Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart.

Endoplasmic Reticulum (ER) stress and oxidative stress have been highly implicated in the pathogenesis of cardiac hypertrophy and heart failure (HF). However, the mechanisms involved in the interplay between these processes in the heart are not fully understood. The present study sought to determine a causative link between Pak2-dependent UPR activation and oxidative stress via Nrf2 regulation under pathological ER stress. We report that sustained ER stress and Pak2 deletion in cardiomyocytes enhance Nrf2 expression. Conversely, AAV9 mediated Pak2 delivery in the heart leads to a significant decrease in Nrf2 levels. Pak2 overexpression enhances the XBP1-Hrd1 UPR axis and ameliorates tunicamycin induced cardiac apoptosis and dysfunction in mice. We found that Pak2 deletion and altered proteostasis render Nrf2 detrimental by switching from its antioxidant role to renin-angiotensin aldosterone system (RAAS) gene regulator. Mechanistically, Pak2 mediated Hrd1 expression targets Nrf2 for ubiquitination and degradation thus preventing its aberrant activation. Moreover, we find a significant increase in Nrf2 with a decrease in Pak2 in human myocardium of dilated heart disease. Using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we find that Pak2 is able to ameliorate Nrf2 induced RAAS activation under ER stress. These findings demonstrate that Pak2 is a novel Nrf2 regulator in the stressed heart. Activation of XBP1-Hrd1 is attributed to prevent ER stress-induced Nrf2 RAAS component upregulation. This mechanism explains the functional dichotomy of Nrf2 in the stressed heart. Thus, Pak2 regulation of Nrf2 homeostasis may present as a potential therapeutic route to alleviate detrimental ER stress and heart failure.

Accurate Location of Catheter Tip With the Free-to-Total Metanephrine Ratio During Adrenal Vein Sampling.

Background: The selectivity index (SI) of cortisol is used to document correct catheter placement during adrenal vein sampling (AVS) in patients with primary aldosteronism (PA). We aimed to determine the cutoff values of the SIs based on cortisol, free metanephrine, and the free-to-total metanephrine ratio (FTMR) using an adapted AVS protocol in combination with CT. Methods: Adults with PA and referred for AVS were recruited in two hypertension centers. The cortisol and free metanephrine-derived SIs were calculated as the concentration of the analyte in adrenal veins divided by the concentration of the analyte in the distal vena cava. The FTMR-derived SI was calculated as the concentration of free metanephrine in the adrenal vein divided by that of total metanephrine in the ipsilateral adrenal vein. The AVS was classified as an unequivocal radiological success (uAVS) if the tip of the catheter was seen in the adrenal vein. The SI cutoffs of each index marker were established using receiver operating characteristic curve analysis. Results: Out of 125 enrolled patients, 65 patients had an uAVS. The SI cutoffs were 2.6 for cortisol, 10.0 for free metanephrine, 0.31 for the FTMR on the left side, and 2.5, 9.9, and 0.25 on the right side. Compared to free metanephrine and the FTMR, cortisol misclassified AVS as unsuccessful in 36.6% and 39.0% of the cases, respectively. Conclusion: This study is the first to calculate the SIs of cortisol, free metanephrine, and the FTMR indices for the AVS procedure. It confirms that free metanephrine-based SIs are better than those based on cortisol.

[Year in review : geriatrics]. / Gériatrie.

In 2018, new recommendations about the prevention of falls and fractures emphasized the benefits from exercise and from multimodal prevention programs but did not endorse any more vitamin D supplementation for falls prevention. Results were contrasted for several studies testing exercise (negative) and cognitive training (mixed results) in the management of older patients suffering from neurocognitive disorders. The new direct oral anticoagulants are increasingly prescribed in older patients despite the paucity of data. New information has been released in 2018 from « real-world ¼ data that seem reassuring about their risk/benefit ratio in old-old patients, provided a careful prescription. Finally, the Mediterranean diet is still gaining credit with a new study showing its benefits in preventing frailty in community-dwelling older persons.

En 2018, l'intérêt de l'activité physique et des programmes de prévention multimodaux est confirmé pour la prévention des chutes, mais l'utilisation de la vitamine D dans cette indication est remise en question. Pour les pathologies neurocognitives, les résultats sont contrastés concernant l'activité physique, alors qu'une revue systématique confirme les bénéfices, certes modestes, de l'entraînement cognitif sur les performances cognitives et la qualité de vie des patients et de leurs proches. Les nouveaux anticoagulants sont de plus en plus largement utilisés chez les patients âgés malgré des données encore limitées, mais plusieurs études du « monde réel ¼ semblent confirmer leur bon rapport risques/bénéfices aussi chez ces patients. Le régime méditerranéen a le vent en poupe, une étude rapporte un bénéfice sur l'incidence de la fragilité.