When should cardiovascular prevention begin? The importance of antenatal, perinatal and primordial prevention

Cardiovascular diseases represent a major health problem, being one of the leading causes of morbidity and mortality worldwide. Therefore, in this scenario, cardiovascular prevention plays an essential role although it is difficult to establish when promoting and implementing preventive strategies. However, there is growing evidence that prevention should start even before birth, during pregnancy, aiming to avoid the onset of cardiovascular risk factors, since events that occur early in life have a great impact on the cardiovascular risk profile of an adult. The two pillars of this early preventive strategy are nutrition and physical exercise, together with prevention of cardio-metabolic diseases during pregnancy. This review attempts to gather the growing evidence of the benefits of antenatal, perinatal and primordial prevention, discussing also the possibility to reverse or to mitigate the cardiovascular profile developed in the initial stages of life. This could pave the way for future research, investigating the optimal time and duration of these preventing measures, their duration and maintenance in adulthood, and the most effective interventions according to the different age and guiding in the next years, the best clinical practice and the political strategies to cope with cardiovascular disease

Calcium-Activated Potassium Channels BK and IK1 Are Functionally Expressed in Human Gliomas but Do Not Regulate Cell Proliferation

Gliomas are morbid brain tumors that are extremely resistant to available chemotherapy and radiology treatments. Some studies have suggested that calcium-activated potassium channels contribute to the high proliferative potential of tumor cells, including gliomas. However, other publications demonstrated no role for these channels or even assigned them antitumorogenic properties. In this work we characterized the expression and functional contribution to proliferation of Ca2+-activated K+ channels in human glioblastoma cells. Quantitative RT-PCR detected transcripts for the big conductance (BK), intermediate conductance (IK1), and small conductance (SK2) K+ channels in two glioblastoma-derived cell lines and a surgical sample of glioblastoma multiforme. Functional expression of BK and IK1 in U251 and U87 glioma cell lines and primary glioma cultures was verified using whole-cell electrophysiological recordings. Inhibitors of BK (paxilline and penitrem A) and IK1 channels (clotrimazole and TRAM-34) reduced U251 and U87 proliferation in an additive fashion, while the selective blocker of SK channels UCL1848 had no effect. However, the antiproliferative properties of BK and IK1 inhibitors were seen at concentrations that were higher than those necessary to inhibit channel activity. To verify specificity of pharmacological agents, we downregulated BK and IK1 channels in U251 cells using gene-specific siRNAs. Although siRNA knockdowns caused strong reductions in the BK and IK1 current densities, neither single nor double gene silencing significantly affected rates of proliferation. Taken together, these results suggest that Ca2+-activated K+ channels do not play a critical role in proliferation of glioma cells and that the effects of pharmacological inhibitors occur through their off-target actions

Multi-year characterisation of the broad-band emission from the intermittent extreme BL Lac 1ES~2344+514

The BL Lac 1ES 2344+514 is known for temporary extreme properties (e.g., a shift of the synchrotron SED peak energy $\nu_{synch,p}$ above 1keV). While those extreme states were so far observed only during high flux levels, additional multi-year observing campaigns are required to achieve a coherent picture. Here, we report the longest investigation of the source from radio to VHE performed so far, focusing on a systematic characterisation of the intermittent extreme states. While our results confirm that 1ES 2344+514 typically exhibits $\nu_{synch,p}>$1keV during elevated flux periods, we also find periods where the extreme state coincides with low flux activity. A strong spectral variability thus happens in the quiescent state, and is likely caused by an increase of the electron acceleration efficiency without a change in the electron injection luminosity. We also report a strong X-ray flare (among the brightest for 1ES 2344+514) without a significant shift of $\nu_{synch,p}$. During this particular flare, the X-ray spectrum is among the softest of the campaign. It unveils complexity in the spectral evolution, where the common harder-when-brighter trend observed in BL Lacs is violated. During a low and hard X-ray state, we find an excess of the UV flux with respect to an extrapolation of the X-ray spectrum to lower energies. This UV excess implies that at least two regions contribute significantly to the infrared/optical/ultraviolet/X-ray emission. Using the simultaneous MAGIC, XMM-Newton, NuSTAR, and AstroSat observations, we argue that a region possibly associated with the 10 GHz radio core may explain such an excess. Finally, we investigate a VHE flare, showing an absence of simultaneous variability in the 0.3-2keV band. Using a time-dependent leptonic modelling, we show that this behaviour, in contradiction to single-zone scenarios, can instead be explained by a two-component model.Comment: Accepted for publication in Astronomy & Astrophysic

Ablation therapy for ventricular arrhythmias in patients with LVAD: Multiple faces of an electrophysiological challenge

Left ventricular assist device implantation is a recognized treatment option for patients with advanced heart failure refractory to medical therapy and can be used both as bridge to transplantation and as destination therapy. The risk of ventricular arrhythmias is common after left ventricular assist device implantation and is influenced by pre-, peri and post-operative determinants. The management of ventricular arrhythmias can be a challenge when they become refractory to medication or to device therapy and their impact on prognosis can be detrimental despite the mechanical support. In this setting, catheter ablation is being increasingly recognized as a feasible option for patients in which standard therapeutic strategies fail, but also with preventive purpose. Catheter ablation is being increasingly considered for the management of ventricular arrhythmias in patients with left ventricular assist device despite complex clinical and technical peculiarities due to the characteristics of the mechanical support. Much conflicting data exist regarding the predictors of success of the procedure and the rate of recurrence. In this review we discuss the latest evidences regarding catheter ablation of ventricular arrhythmias in this subset of patients, focusing on clinical characteristics, arrhythmia etiology, technical aspects and postprocedural features which must be considered by the electrophysiologist

Risk stratification in cardiogenic shock: a focus on the available evidence

Cardiogenic shock is a clinical syndrome which is defined as the presence of primary cardiac disorder that results in hypotension together with signs of organ hypoperfusion in the state of normovolaemia or hypervolaemia. It represents a complex life-threatening condition, characterized by a high mortality rate, that requires urgent diagnostic assessment as well as treatment; therefore, it is of paramount important to advocate for a thorough risk stratification. In fact, the early identification of patients that could benefit the most from more aggressive and invasive approaches could facilitate a more efficient resource allocation. This review attempts to critically analyse the current evidence on prognosis in cardiogenic shock, focusing in particular on clinical, laboratoristic and echocardiographic prognostic parameters. Furthermore, it focuses also on the available prognostic scores, highlighting the strengths and the possible pitfalls. Finally, it provides insights into future direction that could be followed in order to ameliorate risk stratification in this delicate subset of patients

The role of the left atrial function in the surgical management of aortic and mitral valve disease

The right management of both mitral and aortic disease can be challenging, especially in asymptomatic patients. The current guidelines recommend valve repair or replacement when symptoms arise or when there is an evident left ventricular dysfunction. However, deciding the optimal surgical timing can be very difficult, since the line between the absence of symptoms and being minimally symptomatic, especially in the elderly, is blurred. Another relevant issue regards the second surgical criterion: operating on a patient with a reduced left ventricular ejection fraction or with a dilated left ventricle might jeopardize the possibility of a fully reverse remodeling of the heart after surgery. In this scenario, the left atrium might play an important role. In particular, left atrial deformation might be a very useful tool to detect early ultrastructural alterations, and help or support guiding a patient-tailored treatment at an early stage, optimizing the outcome in the long term. © 2019 Wiley Periodicals, Inc

Investigating the hydrogen-bond acceptor site of the nicotinic pharmacophore model : a computational and experimental study using epibatidine-related molecular probes

The binding mode of nicotinic agonists has been thoroughly investigated in the last decades. It is now accepted that the charged amino group is bound by a cation-\u3c0 interaction to a conserved tryptophan residue, and that the aromatic moiety is projected into a hydrophobic pocket deeply located inside the binding cleft. A hydrogen bond donor/acceptor, maybe a water molecule solvating this receptor subsite, contributes to further stabilize the nicotinic ligands. The position of this water molecule has been established by several X-ray structures of the acetylcholine-binding protein. In this study, we computationally analyzed the role of this water molecule as a putative hydrogen bond donor/acceptor moiety in the agonist binding site of the three most relevant heteromeric (\u3b14\u3b22, \u3b13\u3b24) and homomeric (\u3b17) neuronal nicotinic acetylcholine receptor (nAChR) subtypes. Our theoretical investigation made use of epibatidine 1 and deschloroepibatidine 2 as molecular probes, and was then extended to their analogues 3 and 4, which were subsequently synthesized and tested at the three target receptor subtypes. Although the pharmacological data for the new ligands 3 and 4 indicated a reduction of the affinity at the studied nAChRs with respect to reference agonists, a variation of the selectivity profile was clearly evidenced

An unbalanced synaptic transmission: Cause or consequence of the amyloid oligomers neurotoxicity?

Amyloid-β (Aβ) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer’s disease (AD). Whereas in AD, Aβ is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aβ aggregated species, soluble oligomers are suggested to be responsible for most of Aβ’s toxic effects. Aβ oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hy-perexcitability and neural circuit dysfunction, which in turn increase Aβ deposition and facilitate neurodegeneration, resulting in an Aβ-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aβ induces on synaptic dysfunction and network disorganization

M2 acetylcholine receptor activation shows anti-proliferative and pro-apoptotic effects in human glioblastoma cells

Introduction. Muscarinic receptors are expressed in several primary and metastatic tumors and appear involved in their growth and propagation. In the present work we have studied the effects of M2 receptor activation on cell growth and survival of human glioblastoma cells. Materials and Methods. Glioma cell lines and primary cultures from biopsies were used for our analysis. FACS analysis was used to evaluate cell proliferation and apoptosis. Real time PCR, immunocytochemistry, western blot and Elisa were also used to analyze the modulated expression of genes and proteins involved in cell cycle arrest and apoptosis. Results. We demonstrated that the activation of M2 receptor by selective agonist arecaidine caused the arrest of cell cycle progression in two glioblastoma cell lines (U251MG and U87MG), with cell accumulation in G1 phase for U87 and in G2/M for U251 cells. Moreover FACS analysis and Elisa for cytoplasmic nucleosomes have demonstrated that arecaidine induced apoptosis in glioblastoma cells. The same effects were also observed in primary cell cultures. Apoptotic cell death was counteracted by the treatment with N-acetyl-L-cysteine, a scavenger of ROS, suggesting that arecaidine induced oxidative stress in glioblastoma cells. In particular in U251 cells, the oxidative stress caused DNA damage, cell cycle arrest in M phase, disregulation of mitotic spindle assembly and misalignment of chromosomes. Conclusion. Our data demonstrate that M2 receptor activation, counteracting glioblastoma cell proliferation and survival may represent a new interesting therapeutic target in glioblastoma therapy. This project was supported by Cofin-Prin 2007 fund