bluuebunny/crossref_metadata_2025 huggingface dataset:
Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand
Authors: Britton P. N. , Eastwood K. , Paterson B. , Durrheim D. N. , Dale R. C. , Cheng A. C. , Kenedi C. , Brew B. J. , Burrow J. , Nagree Y. , Leman P. , Smith D. W. , Read K. , Booy R. , Jones C. A. ,   Australasian Society of I nfectious D iseases ( ASID ),   Australasian College of Emergency Medicine ( ACEM ),   A ustralian and N ew Z ealand A ssociation of N eurologists ( ANZAN ),   the P ublic H ealth A ssociation of A ustralia ( PHAA )
Published: May 2015

Encephalitis is a complex neurological syndrome caused by inflammation of the brain parenchyma. The management of encephalitis is challenging because: the differential diagnosis of encephalopathy is broad; there is often rapid disease progression; it often requires intensive supportive management; and there are many aetiologic agents for which there is no definitive treatment. Patients with possible meningoencephalitis are often encountered in the emergency care environment where clinicians must consider differential diagnoses, perform appropriate investigations and initiate empiric antimicrobials. For patients who require admission to hospital and in whom encephalitis is likely, a staged approach to investigation and management is preferred with the potential involvement of multiple medical specialties. Key considerations in the investigation and management of patients with encephalitis addressed in this guideline include: Which first‐line investigations should be performed?; Which aetiologies should be considered possible based on clinical features, risk factors and radiological features?; What tests should be arranged in order to diagnose the common causes of encephalitis?; When to consider empiric antimicrobials and immune modulatory therapies?; and What is the role of brain biopsy?
Sintering Mechanisms and Kinetics for Reaction Hot‐Pressed ZrB2
Authors: Lonergan Jason M. , Fahrenholtz William G. , Hilmas Greg E.
Published: May 2015

Sintering mechanisms and kinetics were investigated for ZrB2 ceramics produced using reaction hot pressing. Specimens were sintered at temperatures ranging from 1800°C to 2100°C for times up to 120 min. ZrB2 was the primary phase, although trace amounts of ZrO2 and C were also detected. Below 2000°C, the densification mechanism was grain‐boundary diffusion with an activation energy of 241 ± 41 kJ/mol. At higher temperatures, the densification mechanism was lattice diffusion with an activation energy of 695 ± 62 kJ/mol. Grain growth exponents were determined to be ~4.5, which indicated that a grain pinning mechanism was active in both temperature regimes. The diffusion coefficients for grain growth were 1.5 × 10−16 cm4/s at 1900°C and 2.1 × 10−15 cm4/s at 2100°C. This study revealed that dense ZrB2 ceramics can be produced by reactive hot pressing in shorter times and at lower temperatures than conventional hot pressing of commercial powders.
Chemical Synthesis, Sintering and Piezoelectric Properties of Ba0.85Ca0.15 Zr0.1Ti0.9O3 Lead‐Free Ceramics
Authors: Castkova Klara , Maca Karel , Cihlar Jaroslav , Hughes Hana , Matousek Ales , Tofel Pavel , Bai Yang , Button Tim W.
Published: May 2015

The preparation of Ba0.85Ca0.15 Zr0.1Ti0.9O3 (BCZT) powders by wet chemical methods has been investigated, and the powders used to explore relationships between the microstructure and piezoelectric properties (d33 coefficient) of sintered BCZT ceramics. Sol–gel synthesis has been shown to be a successful method for the preparation of BCZT nanopowders with a pure tetragonal perovskite phase structure, specific surface area up to 21.8 m2/g and a mean particle size of 48 nm. These powders were suitable for the fabrication of dense BCZT ceramics with fine‐grain microstructures. The ceramics with the highest density of 95% theoretical density (TD) and grain size of 1.3 μm were prepared by uniaxial pressing followed by a two‐step sintering approach which contributed to the refinement of the BCTZ microstructure. A decrease in the grain size to 0.8–0.9 μm was achieved when samples were prepared using cold isostatic pressing. Using various sintering schedules, BCZT ceramics with broad range of grain sizes (0.8–60.5 μm) were prepared. The highest d33 = 410.8 ± 13.2 pC/N was exhibited by ceramics prepared from sol–gel powder sintered at 1425°C, with the relative density of 89.6%TD and grain size of 36 μm.
Facile Fabrication of Highly Transparent Yttria Ceramics with Fine Microstructures by a Hot‐Pressing Method
Authors: Gan Lin , Park Young‐Jo , Park Mi‐Jung , Kim Haneul , Kim Jin‐Myung , Ko Jae‐Woong , Lee Jae‐Wook
Published: May 2015

In this study, we report highly transparent yttria ceramics fabricated by a facile hot‐pressing method with tantalum foil shielding which effectively prevents the ceramic samples from carbon contamination caused by the graphite mold used during the process. The hot‐pressed sample was already highly transparent without a post‐annealing step or hot isostatic pressing. For a 2‐mm‐thick specimen doped with 1 at.% ZrO2, the in‐line transmittance reaches 74.4% at 400 nm and 81.1% at 1100 nm. The sample shows a very fine microstructure with an average grain size of about 1 μm owing to the low sintering temperature of only 1600°C. The study results indicate that it is possible to produce transparent yttria ceramics with excellent optical transparency using the economical and convenient hot‐pressing method.
Can Luck Egalitarianism Justify the Fact that Some are Worse Off than Others?
Authors: Huseby Robert
Published: May 2015

According to luck egalitarianism it is bad or unjust if someone is worse off than another through no fault or choice of her own. This article argues that there is a tension in standard luck egalitarian theory between justifying absolute and comparative welfare levels. If a person responsibly acts in a way that brings her welfare level below that of others, this is justified according to the theory. However, even if we can say that the person's new welfare level is justified in absolute terms, it is less clear that her now being worse off than others, is justified (a similar idea is explored by Susan Hurley). The reason is that while she has in one sense chosen her (new) welfare level, she has not chosen to be worse off than others. Her relative standing, something with which egalitarians ought to be concerned, is determined by her choices in conjunction with the choices of all others. But no individual controls the choices of all others. Hence, for any one individual it is the case that her relative standing is beyond her control. Some responses to this problem are available. It is doubtful, however, that these are entirely successful.
Study of three non‐syndromic cases of congenital thumb aplasia in captive rhesus monkeys
Authors: Goldschmidt B. , Meireles B.C.S. , Calado M.I.Z. , França F.G.O. , Oliveira A. , Resende F.C.
Published: May 2015

Although congenital thumb absence has been reported frequently in humans, their occurrence in macaques is rare. We observed three cases of spontaneous thumb defects in captive female rhesus monkeys. One animal exhibited bilateral absence and two other presented unilateral thumb absence, all with metacarpal integrity. This report presents the clinical, radiological, and genealogical details as well as possible etiologies in an attempt to draw a parallel with humans and other primate species.
Tetramethylpyrazine inhibits CoCl2‐induced neurotoxicity through enhancement of Nrf2/GCLc/GSH and suppression of HIF1α/NOX2/ROS pathways
Authors: Guan Dongsheng , Su Yufei , Li Yingxia , Wu Chuanjie , Meng Yi , Peng Xin , Cui Yinglin
Published: May 2015

Hypoxia‐mediated neurotoxicity contributes to various neurodegenerative disorders, including Alzheimer's disease and multiple sclerosis. Tetramethylpyrazine (TMP), a major bioactive component purified from Ligusticum wallichii Franchat, exhibited potent neuroprotective effect. However, the mechanism of TMP‐exerted neuroprotective effect against hypoxia was not clear. In the study, we investigated the mechanism of the neuroprotective effect of TMP against hypoxia induced by CoCl2 in vitro and in vivo. The results showed that TMP could protect against CoCl2‐induced neurotoxicity in PC12 cells and in rats, as evidenced by enhancement of cell viability in PC12 cells and improvement of learning and memory ability in rats treated with CoCl2. TMP could inhibit mitochondrial dysfunction, mitochondrial apoptotic molecular events, and thus apoptosis induced by CoCl2. TMP inhibited CoCl2‐increased reactive oxygen species (ROS) level, which may contribute to hypoxia‐related neurotoxicity induced by CoCl2. The antioxidant and neuroprotective activities of TMP involved two pathways: one was the enhancement of nuclear factor erythroid 2‐related factor 2 (Nrf2)/catalytic subunit of γ‐glutamylcysteine ligase‐mediated regulation of GSH and the other was the inhibition of hypoxia‐inducible factor 1 α/NADPH oxidase 2 (NOX2)‐mediated ROS generation. These two pathways contributed to improvement of oxidative stress and thus the amelioration of apoptosis under hypoxic conditions. These results have appointed a new path toward the understanding of pathogenesis and TMP‐related therapy of hypoxia‐related neurodegenerative diseases.

image

We proposed two cascades for tetramethylpyrazine‐exhibited protective effects against CoCl2‐induced neurotoxicity: One is enhancement of nuclear factor erythroid 2‐related factor 2‐catalytic subunit of γ‐glutamylcysteine ligase‐mediated regulation of glutathone and the other was the inhibition of hypoxia‐inducible factor 1 α‐NADPH oxidase‐2‐mediated ROS generation. We think these findings should provide a new understanding of pathogenesis and tetramethylpyrazine‐related therapy of hypoxia‐related neurodegenerative diseases.
Consistent Estimation of the Value at Risk When the Error Distribution of the Volatility Model is Misspecified
Authors: El Ghourabi Mohamed , Francq Christian , Telmoudi Fedya
Published: May 2015

A two‐step approach for conditional value at risk estimation is considered. First, a generalized quasi‐maximum likelihood estimator is employed to estimate the volatility parameter, then the empirical quantile of the residuals serves to estimate the theoretical quantile of the innovations. When the instrumental density h of the generalized quasi‐maximum likelihood estimator is not the Gaussian density, both the estimations of the volatility and of the quantile are generally asymptotically biased. However, the two errors counterbalance and lead to a consistent estimator of the value at risk. We obtain the asymptotic behavior of this estimator and show how to choose optimally h.
Relation of Complementary‐Alternative Medicine use with glomerular filtration rate and depression in patients with chronic kidney disease at predialysis stage
Authors: Esen Bennur , Atay Ahmet Engin , Gokmen Emel Saglam , Karakoc Ayten , Sari Hakan , Sarisakal Samprie , Kahvecioglu Serdar , Kayabasi Hasan , Sit Dede
Published: May 2015

Aim

Complementary and alternative medicine is a broad field of health including all health care practices and methods, and their accompanying theories and beliefs. In the present study, we aimed to examine the frequency of complementary‐alternative medicine use, and its relation with glomerular filtration rate and depression in patients with chronic kidney disease at predialysis stage.

Methods

A total of 1053 predialysis patients; 518 female and 535 male, that were followed up with chronic kidney disease for at least 3 months were enrolled into the study. Demographic features, biochemical parameters and findings of physical examination were recorded. Their compliance to diet, and knowledge about disease were questioned. Beck depression inventory and questionnaire regarding complementary‐alternative medicine use were performed.

Results

The overall frequency of complementary‐alternative medicine use was 40.3% . Total ratio of herbal products was 46%. Complementary‐alternative medicine use was significantly more frequent in female or single patients, and patients that informed about chronic kidney disease or under strict diet (P = 0.007, P = 0.016, P = 0.02, P = 0.016, respectively). When glomerular filtration rate of participants were considered, complementary‐alternative medicine use was similar in different stages of kidney disease. Depression was observed in 41.9% of patients and significantly frequent in patients with alternative method use (P = 0.002). Depression score was higher as creatinine increases and glomerular filtration rate decreases (P = 0.002; r = 0.093).

Conclusion

We determined that complementary‐alternative medicine use gradually increases at predialysis stage as glomerular filtration rate decreases and there is a strict relation between complementary‐alternative medicine use and depression or female gender. Disorder related stressors may lead to seeking of alternative methods.
Congressional dysfunction: An information processing perspective
Authors: Lewallen Jonathan , Theriault Sean M. , Jones Bryan D.
Published: May 2015

The public's approval of Congress is at an all time low. The parties seem to have taken the legislative process hostage for their own electoral gain. Whereas traditional arguments about congressional dysfunction focus on polarized voting coalitions or outputs – particularly legislation – in this article we highlight congressional information processing and how it has changed in this highly partisan era. By coding congressional hearings according to the kind of information on which they focus, we find that members of Congress are receiving one‐sided information to a greater degree and are spending less time learning about potential solutions. We use these results to make numerous recommendations for improving how Congress gathers its information.
Ancient mantle lithosphere beneath the Khanka massif in the Russian Far East: in situ Re–Os evidence
Authors: Wang Kuo‐Lung , Prikhodko Vladimir , O'Reilly Suzanne Y. , Griffin William L. , Pearson Norman J. , Kovach Victor , Iizuka Yoshiyuki , Chien Yu‐Hsian
Published: May 2015

The Os‐isotope compositions of sulphides in mantle xenoliths hosted by Late Miocene alkali basalts from the Sviyaginsky volcano, Russian Far East, reveal the presence of Archaean–Proterozoic subcontinental lithospheric mantle beneath the Khanka massif. Their TMA and TRD model ages reveal similar peaks at 1.1 and 0.8 Ga suggesting later thermotectonic events in the subcontinental lithospheric mantle, whereas TRD model ages range back to 2.8 ± 0.5 (2σ) Ga. The events recognized in the subcontinental lithospheric mantle are consistent with those recorded in the crust of the Khanka massif. The sulphide Os‐isotope data show that the subcontinental lithospheric mantle beneath the Khanka massif had formed at least by the Mesoproterozoic, and was subsequently metasomatized by juvenile crustal‐growth events related to the evolution of the Altaids. The Khanka massif is further proposed to have tectonic affinity to the Siberia Craton and should originate from it accordingly.
Origin and differentiation of vascular smooth muscle cells
Authors: Wang Gang , Jacquet Laureen , Karamariti Eirini , Xu Qingbo
Published: May 2015

image

Vascular smooth muscle cells (SMCs), a major structural component of the vessel wall, not only play a key role in maintaining vascular structure but also perform various functions. During embryogenesis, SMC recruitment from their progenitors is an important step in the formation of the embryonic vascular system. SMCs in the arterial wall are mostly quiescent but can display a contractile phenotype in adults. Under pathophysiological conditions, i.e. vascular remodelling after endothelial dysfunction or damage, contractile SMCs found in the media switch to a secretory type, which will facilitate their ability to migrate to the intima and proliferate to contribute to neointimal lesions. However, recent evidence suggests that the mobilization and recruitment of abundant stem/progenitor cells present in the vessel wall are largely responsible for SMC accumulation in the intima during vascular remodelling such as neointimal hyperplasia and arteriosclerosis. Therefore, understanding the regulatory mechanisms that control SMC differentiation from vascular progenitors is essential for exploring therapeutic targets for potential clinical applications. In this article, we review the origin and differentiation of SMCs from stem/progenitor cells during cardiovascular development and in the adult, highlighting the environmental cues and signalling pathways that control phenotypic modulation within the vasculature.
Relationship between subthalamic nucleus neuronal activity and electrocorticogram is altered in the R6/2 mouse model of Huntington's disease
Authors: Callahan Joshua W. , Abercrombie Elizabeth D.
Published: May 2015

Key points

Neural synchrony between the subthalamic nucleus (STN) and cortex is critical for proper information processing in basal ganglia circuits.

Using in vivo extracellular recordings in urethane‐anaesthetized mice, we demonstrate that single units and local field potentials from the STN exhibit oscillatory entrainment to low‐frequency (0.5–4 Hz) rhythms when the cortex is in a synchronized state.

Here we report novel findings in the R6/2 transgenic mouse model of Huntington's disease (HD) by demonstrating that STN activity is reduced and less phase‐locked to cortical low‐frequency oscillations.

The spectral power of low‐frequency oscillations in ECoG recordings of R6/2 mice is diminished while the spectral power of higher frequencies is augmented and such altered cortical patterning could lead to decreased synchrony in corticosubthalamic circuits.

Our data establish that cortical entrainment of STN neural activity is disrupted in R6/2 mice and may be one of the mechanisms contributing to disordered motor control in HD.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder in which impairments in the processing of information between the cortex and basal ganglia are fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a pivotal role in motor selection and blockade of neuronal activity in the subthalamic nucleus (STN) results in a hyperkinetic movement syndrome, similar to the HD phenotype. The aim of the present study was to examine the relationship between neuronal activity in the STN and cortex in an animal model of HD. We performed in vivo extracellular recordings in the STN to measure single‐unit activity and local field potentials in the R6/2 transgenic mouse model of HD. These recordings were obtained during epochs of simultaneously acquired electrocorticogram (ECoG) in discrete brain states representative of global cortical network synchronization or desynchronization. Cortically patterned STN neuronal activity was less phase‐locked in R6/2 mice, which is likely to result in less efficient coding of cortical inputs by the basal ganglia. In R6/2 mice, the power of the ECoG in lower frequencies (0.5–4 Hz) was diminished while the power expressed in higher frequencies (13–100 Hz) was increased. In addition, the spontaneous activity of STN neurons in R6/2 mice was reduced and neurons exhibited a more irregular firing pattern. Glutamatergic STN neurons provide the major excitatory drive to the output nuclei of the basal ganglia and altered discharge patterns could lead to aberrant basal ganglia output and disordered motor control in HD.
Three brainstem areas involved in respiratory rhythm generation in bullfrogs
Authors: Baghdadwala Mufaddal I. , Duchcherer Maryana , Paramonov Jenny , Wilson Richard J. A.
Published: May 2015

Key points

For most multiphasic motor patterns, rhythm and pattern are produced by the same circuit elements. For respiration, however, these functions have long been assumed to occur separately.

In frogs, the ventilatory motor pattern produced by the isolated brainstem consists of buccal and biphasic lung bursts. Previously, two discrete necessary and sufficient sites for lung and buccal bursts were identified.

Here we identify a third site, the Priming Area, important for and having neuronal activity correlated with the first phase of biphasic lung bursts.

As each site is important for burst generation of a separate phase, we suggest each major phase of ventilation is produced by an anatomically distinct part of an extensive brainstem network.

Embedding of discrete circuit elements producing major phases of respiration within an extensive rhythmogenic brainstem network may be a shared architectural characteristic of vertebrates.

Ventilation in mammals consists of at least three distinct phases: inspiration, post‐inspiration and late‐expiration. While distinct brainstem rhythm generating and pattern forming networks have long been assumed, recent data suggest the mammalian brainstem contains two coupled neuronal oscillators: one for inspiration and the other for active expiration. However, whether additional burst generating ability is required for generating other phases of ventilation in mammals is controversial. To investigate brainstem circuit architectures capable of producing multiphasic ventilatory rhythms, we utilized the isolated frog brainstem. This preparation produces two types of ventilatory motor patterns, buccal and lung bursts. Lung bursts can be divided into two phases, priming and powerstroke. Previously we identified two putative oscillators, the Buccal and Lung Areas. The Lung Area produces the lung powerstroke and the Buccal Area produces buccal bursts and – we assumed – the priming phase of lung bursts. However, here we identify an additional brainstem region that generates the priming phase. This Priming Area extends rostral and caudal of the Lung Area and is distinct from the Buccal Area. Using AMPA microinjections and reversible synaptic blockade, we demonstrate selective excitation and ablation (respectively) of priming phase activity. We also demonstrate that the Priming Area contains neurons active selectively during the priming phase. Thus, we propose that three distinct neuronal components generate the multiphase respiratory motor pattern produced by the frog brainstem: the buccal, priming and powerstroke burst generators. This raises the possibility that a similar multi‐burst generator architecture mediates the three distinct phases of ventilation in mammals.
From one generation to the next: a comprehensive account of sympathetic receptor control in branching arteriolar trees
Authors: Al‐Khazraji Baraa K. , Saleem Amani , Goldman Daniel , Jackson Dwayne N.
Published: May 2015

Key points

The sympathetic nervous system increases skeletal muscle arteriolar resistance by activating adrenergic, peptidergic and purinergic receptors, which may depend on network topology.

To date, there has been limited work conducted on topologically‐dependent sympathetic nervous system control in continuously branching skeletal muscle microvascular networks.

In the present study, we investigated how arterioles respond to activation of receptors for sympathetic neurotransmitters based on their location within continuously branching arteriolar trees in skeletal muscle.

For the first time, we show differential order‐dependent responses to adrenergic, peptidergic and purinergic agonists in continuously branching arteriolar trees.

These results provide novel and detailed network data describing full‐range sympathetic control in the skeletal muscle microcirculation. This work provides much needed experimental data, which can be applied to mathematical models of skeletal muscle blood flow and oxygen transport.

The effect of the sympathetic nervous system on blood flow distribution within skeletal muscle microvasculature is conditional upon regional activation of receptors for sympathetic neurotransmitters. Previous studies have shown that proximal arterioles are largely governed by adrenergic activation, whereas it is speculated that distal branches are controlled by peptidergic and purinergic activation. However, no study has systematically evaluated the activation of adrenergic, peptidergic and purinergic receptors in continuously branching arteriolar trees of an individual skeletal muscle model. Therefore, in the present study, sympathetic agonists were used to evaluate the constriction responses along first to fifth order arterioles in continuously branching arteriolar trees of a in vivo rat gluteus maximus muscle preparation with respect to specific activation of receptors for sympathetic neurotransmitters (α1R, α2R, NPY1R and P2X1R). Constriction responses were incorporated into a mathematical blood flow model to estimate the total flow, resistance and red blood cell flow heterogeneity within a computationally reconstructed gluteus maximus arteriolar network. For the first time, the effects of activating receptors for sympathetic neurotransmitters on vasoconstrictor responses and the ensuing haemodynamics in continuously branching arteriolar trees of skeletal muscle were characterized, where proximal arterioles responded most to α1R and α2R adrenergic activation, whereas distal arterioles responded most to Y1R and P2X1R activation. Total flow and resistance changed with activation of all receptors, whereas red blood cell flow heterogeneity was largely affected by peptidergic and purinergic activation in distal arterioles. The reported data highlight the functional consequences of topologically‐dependent sympathetic control and may serve as novel input parameters in computational modelling of network flow.
A Particular Solutions for a Two-Phase Model with a Sharp Interface
Authors: Ekrut David Allen , Cogan Nicholas G.
Published: May 2015

Two-phase models can be used to describe the dynamics of mixed materials and can be applied to many physical and biological phenomena. For example, these types of models have been used to describe the dynamics of cancer, biofilms, cytoplasm, and hydrogels. Frequently the physical domain separates into a region of mixed material immersed in a region of pure fluid solvent. Previous works have found a perturbation solution to capture the front velocity at the initial time of contact between the polymer network and pure solvent, then approximated the solution to the sharp-interface at other points in time. The primary purpose of this work is to use a symmetry transformation to capture an exact solution to this two-phase problem with asharp-interface. This solution is useful for a variety of reasons. First, the exact solution replicates the numeric results, but it also captures the dynamics of the volume profile at the boundary between phases for arbitrary time scales. Also, the solution accounts for dispersion of the network further away from the boundary. Further, our findings suggest that an infinite number of exact solutions of various classes exist for the two-phase system, which may give further insights into the behaviors of the general two-phase model.
Exposure to ideologically diverse news and opinion on Facebook
Authors: Bakshy Eytan , Messing Solomon , Adamic Lada A.
Published: May 2015

Not getting all sides of the news?

People are increasingly turning away from mass media to social media as a way of learning news and civic information. Bakshy
et al.
examined the news that millions of Facebook users' peers shared, what information these users were presented with, and what they ultimately consumed (see the Perspective by Lazer). Friends shared substantially less cross-cutting news from sources aligned with an opposing ideology. People encountered roughly 15% less cross-cutting content in news feeds due to algorithmic ranking and clicked through to 70% less of this cross-cutting content. Within the domain of political news encountered in social media, selective exposure appears to drive attention.

Science
, this issue p.
1130
; see also p.
1090
2.2 Å resolution cryo-EM structure of β-galactosidase in complex with a cell-permeant inhibitor
Authors: Bartesaghi Alberto , Merk Alan , Banerjee Soojay , Matthies Doreen , Wu Xiongwu , Milne Jacqueline L. S. , Subramaniam Sriram
Published: May 2015

Pushing the limits of electron microscopy

Recent advances in cryo–electron microscopy (cryo-EM) allow structures of large macromolecules to be determined at near-atomic resolution. So far, though, resolutions approaching 2 Å, where features key to drug design are revealed, remain the province of x-ray crystallography. Bartesaghi
et al.
achieved a resolution of 2.2 Å for a 465-kD ligand-bound protein complex using cryo-EM. The density map is detailed enough to show close to 800 water molecules, magnesium and sodium ions, and precise side-chain conformations. These results bring routine use of cryo-EM in rational drug design a step closer.

Science
, this issue p.
1147
THE STORM (acute coronary Syndrome in paTients end Of life and Risk assesMent) study
Authors: Moretti Claudio , Quadri Giorgio , D'Ascenzo Fabrizio , Bertaina Maurizio , Giusto Federico , Marra Sebastiano , Moiraghi Corrado , Scaglione Luca , Torchio Mauro , Montrucchio Giuseppe , Bo Mario , Porta Massimo , Cavallo Perin Paolo , Marinone Carlo , Riccardini Franco , Iqbal Javaid , Omedè Pierluigi , Bergerone Serena , Veglio Franco , Gaita Fiorenzo
Published: May 2015

Introduction

Elderly patients with coexisting frailty and multiple comorbidities frequently present to the emergency department (ED). Because non-cardiovascular comorbidities and declining health status may affect their life expectancy, management of these patients should start in the ED. This study evaluated the role of Gold Standards Framework (GSF) criteria for identifying patients with acute coronary syndromes (ACS) approaching end of life.

Methods

All consecutive patients admitted to the ED and hospitalised with a diagnosis of ACS between May 2012 and July 2012 were included. According to GSF criteria, patients were labelled as positive GSF status when they met at least one general criterion and two heart disease criteria; furthermore, traditional cardiovascular risk scores (the Global Registry for Acute Coronary Events (GRACE) score and the Age, Creatinine and Ejection Fraction (ACEF) score) were calculated and WHOQOL-BREF was assessed. Mortality and repeat hospitalisation due to cardiovascular and non-cardiovascular causes were evaluated at 3-month and 12-month follow-up.

Results

From a total of 156 patients with ACS enrolled, 22 (14%) had a positive GSF. A positive GSF was associated with higher rate of non-cardiovascular events (22.7% vs 6.7%; p=0.03) at 3 months and higher rates of both cardiovascular and non-cardiovascular events (36% vs 16.4%; p=0.04 and 27.3% vs 6.7%; p=0.009, respectively) at 12 months. In multivariate analysis, an in-hospital GRACE score was a predictor of cardiovascular events, while a positive GSF independently predicted non-cardiovascular events.

Conclusions

The GSF score independently predicts non-cardiovascular events in patients presenting with ACS and may be used along with traditional cardiovascular risk scores in choosing wisely the most appropriate treatment. The present results need to be externally validated on larger samples.
Scald burns in children under 3 years: an analysis of NEISS narratives to inform a scald burn prevention program
Authors: Shields Wendy C , McDonald Eileen M , Pfisterer Kaitlin , Gielen Andrea C
Published: May 2015

Background objectives

To determine the incidence of paediatric scald burns for children under 3 years of age treated in US hospital emergency departments. To quantify injury patterns associated with scald burns to inform prevention recommendation messaging.

Methods

The National Electronic Injury Surveillance System (NEISS) coding manual was reviewed for cause of injury. Its database was queried to identify cases among patients up to age 3 years old with a diagnosis of scald burns between 1 January 2009 and 31 December 2012. The resulting data set was downloaded and case narratives were reviewed to identify injury patterns associated with scald burns.

Results

The NEISS query identified 2104 scald burn cases between 2009 and 2012, yielding a national estimate of 11 028 scald burns in children younger than 3 years old annually. The analysis of the case narratives resulted in the identification of six precipitating and/or contributing factors including: grabbed/pulled, cooking, bathing, consuming, appliance and other.

Conclusions

NEISS is a valuable tool to identify scald burn risks. The NEISS data system provided an opportunity to identify and examine scald burns in children under 3 years of age. Interpretation of NEISS results is limited due to the lack of consistency and detail in narratives about the injury event. Nevertheless, the information that was available on precipitating and/or contributing factors suggests that caretakers should test the temperature of their water heaters, test bath water before bathing children and be made aware of risk of scalds from hot liquids so that they exercise close supervision of children.
High intensity of cytoplasmic peroxiredoxin VI expression is associated with adverse outcome in diffuse large B-cell lymphoma independently of International Prognostic Index
Authors: Kuusisto Milla Elvi Linnea , Haapasaari Kirsi-Maria , Turpeenniemi-Hujanen Taina , Jantunen Esa , Soini Ylermi , Peroja Pekka , Bloigu Risto , Karihtala Peeter , Kuittinen Outi
Published: May 2015

Aims

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially fatal disease. Prediction of risk of relapse is based on clinical markers. There is a need for more accurate biomarkers to select patients for more aggressive first-line treatments. Peroxiredoxins (Prxs) are a family of potent antioxidant proteins. Their prognostic role in DLBCL is unknown.

Methods

Altogether, 103 diagnostic biopsy samples from patients with DLBCL were immunohistochemically stained for Prxs I, II, III, V and VI.

Results

Strong Prx VI expression was associated with the presence of B-symptoms. There were no other significant associations with traditional risk factors. Five-year disease-specific survival was 68.6% in patients with high cytoplasmic Prx VI intensity vs 97.0% in those with low intensity. In multivariate analysis, high Prx VI expression (HR 12.846, 95% CI 1.722 to 95.807, p=0.013) was an independent risk factor of lymphoma-associated death not related to International Prognostic Index score (HR 2.514, 95% CI 1.040 to 6.073, p=0.041).

Conclusions

High intensity of cytoplasmic Prx VI expression in pretreatment DLBCL samples predicts worse outcome in patients with DLBCL. Whether Prx VI is associated with chemoresistance, and therefore a poorer outcome, needs to be evaluated. If Prx VI is a predictive marker and it proves causality, it would be crucial to study Prx VI ability to become a target enzyme for treatment.
u-CARE: user-friendly Comprehensive Antibiotic resistance Repository ofEscherichia coli
Authors: Saha Saurav B , Uttam Vishwas , Verma Vivek
Published: May 2015

Background and aims

Despite medical advancements,Escherichia coli-associated infections remain a major public health concern and although an abundant information aboutE. coliand its antibiotic resistance mechanisms is available, no effective tool exists that integrates gene and genomic data in context to drug resistance, thus raising a need to develop a repository that facilitates integration and assimilation of factors governing drug resistance inE. coli.

Descriptions

User-friendly Comprehensive Antibiotic resistance Repository ofEscherichia coli(u-CARE) is a manually curated catalogue of 52 antibiotics with reported resistance, 107 genes, transcription factors and single nucleotide polymorphism (SNPs) involved in multiple drug resistance of this pathogen. Each gene page provides detailed information about its resistance mechanisms, while antibiotic page consists of summary, chemical description and structural descriptors with links to external public databases like GO, CDD, DEG, Ecocyc, KEGG, Drug Bank, PubChem and UniProt. Moreover, the database integrates this reductive information to holistic data such as strain-specific and segment-specific pathogenic islands and operons. In addition, the database offers rich user interface for the visualisation and retrieval of information using various search criteria such as sequence, keyword, image and class search.

Conclusions

u-CARE is aimed to cater to the needs of researchers working in the field of antimicrobial drug resistance with minimal knowledge of bioinformatics. This database is also intended as a guide book to medical practitioners to avoid use of antibiotics against which resistance has already been reported inE. coli.The database is available from:http://www.e-bioinformatics.net/ucare
Impact of changes in mode of travel to work on changes in body mass index: evidence from the British Household Panel Survey
Authors: Martin Adam , Panter Jenna , Suhrcke Marc , Ogilvie David
Published: May 2015

Background

Active commuting is associated with various health benefits, but little is known about its causal relationship with body mass index (BMI).

Methods

We used cohort data from three consecutive annual waves of the British Household Panel Survey, a longitudinal study of nationally representative households, in 2004/2005 (n=15 791), 2005/2006 and 2006/2007. Participants selected for the analyses (n=4056) reported their usual main mode of travel to work at each time point. Self-reported height and weight were used to derive BMI at baseline and after 2 years. Multivariable linear regression analyses were used to assess associations between switching to and from active modes of travel (over 1 and 2 years) and change in BMI (over 2 years) and to assess dose–response relationships.

Results

After adjustment for socioeconomic and health-related covariates, the first analysis (n=3269) showed that switching from private motor transport to active travel or public transport (n=179) was associated with a significant reduction in BMI compared with continued private motor vehicle use (n=3090; −0.32 kg/m2, 95% CI −0.60 to −0.05). Larger adjusted effect sizes were associated with switching to active travel (n=109; −0.45 kg/m2, −0.78 to −0.11), particularly among those who switched within the first year and those with the longest journeys. The second analysis (n=787) showed that switching from active travel or public transport to private motor transport was associated with a significant increase in BMI (0.34 kg/m2, 0.05 to 0.64).

Conclusions

Interventions to enable commuters to switch from private motor transport to more active modes of travel could contribute to reducing population mean BMI.
Beam Buckling Analysis by Nonlocal Integral Elasticity Finite Element Method
Authors: Taghizadeh M. , Ovesy H. R. , Ghannadpour S. A. M.
Published: May 2015

In this study, a finite element method (FEM) based on the size dependent nonlocal integral elasticity theory is implemented for buckling analysis of nanoscaled beams with various boundary conditions. The method is based on the principle of total potential energy. The variations of buckling load with respect to the scaling effect parameter and to the length-to-thickness ratio are investigated. Furthermore, the effect of attenuation function type on the buckling load is examined. The results are compared with the corresponding solutions of governing stability equations which are derived in the context of nonlocal differential elasticity theory. It is found that the small scale coefficient has a noticeable effect on the buckling load of nanobeams.
Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function
Authors: Sussan Thomas E. , Gajghate Sachin , Chatterjee Samit , Mandke Pooja , McCormick Sarah , Sudini Kuladeep , Kumar Sarvesh , Breysse Patrick N. , Diette Gregory B. , Sidhaye Venkataramana K. , Biswal Shyam
Published: May 2015

Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 ( Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress. We previously demonstrated that Nrf2-deficient mice have heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus, and airway hyperresponsiveness (AHR) (Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. J Exp Med 202: 47–59, 2005). Here we dissected the role of Nrf2 in lung epithelial cells and tested whether genetic or pharmacological activation of Nrf2 reduces allergic asthma in mice. Cell-specific activation of Nrf2 in club cells of the airway epithelium significantly reduced allergen-induced AHR, inflammation, mucus, Th2 cytokine secretion, oxidative stress, and airway leakiness and increased airway levels of tight junction proteins zonula occludens-1 and E-cadherin. In isolated airway epithelial cells, Nrf2 enhanced epithelial barrier function and increased localization of zonula occludens-1 to the cell surface. Pharmacological activation of Nrf2 by 2-trifluoromethyl-2′-methoxychalone during the allergen challenge was sufficient to reduce allergic inflammation and AHR. New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility.
A Longitudinal Computed Tomography Imaging in the Diagnosis of Gallbladder Cancer
Authors: Iwama Atsuko , Yamazaki Shintaro , Mitsuka Yusuke , Yoshida Nao , Moriguchi Masamichi , Higaki Tokio , Takayama Tadatoshi
Published: May 2015

Background/Aim. To assess whether the diagnostic power of longitudinal multiplanar reformat (MPR) images is superior to that of conventional horizontal images for gallbladder cancer (GBC).Methods.Between 2006 and 2010, a total of 54 consecutive patients with preoperatively diagnosed gallbladder neoplasms located in gallbladder bed were analyzed. These patients underwent cholecystectomy with resection of the adjacent liver parenchyma. The patients were divided into the GBC group (n=30) and the benign group (n=24). MPR images obtained by preoperative multidetector row CT (MDCT) were assessed.Results.Mucosal line was more significantly disrupted in GBC group than that in benign group (93% [28/30 patients] versus 13% [3/24],p<0.001). Maximum (9.3 [4.2–24.8] versus 7.0 mm [2.4–22.6],p=0.29) and minimum (1.2 [1.0–2.4] versus 1.3 mm [1.0–2.6],p=0.23) wall thicknesses on a single MPR plane did not differ significantly; however, the wall thickness ratio (max/min) differed significantly (6.8 [1.92–14.0] versus 5.83 [2.3–8.69],p=0.04). Partial liver enhancement adjacent to tumor on longitudinal images was more common in GBC (40.0% [12/30 patients] versus 12.5% [3/24],p=0.03). Mucosal line disruption was the most reliable independent predictor of diagnosis (odds ratio, 8.5; 95% CI, 5.99–28.1,p<0.001).Conclusion.Longitudinal MPR images are more useful than horizontal images for the diagnosis of GBC.
National Helpline for Problem Gambling: A Profile of Its Users’ Characteristics
Authors: Bastiani Luca , Fea Maurizio , Potente Roberta , Luppi Claudia , Lucchini Fabio , Molinaro Sabrina
Published: May 2015

Gambling has seen a significant increase in Italy in the last 10 years and has rapidly become a public health issue, and for these reasons the first National Helpline for Problem Gambling (GR-Helpline) has been established. The aims of this study are to describe the GR-Helpline users’ characteristics and to compare the prevalence rates of the users with those of moderate-risk/problematic gamblers obtained from the national survey (IPSAD 2010-2011). Statistical analysis was performed on data obtained from the counselling sessions (phone/e-mail/chat) carried out on 5,805 users (57.5% gamblers; 42.5% families/friends). This confirms that the problems related to gambling concern not only the gamblers but also their families and friends. Significant differences were found between gamblers and families/friends involving gender (74% of gamblers were male; 76.9% of families/friends were female), as well as age-classes and geographical area. Female gamblers had a higher mean age (47.3 versus 40.2 years) and preferred nonstrategy-based games. Prevalence rates of GR-Helpline users and of moderate risk/problematic gamblers were correlated (Rho = 0.58;p=0.0113). The results highlight the fact that remote access to counselling can be an effective means of promoting treatment for problem gamblers who do not otherwise appeal directly for services.
Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer
Authors: Takeuchi Shintaro , Baghdadi Muhammad , Tsuchikawa Takahiro , Wada Haruka , Nakamura Toru , Abe Hirotake , Nakanishi Sayaka , Usui Yuu , Higuchi Kohtaro , Takahashi Mizuna , Inoko Kazuho , Sato Syoki , Takano Hironobu , Shichinohe Toshiaki , Seino Ken-ichiro , Hirano Satoshi
Published: May 2015

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancies. PDAC builds a tumor microenvironment that plays critical roles in tumor progression and metastasis. However, the relationship between chemotherapy and modulation of PDAC-induced tumor microenvironment remains poorly understood. In this study, we report a role of chemotherapy-derived inflammatory response in the enrichment of PDAC microenvironment with immunosuppressive myeloid cells. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a major cytokine associated with oncogenic KRAS in PDAC cells. GM-CSF production was significantly enhanced in various PDAC cell lines or PDAC tumor tissues from patients after treatment with chemotherapy, which induced the differentiation of monocytes into myeloid-derived suppressor cells (MDSC). Furthermore, blockade of GM-CSF with monoclonal antibodies helped to restore T-cell proliferation when cocultured with monocytes stimulated with tumor supernatants. GM-CSF expression was also observed in primary tumors and correlated with poor prognosis in PDAC patients. Together, these results describe a role of GM-CSF in the modification of chemotherapy-treated PDAC microenvironment and suggest that the targeting of GM-CSF may benefit PDAC patients' refractory to current anticancer regimens by defeating MDSC-mediated immune escape. Cancer Res; 75(13); 2629–40. ©2015 AACR.
Oral Propranolol: A New Treatment for Infants with Retinopathy of Prematurity?
Authors: Bührer Christoph , Bassler Dirk
Published: May 2015

Introduction: Oral propranolol has improved the treatment of infantile hemangiomas, and a pediatric oral solution of propranolol has recently been licensed in the USA and Europe. In very preterm infants, infantile hemangiomas are associated with the occurrence of retinopathy of prematurity (ROP), and both diseases share a peculiar time course, featuring a lag phase after birth followed by rapid growth and then gradual regression. Objectives: To identify clinical studies evaluating the use of oral propranolol in preterm infants with ROP. Results: Two small bicentric, pilot, randomized controlled trials found a nonsignificant reduction of ROP requiring intervention by laser treatment or bevacizumab injection of similar magnitude. Together, 6 of 35 (17%) infants who had been receiving oral propranolol underwent ROP intervention, as opposed to 14 of 36 (39%) controls (relative risk 0.42, 95% CI: 0.15-1.16). Randomized controlled trials are ongoing that investigate early preventive oral propranolol starting at 1 week of age and propranolol eye drops in preterm infants with stage 2 ROP. Conclusion: Further, large interventional studies are required to determine the clinical benefit-risk ratio of oral propranolol to prevent vision-threatening ROP in very preterm infants.