Glutathione infusion before primary percutaneous coronary intervention: A randomised controlled pilot study

Objective: In the setting of reperfused ST-elevation myocardial infarction (STEMI), increased production of reactive oxygen species (ROS) contributes to reperfusion injury. Among ROS, hydrogen peroxide (H2O2) showed toxic effects on human cardiomyocytes and may induce microcirculatory impairment. Glutathione (GSH) is a water-soluble tripeptide with a potent oxidant scavenging activity. We hypothesised that the infusion of GSH before acute reoxygenation might counteract the deleterious effects of increased H2O2 generation on myocardium. Methods: Fifty consecutive patients with STEMI, scheduled to undergo primary angioplasty, were randomly assigned, before intervention, to receive an infusion of GSH (2500 mg/25 mL over 10 min), followed by drug administration at the same doses at 24, 48 and 72 hours elapsing time or placebo. Peripheral blood samples were obtained before and at the end of the procedure, as well as after 5 days. H2O2 production, 8-iso-prostaglandin F2α (PGF2α) formation, H2O2 breakdown activity (HBA) and nitric oxide (NO) bioavailability were determined. Serum cardiactroponin T (cTpT) was measured at admission and up to 5 days. Results: Following acute reperfusion, a significant reduction of H2O2 production (p=0.0015) and 8-iso-PGF2α levels (p=0.0003), as well as a significant increase in HBA (p<0.0001)and NO bioavailability (p=0.035), was found in the GSH group as compared with placebo. In treated patients, attenuated production of H2O2 persisted up to 5 days from the index procedure (p=0.009) and these changes was linked to those of the cTpT levels (r=0.41, p=0.023). Conclusion: The prophylactic and prolonged infusion of GSH seems to determine a rapid onset and persistent blunting of H2O2 generation improving myocardial cell survival. Nevertheless, a larger trial, adequately powered for evaluation of clinical endpoints, is ongoing to confirm the current finding

Gender- and Age-Dependent γ-Secretase Activity in Mouse Brain and Its Implication in Sporadic Alzheimer Disease

Alzheimer disease (AD) is an age-related disorder. Aging and female gender are two important risk factors associated with sporadic AD. However, the mechanism by which aging and gender contribute to the pathogenesis of sporadic AD is unclear. It is well known that genetic mutations in γ-secretase result in rare forms of early onset AD due to the aberrant production of Aβ42 peptides, which are the major constituents of senile plaques. However, the effect of age and gender on γ-secretase has not been fully investigated. Here, using normal wild-type mice, we show mouse brain γ-secretase exhibits gender- and age-dependent activity. Both male and female mice exhibit increased Aβ42∶Aβ40 ratios in aged brain, which mimics the effect of familial mutations of Presenilin-1, Presenlin-2, and the amyloid precursor protein on Aβ production. Additionally, female mice exhibit much higher γ-secretase activity in aged brain compared to male mice. Furthermore, both male and female mice exhibit a steady decline in Notch1 γ-secretase activity with aging. Using a small molecule affinity probe we demonstrate that male mice have less active γ-secretase complexes than female mice, which may account for the gender-associated differences in activity in aged brain. These findings demonstrate that aging can affect γ-secretase activity and specificity, suggesting a role for γ-secretase in sporadic AD. Furthermore, the increased APP γ-secretase activity seen in aged females may contribute to the increased incidence of sporadic AD in women and the aggressive Aβ plaque pathology seen in female mouse models of AD. In addition, deceased Notch γ-secretase activity may also contribute to neurodegeneration. Therefore, this study implicates altered γ-secretase activity and specificity as a possible mechanism of sporadic AD during aging

Food Catches the Eye but Not for Everyone: A BMI–Contingent Attentional Bias in Rapid Detection of Nutriments

An organism's survival depends crucially on its ability to detect and acquire nutriment. Attention circuits interact with cognitive and motivational systems to facilitate detection of salient sensory events in the environment. Here we show that the human attentional system is tuned to detect food targets among nonfood items. In two visual search experiments participants searched for discrepant food targets embedded in an array of nonfood distracters or vice versa. Detection times were faster when targets were food rather than nonfood items, and the detection advantage for food items showed a significant negative correlation with Body Mass Index (BMI). Also, eye tracking during searching within arrays of visually homogenous food and nonfood targets demonstrated that the BMI-contingent attentional bias was due to rapid capturing of the eyes by food items in individuals with low BMI. However, BMI was not associated with decision times after the discrepant food item was fixated. The results suggest that visual attention is biased towards foods, and that individual differences in energy consumption - as indexed by BMI - are associated with differential attentional effects related to foods. We speculate that such differences may constitute an important risk factor for gaining weight

Increased Expression of PS1 Is Sufficient to Elevate the Level and Activity of γ-Secretase In Vivo

Increase in the generation and deposition of amyloid-β (Aβ) plays a central role in the development of Alzheimer's Disease (AD). Elevation of the activity of γ-secretase, a key enzyme required for the generation for Aβ, can thus be a potential risk factor in AD. However, it is not known whether γ-secretase can be upregulated in vivo. While in vitro studies showed that expression of all four components of γ-secretase (Nicastrin, Presenilin, Pen-2 and Aph-1) are required for upregulation of γ-secretase, it remains to be established as to whether this is true in vivo. To investigate whether overexpressing a single component of the γ-secretase complex is sufficient to elevate its level and activity in the brain, we analyzed transgenic mice expressing either wild type or familial AD (fAD) associated mutant PS1. In contrast to cell culture studies, overexpression of either wild type or mutant PS1 is sufficient to increase levels of Nicastrin and Pen-2, and elevate the level of active γ-secretase complex, enzymatic activity of γ-secretase and the deposition of Aβ in brains of mice. Importantly, γ-secretase comprised of mutant PS1 is less active than that of wild type PS1-containing γ-secretase; however, γ-secretase comprised of mutant PS1 cleaves at the Aβ42 site of APP-CTFs more efficiently than at the Aβ40 site, resulting in greater accumulation of Aβ deposits in the brain. Our data suggest that whereas fAD-linked PS1 mutants cause early onset disease, upregulation of PS1/γ-secretase activity may be a risk factor for late onset sporadic AD

Presenilin 2 Is the Predominant γ-Secretase in Microglia and Modulates Cytokine Release

Presenilin 1 (PS1) and Presenilin 2 (PS2) are the enzymatic component of the γ-secretase complex that cleaves amyloid precursor protein (APP) to release amyloid beta (Aβ) peptide. PS deficiency in mice results in neuroinflammation and neurodegeneration in the absence of accumulated Aβ. We hypothesize that PS influences neuroinflammation through its γ-secretase action in CNS innate immune cells. We exposed primary murine microglia to a pharmacological γ-secretase inhibitor which resulted in exaggerated release of TNFα and IL-6 in response to lipopolysaccharide. To determine if this response was mediated by PS1, PS2 or both we used shRNA to knockdown each PS in a murine microglia cell line. Knockdown of PS1 did not lead to decreased γ-secretase activity while PS2 knockdown caused markedly decreased γ-secretase activity. Augmented proinflammatory cytokine release was observed after knockdown of PS2 but not PS1. Proinflammatory stimuli increased microglial PS2 gene transcription and protein in vitro. This is the first demonstration that PS2 regulates CNS innate immunity. Taken together, our findings suggest that PS2 is the predominant γ-secretase in microglia and modulates release of proinflammatory cytokines. We propose PS2 may participate in a negative feedback loop regulating inflammatory behavior in microglia

The structure and function of Alzheimer's gamma secretase enzyme complex

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer’s disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity

Three-dimensional speckle tracking echocardiography in the assessment of right ventricular dysfunction after surgical repair of tetralogy of Fallot.

Background: The combined effects of preoperative hypertrophy and hypoxia, possible intraoperative myocardial damage, type of reconstruction, and acquired postoperative lesions such as pulmonary regurgitation may result in impaired RV deformation in post-operative tetralogy of Fallot (TF). Recently 3D speckle tracking echocardiography (3DSTE) has been proposed to assess mechanical dyssynchrony in these patients but the role of electromechanical dysfunction is not completely clear. Methods: Sixteen patients after TF repair (aged 17-53years) with dilated right ventricle, right bundle branch block (QRS >120ms), and NYHA class I or greater were studied with twodimensional and three-dimensional speckle tracking echocardiography. Right ventricular enddiastolic and end-systolic volumes were measured from three-dimensional datasets and right ventricular ejection fraction (3D-RVEF) was obtained. Right intraventricular dyssynchrony was determined as the difference between the longest and shortest electromechanical coupling times in the basal septal and lateral RV segments. Interventricular dyssynchrony was determined as the difference between electromechanical coupling times in the basal lateral LV segment and the most delayed RV segment. Sixteeen age-matched healthy subjects were selected as controls. Results: Right intraventricular dyssynchrony (77.1+/-24.2ms vs 13.1+/-8.9ms) and interventricular dyssynchrony (74.7+/-22.2ms vs 11.4+/-7.9ms) were shown in patients compared to normal controls. Right intraventricular dyssynchrony correlated with RV longitudinal strain (r=0.62, p<0.005), 3D RV end-systolic volume (r=0.47, p=0.02), and QRS duration (r=0.39, p=0.03). Interventricular dyssynchrony correlated with RV longitudinal strain (r=0.73, p<0.001), RV systolic pressure (r=0.59, p<0.005), 3D-RVEF (r=0.53, p=0.003), and QRS duration (r=-0.44, p=0.031). Reduced RV strain, 3D-RVEF and prolonged QRS duration were the main determinant factors predicting RV dyssynchrony by multivariate analysis. On ROC curves RV strain and 3DRVEF had optimal predictive accuracy of the NYHA functional class and a larger area under the receiver operating characteristic curve than the QRS duration. Conclusions: In patients with repaired TF RV dyssynchrony is associated with reduced 3D-RVEF and RV 3DSTE parameters