bluuebunny/crossref_metadata_2025_split huggingface dataset:
mTORC2 controls Th9 polarization and allergic airway inflammation
Authors: Chen H. , Zhang L. , Wang P. , Su H. , Wang W. , Chu Z. , Zhang L. , Zhang X. , Zhao Y. 
Published: March 2017

AbstractBackgroundT helper type 9 (Th9) cells, a subpopulation of CD4+ T cells, play a critical role in the pathogenesis of allergic airway inflammation. However, it remains unknown whether mTORC2 regulates Th9 differentiation or function during allergic inflammation.MethodsT‐cell‐specific Rictor‐deficient mice, a mouse model of allergic airway inflammation induced by ovalbumin (OVA) sensitization and a mouse model of adoptive transfer of induced Th9 cells, were used to address the roles of mTORC2 in the pathogenesis of allergic airway inflammation. The in vitro Th9 induction, multiple colors flow cytometry, real‐time PCR, and Western blots were used to investigate the molecular effects of mTORC2 in Th9 induction.ResultsThe differentiation of naïve CD4+ T cells into Th9 cells was significantly diminished in the absence of Rictor, the core component of mTORC2. Using a mouse model of allergic airway inflammation induced by OVA sensitization, T‐cell‐specific Rictor‐deficient mice show much less severe allergic airway inflammation characterized by decreased pathological alterations and fibrosis of the lungs, which was accompanied with reduced Th9 differentiation and infiltration. Importantly, the isolated Rictor‐deficient Th9 cells mediate less severe allergic pathogenesis upon adoptive transfer. Rictor deficiency impairs Th9 cell differentiation by reducing IRF4 expression rather than affecting Foxo1/Foxo3a transcriptional activity, which is likely due to decreased Akt and/or STAT6 activation.ConclusionsThese findings uncover a novel role of mTORC2 in Th9 cell differentiation and may have important implications for therapeutic intervention of allergic diseases.
NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy
Authors: Loukovaara Sirpa , Piippo Niina , Kinnunen Kati , Hytti Maria , Kaarniranta Kai , Kauppinen Anu 
Published: March 2017

AbstractPurposeInnate immunity and dysregulation of inflammatory processes play a role in vascular diseases like atherosclerosis or diabetes. Nucleotide‐binding domain and Leucine‐rich repeat Receptor containing a Pyrin domain 3 (NLRP3) inflammasomes are pro‐inflammatory signalling complexes that were found in 2002. In addition to pathogens and other extracellular threats, they can be activated by various endogenous danger signals. The purpose of this study was to find out whether NLRP3 activation occurs in patients with sight‐threatening forms of diabetic retinopathy (DR).MethodsInflammasome components NLRP3 and caspase‐1, inflammasome‐related pro‐inflammatory cytokines IL‐1β and IL‐18, vascular endothelial growth factor (VEGF), acute‐phase cytokines TNF‐α and IL‐6, as well as adaptive immunity‐related cytokine interferon gamma (IFN‐γ) were measured from the vitreous samples of 15 non‐proliferative diabetic retinopathy (non‐PDR) and 23 proliferative diabetic retinopathy (PDR) patients using the enzyme‐linked immunosorbent assay (ELISA) method. The adaptor protein apoptosis‐associated speck‐like protein containing a CARD (ASC) was determined using the Western blot technique.ResultsInflammasome components were present in the vitreous of DR patients. Along with VEGF, the levels of caspase‐1 and IL‐18 were significantly increased, especially in PDR eyes. Interestingly, clearly higher levels of NLRP3 were found in the PDR eyes with tractional retinal detachment (TRD) than from PDR eyes with fully attached retina. There were no significant differences in the amounts of IL‐1β, TNF‐α, IL‐6, and IFN‐γ that were detectable in the vitreous of both non‐PDR and PDR patients.ConclusionOur results suggest that NLRP3 inflammasome activation can be associated especially with the pathogenesis of PDR. The lack of differences in TNF‐α, IL‐6, and IFN‐γ also alludes that acute inflammation or T‐cell‐mediated responses do not dominate in PDR pathogenesis.
Psychotropics and weak opioid analgesics in plasma samples of older hip fracture patients – detection frequencies and consistency with drug records
Authors: Waade Ragnhild Birkeland , Molden Espen , Martinsen Mette Irene , Hermann Monica , Ranhoff Anette Hylen 
Published: March 2017

AimsTo determine use of psychotropic drugs and weak opioids in hip fracture patients by analysing plasma samples at admission, and compare detected drug frequencies with prescription registry data and drug records.MethodsPlasma from 250 hip fracture patients aged ≥65 years sampled at hospital admission were analysed by ultra‐performance liquid chromatography–tandem mass spectrometry methods for detection of psychotropic drugs and weak opioid analgesics (alcohol also determined). Odds ratios for drugs detected in plasma of hip fracture patients vs. prescription frequencies of the same drugs in an age‐, time‐ and region‐matched reference population were calculated. Moreover, recorded and measured drugs were compared.ResultsPsychotropic drugs and/or weak opioid analgesics were detected in 158 (63%) of the patients (median age 84 years; 76% females), while alcohol was found in 19 patients (7.6%). The occurrence of diazepam (odds ratio 1.6; 95% confidence interval 1.1–2.4), nitrazepam (2.3; 1.3–4.1), selective serotonin reuptake inhibitors (1.9; 1.3–2.9) and mirtazapine (2.3; 1.2–4.3) was significantly higher in plasma samples of hip fracture patients than in prescription data from the reference population. Poor consistency between recorded and measured drugs was disclosed for z‐hypnotics and benzodiazepines; e.g. diazepam was detected in 29 (11.6%), but only recorded in six (2.4%) of the patients.ConclusionsPlasma analysis shows that use of antidepressants and benzodiazepines in hip fracture patients is significantly more frequent than respective prescription frequencies in the general elderly population. Moreover, consistency between recorded and actual use of psychotropic fall‐risk drugs is poor at hospital admission of hip fracture patients.
Sequence Robust Association Test for Familial Data
Authors: Dai Wei , Yang Ming , Wang Chaolong , Cai Tianxi 
Published: March 2017

Summary
Genome-wide association studies (GWAS) and next generation sequencing studies (NGSS) are often performed in family studies to improve power in identifying genetic variants that are associated with clinical phenotypes. Efficient analysis of genome-wide studies with familial data is challenging due to the difficulty in modeling shared but unmeasured genetic and/or environmental factors that cause dependencies among family members. Existing genetic association testing procedures for family studies largely rely on generalized estimating equations (GEE) or linear mixed-effects (LME) models. These procedures may fail to properly control for type I errors when the imposed model assumptions fail. In this article, we propose the Sequence Robust Association Test (SRAT), a fully rank-based, flexible approach that tests for association between a set of genetic variants and an outcome, while accounting for within-family correlation and adjusting for covariates. Comparing to existing methods, SRAT has the advantages of allowing for unknown correlation structures and weaker assumptions about the outcome distribution. We provide theoretical justifications for SRAT and show that SRAT includes the well-known Wilcoxon rank sum test as a special case. Extensive simulation studies suggest that SRAT provides better protection against type I error rate inflation, and could be much more powerful for settings with skewed outcome distribution than existing methods. For illustration, we also apply SRAT to the familial data from the Framingham Heart Study and Offspring Study to examine the association between an inflammatory marker and a few sets of genetic variants.
Outcome-Adaptive Lasso: Variable Selection for Causal Inference
Authors: Shortreed Susan M. , Ertefaie Ashkan 
Published: March 2017

SummaryMethodological advancements, including propensity score methods, have resulted in improved unbiased estimation of treatment effects from observational data. Traditionally, a “throw in the kitchen sink” approach has been used to select covariates for inclusion into the propensity score, but recent work shows including unnecessary covariates can impact both the bias and statistical efficiency of propensity score estimators. In particular, the inclusion of covariates that impact exposure but not the outcome, can inflate standard errors without improving bias, while the inclusion of covariates associated with the outcome but unrelated to exposure can improve precision. We propose the outcome-adaptive lasso for selecting appropriate covariates for inclusion in propensity score models to account for confounding bias and maintaining statistical efficiency. This proposed approach can perform variable selection in the presence of a large number of spurious covariates, that is, covariates unrelated to outcome or exposure. We present theoretical and simulation results indicating that the outcome-adaptive lasso selects the propensity score model that includes all true confounders and predictors of outcome, while excluding other covariates. We illustrate covariate selection using the outcome-adaptive lasso, including comparison to alternative approaches, using simulated data and in a survey of patients using opioid therapy to manage chronic pain.
Reintroduction of anti‐thrombotic therapy after a gastrointestinal haemorrhage: if and when?
Authors: Scott Martin J. , Veitch Andrew , Thachil Jecko 
Published: March 2017

SummaryGastrointestinal haemorrhage is a common clinical scenario and, in those using antithrombotic agents, the risk is significantly increased. Management of these patients, in terms of initial resuscitation is well established and numerous guidelines exist in this area. However, few studies have addressed the subsequent dilemma of if and when antithrombotic agents should be reintroduced. Consequently, practice is variable and not necessarily evidenced‐based. Overall, for patients that are either anticoagulated or using antiplatelet drugs for secondary prophylaxis, there is a clear benefit to restarting these agents. However, there is limited data to guide when this should occur. For individuals at low risk of re‐bleeding, current guidelines suggest single agent aspirin can be continued without interruption, assuming haemostatic control has been confirmed endoscopically. For those at higher bleeding risk, aspirin should be withheld, but reintroduced early (within 3 days of index endoscopy). However, randomised evidence is lacking, as are studies including more modern agents or combined anticoagulant/ antiplatelet regimens. As such, guidance statements are limited and management suggestions must be extrapolated from clinical trials, retrospective studies and data relating specifically to warfarin and aspirin. The intention of this review is to summarise what evidence is available and, where this is lacking, suggest pragmatic management options based on a risk‐benefit assessment of thromboembolism and recurrent bleeding.
What do Demand‐Control and Effort‐Reward work stress questionnaires really measure? A discriminant content validity study of relevance and representativeness of measures
Authors: Bell Cheryl , Johnston Derek , Allan Julia , Pollard Beth , Johnston Marie 
Published: March 2017

ObjectivesThe Demand‐Control (DC) and Effort‐Reward Imbalance (ERI) models predict health in a work context. Self‐report measures of the four key constructs (demand, control, effort, and reward) have been developed and it is important that these measures have good content validity uncontaminated by content from other constructs. We assessed relevance (whether items reflect the constructs) and representativeness (whether all aspects of the construct are assessed, and all items contribute to that assessment) across the instruments and items.MethodsTwo studies examined fourteen demand/control items from the Job Content Questionnaire and seventeen effort/reward items from the Effort‐Reward Imbalance measure using discriminant content validation and a third study developed new methods to assess instrument representativeness. Both methods use judges’ ratings and construct definitions to get transparent quantitative estimates of construct validity. Study 1 used dictionary definitions while studies 2 and 3 used published phrases to define constructs.ResultsOverall, 3/5 demand items, 4/9 control items, 1/6 effort items, and 7/11 reward items were uniquely classified to the appropriate theoretical construct and were therefore ‘pure’ items with discriminant content validity (DCV). All pure items measured a defining phrase. However, both the DC and ERI assessment instruments failed to assess all defining aspects.ConclusionsFinding good discriminant content validity for demand and reward measures means these measures are usable and our quantitative results can guide item selection. By contrast, effort and control measures had limitations (in relevance and representativeness) presenting a challenge to the implementation of the theories.
Statement of contribution

What is already known on this subject?

While the reliability and construct validity of Demand‐Control and Effort‐Reward‐Imbalance (DC and ERI) work stress measures are routinely reported, there has not been adequate investigation of their content validity. This paper investigates their content validity in terms of both relevance and representativeness and provides a model for the investigation of content validity of measures in health psychology more generally.

What does this study add?

A new application of an existing method, discriminant content validity, and a new method of assessing instrument representativeness.

‘Pure’ DC and ERI items are identified, as are constructs that are not fully represented by their assessment instruments.

The findings are important for studies attempting to distinguish between the main DC and ERI work stress constructs.

The quantitative results can be used to guide item selection for future studies.
Cerebellar compartmentation of prion pathogenesis
Authors: Ragagnin Audrey , Ezpeleta Juliette , Guillemain Aurélie , Boudet‐Devaud François , Haeberlé Anne‐Marie , Demais Valérie , Vidal Catherine , Demuth Stanislas , Béringue Vincent , Kellermann Odile , Schneider Benoit , Grant Nancy J. , Bailly Yannick 
Published: March 2017

AbstractIn prion diseases, the brain lesion profile is influenced by the prion “strain” properties, the invasion route to the brain, and still unknown host cell‐specific parameters. To gain insight into those endogenous factors, we analyzed the histopathological alterations induced by distinct prion strains in the mouse cerebellum. We show that 22L and ME7 scrapie prion proteins (PrP22L, PrPME7), but not bovine spongiform encephalopathy PrP6PB1, accumulate in a reproducible parasagittal banding pattern in the cerebellar cortex of infected mice. Such banding pattern of PrP22L aggregation did not depend on the neuroinvasion route, but coincided with the parasagittal compartmentation of the cerebellum mostly defined by the expression of zebrins, such as aldolase C and the excitatory amino acid transporter 4, in Purkinje cells. We provide evidence that Purkinje cells display a differential, subtype‐specific vulnerability to 22L prions with zebrin‐expressing Purkinje cells being more resistant to prion toxicity, while in stripes where PrP22L accumulated most zebrin‐deficient Purkinje cells are lost and spongiosis accentuated. In addition, in PrP22L stripes, enhanced reactive astrocyte processes associated with microglia activation support interdependent events between the topographic pattern of Purkinje cell death, reactive gliosis and PrP22L accumulation. Finally, we find that in preclinically‐ill mice prion infection promotes at the membrane of astrocytes enveloping Purkinje cell excitatory synapses, upregulation of tumor necrosis factor‐α receptor type 1 (TNFR1), a key mediator of the neuroinflammation process. These overall data show that Purkinje cell sensitivity to prion insult is locally restricted by the parasagittal compartmentation of the cerebellum, and that perisynaptic astrocytes may contribute to prion pathogenesis through prion‐induced TNFR1 upregulation.
Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety‐related and substance abuse disorders
Authors: Lee Jonathan L C , Bertoglio Leandro J , Guimarães Francisco S , Stevenson Carl W 
Published: March 2017

Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour, but the inappropriate expression of conditioned responding to fear‐ and drug‐related stimuli can develop into anxiety‐related and substance abuse disorders respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non‐psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via 5‐HT1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. There is also accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing indicating that it reduces learned fear in paradigms that are translationally relevant to phobias and post‐traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in a lasting reduction of learned fear. Recent studies have also begun to elucidate the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. The findings suggest that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here, we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use as a treatment for anxiety‐related and substance abuse disorders.Linked ArticlesThis article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc
Imagining Duckland: Postnationalism, waterfowl migration, and ecological commons
Authors: Hatvany Matthew G. 
Published: March 2017

Foreign place names reflecting the names of American hunter‐conservationists and places mark the geography of Western Canada. This exogenous place naming dates to the 1930s when one of Canada's most successful NGOs—Ducks Unlimited Canada—launched “The Lake that Waits” project. Emerging out of the Dust Bowl and declining waterfowl populations, the project combined geographical imagination, foreign toponyms, and ecological knowledge to incite American waterfowlers to invest in the rehabilitation of Canadian wetlands. It is insinuated that this renaming re‐colonized in the name of nature conservation. When theorized within a postnational ecological and historical context, however, the use of foreign toponyms may be interpreted as a means to positively influence perceptions of identity and sense of place. It was a social construction of nature encouraging recognition of the shared ethical responsibilities of continental waterfowlers who needed to re‐envision waterfowl migration within an ecological common—Duckland. Renaming was a means to effect both environmental and cultural change resulting in the conservation of millions of acres of waterfowl habitat, leaving an enduring mark on North American geography.Imaginer Canardia : le postnationalisme, la migration de la sauvagine et le collectif écologiqueLes toponymes étrangers inspirés des noms de chasseurs‐écologistes américains et de lieux américains sont un trait caractéristique de la géographie de l'Ouest canadien. Cette façon exogène de désigner les lieux remonte aux années 1930, à l'époque du lancement du projet « The Lake that Waits » par Canards Illimités Canada. Le projet a débuté lors des années du Dust Bowl et du déclin important des populations de sauvagine. Il conjuguait l'imaginaire géographique, les toponymes étrangers et les savoirs écologiques afin d'inciter les sauvaginiers américains à investir dans la réhabilitation des milieux humides canadiens. Certains font allusion au fait que ces changements de nom représentent une forme de recolonisation. Toutefois, en prenant une perspective théorique postnationale, l'utilisation de toponymes étrangers serait alors vue comme un moyen d'influencer positivement les sentiments d'appartenance aux lieux. Il s'agissait d'une construction sociale de la nature qui favorise la reconnaissance du partage des responsabilités éthiques des sauvaginiers qui devaient réimaginer la migration de la sauvagine au sein d'un collectif écologique — Canardia. Grâce aux changements de toponymes, les conditions environnementales et culturelles ont pu évoluer, ce qui a permis de conserver des millions d'acres de l'habitat de la sauvagine et de laisser une marque durable sur la géographie nord‐américaine.
Public attitudes towards Indigeneity in Canadian prairie urbanism
Authors: Walker Ryan , Berdahl Loleen , Lashta Erin , Newhouse David , Belanger Yale 
Published: March 2017

Prairie cities have large and growing Indigenous populations. The great resurgence of strong Indigenous cultures in Canada should foretell the impact Indigeneity will have over coming years across the full spectrum of urban geography. The study uses original 2014 survey data collected from seven prairie cities to examine the following question: What does the non‐Indigenous majority public think about increasing the role of Indigeneity in the procedural and material approaches to urbanism in prairie cities? Based on our findings we suggest that public attitudes among the non‐Indigenous populations of prairie cities are changing and becoming more positive towards trying new approaches to enabling Indigenous urbanism. Support is somewhat greater for municipal‐Indigenous governance options than for specific actions to infuse Indigeneity into the design and naming of public spaces.L'attitude du public face à l'indigénisme dans l'urbanisme des Prairies canadiennesLa population indigène qui habite dans les villes des Prairies est nombreuse et grandissante. La forte recrudescence des cultures indigènes au Canada permettrait d'anticiper l'impact que l'indigénisme aura au cours des prochaines années sur l'ensemble de la géographie urbaine. Cet article propose d'explorer la question qui suit à partir des données originales d'enquête recueillies dans sept villes des Prairies en 2014: qu'est‐ce que les personnes de la majorité non indigène pensent de l'augmentation du rôle de l'indigénisme dans les démarches opérationnelles et substantielles de l'urbanisme des villes des Prairies? Les constats qui se dégagent de nos travaux montrent que l'attitude du public chez les populations non autochtones des villes des Prairies évolue et devient plus encline à essayer de nouvelles approches en matière d'urbanisme indigène. On est plutôt partisan des modes de gouvernance municipale indigène que des actions spécifiques visant à incorporer l'indigénisme dans la conception et la toponymie des espaces publics.