Prevention of the β-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures

<p>Abstract</p> <p>Background</p> <p>Inflammation may be involved in the pathogenesis of Alzheimer's disease (AD). There has been little success with anti-inflammatory drugs in AD, while the promise of anti-inflammatory treatment is more evident in experimental models. A new anti-inflammatory strategy requires a better understanding of molecular mechanisms. Among the plethora of signaling pathways activated by β-amyloid (Aβ) peptides, the nuclear factor-kappa B (NF-κB) pathway could be an interesting target. In virus-infected cells, double-stranded RNA-dependent protein kinase (PKR) controls the NF-κB signaling pathway. It is well-known that PKR is activated in AD. This led us to study the effect of a specific inhibitor of PKR on the Aβ42-induced inflammatory response in primary mixed murine co-cultures, allowing interactions between neurons, astrocytes and microglia.</p> <p>Methods</p> <p>Primary mixed murine co-cultures were prepared in three steps: a primary culture of astrocytes and microglia for 14 days, then a primary culture of neurons and astrocytes which were cultured with microglia purified from the first culture. Before exposure to Aβ neurotoxicity (72 h), co-cultures were treated with compound C16, a specific inhibitor of PKR. Levels of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, and IL-6 were assessed by ELISA. Levels of P_T451-PKR and activation of IκB, NF-κB and caspase-3 were assessed by western blotting. Apoptosis was also followed using annexin V-FITC immunostaining kit. Subcellular distribution of P_T451-PKR was assessed by confocal immunofluorescence and morphological structure of cells by scanning electron microscopy. Data were analysed using one-way ANOVA followed by a Newman-Keuls' post hoc test</p> <p>Results</p> <p>In these co-cultures, PKR inhibition prevented Aβ42-induced activation of IκB and NF-κB, strongly decreased production and release of tumor necrosis factor (TNFα) and interleukin (IL)-1β, and limited apoptosis.</p> <p>Conclusion</p> <p>In spite of the complexity of the innate immune response, PKR inhibition could be an interesting anti-inflammatory strategy in AD.</p

Statin treatment and mortality in community-dwelling frail older patients with diabetes mellitus

Background: Older adults are often excluded from clinical trials. Decision making for administration of statins to older patients with diabetes mellitus (DM) is under debate, particularly in frail older patients with comorbidity and high mortality risk. We tested the hypothesis that statin treatment in older patients with DM was differentially effective across strata of mortality risk assessed by the Multidimensional Prognostic Index (MPI), based on information collected with the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA). Methods: In this retrospective observational study, we estimated the mortality risk in 1712 community-dwelling subjects with DM ≥ 65 years who underwent a SVaMA evaluation to establish accessibility to homecare services/nursing home admission from 2005 to 2013 in the Padova Health District, Italy. Mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), and high (MPI-SVaMA-3) risk of mortality at baseline and propensity score-adjusted hazard ratios (HR) of three-year mortality were calculated according to statin treatment. Results: Higher MPI-SVaMA scores were associated with lower rates of statin treatment (MPI-SVaMA-1 = 39% vs MPI-SVaMA-2 = 36% vs MPI-SVaMA-3 = 24.9%. p<0.001) and higher three-year mortality (MPI-SVaMA-1 = 12.9% vs MPI-SVaMA-2 = 24% vs MPI-SVaMA-3 = 34.4%, p<0.001). After adjustment for propensity score quintiles, statin treatment was significantly associated with lower three-year mortality irrespective of MPI-SVaMA group (interaction test p = 0.303). HRs [95% confidence interval (CI)] were 0.19 (0.14-0.27), 0.28 (0.21-0.36), and 0.26 (0.20-0.34) in the MPI-SVaMA-1, MPI-SVaMA-2, and MPI-SVaMA-3 groups, respectively. Subgroup analyses showed that statin treatment was also beneficial irrespective of age. HRs (95% CI) were 0.21 (0.15-0.31), 0.26 (0.20-0.33), and 0.26 (0.20-0.35) among patients aged 65-74, 75-84, and ≥ 85 years, respectively (interaction test p=0.812). Conclusions: Statin treatment was significantly associat

When Your Decisions Are Not (Quite) Your Own: Action Observation Influences Free Choices

A growing number of studies have begun to assess how the actions of one individual are represented in an observer. Using a variant of an action observation paradigm, four experiments examined whether one person's behaviour can influence the subjective decisions and judgements of another. In Experiment 1, two observers sat adjacent to each other and took turns to freely select and reach to one of two locations. Results showed that participants were less likely to make a response to the same location as their partner. In three further experiments observers were asked to decide which of two familiar products they preferred or which of two faces were most attractive. Results showed that participants were less likely to choose the product or face occupying the location of their partner's previous reaching response. These findings suggest that action observation can influence a range of free choice preferences and decisions. Possible mechanisms through which this influence occurs are discussed

Does Observation of Postural Imbalance Induce a Postural Reaction?

Import JabRef | WosArea Life Sciences and Biomedicine - Other TopicsInternational audienceBackground: Several studies bring evidence that action observation elicits contagious responses during social interactions. However automatic imitative tendencies are generally inhibited and it remains unclear in which conditions mere action observation triggers motor behaviours. In this study, we addressed the question of contagious postural responses when observing human imbalance. Methodology/Principal Findings: We recorded participants' body sway while they observed a fixation cross (control condition), an upright point-light display of a gymnast balancing on a rope, and the same point-light display presented upside down. Our results showed that, when the upright stimulus was displayed prior to the inverted one, centre of pressure area and antero-posterior path length were significantly greater in the upright condition compared to the control and upside down conditions. Conclusions/Significance: These results demonstrate a contagious postural reaction suggesting a partial inefficiency of inhibitory processes. Further, kinematic information was sufficient to trigger this reaction. The difference recorded between the upright and upside down conditions indicates that the contagion effect was dependent on the integration of gravity constraints by body kinematics. Interestingly, the postural response was sensitive to habituation, and seemed to disappear when the observer was previously shown an inverted display. The motor contagion recorded here is consistent with previous work showing vegetative output during observation of an effortful movement and could indicate that lower level control facilitates contagion effects

The novel RAGE interactor PRAK is associated with autophagy signaling in Alzheimer’s disease pathogenesis

BACKGROUND: The receptor for advanced glycation end products (RAGE) has been found to interact with amyloid β (Aβ). Although RAGE does not have any kinase motifs in its cytosolic domain, the interaction between RAGE and Aβ triggers multiple cellular signaling involved in Alzheimer’s disease (AD). However, the mechanism of signal transduction by RAGE remains still unknown. Therefore, identifying binding proteins of RAGE may provide novel therapeutic targets for AD. RESULTS: In this study, we identified p38-regulated/activated protein kinase (PRAK) as a novel RAGE interacting molecule. To investigate the effect of Aβ on PRAK mediated RAGE signaling pathway, we treated SH-SY5Y cells with monomeric form of Aβ. We demonstrated that Aβ significantly increased the phosphorylation of PRAK as well as the interaction between PRAK and RAGE. We showed that knockdown of PRAK rescued mTORC1 inactivation induced by Aβ treatment and decreased the formation of Aβ-induced autophagosome. CONCLUSIONS: We provide evidence that PRAK plays a critical role in AD pathology as a key interactor of RAGE. Thus, our data suggest that PRAK might be a potential therapeutic target of AD involved in RAGE-mediated cell signaling induced by Aβ. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0068-5) contains supplementary material, which is available to authorized users

Redécouverte d'une eau minérale bicarbonatée mixte (eau Arvie) : étude sur la fonction rénale, les paramètres glucidiques et lipidiques chez le volontaire sain

A partir de l'eau Arvie, eau bicarbonatée mixte sodique et calcique carbo-gazeuse, une étude a été menée pour évaluer ses effets sur les paramètres lipidiques, glucidiques et la fonction rénale chez le volontaire sain. Vingt sujets entraient dans l'essai en ouvert comparant sur deux périodes consécutives de 1 mois chacune les effets de 1,5 litres/j d'eau Arvie à ceux de 1,5 litres/j d'eau d'adduction. Les critères d'évaluation étaient dans le plasma : electrolytes, urée, créatinine, acide urique, calcémie, glycémie, paramètres lipidiques, et dans les urines : volume urinaire, electrolytes, clairance de l'eau libre. Les critères de tolérance étaient : le poids et la pression artérielle. L'eau Arvie n entraînait aucune modification des paramètres plasmatiques, la diurèse n'était pas significativement augmentée, mais l'élimination urinaire du sodium était significativement augmentée et la clairance de l'eau libre était plus négative. La tolérance était excellente car ni le poids, ni la pression artérielle ne subissaient de variation. En conclusion, l'eau Arvie entraîne chez le volontaire sain une élimination accrue de sodium sans modifier la natrémie ou la diurèse, la tolérance tensionnelle est excellente

Cost-Effectiveness of Adjuvanted Quadrivalent Influenza Vaccine for Adults over 65 in France

Background: In France, influenza accounts for an average of over one million consultations with GPs, 20,000 hospitalizations, and 9000 deaths per year, particularly among the over-65s. This study evaluates the cost-effectiveness of the adjuvanted quadrivalent influenza vaccine (aQIV) compared to standard (SD-QIV) and high-dose (HD-QIV) quadrivalent influenza vaccines for individuals aged 65 and older in France. Methods: The age-structured SEIR transmission model, calibrated to simulate a mean influenza season, incorporates a contact matrix to estimate intergroup contact rates. Epidemiological, economic, and utility outcomes are evaluated. Vaccine effectiveness and costs are derived from literature and national insurance data. Quality of life adjustments for influenza attack rates and hospitalizations are applied. Deterministic and probabilistic analyses are also conducted. Results: Compared to SD-QIV, aQIV demonstrates substantial reductions in healthcare utilization and mortality, avoiding 89,485 GP consultations, 2144 hospitalizations, and preventing 1611 deaths. Despite an investment of EUR 110 million, aQIV yields a net saving of EUR 14 million in healthcare spending. Compared to HD-QIV, aQIV saves 62 million euros on vaccination costs. Cost-effectiveness analysis reveals an incremental cost-effectiveness ratio of EUR 7062 per QALY. Conclusions: This study highlights the cost-effectiveness of aQIV versus SD-QIV and HD-QIV, preventing influenza cases, hospitalizations, and deaths

Comparison of two saturated fatty acid intakes with steady intakes in unsaturated fatty acids on plasma lipids and fatty acids in a monk collectivity study

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