results revealed a clear network re-organization, in terms of MST modification, toward a more integrated architecture in patients responding to the VNS. In particular, the results show a significant interaction effect between benefit from VNS (responders/non-responders) and condition (pre/post VNS implantation) in the theta band. This finding suggests that the positive effect induced by VNS add-on treatment in epileptic patients is related to a clear network re-organization and that this network modification can reveal the long debated mechanism of action of VNS. Therefore, MST analysis could be useful in evaluating and monitoring the efficacy of VNS add-on treatment potentially in both epilepsy and psychiatric diseases. | 25,123,446 | [
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0.2697386,
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QoS-aware health monitoring system using cloud-based WBANs. | Wireless Body Area Networks (WBANs) are amongst the best options for remote health monitoring. However, as standalone systems WBANs have many limitations due to the large amount of processed data, mobility of monitored users, and the network coverage area. Integrating WBANs with cloud computing provides effective solutions to these problems and promotes the performance of WBANs based systems. Accordingly, in this paper we propose a cloud-based real-time remote health monitoring system for tracking the health status of non-hospitalized patients while practicing their daily activities. Compared with existing cloud-based WBAN frameworks, we divide the cloud into local one, that includes the monitored users and local medical staff, and a global one that includes the outer world. The performance of the proposed framework is optimized by reducing congestion, interference, and data delivery delay while supporting users' mobility. Several novel techniques and algorithms are proposed to accomplish our objective. First, the concept of data classification and aggregation is utilized to avoid clogging the network with unnecessary data traffic. Second, a dynamic channel assignment policy is developed to distribute the WBANs associated with the users on the available frequency channels to manage interference. Third, a delay-aware routing metric is proposed to be used by the local cloud in its multi-hop communication to speed up the reporting process of the health-related data. Fourth, the delay-aware metric is further utilized by the association protocols used by the WBANs to connect with the local cloud. Finally, the system with all the proposed techniques and algorithms is evaluated using extensive ns-2 simulations. The simulation results show superior performance of the proposed architecture in optimizing the end-to-end delay, handling the increased interference levels, maximizing the network capacity, and tracking user's mobility. | 25,123,456 | [
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0.07712266,
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Time- and computation-efficient calibration of MEMS 3D accelerometers and gyroscopes. | We propose calibration methods for microelectromechanical system (MEMS) 3D accelerometers and gyroscopes that are efficient in terms of time and computational complexity. The calibration process for both sensors is simple, does not require additional expensive equipment, and can be performed in the field before or between motion measurements. The methods rely on a small number of defined calibration measurements that are used to obtain the values of 12 calibration parameters. This process enables the static compensation of sensor inaccuracies. The values detected by the 3D sensor are interpreted using a generalized 3D sensor model. The model assumes that the values detected by the sensor are equal to the projections of the measured value on the sensor sensitivity axes. Although this finding is trivial for 3D accelerometers, its validity for 3D gyroscopes is not immediately apparent; thus, this paper elaborates on this latter topic. For an example sensor device, calibration parameters were established using calibration measurements of approximately 1.5 min in duration for the 3D accelerometer and 2.5 min in duration for the 3D gyroscope. Correction of each detected 3D value using the established calibration parameters in further measurements requires only nine addition and nine multiplication operations. | 25,123,469 | [
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0.18... |
Laparoscopic common bile duct exploration. | Laparoscopic common bile duct exploration (LCBDE) is a safe and effective single-stage treatment for choledocholithiasis in the elective setting. The outcomes after LCBDE in the emergency setting are unknown. The aim of this study was to compare the outcomes following elective and emergency LCBDE for choledocholithiasis. Details of all patients who underwent LCBDE for choledocholithiasis between August 2003 and August 2013 were analysed retrospectively. The primary outcome measure was common bile duct (CBD) stone clearance rate. Secondary outcome measures were conversion rate, morbidity, mortality and length of hospital stay. Some 215 consecutive patients (57 male; median age 65 (range 14-92) years) underwent LCBDE. Some 121 procedures were performed electively and 94 as an emergency. Forty-five patients (48 per cent) presented with obstructive jaundice or cholangitis in the emergency LCBDE group compared with 15 (12·4 per cent) in the elective group (P < 0·001). The CBD stone clearance rate was similarly high in both groups (96 versus 96·7 per cent respectively; P = 0·557). There were no significant differences in conversion rate (6 versus 4·1 per cent), morbidity (5 versus 6·6 per cent), mortality (2 versus 0 per cent) or median length of stay (3 days) between groups. Two patients died, both following emergency LCBDE. LCBDE can be performed safely and effectively in both elective and emergency settings. | 25,123,479 | [
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Structural biology. Crystal structure of a CRISPR RNA-guided surveillance complex bound to a ssDNA target. | In prokaryotes, RNA derived from type I and type III CRISPR loci direct large ribonucleoprotein complexes to destroy invading bacteriophage and plasmids. In Escherichia coli, this 405-kilodalton complex is called Cascade. We report the crystal structure of Cascade bound to a single-stranded DNA (ssDNA) target at a resolution of 3.03 angstroms. The structure reveals that the CRISPR RNA and target strands do not form a double helix but instead adopt an underwound ribbon-like structure. This noncanonical structure is facilitated by rotation of every sixth nucleotide out of the RNA-DNA hybrid and is stabilized by the highly interlocked organization of protein subunits. These studies provide insight into both the assembly and the activity of this complex and suggest a mechanism to enforce fidelity of target binding. | 25,123,481 | [
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The effect of hazelnut roasted skin from different cultivars on the quality attributes, polyphenol content and texture of fresh egg pasta. | Hazelnut skin is the perisperm of the hazelnut kernel. It is separated from the kernel during the roasting process and is normally discarded. Recent studies have reported that hazelnut skin is a rich source of dietary fibre as well as of natural antioxidants owing to the presence of phenolic compounds. The aim of this study was to assess the use of hazelnut skins obtained from different cultivars for enhancing the nutritional value of fresh egg pasta. Skins obtained from roasted hazelnuts of four different varieties were used at three concentrations as a flour replacement in fresh egg pasta. Hazelnut skin concentration significantly influenced all evaluated physicochemical parameters as well as consumers' appreciation for the pasta, but significant differences were also observed between the four varieties. Although pasta produced with 10 and 15% hazelnut skin displayed the highest content of polyphenolic compounds and antioxidant activity in vitro, pasta containing 5% Tombul hazelnut skin showed maximum consumer preference. The results obtained in the present study highlighted that it is possible to use hazelnut skin in fresh pasta production to obtain a fortified food with high fibre content and antioxidant activity. The characteristics of the resulting pasta were strictly correlated with the hazelnut variety used for skin production and, of course, with the percentage of skin that was added. | 25,123,494 | [
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... |
Hydrogen sulfide is essential for Schwann cell responses to peripheral nerve injury. | Hydrogen sulfide (H2 S) functions as a physiological gas transmitter in both normal and pathophysiological cellular events. H2 S is produced from substances by three enzymes: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST). In human tissues, these enzymes are involved in tissue-specific biochemical pathways for H2 S production. For example, CBS and cysteine aminotransferase/MST are present in the brain, but CSE is not. Thus, we examined the expression of H2 S production-related enzymes in peripheral nerves. Here, we found that CSE and MST/cysteine aminotransferase, but not CBS, were present in normal peripheral nerves. In addition, injured sciatic nerves in vivo up-regulated CSE in Schwann cells during Wallerian degeneration (WD); however, CSE was not up-regulated in peripheral axons. Using an ex vivo sciatic nerve explant culture, we found that the inhibition of H2 S production broadly prevented the process of nerve degeneration, including myelin fragmentation, axonal degradation, Schwann cell dedifferentiation, and Schwann cell proliferation in vitro and in vivo. Thus, these results indicate that H2 S signaling is essential for Schwann cell responses to peripheral nerve injury. Hydrogen sulfide (H2 S) functions as a physiological gas transmitter in both normal and pathophysiological cellular events. H2 S is produced from cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfur transferase (MST). Here, we found that CSE and MST/CAT were present in normal peripheral nerves. Injured static nerves in vivo up-regulated CSE in Schwann cells during Wallerian degeneration, but CSE was not up-regulated in peripheral axons. | 25,123,509 | [
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0.2559484,
-0.1695424,
... |
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