Miracle-dz/UniFAR-FTUs huggingface dataset:
Synaptic Release Generates a Tonic GABAA Receptor-Mediated Conductance That Modulates Burst Precision in Thalamic Relay Neurons

Tonic inhibition has emerged as a key regulator of neuronal excitability in the CNS. Thalamic relay neurons of the dorsal lateral geniculate nucleus (dLGN) exhibit a tonic GABAA receptor (GABAAR)-mediated conductance that is correlated with δ-subunit expression. Indeed, consistent with the absence of δ-subunit expression, no tonic conductance is found in the adjacent ventral LGN. We show that, in contrast to the situation in cerebellar granule cells, thalamic δ-subunit-containing GABAARs (δ-GABAARs) do not contribute to a spillover component of IPSCs in dLGN. However, tonic activation of thalamic δ-GABAARs is sensitive to the global level of inhibition, showing an absolute requirement on the synaptic release of GABA. Thus, the tonic conductance is abolished when transmitter release probability is reduced or action potential-evoked release is blocked. We further show that continuous activation of δ-GABAARs introduces variability into the timing of low-threshold rebound bursts. Hence, activation of δ-GABAARs could act to destabilize thalamocortical oscillations and therefore have an important impact on behavioral state.
Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling

Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments (i) metformin induces PP2A activity before and at lower levels than AMPK activity and (ii) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-α4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.
The modulatory effect of cell–cell contact on the tumourigenic potential of pre-malignant epithelial cells: a computational exploration

Malignant development cannot be attributed alone to genetic changes in a single cell, but occurs as a result of the complex interplay between the failure of cellular regulation mechanisms and the presence of a permissive microenvironment. Although E-cadherin is classified as a ‘metastasis suppressor’ owing to its role in intercellular adhesion, the observation that it may be downregulated at a premalignant stage is indicative of additional roles in neoplastic development. We have used an agent-based computational model to explore the emergent behaviour resulting from the interaction of single and subpopulations of E-cadherin-compromised cells with unaffected normal epithelial cells within a monolayer environment. We have extended this to investigate the importance of local tissue perturbations in the form of scratch-wounding, or ablation of randomly-dispersed normal cells, on the growth of a single cell exhibiting E-cadherin loss. Our results suggest that the microenvironment with respect to localized cell density and normal/E-cadherin-compromised neighbours is crucial in determining whether an abnormal individual cell proliferates or remains dormant within the monolayer. These predictions raise important questions relating to the propensity for individual mutations to give rise to disease, and future experimental exploration of these will enhance our understanding of a complex, multifactorial pathological process.
The reliability of the modified reverse-6 taping procedure with elastic tape to alter the height and width of the medial longitudinal arch.

PURPOSE/BACKGROUND Anti-pronation-taping utilizing both inelastic and elastic tape has been advocated to reduce pain and symptoms associated with excessive foot pronation. An important question regarding the use of taping is whether it can be applied consistently from one therapist to the next, from one session to the next or from one day to the next. Thus, the purpose of this study was to determine whether the "modified" Reverse-6 taping procedure using elastic tape could be applied to produce a consistent within-day and between-day change in the height and width of the medial longitudinal arch for a single clinician as well as between clinicians. A second purpose was to determine if the amount of general clinical experience influenced this consistency. METHODS Fifteen asymptomatic individuals (10 female and 5 male) with a mean age of 28.7 years were recruited to participate in this study. The height and width of the midfoot at 50% of each subject's foot length was measured in standing using a digital gauge and caliper. These measurements were done twice on the same day, on two different days and again by two clinicians with different levels of experience before and after having their feet taped using the "modified" Reverse-6 taping technique using elastic tape. Both clinicians received a one-hour training session on how to apply the taping technique and were also given a DVD showing the technique that they could review. In addition to descriptive statistics, intra-class correlation coefficients (ICC) were used to assess each clinician's within-day and between-day reliability. Between-clinician reliability was also determined. RESULTS The mean dorsal arch height and midfoot width before the application of tape was 62.7 and 78.9 mm. The mean dorsal arch height and width after the application of tape was 66.6 and 78.8 mm. The within-day reliability ICC(2,1) values for the two clinicians ranged from . 865 to . 991. The between-day reliability ICC(2,1) values for the two clinicians ranged from . 874 to . 985. The between-clinician reliability ICC(2,1) values ranged from . 918 to . 993. CONCLUSIONS The results of this study indicate that the "modified" Reverse-6 foot taping technique using elastic tape can be used by more than one therapist for the same patient as well as from one session to the next with excellent reliability. LEVEL OF EVIDENCE Level 2, Prospective Cohort Study.
Revascularisation for acute coronary syndromes in older people

Background: randomised controlled trials have demonstrated that early revascularisation improves outcome in patients with acute coronary syndromes. However, since older people were excluded from these trials, it is not known whether the findings are applicable to them. Objectives: to evaluate the outcome of revascularisation by percutaneous coronary intervention or coronary artery bypass surgery in older people with acute coronary syndromes. To determine the factors which predict outcome of revascularisation in these patients. Design: systematic review of studies obtained from the Medline and Embase electronic databases and through bibliographic searches. Analysis by descriptive overview and statistical meta-analysis using pooled proportions. Included studies: studies published from 1990 onwards describing the outcome of percutaneous coronary intervention or coronary artery bypass surgery in patients ≥ 75 or ≥ 80 years, of whom 75% or more were classified as unstable angina. Studies published from 1990 onwards describing the factors predicting outcome of percutaneous coronary intervention or coronary artery bypass surgery in all patients ≥ 75 or ≥ 80 years. Results: 26 studies were included. In-hospital mortality from percutaneous coronary intervention was 5.4% (95% confidence interval 3.9% to 7.0%) and after coronary artery bypass surgery was 12.1% (9.5% to 14.7%). Large observational studies indicate expected 30-day mortality of 6-12% with medical treatment. Serious complications following percutaneous coronary intervention were rare, but there was a high rate of major adverse cardiac events over the following year. Major complications, including stroke, were common after coronary artery bypass. However, long-term survival and functional outcome in those who survived the peri-operative period were excellent. Clinical variables predicted those at highest risk from both percutaneous coronary intervention and coronary artery bypass. Conclusions: percutaneous coronary intervention offers an attractive option for the management of older people with acute coronary syndromes and may improve outcome over conservative treatment. In contrast, coronary artery bypass carries a substantial mortality and morbidity, and is likely to be reserved for patients with refractory symptoms unsuitable for percutaneous intervention. Further data from randomised controlled trials are required.
Treatment of pure membranous lupus nephropathy with prednisone and azathioprine: an open-label trial.

BACKGROUND The aim of this study was to report the outcome of pure membranous lupus nephropathy treated with prednisone and azathioprine (AZA). METHODS Consecutive patients with pure membranous lupus glomerulonephritis (World Health Organization [WHO] Va and Vb) from 4 regional hospitals were recruited for an open-label treatment trial consisting of prednisone and AZA. Remission status was evaluated at 12 months. Maintenance treatment with low-dose prednisone and AZA was continued indefinitely for those who achieved remission. Factors predictive of initial renal remission and subsequent relapse were studied by statistical analyses. RESULTS Thirty-eight patients (31 women and 7 men) were studied. The mean age was 35.0 +/- 9.2 years, and the duration of systemic lupus erythematosus was 48.5 +/- 59 months. Seventeen (45%) patients had WHO class Va lupus nephritis, whereas 21 (55%) had class Vb disease. Two patients withdrew from the protocol because of idiosyncratic reactions to AZA. At 12 months, 24 (67%) patients achieved complete remission (CR), 8 (22%) achieved partial remission (PR), and 4 (11%) were treatment resistant. Patients who achieved CR or PR were maintained on low-dose prednisone and AZA. Over a mean follow-up period of 90.4 +/- 59 months, 6 (19%) patients had relapse of nephritis (proteinuric flare in 4 and nephritic flare in 2). The cumulative risk of renal relapse was 12% at 36 months and 16% at 60 months. No particular clinical variables were found to predict renal remission or relapses. Over a mean follow-up of 90 months, 13% of patients had decline of creatinine clearance by 20%, but none had doubling of serum creatinine. Renal outcome was not significantly worse in patients presenting with nephrotic syndrome. Treatment generally was well tolerated. CONCLUSION A combination of prednisone and AZA is reasonably effective for the initial treatment of pure membranous lupus nephritis. Severe adverse effects are uncommon. The additional efficacy of AZA in comparison with prednisone alone has to be confirmed with randomized, controlled trials.
Influences of Subanesthetic Isoflurane on Ventilatory Control in Humans

Background The purpose of this study was to quantify in humans the effects of subanesthetic isoflurane on the ventilatory control system, in particular on the peripheral chemoreflex loop. Therefore we studied the dynamic ventilatory response to carbon dioxide, the effect of isoflurane wash-in upon sustained hypoxic steady-state ventilation, and the ventilatory response at the onset of 20 min of isocapnic hypoxia.
Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence.

OBJECTIVES The notion that sufferers of bipolar disorder achieve complete syndromal and functional recovery between illness episodes has been brought into question by evidence that a large proportion of patients fail to regain premorbid levels of functioning after the resolution of major affective symptoms. A growing body of evidence suggests that bipolar patients exhibit neuropsychological impairment that persists even during the euthymic state, which may be a contributory factor to poor psychosocial outcome. However, the aetiology of such impairment and its relation to progression of illness are not well understood. This review aims to consider evidence from studies investigating both the relationship between cognitive impairment and clinical outcome and studies of neurocognitive function in unaffected first-degree relatives (FDRs) of bipolar sufferers to address issues of the temporal evolution of cognitive impairment in bipolar disorder. METHODS Systematic literature review. RESULTS The weight of evidence suggests that greater neuropsychological dysfunction in bipolar disorder is associated with a worse prior course of illness, particularly the number of manic episodes, hospitalizations and length of illness. The most consistent finding was a negative relationship between the number of manic episodes and verbal declarative memory performance. Impairment in unaffected FDRs was reported in verbal declarative memory and some facets of executive function. CONCLUSIONS Cognitive impairment may be a trait vulnerability factor for bipolar disorder that is present before illness onset and worsens as the illness progresses. Further investigation into the causal relationship between cognitive impairment and illness course is essential.
IL-1 mediates pulmonary and systemic inflammatory responses to chorioamnionitis induced by lipopolysaccharide.

RATIONALE Chorioamnionitis frequently associates with preterm delivery and increased amniotic fluid IL-1, and causes fetal lung and systemic inflammation. However, chorioamnionitis is also associated with a paradoxical reduction in the incidence of surfactant deficiency-related respiratory distress syndrome in preterm infants. OBJECTIVES To identify the role of IL-1 signaling in the mediation of pulmonary and systemic inflammation and lung maturation in a fetal sheep model of lipopolysaccharide (LPS) induced chorioamnionitis. METHODS After confirming the efficacy of recombinant human IL-1 receptor antagonist (rhIL-1ra), fetal sheep were exposed to intraamniotic (IA) injections of Escherichia coli LPS with or without prior IA injections of rhIL-1ra. Preterm lambs were delivered at 82% of term gestation. MEASUREMENTS AND MAIN RESULTS rhIL-1ra decreased IA LPS-induced lung inflammation assessed by decreased lung neutrophil and monocyte influx, inducible nitric oxide synthase expression, lung IL-6 and IL-1beta mRNA expression, and airway myeloperoxidase concentrations. rhIL-1ra inhibited IA LPS-induced fetal systemic inflammation assessed by decreased plasma IL-8, protein carbonyls, blood neutrophilia, and the expression of serum amyloid A3 mRNA in the liver. rhIL-1ra also partially blocked the lung maturational effects of IA LPS. Therefore blockade of IL-1 signaling in the amniotic compartment inhibited fetal lung and systemic inflammation and lung maturation in response to LPS-induced chorioamnionitis. CONCLUSIONS IL-1 plays a central role in the pathogenesis of chorioamnionitis-induced fetal inflammatory responses.
Modeling of congenital erythropoietic porphyria by RNA interference: a new tool for preclinical gene therapy evaluation

Congenital erythropoietic porphyria (CEP) is a severe autosomal recessive disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. We recently demonstrated the definitive cure of a murine model of CEP by lentiviral vector‐mediated hematopoietic stem cell (HSC) gene therapy. In the perspective of a gene therapy clinical trial, human cellular models are required to evaluate the therapeutic potential of lentiviral vectors in UROS‐deficient cells. However, the rare incidence of the disease makes difficult the availability of HSCs derived from patients.
Defining the Turkey MHC: Sequence and Genes of the B Locus12

The MHC, the most polymorphic and gene dense region in the vertebrate genome, contains many loci essential to immunity. In mammals, this region spans ∼4 Mb. Studies of avian species have found the MHC to be greatly reduced in size and gene content with an overall locus organization differing from that of mammals. The chicken MHC has been mapped to two distinct regions (MHC-B and -Y) of a single chromosome. MHC-B haplotypes possess tightly linked genes encoding the classical MHC molecules and few other disease resistance genes. Furthermore, chicken haplotypes possess a dominantly expressed class I and class II B locus that have a significant effect on the progression or regression of pathogenic disease. In this study, we present the MHC-B region of the turkey (Meleagris gallopavo) as a similarly constricted locus, with 34 genes identified within a 0.2-Mb region in near-perfect synteny with that of the chicken MHC-B. Notable differences between the two species are three BG and class II B loci in the turkey compared with one BG and two class II B loci in the chicken MHC-B. The relative size and high level of similarity of the turkey MHC in relation to that of the chicken suggest that similar associations with disease susceptibility and resistance may also be found in turkey.
Assessment of the cerebral circulation in adults with coarctation of the aorta.

AIMS There is a fivefold increase in the frequency of intracranial aneurysm (IA) in adults with coarctation of the aorta (CoA). Current guidelines for management of adults with CoA recommend computed tomography angiography (CTA) or magnetic resonance imaging of the intracranial vessels. However, this recommendation has not been universally accepted. The purpose of our study was to prospectively perform CTA of the intracranial vessels in adults with CoA to evaluate the prevalence and identify high-risk features of this complication. METHODS AND RESULTS From January 2008 to February 2011, adults ≥18 years of age with CoA were prospectively enrolled in a screening program with CTA of the intracranial vessels. Analyses of prognostic variables were performed with both Fisher's exact and two sample t-test. Forty-three patients (58% female, 33.55 ± 10.21 years) with CoA completed CTA of the intracranial vessels. Five patients (11%) were found to have IA. Patients with IA were older than those without (45.6 ± 8.17 vs. 30.89 ± 7.89, P = 0.0003). There were no statistically significant differences detected between measurements of fasting lipid profiles, C-reactive protein, brain natriuretic peptide, and homocysteine levels among CoA patients with and without IA (P = not significant). CONCLUSION Prospective screening of adults with CoA confirmed the increased prevalence of IA but also identified increased age as the sole risk factor. These data suggested that screening is justified particularly in the fourth and fifth decades of life. Further studies are required that focus on the development, natural history, and treatment of IA.
Two Decades of Income Inequality in Britain: The Role of Wages, Household Earnings and Redistribution

We study earnings and income inequality in Britain over the past two decades, including the period of relatively “inclusive” growth from 1997-2004 and the Great Recession. We focus on the middle 90%, where trends have contrasted strongly with the “new inequality” at the very top. Household earnings inequality has risen, driven by male earnings – although a ‘catch-up’ of female earnings did hold down individual earnings inequality and reduce within-household inequality. Nevertheless, net household income inequality fell due to deliberate increases in redistribution, the tax and transfer system’s insurance role during the Great Recession, falling household worklessness, and rising pensioner incomes.
Mutual Funds in Greece: Case Study of Domestic Equity Mutual Funds During Financial Crisis

Purpose - The purpose of this paper is to examine the performance of Greek equity mutual funds for the period 2012-2016, analyzing further the selectivity and market timing ability, and short-term performance persistence for the period 2015-2016. Design/methodology/approach - Utilizing a survivorship-bias-controlled sample of 25 funds and daily data, the authors use single-index (Jensen, 1968) and multi-factor (Carhart, 1997) models to evaluate risk-adjusted returns using the General Index of Athens Stock Exchange as a benchmark. The Treynor-Mazuy (1966) and Henriksson-Merton (1981) models are used to assess the stock selection and market timing abilities of fund managers. In order to investigate short-term performance persistence, the authors implement a variety of parametric (Bollen and Busse, 2005) and nonparametric tests (Malkiel, 1995; Brown and Goetzmann, 1995; Kahn and Rudd, 1995). Findings - Results show that the funds underperformed the General Index, mainly due to the managers’ market timing inability. Furthermore, weak evidence for short-term performance persistence has been documented. Research limitations/implications - Checking for performance persistence, it was impossible to rank funds and form deciles according to their estimated abnormal returns, as in Bollen and Busse (2005), due to the small number of mutual funds operating in Greece. Originality/value - Empirical studies regarding the performance of Greek equity mutual funds are still limited. Therefore, this paper intends to fill this gap by providing further evidence of performance evaluation.
Clinical characteristics and long‐term outcome of migraine with aura in children and adolescents

A population of 45 young subjects, 16 males and 29 females, affected by migraine with aura were studied prospectively. The mean follow‐up was 7 years 6 months. The clinical characteristics and modifications during migraine aura attacks were evaluated. The aura propagated slowly with a pattern corresponding to a cortical pathway in the posteroanterior direction in 71% of the series, and was visual alone in 40%. Analysis of the relation between the course, and therefore prognosis, and the aura type showed that headache has a better prognosis when symptoms continue to be only visual. The International Headache Society (IHS) classification subdivides migraine with aura into six categories based on the duration of symptoms and the clinical characteristics (hemiplegic, basilar). Our results suggest that subjects with only visual aura should be considered separately, possibly as a seventh category, because they may have a more favourable prognosis.