The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

The Epistemic Status of Processing Fluency as Source for Judgments of Truth

This article combines findings from cognitive psychology on the role of processing fluency in truth judgments with epistemological theory on justification of belief. We first review evidence that repeated exposure to a statement increases the subjective ease with which that statement is processed. This increased processing fluency, in turn, increases the probability that the statement is judged to be true. The basic question discussed here is whether the use of processing fluency as a cue to truth is epistemically justified. In the present analysis, based on Bayes’ Theorem, we adopt the reliable-process account of justification presented by Goldman (1986) and show that fluency is a reliable cue to truth, under the assumption that the majority of statements one has been exposed to are true. In the final section, we broaden the scope of this analysis and discuss how processing fluency as a potentially universal cue to judged truth may contribute to cultural differences in commonsense beliefs

Mirroring Intentional Forgetting in a Shared-Goal Learning Situation

Background: Intentional forgetting refers to the surprising phenomenon that we can forget previously successfully encoded memories if we are instructed to do so. Here, we show that participants cannot only intentionally forget episodic memories but they can also mirror the ‘‘forgetting performance’ ’ of an observed model. Methodology/Principal Findings: In four experiments a participant observed a model who took part in a memory experiment. In Experiment 1 and 2 observers saw a movie about the experiment, whereas in Experiment 3 and 4 the observers and the models took part together in a real laboratory experiment. The observed memory experiment was a directed forgetting experiment where the models learned two lists of items and were instructed either to forget or to remember the first list. In Experiment 1 and 3 observers were instructed to simply observe the experiment (‘‘simple observation’ ’ instruction). In Experiment 2 and 4, observers received instructions aimed to induce the same learning goal for the observers and the models (‘‘observation with goal-sharing’ ’ instruction). A directed forgetting effect (the reliably lower recall of to-be-forgotten items) emerged only when models received the ‘‘observation with goal-sharing’ ’ instruction (P,.001 in Experiment 2, and P,.05 in Experiment 4), and it was absent when observers received the ‘‘simple observation’’ instruction (P..1 in Experiment 1 and 3). Conclusion: If people observe another person with the same intention to learn, and see that this person is instructed t

The possible benefits of reduced errors in the motor skills acquisition of children

An implicit approach to motor learning suggests that relatively complex movement skills may be better acquired in environments that constrain errors during the initial stages of practice. This current concept paper proposes that reducing the number of errors committed during motor learning leads to stable performance when attention demands are increased by concurrent cognitive tasks. While it appears that this approach to practice may be beneficial for motor learning, further studies are needed to both confirm this advantage and better understand the underlying mechanisms. An approach involving error minimization during early learning may have important applications in paediatric rehabilitation

Different Patterns of Inappropriate Antimicrobial Use in Surgical and Medical Units at a Tertiary Care Hospital in Switzerland: A Prevalence Survey

Audits of individual patient care provide important data to identify local problems in antimicrobial prescription practice. In our study, antimicrobial prescriptions without indication, and divergence from institutional guidelines were frequent errors. Based on these results, we will tailor education, amend institutional guidelines and further develop the infectious diseases consultation service

Improving implementation of evidence-based practice in mental health service delivery: protocol for a cluster randomised quasi-experimental investigation of staff-focused values interventions

BACKGROUND: There is growing acceptance that optimal service provision for individuals with severe and recurrent mental illness requires a complementary focus on medical recovery (i.e., symptom management and general functioning) and personal recovery (i.e., having a ‘life worth living’). Despite significant research attention and policy-level support, the translation of this vision of healthcare into changed workplace practice continues to elude. Over the past decade, evidence-based training interventions that seek to enhance the knowledge, attitudes, and skills of staff working in the mental health field have been implemented as a primary redress strategy. However, a large body of multi-disciplinary research indicates disappointing rates of training transfer. There is an absence of empirical research that investigates the importance of worker-motivation in the uptake of desired workplace change initiatives. ‘Autonomy’ is acknowledged as important to human effectiveness and as a correlate of workplace variables like productivity, and wellbeing. To our knowledge, there have been no studies that investigate purposeful and structured use of values-based interventions to facilitate increased autonomy as a means of promoting enhanced implementation of workplace change. METHODS: This study involves 200 mental health workers across 22 worksites within five community-managed organisations in three Australian states. It involves cluster-randomisation of participants within organisation, by work site, to the experimental (values) condition, or the control (implementation). Both conditions receive two days of training focusing on an evidence-based framework of mental health service delivery. The experimental group receives a third day of values-focused intervention and 12 months of values-focused coaching. Well-validated self-report measures are used to explore variables related to values concordance, autonomy, and self-reported implementation success. Audits of work files and staff work samples are reviewed for each condition to determine the impact of implementation. Self-determination theory and theories of organisational change are used to interpret the data. DISCUSSION: The research adds to the current knowledge base related to worker motivation and uptake of workplace practice. It describes a structured protocol that aims to enhance worker autonomy for imposed workplace practices. The research will inform how best to measure and conceptualise transfer. These findings will apply particularly to contexts where individuals are not ‘volunteers’ in requisite change processes. TRIAL REGISTRATION: ACTRN: ACTRN12613000353796

Effects of Imatinib Mesylate (Gleevec) on Human Islet NF-kappaB Activation and Chemokine Production In Vitro

Imatinib Mesylate (Gleevec) is a drug that potently counteracts diabetes both in humans and in animal models for human diabetes. We have previously reported that this compound in human pancreatic islets stimulates NF-κB signaling and islet cell survival. The aim of this study was to investigate control of NF-κB post-translational modifications exerted by Imatinib and whether any such effects are associated with altered islet gene expression and chemokine production in vitro.Human islets were either left untreated or treated with Imatinib for different timepoints. IκB-α and NF-κB p65 phosphorylation and methylation were assessed by immunoblot analysis. Islet gene expression was assessed using a commercial Pathway Finder microarray kit and RT-PCR. Islet chemokine production was determined by flow cytometric bead array analysis.Human islet IκB-α and Ser276-p65 phosphorylation were increased by a 20 minute Imatinib exposure. Methylation of p65 at position Lys221 was increased after 60 min of Imatinib exposure and persisted for 3 hours. Microarray analysis of islets exposed to Imatinib for 4 hours revealed increased expression of the inflammatory genes IL-4R, TCF5, DR5, I-TRAF, I-CAM, HSP27 and IL-8. The islet release of IL-8 was augmented in islets cultured over night in the presence of Imatinib. Following 30 hours of Imatinib exposure, the cytokine-induced IκB-α and STAT1 phosphorylation was abolished and diminished, respectively. The cytokine-induced release of the chemokines MIG and IP10 was lower in islets exposed to Imatinib for 30 hours.Imatinib by itself promotes a modest activation of NF-κB. However, a prolonged exposure of human islets to Imatinib is associated with a dampened response to cytokines. It is possible that Imatinib induces NF-κB preconditioning of islet cells leading to lowered cytokine sensitivity and a mitigated islet inflammation

Similar or Different? The Role of the Ventrolateral Prefrontal Cortex in Similarity Detection

Patients with frontal lobe syndrome can exhibit two types of abnormal behaviour when asked to place a banana and an orange in a single category: some patients categorize them at a concrete level (e.g., “both have peel”), while others continue to look for differences between these objects (e.g., “one is yellow, the other is orange”). These observations raise the question of whether abstraction and similarity detection are distinct processes involved in abstract categorization, and that depend on separate areas of the prefrontal cortex (PFC). We designed an original experimental paradigm for a functional magnetic resonance imaging (fMRI) study involving healthy subjects, confirming the existence of two distinct processes relying on different prefrontal areas, and thus explaining the behavioural dissociation in frontal lesion patients. We showed that: 1) Similarity detection involves the anterior ventrolateral PFC bilaterally with a right-left asymmetry: the right anterior ventrolateral PFC is only engaged in detecting physical similarities; 2) Abstraction per se activates the left dorsolateral PFC