Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Date of Acceptance: 28/07/2015 The authors are grateful to the staff of the Medical Research Facility for their help with the animal care. This work was supported by the NHS Endowment fund 09/03 and the Wellcome Trust (WT080782MF). We thank Merck & Co. Inc., Rathway NJ, USA for the supply of DFU.Peer reviewedPublisher PD

Quantitative Analyses Reveal How Hypoxia Reconfigures the Proteome of Primary Cytotoxic T Lymphocytes

Metabolic and nutrient-sensing pathways play an important role in controlling the efficacy of effector T cells. Oxygen is a critical regulator of cellular metabolism. However, during immune responses T cells must function in oxygen-deficient, or hypoxic, environments. Here, we used high resolution mass spectrometry to investigate how the proteome of primary murine CD8+ cytotoxic T lymphocytes (CTLs) is reconfigured in response to hypoxia in vitro. We identified and quantified over 7,600 proteins and discovered that hypoxia increased the abundance of a selected number of proteins in CTLs. This included glucose transporters, metabolic enzymes, transcription factors, cytolytic effector molecules, checkpoint receptors and adhesion molecules. While some of these proteins may augment the effector functions of CTLs, others may limit their cytotoxicity. Moreover, we determined that hypoxia could inhibit IL-2-induced proliferation cues and antigen-induced pro-inflammatory cytokine production in CTLs. These data provide a comprehensive resource for understanding the magnitude of the CTL response to hypoxia and emphasise the importance of oxygen-sensing pathways for controlling CD8+ T cells. Additionally, this study provides new understanding about how hypoxia may promote the effector function of CTLs, while contributing to their dysfunction in some contexts

Neural signatures of cognitive flexibility and reward sensitivity following nicotinic receptor stimulation in dependent smokers : a randomized trial

IMPORTANCE Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment. OBJECTIVE To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task. DESIGN, SETTING, AND PARTICIPANTS Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016. MAIN OUTCOME AND MEASURES A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility. RESULTS The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P<.05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P<.05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline. CONCLUSIONS AND RELEVANCE There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others

Developing an evidence-based program sustainability training curriculum: A group randomized, multi-phase approach

Abstract Background The emergence of dissemination and implementation (D&I) science has driven a rapid increase in studies of how new scientific discoveries are translated and developed into evidence-based programs and policies. However, D&I science has paid much less attention to what happens to programs once they have been implemented. Public health programs can only deliver benefits if they reach maturity and sustain activities over time. In order to achieve the full benefits of significant investment in public health research and program development, there must be an understanding of the factors that relate to sustainability to inform development of tools and trainings to support strategic long-term program sustainability. Tobacco control programs, specifically, vary in their abilities to support and sustain themselves over time. As of 2018, most states still do not meet the CDC-recommended level for funding their TC program, allowing tobacco use to remain the leading cause of preventable disease and death in the USA. The purpose of this study is to empirically develop, test, and disseminate training programs to improve the sustainability of evidence-based state tobacco control programs and thus, tobacco-related health outcomes. Methods This paper describes the methods of a group randomized, multi-phase study that evaluates the empirically developed “Program Sustainability Action Planning Training” and technical assistance in US state-level tobacco control programs. Phase 1 includes developing the sustainability action planning training curriculum and technical assistance protocol and developing measures to assess long-term program sustainability. Phase 2 includes a group randomized trial to test the effectiveness of the training and technical assistance in improving sustainability outcomes in 24 state tobacco control programs (12 intervention, 12 comparison). Phase 3 includes the active dissemination of final training curricula materials to a broader public health audience. Discussion Empirical evidence has established that program sustainability can improve through training and technical assistance; however, to our knowledge, no evidence-based sustainability training curriculum program exists. Therefore, systematic methods are needed to develop, test, and disseminate a training that improves the sustainability of evidence-based programs. Trial registration NCT03598114. Registered 25 July 2018—retrospectively registered

A national survey of 'inactive' physicians in the United States of America: enticements to reentry

<p>Abstract</p> <p>Background</p> <p>Physicians leaving and reentering clinical practice can have significant medical workforce implications. We surveyed inactive physicians younger than typical retirement age to determine their reasons for clinical inactivity and what barriers, real or perceived, there were to reentry into the medical workforce.</p> <p>Methods</p> <p>A random sample of 4975 inactive physicians aged under 65 years was drawn from the Physician Masterfile of the American Medical Association in 2008. Physicians were mailed a survey about activity in medicine and perceived barriers to reentry. Chi-square statistics were used for significance tests of the association between categorical variables and t-tests were used to test differences between means.</p> <p>Results</p> <p>Our adjusted response rate was 36.1%. Respondents were fully retired (37.5%), not currently active in medicine (43.0%) or now active (reentered, 19.4%). Nearly half (49.5%) were in or had practiced primary care. Personal health was the top reason for leaving for fully retired physicians (37.8%) or those not currently active in medicine (37.8%) and the second highest reason for physicians who had reentered (28.8%). For reentered (47.8%) and inactive (51.5%) physicians, the primary reason for returning or considering returning to practice was the availability of part-time work or flexible scheduling. Retired and currently inactive physicians used similar strategies to explore reentry, and 83% of both groups thought it would be difficult; among those who had reentered practice, 35.9% reported it was difficult to reenter. Retraining was uncommon for this group (37.5%).</p> <p>Conclusion</p> <p>Availability of part-time work and flexible scheduling have a strong influence on decisions to leave or reenter clinical practice. Lack of retraining before reentry raises questions about patient safety and the clinical competence of reentered physicians.</p

Exploring the benefits of doll play through neuroscience

It has long been hypothesized that pretend play is beneficial to social and cognitive development. However, there is little evidence regarding the neural regions that are active while children engage in pretend play. We examined the activation of prefrontal and posterior superior temporal sulcus (pSTS) regions using near-infrared spectroscopy while 42 4- to 8-year-old children freely played with dolls or tablet games with a social partner or by themselves. Social play activated right prefrontal regions more than solo play. Children engaged the pSTS during solo doll play but not during solo tablet play, suggesting they were rehearsing social cognitive skills more with dolls. These findings suggest social play utilizes multiple neural regions and highlight how doll play can achieve similar patterns of activation, even when children play by themselves. Doll play may provide a unique opportunity for children to practice social interactions important for developing social-emotional skills, such as empathy

Being an Early-Career CMS Academic in the Context of Insecurity and ‘Excellence’: The Dialectics of Resistance and Compliance

Drawing on a dialectical approach to resistance, we conceptualise the latter as a multifaceted, pervasive and contradictory phenomenon. This enables us to examine the predicament in which early-career Critical Management Studies academics find themselves in the current times of academic insecurity and ‘excellence’, as gleaned through this group’s understandings of themselves as resisters and participants in the complex and contradictory forces constituting their field. We draw on 24 semi-structured interviews to map our participants’ accounts of themselves as resisters in terms of different approaches to tensions and contradictions between, on the one hand, the interviewees’ Critical Management Studies alignment and, on the other, the ethos of business school neoliberalism. Emerging from this analysis are three contingent and interlinked narratives of resistance and identity – diplomatic, combative and idealistic – each of which encapsulates a particular mode (negotiation, struggle, and laying one’s own path) of engaging with the relationship between Critical Management Studies and the business school ethos. The three narratives show how early-career Critical Management Studies academics not only use existing tensions, contradictions, overlaps and alliances between these positions to resist and comply with selected forces within each, but also contribute to the (re-)making of such overlaps, alliances, tensions and contradictions. Through this reworking of what it means to be both Critical Management Studies scholars and business school academics, we argue, early-career Critical Management Studies academics can be seen as active resisters and re-constituters of their complex field