Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 hours, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory

β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells

β-Hydroxy-β-methylbutyrate (HMB) has been shown to enhance cell survival, differentiation and protein turnover in muscle, mainly activating phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinases/ extracellular-signal-regulated kinases (MAPK/ERK) signaling pathways. Since these two pathways are related to neuronal survival and differentiation, in this study, we have investigated the neurotrophic effects of HMB in mouse neuroblastoma Neuro2a cells. In Neuro2a cells, HMB promotes differentiation to neurites independent from any effects on proliferation. These effects are mediated by activation of both the PI3K/Akt and the extracellular-signal-regulated kinases (ERK1/2) signaling as demonstrated by the use of specific inhibitors of these two pathways. As myocyte-enhancer factor 2 (MEF2) family of transcription factors are involved in neuronal survival and plasticity, the transcriptional activity and protein levels of MEF2 were also evaluated. HMB promoted MEF2-dependent transcriptional activity mediated by the activation of Akt and ERK1/2 pathways. Furthermore, HMB increases the expression of brain glucose transporters 1 (GLUT1) and 3 (GLUT3), and mTOR phosphorylation, which translates in a higher protein synthesis in Neuro2a cells. Furthermore, Torin1 and rapamycin effects on MEF2 transcriptional activity and HMB-dependent neurite outgrowth support that HMB acts through mTORC2. Together, these findings provide clear evidence to support an important role of HMB in neurite outgrowth.This project has been funded by Abbott Nutrition R&D

The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway

Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures

Evolution of Pulmonary Embolism Response Teams in the United States: A Review of the Literature

Pulmonary embolism (PE) is a significant cause of cardiovascular mortality, with varying presentations and management challenges. Traditional treatment approaches often differ, particularly for submassive/intermediate-risk PEs, because of the lack of clear guidelines and comparative data on treatment efficacy. The introduction of pulmonary embolism response teams (PERTs) aims to standardize and improve outcomes in acute PE management through multidisciplinary collaboration. This review examines the conception, evolution, and operational mechanisms of PERTs while providing a critical analysis of their implementation and efficacy using retrospective trials and recent randomized trials. The study also explores the integration of advanced therapeutic devices and treatment protocols facilitated by PERTs. PERT programs have significantly influenced the management of both massive and submassive PEs, with notable improvements in clinical outcomes such as decreased mortality and reduced length of hospital stay. The utilization of advanced therapies, including catheter-directed thrombolysis and mechanical thrombectomy, has increased under PERT guidance. Evidence from various studies, including those from the National PERT Consortium, underscores the benefits of these multidisciplinary teams in managing complex PE cases, despite some studies showing no significant difference in mortality. PERT programs have demonstrated potentials to reduce morbidity and mortality, streamlining the use of healthcare resources and fostering a model of sustainable practice across medical centers. PERT program implementation appears to have improved PE treatment protocols and innovated advanced therapy options, which will be further refined as they are employed in clinical practice. The continued expansion of the capabilities of PERTs and the forthcoming results from ongoing randomized trials are expected to further define and optimize management protocols for acute PEs

Allogeneic cardiosphere-derived cells for the treatment of heart failure with reduced ejection fraction: The Dilated cardiomYopathy iNtervention with Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial

Aims: The DYNAMIC trial assessed the safety and explored the efficacy of multivessel intracoronary infusion of allogeneic cardiosphere-derived cells (CDCs) in patients with heart failure and reduced ejection fraction (HFrEF). Here we report the results of the DYNAMIC trial. Methods and results: We enrolled 14 patients with EF ≤35% and NYHA Class III-IV despite maximal medical and device-based therapy in this single-centre, open-label trial. Intracoronary catheterisation delivered four escalating doses (totalling 37.5-75 million cells) by sequential non-occlusive technique to all three major coronary arteries. The primary safety endpoint was a composite of post-infusion TIMI flow, ventricular tachycardia/fibrillation, sudden death, major adverse cardiac events or acute myocarditis within 72 hours. Twelve patients were male and EF averaged 23.0% (±4.5%). No primary safety endpoints were observed. Two patients died of HFrEF progression nine and 12 months following infusion. Compared to baseline, there was an improvement in EF (26.8% vs 22.9%, p=0.023) and left ventricular end-systolic volume (139.5 vs 177.8 cm3, p=0.03) at six months. Quality of life (QoL) scores and NYHA class (p=0.006) improved at six months. At 12 months, the improvement in EF and QoL remained significant. Conclusions: Global intracoronary infusion of allogeneic CDCs is safe and feasible. The efficacy of allogeneic CDCs in HFrEF needs to be tested in larger randomised trials. © Europa Digital & Publishing 2020. All rights reserved

Cardio-Oncology and Multi-Imaging Modalities

Early detection and the rise of targeted cancer treatment have led to increased overall survival and decreased mortality among cancer patients. As the cancer survivor population ages, there is an increased risk for cardiovascular disease due to pre-existing comorbidities, deconditioning during therapy, or the natural progression of aging. Furthermore, with emerging oncologic therapies, there is an increased recognition of their potential cardiovascular toxicities. Indeed, heart disease is the leading cause of death in cancer survivors, which may reflect upon both the success of novel oncologic therapies and their potential cardiovascular toxicities. This recognition has driven the development of cardio-oncology, a multi-disciplinary field that involves collaboration between hematologists, oncologists, and cardiologists to screen, prevent, and manage cardiovascular disease in cancer patients and cancer survivors. The field focuses on early cardiovascular detection and prevention for these patients before, during, and after their oncologic treatment. As oncologic therapies evolve and our knowledge of short- and long-term adverse cardiovascular effects grows, it is critical for physicians to identify those at risk for increased morbidity and mortality, while also balancing the importance of their oncologic treatment plan. Multimodality cardiac imaging is the crux of the diagnosis and surveillance of these patients within cardio-oncology, and includes echocardiography, nuclear, computed tomography (CT), and cardiac magnetic resonance (CMR). Cardiac imaging is essential to establish the baseline function and assess various cardiotoxicities, including left ventricular dysfunction, heart failure, atherosclerosis, vascular injury, and arrhythmias. This review will discuss common oncologic therapies and their cardiotoxic profiles, the cardiac multimodality imaging modalities used in cardio-oncology, and the various approaches for the diagnosis and surveillance of this population