Functional integrity of the retrosplenial cortex is essential for rapid consolidation and recall of fear memory

Memory storage is a temporally graded process involving different phases and different structures in the mammalian brain. Cortical plasticity is essential to store stable memories, but little is known regarding its involvement in memory processing. Here we show that fear memory consolidation requires early post-training macromolecular synthesis in the anterior part of the retrosplenial cortex (aRSC), and that reversible pharmacological inactivation of this cortical region impairs recall of recent as well as of remote memories. These results challenge the generally accepted idea that neocortical areas are slow encoding systems that participate in the retrieval of remote memories only.Fil: Katche, Cynthia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Dorman, Guido. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Slipczuk, Leandro. Einstein Medical Center; Estados UnidosFil: Cammarota, Martin Pablo. Pontificia Universidade Catolica Do Rio Grande Do Sul; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Medina, Jorge Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentin

BDNF Activates mTOR to Regulate GluR1 Expression Required for Memory Formation

Background: The mammalian target of Rapamycin (mTOR) kinase plays a key role in translational control of a subset of mRNAs through regulation of its initiation step. In neurons, mTOR is present at the synaptic region, where it modulates the activity-dependent expression of locally-translated proteins independently of mRNA synthesis. Indeed, mTOR is necessary for different forms of synaptic plasticity and long-term memory (LTM) formation. However, little is known about the time course of mTOR activation and the extracellular signals governing this process or the identity of the proteins whose translation is regulated by this kinase, during mnemonic processing. Methodology/Principal Findings: Here we show that consolidation of inhibitory avoidance (IA) LTM entails mTOR activation in the dorsal hippocampus at the moment of and 3 h after training and is associated with a rapid and rapamycinsensitive increase in AMPA receptor GluR1 subunit expression, which was also blocked by intra-hippocampal delivery of GluR1 antisense oligonucleotides (ASO). In addition, we found that pre- or post-training administration of function-blocking anti-BDNF antibodies into dorsal CA1 hampered IA LTM retention, abolished the learning-induced biphasic activation of mTOR and its readout, p70S6K and blocked GluR1 expression, indicating that BDNF is an upstream factor controlling mTOR signaling during fear-memory consolidation. Interestingly, BDNF ASO hindered LTM retention only when given into dorsal CA1 1 h after but not 2 h before training, suggesting that BDNF controls the biphasic requirement of mTOR during LT

Association between obesity and infarct size: insight into the obesity paradox.

Abstract: Background: In patients with coronary heart disease, being overweight or obese is associated with better outcomes, a phenomenon known as the \u27obesity paradox\u27. Despite the high prevalence of obesity in the United Sates, its effects on infarct size are largely unexplored. Methods: Prospective cross-sectional study of 102 consecutive patients admitted with acute myocardial infarction (MI). Standardized forms were used to collect data on body mass index (BMI), waist circumference (WC), cardiovascular risk factors, and medications. Peak troponin I and creatinine phosphokinase (CPK) were used to estimate infarct size. Epicardial and pericardial fat were measured by echocardiography. We used univariate and multivariate analyses to assess whether obesity was associated with infarct size. Correlations between BMI, WC and cardiac fat with cardiac biomarkers were also performed. Results: Mean age was 62±12 years, and 55% were men. Obesity was diagnosed in 69%. On multivariate analysis, obesity was associated with greater infarct size in non-ST elevation MI (p=0.02). A positive correlation was observed between BMI and peak troponin I (rho=0.24, p=0.03), and both, BMI and WC had a positive correlations with CPK levels (rho=0.28, & rho=0.28, both p=0.02). However, in ST elevation MI, obesity was associated with smaller infarct size (p=0.05). Epicardial fat + pericardial fat had a negative correlation with peak CPK levels (rho=-0.36, p=0.05). Conclusions: We observed an opposite association between obesity and infarct size depending on the type of MI. These results were unexpected and may provide insight into the pathophysiology of the obesity paradox

Monoclonal Antibodies, Gene Silencing and Gene Editing (CRISPR) Therapies for the Treatment of Hyperlipidemia—The Future Is Here

Hyperlipidemia is a significant risk factor for atherosclerotic cardiovascular disease. Undertreatment of elevated lipids persists despite existing therapies. Here, we provide an update on monoclonal antibodies, gene silencing therapies, and gene editing techniques for the management of hyperlipidemia. The current era of cutting-edge pharmaceuticals targeting low density lipoprotein cholesterol, PCSK9, lipoprotein (a), angiopoietin-like 3, and apolipoprotein C3 are reviewed. We outline what is known, studies in progress, and futuristic goals. This review of available and upcoming biotechnological lipid therapies is presented for clinicians managing patients with familial hyperlipidemia, statin intolerance, hypertriglyceridemia, or elevated lipoprotein (a) levels

What is really new in triglyceride guidelines?

Purpose of review: In this review, we will summarize some of the landmark clinical trials of triglyceride-lowering therapies and review updates in clinical guidelines with regards to treatment of elevated triglyceride levels.Recent findings: Accumulating evidence from epidemiologic and Mendelian randomization studies has shown that triglyceride and are causally linked to atherosclerotic cardiovascular disease (ASCVD) and contribute to atherosclerosis. However, most clinical trials evaluating use of triglyceride-lowering therapies, including fibrates, niacin and fish oils [combined eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] have not been able to demonstrate significant cardiovascular risk reduction. REDUCE-IT is the only randomized clinical trial that showed significant cardiovascular benefit with the use of icosapent ethyl esters (a purified EPA), in patients with ASCVD or diabetes with elevated risk on maximally tolerate statin. Summary: Current guidelines and expert consensus documents from multiple societies strongly endorse therapeutic lifestyle interventions to effectively lower TG as the first-line therapy for treatment of hypertriglyceridemia. Evaluation and treatment of secondary causes of hypertriglyceridemia including optimal glycaemic control is crucial. Statins lower ASCVD risk in patients with elevated triglycerides and are first-line for treatment of elevated triglyceride. In a patient with residual mild to moderate hypertriglyceridemia on maximally tolerate statin and elevated cardiovascular risk icosapent, ethyl ester may be used for further ASCVD risk reduction

The clinical efficacy and safety of bempedoic acid in patients at elevated risk of cardiovascular disease: A meta-analysis of randomized clinical trials

Purpose: Statins are first-line agents to reduce low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, however, they are insufficient and/or intolerable in many patients. To that end, we conducted a meta-analysis of Bempedoic Acid (BA), a novel LDL-C lowering agent. Methods: We retrieved randomized clinical trials (RCTs) of BA by searching Pubmed, the Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov. We used the Mantel-Haenszel method to pool estimates. The I2 measure was used to quantify heterogeneity. Treatment effects are provided as relative risks (RR), absolute risk differences (ARD), and number needed to treat/harm (NNTB/H). Analyses were conducted using R, version 4.1.2. Results: 11 trials enrolling 18,496 patients were included. Compared to placebo, BA reduced the risk of major adverse cardiovascular events (RR: 0.87; 95% CI: 0.80 to 0.95; ARD: -1.63%; NNT: 62), myocardial infarction (RR: 0.76; 95% CI: 0.66 to 0.89; ARD: -1.03%; NNT: 98), unstable angina hospitalization (RR: 0.70; 95%: CI: 0.55 to 0.89; ARD: -0.57%; NNT: 177), revascularization (RR: 0.81; 95% CI: 0.72 to 0.91; ARD: -1.31%; NNT: 77), and myalgia (RR: 0.85; 95% CI: 0.75 to 0.95; ARD: -0.99%; NNT: 102). BA significantly increased the risk of gout (RR: 1.56; 95% CI: 1.27 to 1.91; ARD: 0.99%; NNH: 101), renal impairment (RR: 1.35; 95% CI: 1.22 to 1.49; ARD: 2.54%; NNH: 40), and cholelithiasis (RR: 1.87; 95% CI: 1.43 to 2.44; ARD: 1.01%; NNH: 100). Conclusion: BA effectively reduces the risk of cardiovascular events and myalgia but increases the risk of gout, cholelithiasis, and renal impairmen

Attenuating the persistence of fear memory storage using a single dose of antidepressant

Enhanced memory for emotionally arousing events is a highly adaptive phenomenon that helps us remember both dangerous and favorable situations. However, under certain conditions, intrusive and persistent traumatic memories can lead to anxiety disorders, like posttraumatic stress disorder. Current therapies for anxiety disorders involve pharmacological or behavioral manipulations of long-lasting fear memories in which patients explicitly recall the painful traumatic experience. Despite recent advances, a major question of how to effectively attenuate persistent fear memories in a safe and less distressful manner remains unresolved.Fil: Slipczuk, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Tomaiuolo, Micol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Garagoli, F.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Weisstaub, Noelia V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Katche, Cynthia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Bekinschtein, Pedro Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Medina, Jorge Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Infective endocarditis epidemiology over five decades: a systematic review.

AIMS: To Assess changes in infective endocarditis (IE) epidemiology over the last 5 decades. METHODS AND RESULTS: We searched the published literature using PubMed, MEDLINE, and EMBASE from inception until December 2011. DATA FROM: Einstein Medical Center, Philadelphia, PA were also included. Criteria for inclusion in this systematic review included studies with reported IE microbiology, IE definition, description of population studied, and time frame. Two authors independently extracted data and assessed manuscript quality. One hundred sixty studies (27,083 patients) met inclusion criteria. Among hospital-based studies (n=142; 23,606 patients) staphylococcal IE percentage increased over time, with coagulase-negative staphylococcus (CNS) increasing over each of the last 5 decades (p<0.001) and Staphylococcus aureus (SA) in the last decade (21% to 30%; p<0.05). Streptococcus viridans (SV) and culture negative (CN) IE frequency decreased over time (p<0.001), while enterococcal IE increased in the last decade (p<0.01). Patient age and male predominance increased over time as well. In subgroup analysis, SA frequency increased in North America, but not the rest of the world. This was due, in part, to an increase in intravenous drug abuse IE in North America (p<0.001). Among population-based studies (n=18; 3,477 patients) no significant changes were found. CONCLUSION: Important changes occurred in IE epidemiology over the last half-century, especially in the last decade. Staphylococcal and enterococcal IE percentage increased while SV and CN IE decreased. Moreover, mean age at diagnosis increased together with male:female ratio. These changes should be considered at the time of decision-making in treatment of and prophylaxis for IE