bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbial Community Analysis Provides Insights into the Effects of Tetrahydrofuran on 1,4-Dioxane Biodegradation
Authors: Xiong Yi , Mason Olivia U. , Lowe Ashlee , Zhou Chao , Chen Gang , Tang Youneng
Published: March 2019

Widespread in groundwater and carcinogenic to humans, 1,4-dioxane (dioxane) is attracting significant attention in recent years. Advanced oxidation processes can effectively remove dioxane but require high energy consumption and operation costs. Biological removal of dioxane is of particular interest due to the ability of some bacteria to mineralize dioxane at a low energy cost. Although dioxane is generally considered recalcitrant to biodegradation, more than 20 types of bacteria can degrade dioxane as the sole electron donor substrate or the secondary electron donor substrate. In the latter case, tetrahydrofuran (THF) is commonly studied as the primary electron donor substrate. Previous work has shown that THF promotes dioxane degradation at a low THF concentration but inhibits dioxane degradation at a high THF concentration. Our work expanded on the previous work by mechanically examining the effects of THF on dioxane degradation in a microbial community context.
BrucellaPeriplasmic Protein EipB Is a Molecular Determinant of Cell Envelope Integrity and Virulence
Authors: Herrou Julien , Willett Jonathan W. , Fiebig Aretha , Czyż Daniel M. , Cheng Jason X. , Ultee Eveline , Briegel Ariane , Bigelow Lance , Babnigg Gyorgy , Kim Youngchang , Crosson Sean
Published: March 2019

Brucellaspecies cause brucellosis, a global zoonosis. A gene encoding a conserved DUF1849-family protein, which we have named EipB, is present in all sequencedBrucellaand several other genera in the classAlphaproteobacteria. The manuscript provides the first functional and structural characterization of a DUF1849 protein. We show that EipB is secreted to the periplasm where it forms a spiral-shaped antiparallel β protein that is a determinant of cell envelope integrityin vitroand virulence in an animal model of disease.eipBgenetically interacts withttpA, which also encodes a periplasmic protein. We propose that EipB and TtpA function as part of a system required for cell envelope homeostasis in selectAlphaproteobacteria.
Envelope Protein Glycosylation Mediates Zika Virus Pathogenesis
Authors: Carbaugh Derek L. , Baric Ralph S. , Lazear Helen M.
Published: March 2019

It is unclear why the ability of Zika virus (ZIKV) to cause serious disease, including Guillain-Barré syndrome and birth defects, was not recognized until recent outbreaks. One contributing factor could be genetic differences between contemporary ZIKV strains and historical ZIKV strains. All isolates from recent outbreaks encode a viral envelope protein that is glycosylated, whereas many historical ZIKV strains lack this glycosylation. We generated nonglycosylated ZIKV mutants from contemporary and historical strains and evaluated their virulence in mice. We found that nonglycosylated viruses were attenuated and produced lower viral loads in serum and brains. Our studies suggest that envelope protein glycosylation contributes to ZIKV pathogenesis, possibly by facilitating attachment to and infection of lectin-expressing leukocytes.
Spatial and temporal trends in exhumation of the Eastern Himalaya and syntaxis as determined from a multitechnique detrital thermochronological study of the Bengal Fan
Authors: Najman Yani , Mark Chris , Barfod Dan N. , Carter Andy , Parrish Randy , Chew David , Gemignani Lorenzo
Published: March 2019

The Bengal Fan provides a Neogene record of Eastern and Central Himalaya exhumation. We provide the first detrital thermochronological study (apatite and rutile U-Pb, mica Ar-Ar, zircon fission track) of sediment samples collected during International Ocean Discovery Program (IODP) Expedition 354 to the mid–Bengal Fan. Our data from rutile and zircon fission-track thermochronometry show a shift in lag times over the interval 5.59–3.47 Ma. The oldest sample with a lag time of <1 m.y. has a depositional age between 3.76 and 3.47 Ma, and these short lag times continue to be recorded upward in the core to the youngest sediments analyzed, deposited at <1 Ma. We interpret the earliest record of short lag times to represent the onset of extremely rapid exhumation of the Eastern Himalayan syntaxial massif, defined as the syntaxial region north of the Nam La Thrust. Below the interval characterized by short lag times, the youngest sample analyzed with long lag times (>6 m.y.) has a depositional age of 5.59–4.50 Ma, and the zircon and rutile populations then show a static peak until >12 Ma. This interval, from 5.59–4.50 Ma to >12 Ma, is most easily interpreted as recording passive erosion of the Greater Himalaya. However, single grains with lag times of <4 m.y., but with high analytical uncertainty, are recorded over this interval. For sediments older than 10 Ma, these grains were derived from the Greater Himalaya, which was exhuming rapidly until ca. 14 Ma. In sediments younger than 10 Ma, these grains could represent slower, yet still rapid, exhumation of the syntaxial antiform to the south of the massif. Lag times <1 m.y. are again recorded from 14.5 Ma to the base of the studied section at 17 Ma, reflecting a period of Greater Himalayan rapid exhumation. Mica 40Ar/39Ar and apatite U-Pb data are not sensitive to syntaxial exhumation: We ascribe this to the paucity of white mica in syntaxial lithologies, and to high levels of common Pb, resulting in U-Pb ages associated with unacceptably high uncertainties, respectively.
Falling admissions to hospital with febrile seizures in the UK
Authors: Mccrorie Kirsty , Thorburn Joshua , Symonds Joseph , Turner Stephen W
Published: March 2019

Objectives

There was a reduction in febrile seizure admissions in Scotland after 2008. Our hypothesis was that a similar trend would be seen in other countries.

Methods

We obtained the number of febrile and non-febrile seizure admissions in England and Scotland 2000–2013 and the incidence of all seizure admissions 2000–2013 in European countries. We compared the incidence of admission for febrile seizure (Scotland and England) and all seizures (all countries) between 2000–2008 and 2009–2013.

Results

The incidence of febrile seizure admissions per 1000 children in 2009–2013 was lower than 2000–2008 in Scotland (0.79 vs 1.08, p=0.001) and England (0.92 vs 1.20, p<0.001). The incidence of all seizure admissions (but not non-febrile seizures) was lower in 2009–2013 compared with 2000–2008 in Scotland (1.84 vs 2.20, p=0.010) and England (2.71 vs 2.91, p=0.001). Across 12 European countries (including the UK), there was no difference in all seizure admissions after 2008. We explored the possibility that the fall was related to the introduction of routine pneumococcal vaccination in 2006 but there were insufficient data.

Conclusion

A fall in admissions for febrile (but not afebrile) seizures after 2008 in Scotland and England explains a fall in all emergency admissions for seizure. A fall in all seizure admissions has not occurred in other European countries, and more research is required to understand the different outcomes in the UK and non-UK countries.
Consensus outcome rating for international neonatal resuscitation guidelines
Authors: Strand Marya L , Simon Wendy Marie , Wyllie Jonathan , Wyckoff Myra H , Weiner Gary
Published: March 2019

The International Liaison Committee on Resuscitation uses the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group method to evaluate the quality of evidence and the strength of treatment recommendations. This method requires guideline developers to use a numerical rating of the importance of each specified outcome. There are currently no uniform reporting guidelines or outcome measures for neonatal resuscitation science. We describe consensus outcome ratings from a survey of 64 neonatal resuscitation guideline developers representing seven international resuscitation councils. Among 25 specified outcomes, 10 were considered critical for decision-making. The five most critically rated outcomes were death, moderate-severe neurodevelopmental impairment, blindness, cerebral palsy and deafness. These data inform outcome rankings for systematic reviews of neonatal resuscitation science and international guideline development using the GRADE methodology.
Five-year outcomes of retinal vein occlusion treated with vascular endothelial growth factor inhibitors
Authors: Spooner Kimberly , Fraser-Bell Samantha , Hong Thomas , Chang Andrew A
Published: March 2019

Purpose

Report 5-year outcomes of patients receiving anti-vascular endothelial growth factor (VEGF) for the treatment of macular oedema secondary to retinal vein occlusion (RVO.

Methods

Retrospective review of eyes with RVO which initiated anti-VEGF treatment. Data including age, gender, visual acuity (VA) and injection numbers were obtained from medical records. Optical coherence tomography scans were graded for presence or absence of macular oedema and central foveal thickness (CFT). Macular perfusion was assessed on fundus fluorescein angiography by masked graders.

Results

68 eyes (31 branch RVO, BRVO; 35 central RVO, CRVO and 2 hemi-RVO) with 5 years of follow-up after initiation of anti-VEGF treatment. Mean change in VA at 5 years was + 9.6 ± 21.6 letters among CRVO eyes and + 14.2 ± 15.6 letters among eyes with BRVO (p=0.001). Vision of 20/40 or better was achieved in 65 % of treated eyes. The proportion of eyes with a three-line improvement of vision (15 letters) at 5 years was 22 %. Mean CFT decreased by 257.6 ± 249.8 µm in eyes with CRVO and 145.6 ± 143.3 µm in eyes with BRVO.

Conclusion

The results confirm good long-term outcomes can be achieved with anti-VEGF therapy for RVO.
Optimising laboratory monitoring of chronic conditions in primary care: a quality improvement framework
Authors: Whiting Darunee , Croker Richard , Watson Jessica , Brogan Andy , Walker Alex J , Lewis Tom
Published: March 2019

Monitoring of chronic conditions accounts for a significant proportion of blood testing in UK primary care; not all of this is based on evidence or guidelines. National benchmarking shows significant variation in testing rates for common blood tests. This project set out to standardise the blood tests used for monitoring of chronic conditions in primary care across North Devon, and to measure and reduce the harms of unwarranted testing. Chronic disease test groups were developed in line with current guidelines and implemented using one-click electronic test ordering systems. The main difference from previous general practitioner practice algorithms was removing the requirement for full blood count and liver function test monitoring for many conditions. Baseline harms of testing were measured and included significant costs, workload and patient anxiety. By defining the scale of the problem, we were able to leverage change across several cycles of quality improvement, using a pathology optimisation forum for peer-led improvement, and developing a framework focusing on what matters to patients. Overall primary care testing rates in North Devon fell by 14% for full blood count testing and 22% for liver function tests, but without a reduction in the number of tests showing possible significant pathology. We estimate that this has reduced testing costs by £200 000 across a population of around 180 000 people and has reduced downstream referral costs by a similar amount. Introduction of simple chronic disease test groups into primary care electronic ordering systems, when used alongside engagement with clinicians, leads to both quality improvement and reduction in system costs.
Importance of publishing research varies by doctors’ career stage, specialty and location of work
Authors: McGrail Matthew Richard , O’sullivan Belinda G , Bendotti Hollie R , Kondalsamy-Chennakesavan Srinivas
Published: March 2019

Purpose

To investigate whether publishing research is an important aspect of medical careers, and how it varies by specialty and rural or metropolitan location.

Methods

Annual national panel survey (postal or online) of Australian doctors between 2008 and 2016, with aggregated participants including 11 263 junior doctors not enrolled in a specialty (‘pre-registrars’), 9745 junior doctors enrolled as specialist trainees, non-general practitioner (GP) (‘registrars’) and 35 983 qualified as specialist consultants, non-GP (‘consultants’). Main outcome was in agreement that ‘research publications are important to progress my training’ (junior doctors) or ‘research publications are important to my career’ (consultants).

Results

Overall, the highest proportion agreeing were registrars (65%) and pre-registrars (60%), compared with consultants (36%). After accounting for key covariates, rural location was significantly associated with lower importance of publishing research for pre-registrars (OR 0.69, 95% CI 0.61 to 0.78) and consultants (OR 0.69, 95% CI 0.63 to 0.76), but not for registrars. Compared with anaesthetics, research importance was significantly higher for pre-registrars pursuing surgery (OR 4.46, 95% CI 3.57 to 5.57) and obstetrics/gynaecology careers, for registrars enrolled in surgery (OR 2.97, 95% CI 2.34 to 3.75) and internal medicine training, and consultants of internal medicine (OR 1.84, 95% CI 1.63 to 2.08), pathology, radiology and paediatrics.

Conclusions

This study provides new quantitative evidence showing that the importance of publishing research is related to medical career stages, and is most important to junior doctors seeking and undertaking different specialty training options. Embedding research requirements more evenly into specialty college selection criteria may stimulate uptake of research. Expansion of rural training pathways should consider capacity building to support increased access to research opportunities in these locations.
Randomised, double-blind, phase III study comparing the infliximab biosimilar, PF-06438179/GP1111, with reference infliximab: efficacy, safety and immunogenicity from week 30 to week 54
Authors: Alten Rieke , Batko Bogdan , Hala Tomas , Kameda Hideto , Radominski Sebastiao C , Tseluyko Vira , Babic Goran , Cronenberger Carol , Hackley Sarah , Rehman Muhammad , von Richter Oliver , Zhang Min , Cohen Stanley
Published: March 2019

Objective

To investigate the efficacy, safety and immunogenicity of PF-06438179/GP1111 (PF-SZ-IFX) compared with European reference infliximab (Remicade®; ref-IFX) in patients with moderate-to-severe, active rheumatoid arthritis after continued long-term use of PF-SZ-IFX, and in patients who were switched from ref-IFX to PF-SZ-IFX.

Methods

REFLECTIONS B537-02 was a double-blind, active-controlled, multinational study in which patients (N=650) were initially randomised to PF-SZ-IFX or ref-IFX for 30 weeks (treatment period [TP] 1). During weeks 30–54 (TP2), the PF-SZ-IFX group (n=280) continued treatment with PF-SZ-IFX (PF-SZ-IFX/PF-SZ-IFX) and patients in the ref-IFX group (n=286) were rerandomised (1:1) to continue ref-IFX (ref-IFX/ref-IFX) (n=143) or switch to PF-SZ-IFX (ref-IFX/PF-SZ-IFX) (n=143) for a further 24 weeks. Efficacy, safety, immunogenicity and pharmacokinetics were evaluated.

Results

During TP2, patients in all three treatment groups continued to maintain comparable treatment response. At week 54, the American College of Rheumatology (ACR20) response rates were 71.1% (PF-SZ-IFX/PF-SZ-IFX), 64.3% (ref-IFX/ref-IFX) and 70.6% (ref-IFX/PF-SZ-IFX). Observations for other endpoints, including ACR50/70, Disease Activity Score in 28 Joints Based on High-Sensitivity C Reactive Protein(DAS28-CRP) remission, and mean change in DAS28-CRP and Health Assessment Questionnaire-Disability Index, were also comparable. Treatment-emergent adverse events were reported in 36.8% (PF-SZ-IFX/PF-SZ-IFX), 33.6% (ref-IFX/ref-IFX) and 37.8% (ref-IFX/PF-SZ-IFX) of patients; there were no clinically meaningful differences in the safety profiles between groups. The percentage of patients who were antidrug antibody-positive was generally stable through the treatment period and comparable overall between the PF-SZ-IFX/PF-SZ-IFX (52.1%; neutralising: 80.8%), ref-IFX/ref-IFX (60.1%; neutralising: 84.9%) and ref-IFX/PF-SZ-IFX (58.0%; neutralising 78.3%) groups.

Conclusions

The similar efficacy, safety and immunogenicity of PF-SZ-IFX compared with ref-IFX were maintained for up to 54 weeks and were not affected by blinded treatment switch from ref-IFX to PF-SZ-IFX at week 30.

Trial registration number

NCT02222493.
Citicoline protects against lead-induced oxidative injury in neuronal PC12 cells
Authors: Aminzadeh Azadeh , Salarinejad Ayda
Published: March 2019

Lead is a major environmental pollutant that causes serious adverse effects on biological systems and cells. In this study, we examined the effect of citicoline on lead-induced apoptosis in PC12 cells. The PC12 cells were pre-treated with citicoline and then exposed to lead for 48 h. The effect of citicoline on cell survival was examined by MTT assay. In addition, levels of lipid peroxidation (LPO), total thiol groups, total antioxidant power (TAP), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) were evaluated. The levels of Bax, Bcl-2, and caspase-3 were also measured, by Western blot analysis. Citicoline significantly increased the cell viability of PC12 cells exposed to lead. Treatment of PC12 cells with lead increased LPO levels, and citicoline effectively decreased LPO. Levels of total thiol groups and TAP, CAT, SOD, and GSH were significantly increased in citicoline-treated PC12 cells compared with the lead-treated group. Citicoline pretreatment significantly reduced Bax expression, and increased the level of Bcl-2 expression. Citicoline also reduced caspase-3 activation in PC12 cells compared with the lead-treated group. Our findings indicate that citicoline exerts a neuroprotective effect against lead-induced injury in PC12 cells through mitigation of oxidative stress and, at least in part, through suppression of the mitochondria-mediated apoptotic pathway.
Invariant Submanifolds of Genus 5 and a Cantor Staircase in the Nonholonomic Model of a Snakeboard
Authors: Borisov Alexey , Kilin Alexander , Mamaev Ivan
Published: March 2019

In this paper, we address the free (uncontrolled) dynamics of a snakeboard consisting of two wheel pairs fastened to a platform. The snakeboard is one of the well-known sports vehicles on which the sportsman executes necessary body movements. From the theoretical point of view, this system is a direct generalization of the classical nonholonomic system of the Chaplygin sleigh. We carry out a topological and qualitative analysis of trajectories of this dynamical system. An important feature of the problem is that the common level set of first integrals is a compact two-dimensional surface of genus 5. We specify conditions under which the reaction forces infinitely increase during motion and the so-called phenomenon of nonholonomic jamming is observed. In this case, the nonholonomic model ceases to work and it is necessary to use more complex mechanical models incorporating sliding, elasticity, etc.
Dissipative unified dark fluid model
Authors: Elkhateeb Esraa
Published: March 2019

We consider a unified barotropic dark fluid model with dissipation. Our fluid asymptotes between two power laws and so can interpolate between the dust and dark energy (DE) equations-of-state at early and late times. The dissipative part is a bulk viscous part with constant viscosity coefficient. The model is analyzed using the phase-space methodology which helps to understand the dynamical behavior of the model in a robust manner without reference to the system solution. The parameters of the model are constrained through many observational constraints. The model is tested through many physical and observational tests. We first considered the model independent [Formula: see text] test. Results for [Formula: see text] are plotted against the BAO data for this quantity from different authors, which shows that the model is consistent with the data points for the full redshift range. The [Formula: see text] statistics results in the value of [Formula: see text] with a [Formula: see text]-value of [Formula: see text]. The Hubble parameter equation is solved numerically and results are plotted against the recent set of Hubble data. The [Formula: see text] test with the Hubble data resulted in the [Formula: see text] value of [Formula: see text] with a [Formula: see text]-value of [Formula: see text]. The distance modulus at different values of redshift is calculated numerically and results are compared to the newest set of SNe Ia data, the Pantheon Sample. We obtained a [Formula: see text] value of [Formula: see text] with a [Formula: see text]-value of [Formula: see text]. These results show that our model is efficiently consistent with observations. The model expectations for the evolution of the universe are also studied by testing the evolution of the deceleration parameter, the density of the universe, and the effective equation-of-state parameter of the model and of its underlying dark energy candidate. The value of the present day viscosity coefficient of the cosmic fluid, [Formula: see text], is estimated. It is found to be [Formula: see text][Formula: see text]Pa[Formula: see text]s. We argue that this model is able to explain the behavior of the universe evolution.
Dynamical evolution of electromagnetic perturbation in the background of a scalar hairy black hole in Horndeski theory
Authors: Fang Qiong , Chen Songbai , Jing Jiliang
Published: March 2019

We have investigated dynamical evolution of electromagnetic perturbation in a scalar hairy black hole spacetime, which belongs to solutions in Horndeski theory with a logarithmic cubic term. Our results show that the parameter [Formula: see text] affects the existence of event horizon and modifies the asymptotical structure of spacetime at spatial infinity, which imprints on the quasinormal frequency of electromagnetic perturbation. Moreover, we find that the late-time tail of electromagnetic perturbation in this background depends also on the parameter [Formula: see text] due to the existence of solid angle deficit. These imply that the spacetime properties arising from the logarithmic cubic term in the action play important roles in the dynamical evolutions of the electromagnetic perturbation in the background of a scalar hairy black hole.
Determining finite strain: how far have we progressed?
Authors: McCarthy Dave , Meere Patrick , Mulchrone Kieran
Published: March 2019

One of the main aims in the field of structural geology is the identification and quantification of deformation or strain. This pursuit has occupied geologists since the 1800s, but has evolved dramatically since those early studies. The quantification of strain in sedimentary lithologies was initially restricted to lithologies of known initial shape, such as fossils or reduction spots. In 1967, Ramsay presented a series of methods and calculations, which allowed populations of clasts to be used as strain markers. These methods acted as a foundation for modern strain analysis, and have influenced thousands of studies. This review highlights the significance of Ramsay's contribution to modern strain analysis. We outline the advances in the field over the 50 years since publication of
Folding and Fracturing of Rocks
, review the existing limitations of strain analysis methods and look to future developments.
In Situ Stochastic Training of MTJ Crossbars With Machine Learning Algorithms
Authors: Mondal Ankit , Srivastava Ankur
Published: March 2019

Owing to high device density, scalability, and non-volatility, magnetic tunnel junction (MTJ)-based crossbars have garnered significant interest for implementing the weights of neural networks (NNs). The existence of only two stable states in MTJs implies a high overhead of obtaining optimal binary weights in software. This article illustrates that the inherent parallelism in the crossbar structure makes it highly appropriate for in situ training, wherein the network is taught directly on the hardware. It leads to significantly smaller training overhead as the training time is independent of the size of the network, while also circumventing the effects of alternate current paths in the crossbar and accounting for manufacturing variations in the device. We show how the stochastic switching characteristics of MTJs can be leveraged to perform probabilistic weight updates using the gradient descent algorithm. We describe how the update operations can be performed on crossbars implementing NNs and restricted Boltzmann machines, and perform simulations on them to demonstrate the effectiveness of our techniques. The results reveal that stochastically trained MTJ-crossbar feed-forward and deep belief nets achieve a classification accuracy nearly the same as that of real-valued weight networks trained in software and exhibit immunity to device variations.
Poly-Spline Finite-Element Method
Authors: Schneider Teseo , Dumas Jérémie , Gao Xifeng , Botsch Mario , Panozzo Daniele , Zorin Denis
Published: March 2019

We introduce an integrated meshing and finite-element method pipeline enabling solution of partial differential equations in the volume enclosed by a boundary representation. We construct a hybrid hexahedral-dominant mesh, which contains a small number of star-shaped polyhedra, and build a set of high-order bases on its elements, combining triquadratic B-splines, triquadratic hexahedra, and harmonic elements. We demonstrate that our approach converges cubically under refinement, while requiring around 50% of the degrees of freedom than a similarly dense hexahedral mesh composed of triquadratic hexahedra. We validate our approach solving Poisson’s equation on a large collection of models, which are automatically processed by our algorithm, only requiring the user to provide boundary conditions on their surface.
Comparing Platform-aware Control Design Flows for Composable and Predictable TDM-based Execution Platforms
Authors: Valencia Juan , Goswami Dip , Goossens Kees
Published: March 2019

We compare three platform-aware feedback control design flows that are tailored for a composable and predictable Time Division Multiplexing (TDM)-based execution platform. The platform allows for independent execution of multiple applications. Using the precise timing knowledge of the platform execution, we accurately characterise the execution of the control application (i.e., sensing, computing, and actuating operations) to design efficient feedback controllers with high control performance in terms of settling time. The design flows are derived for Single-Rate (SR) and Multi-Rate (MR) sampling schemes. We show the applicability of the design flows based on two design considerations and their trade-off: control performance and resource utilisation. The design flows are validated by means of MATLAB and Hardware-in-the-Loop (HIL) experiments for a motion control application.
Hydrogen sulfide-mediated regulation of cell death signaling ameliorates adverse cardiac remodeling and diabetic cardiomyopathy
Authors: Kar Sumit , Kambis Tyler N. , Mishra Paras K.
Published: March 2019

The death of cardiomyocytes is a precursor for the cascade of hypertrophic and fibrotic remodeling that leads to cardiomyopathy. In diabetes mellitus (DM), the metabolic environment of hyperglycemia, hyperlipidemia, and oxidative stress causes cardiomyocyte cell death, leading to diabetic cardiomyopathy (DMCM), an independent cause of heart failure. Understanding the roles of the cell death signaling pathways involved in the development of cardiomyopathies is crucial to the discovery of novel targeted therapeutics and biomarkers for DMCM. Recent evidence suggests that hydrogen sulfide (H2S), an endogenous gaseous molecule, has cardioprotective effects against cell death. However, very little is known about signaling by which H2S and its downstream targets regulate myocardial cell death in the DM heart. This review focuses on H2S in the signaling of apoptotic, autophagic, necroptotic, and pyroptotic cell death in DMCM and other cardiomyopathies, abnormalities in H2S synthesis in DM, and potential H2S-based therapeutic strategies to mitigate myocardial cell death to ameliorate DMCM.
Activated T-effector seeds: cultivating atherosclerotic plaque through alternative activation
Authors: Xu Maria M. , Murphy Patrick A. , Vella Anthony T.
Published: March 2019

Atherosclerosis is a chronic inflammatory pathology that precipitates substantial morbidity and mortality. Although initiated by physiological patterns of low and disturbed flow that differentially prime endothelial cells at sites of vessel branch points and curvature, the chronic, smoldering inflammation of atherosclerosis is accelerated by comorbidities involving inappropriate activation of the adaptive immune system, such as autoimmunity. The innate contributions to atherosclerosis, especially in the transition of monocyte to lipid-laden macrophage, are well established, but the mechanisms underpinning the infiltration, persistence, and effector dynamics of CD8 T cells in particular are not well understood. Adaptive immunity is centered on a classical cascade of antigen recognition and activation, costimulation, and effector cytokine secretion upon recall of antigen. However, chronic inflammation can generate alternative cues that supplant this behavior pattern and promote the retention and activation of peripherally activated T cells. Furthermore, the atherogenic foci that activated immune cell infiltrate are unique lipid-laden environments that offer a diverse array of stimuli, including those of survival, antigen hyporesponsiveness, and inflammatory cytokine expression. This review will focus on how known cardiovascular comorbidities may be influencing CD8 T-cell activation and how, once infiltrated within atherogenic foci, these T cells face a multitude of cues that skew the classical cascade of T-cell behavior, highlighting alternative modes of activation that may help contextualize associations of autoimmunity, viral infection, and immunotherapy with cardiovascular morbidity.
Strength-duration relationship as a tool to prioritize cardiac tissue properties that govern electrical excitability
Authors: Sayegh Michael N. , Fernandez Natasha , Cho Hee Cheol
Published: March 2019

Gaps exist in the availability of in vitro functional assessment tools that can emulate the integration of regenerative cells and tissues to the host myocardium. We use strength-duration relationships of electrically stimulated two- and three-dimensional myocardial constructs to study the effects of pacing frequency, culture dimensions, anisotropic cell alignment, fibroblast content, and pacemaker phenotype on electrical excitability. Our study delivers electrical strength-duration as a quantifiable parameter to evaluate design parameters of engineered cardiac tissue constructs.
Apoptosis signal-regulating kinase 1 activation by Nox1-derived oxidants is required for TNFα receptor endocytosis
Authors: Choi Hyehun , Stark Ryan J. , Raja Benjamin S. , Dikalova Anna , Lamb Fred S.
Published: March 2019

Tumor necrosis factor-α (TNFα) is a proinflammatory cytokine that is closely linked to the development of cardiovascular disease. TNFα activates NADPH oxidase 1 (Nox1) and reactive oxygen species (ROS), including superoxide (O2·−), production extracellularly is required for subsequent signaling in vascular smooth muscle cells (VSMCs). Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that is activated by oxidation of associated thioredoxin. The role of ASK1 in Nox1-mediated signaling by TNFα is poorly defined. We hypothesized that ASK1 is required for TNFα receptor endocytosis and subsequent inflammatory TNFα signaling. We employed a knockdown strategy to explore the role of ASK1 in TNFα signaling in VSMCs. siRNA targeting ASK1 had no effect on TNFα-induced extracellular O2·− production. However, siASK1 inhibited receptor endocytosis as well as phosphorylation of two endocytosis-related proteins, dynamin1 and caveolin1. Intracellular O2·− production was subsequently reduced, as were other inflammatory signaling steps including NF-κB activation, IL-6 production, inducible nitric oxide synthase and VCAM expression, and VSMC proliferation. Prolonged exposure to TNFα (24 h) increased tumor necrosis factor receptor (TNFR) subtype 1 and 2 expression, and these effects were also attenuated by siASK1. ASK1 coimmunoprecipitated with both Nox1 and the leucine rich repeat containing 8A anion channel, two essential components of the TNFR1 signaling complex. Activation of ASK1 by autophosphorylation at Thr845 occurs following thioredoxin dissociation, and this requires the presence of Nox1. Thus, Nox1 is part of the multiprotein ASK1 signaling complex. In response to TNFα, ASK1 is activated by Nox1-derived oxidants, and this plays a critical role in translating these ROS into a physiologic response in VSMCs.

NEW & NOTEWORTHY Apoptosis signal-regulating kinase 1 (ASK1) drives dynamin1 and caveolin1 phosphorylation and TNFα receptor endocytosis. ASK1 modulates TNFα-induced NF-κB activation, survival, and proliferation. ASK1 and NADPH oxidase 1 (Nox1) physically associate in a multiprotein signaling complex. Nox1 is required for TNFα-induced ASK1 activation.
Transient inhibition of neddylation at neonatal stage evokes reversible cardiomyopathy and predisposes the heart to isoproterenol-induced heart failure
Authors: Zou Jianqiu , Ma Wenxia , Littlejohn Rodney , Li Jie , Stansfield Brian K. , Kim Il-man , Liu Jinbao , Zhou Jiliang , Weintraub Neal L. , Su Huabo
Published: March 2019

Alterations in perinatal conditions (such as preterm birth) is linked to adult health and disease, in particular, the cardiovascular system. Neddylation, a novel posttranslational modification through which the ubiquitin-like protein NEDD8 is conjugated to protein substrates, has emerged as an important mechanism regulating embryonic cardiac chamber maturation. However, the importance of neddylation in postpartum cardiac development has not been investigated. Here, we aimed to determine whether transient, postnatal inhibition of neddylation has immediate and prolonged impact on the structure and function of the neonatal and adult hearts. Sprague-Dawley pups were given three intraperitoneal injections of MLN4924 (MLN), a specific neddylation inhibitor, at postnatal days (P)1, 3, and 5. Cardiac structure and function were temporally assessed during aging and after 2 wk of isoproterenol (ISO) infusion in adulthood. MLN treatment resulted in modest reduction of neddylated proteins in neonatal hearts. The MLN-treated rats developed cardiac hypertrophy and dysfunction by P7, which was accompanied by significantly reduced cardiomyocyte proliferation. At 3 mo of age, cardiac contractile function was restored in MLN-treated rats, but MLN-treated hearts displayed hypertrophic phenotype. Whereas ISO infusion triggered compensatory cardiac hypertrophy without impairing cardiac contractility in the control rats, the MLN-treated rats displayed a similar degree of hypertrophy, which quickly progressed to decompensation with ventricular wall thinning, chamber dilatation, and reduced ejection fraction as well as exacerbated pathological cardiac remodeling. Our findings suggest that neddylation is required for postnatal cardiac development and that perturbation of neddylation during development predisposes adult hearts to cardiac failure under stress conditions.

NEW & NOTEWORTHY Our study demonstrates that perinatal perturbation of neddylation induces cardiomyopathy, impairs postnatal cardiac development, and increases susceptibility to catecholamine-induced cardiac dysfunction. The results reveal a previously unappreciated role of neddylation in postnatal cardiac maturation and call for close monitoring for the potential cardiotoxicity of MLN4924 (pevonedistat) and other agents that modify neddylation, especially in pregnant women and preadolescents.
Der SV12: Entwicklung eines klinischen Inventars zur Erfassung von Sensibilität und deren Verarbeitungsproblematiken
Authors: Hinterberger Thilo , Galuska Devina , Galuska Joachim
Published: March 2019

Hintergrund: Zur Erfassung einer erhöhten Verarbeitungssensibilität bei Patienten in der stationären psychosomatischen Behandlung wurde ein Fragebogen entwickelt, der anders als Fragebögen zur Messung von Hochsensibilität die Konstrukte der Wahrnehmungssensibilität und Verarbeitungsproblematik trennen soll. Methoden: Zunächst wurde eine 30 Items umfassende Version an einer klinischen und einer nichtklinischen Stichprobe mit jeweils 1’103 Patienten erhoben und faktoranalytisch ausgewertet. Daraus konnte eine Kurzform mit 12 Items extrahiert werden, die im klini­schen Einsatz wiederholt validiert wurde. Ergebnisse: Sowohl in der klinischen und der nichtklinischen Stichprobe der Langform als auch in der Kurzform ergeben sich zwei Faktoren mit Cronbachs Alpha von 0,84 und 0,77, welche die Konstrukte der Sensibilität und Verarbeitungsproblematik eindeutig trennen. Weitere faktorielle Unterscheidungen waren nicht einheitlich. Kurz- und Langform zeigten mit Werten zwischen r = 0,87 und 0,94 eine hohe Übereinstimmung. Eine Referenzskala wurde ebenfalls erstellt. Fazit: Durch die differenzierte Erfassung der Sensibilität und der therapeutisch relevanten Aspekte der Verarbeitungspro­blematiken erscheint die Verwendung in der klinischen Dia­gnostik sinnvoll.
Expression of the GBGT1 Gene and the Forssman Antigen in Red Blood Cells in a Palestinian Population
Authors: Abusibaa Wafa Ali , Srour Mahmoud A. , Moslemi Ali-Reza , Svensson Lola , Jesus Carlos , Mendes Fernando , Hesse Camilla
Published: March 2019

Background: The Forssman antigen (FORS1 Ag) is expressed on human red blood cells (RBCs). We investigated its presence on RBCs from Palestinian subjects and Swedish subjects by serological testing and by sequencing part of exon 7 of the GBGT1 gene, which encodes Forssman synthase. ­Materials and Methods: Blood samples from Palestinian subjects (n = 211 adults and n = 73 newborns) and from Swedish subjects (n = 47 adults) were analyzed in the study. RBCs from the Palestinian samples were typed for the FORS1 Ag using a monoclonal anti-Forssman antibody. The GBGT1 gene was genotyped by DNA sequencing (all adult samples) or by using amplification refractory mutation system PCR (newborn samples). Results: All of the studied samples were negative for the FORS1 Ag by serologic typing. DNA sequencing of the 3′ end of exon 7 of the GBGT1 gene, which includes Arg296, showed that all samples had the wild-type Arg296 sequence, which is associated with an inactive form of Forssman synthase. We detected four single nucleotide polymorphisms in the adult samples; two were silent (p.Tyr232=, p.Gly290=), and two were missense (p.Arg243Cys, p.Arg243His). The allele frequencies ranged from 0.2 to 3.6%. The p.Arg243Cys SNP was a novel SNP that was detected in one Palestinian sample. Conclusion: Our results confirmed the allelic diversity of GBGT1 and identified a novel nucleotide polymorphism in this gene, p.Arg243Cys. Our results also confirmed that the FORS blood group system is a low-frequency system.
Real-World Outcomes with Ranibizumab 0.5 mg in Patients with Visual Impairment due to Diabetic Macular Edema: 12-Month Results from the 36-Month BOREAL-DME Study
Authors: Massin Pascale , Creuzot-Garcher Catherine , Kodjikian Laurent , Girmens Jean-François , Delcourt Cecile , Fajnkuchen Frank , Glacet-Bernard Agnès , Guillausseau Pierre-Jean , Ponthieux Anne , Blin Patrick , Grelaud Angela
Published: March 2019

Purpose: To report the real-world effectiveness and safety of ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema (DME). Methods: This is a French, 36-month, multicenter, observational cohort study. Between December 2013 and April 2015, ophthalmologists enrolled diabetic patients aged ≥18 years with DME-related visual impairment and for whom ranibizumab 0.5 mg was initiated. Here, we present the 12-month results from this cohort. The primary endpoint was the mean change in best-corrected visual acuity (BCVA); sample size calculations were based on RESTORE trial data (BCVA mean change = 6.8 letters, precision = 0.7 letters). Secondary endpoints included the change in central subfield thickness (CSFT), number of visits, number of injections received, and frequency of ocular and nonocular adverse events and serious adverse events. Results: Between December 2013 and April 2015, a total of 290 patients with DME were enrolled by 84 ophthalmologists; 12-month data are available for 242 patients (due to low recruitment rates, precision was recalculated for 242 evaluable patients: the precision was then of 1.0 letters). Mean age (± standard deviation) was 66.1 ± 11.0 years and 56.6% were male. The mean baseline BCVA and CSFT were 59.2 letters (95% confidence interval [CI] 57.3, 61.0) and 457 μm (95% CI: 438, 476), respectively. At month 12, the mean gain in BCVA from baseline was 7.4 letters (95% CI: 5.4, 9.4), with 36.8% of patients with BCVA >70 letters versus 13.2% at baseline. Mean change in CSFT was −125 μm (95% CI: −146, −103). The mean number of ranibizumab injections was 5.1 ± 2.3 over an average of 10.4 ± 3.0 visits. No new safety findings were identified. Conclusions: The BOREAL study confirms the effectiveness and safety of ranibizumab for the treatment of DME-related visual impairment in routine clinical practice with fewer injections than reported in clinical trials.
Same-Day Bilateral Intravitreal Anti-Vascular Endothelial Growth Factor Injections: Experience of a Large Canadian Retina Center
Authors: Juncal Verena R. , Francisconi Carolina L.M. , Altomare Filiberto , Chow David R. , Giavedoni Louis R. , Muni Rajeev H. , Berger Alan R. , Wong David T.
Published: March 2019

Objective: To evaluate the outcomes and complications of bilateral same-day intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Methods: This is a single-center, retrospective study that included 524 eyes of 262 patients who received concomitant bilateral intravitreal anti-VEGF injections in 2016 at St. Michael’s Hospital, Toronto. If any of the patients were receiving simultaneous bilateral injections on a regular basis prior to 2016, data pertaining to previous injections were also reviewed. Everyone received bevacizumab, ranibizumab, or aflibercept in an office setting. Results: A total of 9,798 intravitreal anti-VEGF injections (4,899 bilateral injection sessions) were performed in 524 eyes of 262 patients. The average number of bilateral injection sessions per patient was 18.7 ± 14.1. Ranibizumab was the most commonly used anti-VEGF drug (83.8%). The incidence of endophthalmitis was 0.01%, and there were 2 episodes of acute intraocular inflammation among the 9,798 injections (0.02%). All 3 cases occurred after treatment with ranibizumab. There were 2 deaths (0.76%) due to nonvascular causes but no vascular related systemic adverse events were reported. Conclusions: Same-day bilateral intravitreal anti-VEGF injections present a low rate of complications and are well tolerated by patients. This safe practice may reduce the burden on the health-care system and on the patients.
Endoscopic Findings of Esophageal Adenosquamous Carcinoma Diagnosed by Endoscopic Mucosal Resection
Authors: Endo Hiroyuki , Koike Tomoyuki , Hatta Waku , Asanuma Kiyotaka , Uno Kaname , Asano Naoki , Imatani Akira , Watanabe Mika , Kato Katsuaki , Masamune Atsushi
Published: March 2019

Adenosquamous carcinoma (ASC) is a rare histological type of esophageal carcinoma. Esophagogastroduodenoscopy for the health checkup of a 71-year-old male revealed the presence of a slightly elevated lesion like a submucosal tumor at the lower part of the esophagus. The center of it was slightly depressed, and the depressed area was not stained by iodine. Magnifying endoscopy with narrow-band imaging revealed reticular pattern vessels in the depressed area, whereas no irregularity of the microvascular pattern of the surrounding area was evident. One of the biopsied specimens taken from the depressed area was diagnosed as squamous intraepithelial neoplasia, but a malignant tumor with submucosal invasion was suspected based on the findings of endoscopic ultrasonography. Endoscopic mucosal resection using a cap-fitted endoscope was performed, and the lesion was diagnosed as esophageal ASC histologically. Carcinomas that formed nested and ductal structures existed in the lamina propria and invaded to the submucosa. Almost all of them were covered by non-invasive intraepithelial neoplasia, whereas small erosion was seen in the central depressed area. The growing pattern of ASC was quite different from that of typical differentiated squamous cell carcinomas. When we do endoscopic examination for an esophageal lesion like submucosal tumor, we have to consider the possibility of an esophageal carcinoma that has a similar growing pattern. If reticular pattern vessels are seen with magnifying endoscopy, the existence of an invasive carcinoma is suspected, and additional endoscopic ultrasonography is recommended. Possible efforts to gain histological findings have to be made using bowling biopsy, endoscopic resection, and so on.
Cerebral Microbleeds are Associated with Postural Instability and Gait Disturbance Subtype in People with Parkinson’s Disease
Authors: Chiu Wei Ting , Chan Lung , Wu Dean , Ko Tzu Hsiang , Chen David Yen-Ting , Hong Chien-Tai
Published: March 2019

Objectives: The motor symptoms of Parkinson’s disease (PD) vary among patients and have been categorized into 3 subtypes: tremor dominant, akinetic rigidity, and postural instability and gait disturbance (PIGD). Cerebral microbleed (CMB) is prevalent in people with PD and is associated with some nonmotor symptoms. The present study investigated the association between CMB and the motor subtypes of PD. Materials and Methods: From 2009 to 2017, medical records and brain magnetic resonance imaging (MRI) reports of 134 Taiwanese people with early- and mid-stage PD were reviewed. CMBs were quantified according to the Microbleed Anatomical Rating Scale through susceptibility-weighted MRI. Motor subtypes were determined by medical chart review. Student’s t test and multivariable logistic regression were used to analyze the association between the motor subtypes and CMB. Statistical analyses were performed using SPSS 19.0. Results: Overall, 72 (53.7%) participants were women with a mean age of 69.5 ± 9.8 years. The prevalence of CMB was 33.6%, and lobar, deep, and infratentorial CMBs comprised 21.6, 19.4, and 11.9% of cases, respectively. PIGD subtype PD was associated with a significantly higher prevalence of any CMB as well as deep or lobar CMB. After adjustment for age and sex, the PIGD subtype was significantly positively associated with the presence of any, deep, and white matter (WM) and thalamic CMB. Conclusions: CMB was prevalent in Taiwanese people with early- and mid-stage PD, especially the PIGD subtype. Deep, especially thalamic and WM, CMBs exhibited the highest association with the PIGD subtype.
El estado segregador: políticas públicas discriminatorias
Authors: Hechem Antonio Daher
Published: March 2019

Este artículo sostiene la tesis de que el Estado, y no sólo el mercado, es responsable -intencional o inintencionalmente - de la segregación urbana. El análisis de políticas de financiamiento municipal, vivienda social, infraestructuras, transporte, servicios públicos, e incluso de renovación urbana, confirma que ellas, en conjunto, configuran discriminatoriamente las ciudades. La revisión de varias políticas públicas que, aun cuando sectoriales, se complementan en la reproducción y agudización de la segregación urbana, evidencia que estas contradicen muchas veces los programas gubernamentales tendientes a disminuir la desigualdad o mitigar la inequidad