300 research outputs found

    Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells

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    The anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK

    Convergent approach to persistent atrial fibrillation ablation:long-term single-centre safety and efficacy

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    Background:Efforts to maintain sinus rhythm in patients with persistent atrial fibrillation (PsAF) remain challenging, with suboptimal long-term outcomes.Methods:All patients undergoing convergent PsAF ablation at our centre were retrospectively analysed. The Atricure Epi-Sense® system was used to perform surgical radiofrequency ablation of the LA posterior wall followed by endocardial ablation.Results:A total of 24 patients underwent convergent PsAF ablation, and 21 (84%) of them were male with a median age of 63. Twelve (50%) patients were obese. In total, 71% of patients had a severely dilated left atrium, and the majority (63%) had preserved left ventricular function. All were longstanding persistent. Eighteen (75%) patients had an AF duration of >2 years. There were no endocardial procedure complications. At 36 months, all patients were alive with no new stroke/transient ischaemic attack (TIA). Freedom from documented AF at 3, 6, 12, 18, 24, and 36 months was 83%, 78%, 74%, 74%, 74%, and 61%, respectively. There were no major surgical complications, with five minor complications recorded comprising minor wound infection, pericarditic pain, and hernia.Conclusions:Our data suggest that convergent AF ablation is effective with excellent immediate and long-term safety outcomes in a real-world cohort of patients with a significant duration of AF and evidence of established atrial remodelling. Convergent AF ablation appears to offer a safe and effective option for those who are unlikely to benefit from existing therapeutic strategies for maintaining sinus rhythm, and further evaluation of this exciting technique is warranted. Our cohort is unique within the published literature both in terms of length of follow-up and very low rate of adverse events

    Large scale three-dimensional modelling for wave and tidal energy resource and environmental impact : methodologies for quantifying acceptable thresholds for sustainable exploitation

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    We describe a modelling project to estimate the potential effects of wave & tidal stream renewables on the marine environment. • Realistic generic devices to be used by those without access to the technical details available to developers are described. • Results show largely local sea bed effects at the level of the currently proposed renewables developments in our study area. • Large scale 3D modelling is critical to quantify the direct, indirect and cumulative effects of renewable energy extraction. • This is critical to comply with planning & environmental impact assessment regulations and achieve Good Environmental Status

    Stigma and Fear: the 'Psy Professional' in Cultural Artifacts

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    This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The loss of reason called madness provokes perhaps the greatest human fear, for it is reason that dignifies humanity and separates us from beasts. The ‘psy professionals’ - those who prescribe and administer treatments for madness - are frequently portrayed in fiction, film, comics, computer games and entertainments, along with the mad themselves and the asylums that confine them. Overall, these depictions are malign: the reader/watcher/player is encouraged to fear the mad, the madhouse and the mad-doctor. Choosing to use less abrasive vocabulary to name the condition of madness makes no difference to the terror the condition arouses, for the content of many books and games aims to inspire fear. In spite of considerable efforts over many years, the stigma which attaches to mental illness remains firmly in place for patients, while psy professionals also carry their share of “some of the discredit of the stigmatized” (Goffman 1968, p 43) and join patients in a stigmatized group. Popular belief often equates the psy professions with madness (Walter, 1989). This paper explores ways in which the fear of madness, and the stigma which clings to sufferers and their professional carers, is perpetuated by a constant stream of popular cultural artifacts

    Speckle Tracking Echocardiography for the Assessment of the Athlete's Heart: Is It Ready for Daily Practice?

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    PURPOSE OF REVIEW: To describe the use of speckle tracking echocardiography (STE) in the biventricular assessment of athletes' heart (AH). Can STE aid differential diagnosis during pre-participation cardiac screening (PCS) of athletes? RECENT FINDINGS: Data from recent patient, population and athlete studies suggest potential discriminatory value of STE, alongside standard echocardiographic measurements, in the early detection of clinically relevant systolic dysfunction. STE can also contribute to subsequent prognosis and risk stratification. Despite some heterogeneity in STE data in athletes, left ventricular global longitudinal strain (GLS) and right ventricular longitudinal strain (RV ɛ) indices can add to differential diagnostic protocols in PCS. STE should be used in addition to standard echocardiographic tools and be conducted by an experienced operator with significant knowledge of the AH. Other indices, including left ventricular circumferential strain and twist, may provide insight, but further research in clinical and athletic populations is warranted. This review also raises the potential role for STE measures performed during exercise as well as in serial follow-up as a method to improve diagnostic yield

    Slow GABAA mediated synaptic transmission in rat visual cortex

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    <p>Abstract</p> <p>Background</p> <p>Previous reports of inhibition in the neocortex suggest that inhibition is mediated predominantly through GABA<sub>A </sub>receptors exhibiting fast kinetics. Within the hippocampus, it has been shown that GABA<sub>A </sub>responses can take the form of either fast or slow response kinetics. Our findings indicate, for the first time, that the neocortex displays synaptic responses with slow GABA<sub>A </sub>receptor mediated inhibitory postsynaptic currents (IPSCs). These IPSCs are kinetically and pharmacologically similar to responses found in the hippocampus, although the anatomical specificity of evoked responses is unique from hippocampus. Spontaneous slow GABA<sub>A </sub>IPSCs were recorded from both pyramidal and inhibitory neurons in rat visual cortex.</p> <p>Results</p> <p>GABA<sub>A </sub>slow IPSCs were significantly different from fast responses with respect to rise times and decay time constants, but not amplitudes. Spontaneously occurring GABA<sub>A </sub>slow IPSCs were nearly 100 times less frequent than fast sIPSCs and both were completely abolished by the chloride channel blocker, picrotoxin. The GABA<sub>A </sub>subunit-specific antagonist, furosemide, depressed spontaneous and evoked GABA<sub>A </sub>fast IPSCs, but not slow GABA<sub>A</sub>-mediated IPSCs. Anatomical specificity was evident using minimal stimulation: IPSCs with slow kinetics were evoked predominantly through stimulation of layer 1/2 apical dendritic zones of layer 4 pyramidal neurons and across their basal dendrites, while GABA<sub>A </sub>fast IPSCs were evoked through stimulation throughout the dendritic arborization. Many evoked IPSCs were also composed of a combination of fast and slow IPSC components.</p> <p>Conclusion</p> <p>GABA<sub>A </sub>slow IPSCs displayed durations that were approximately 4 fold longer than typical GABA<sub>A </sub>fast IPSCs, but shorter than GABA<sub>B</sub>-mediated inhibition. The anatomical and pharmacological specificity of evoked slow IPSCs suggests a unique origin of synaptic input. Incorporating GABA<sub>A </sub>slow IPSCs into computational models of cortical function will help improve our understanding of cortical information processing.</p
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