The Human MDM2 Oncoprotein Increases the Transcriptional Activity and the Protein Level of the p53 Homolog p63

Genetic alteration of the p53 tumor suppressor gene, which monitors DNA damage and operates cell cycle checkpoints, is a major factor in the development of human malignancies. The p53 protein belongs to a family that also includes two structurally related proteins, p63 and p73. Although all three proteins share similar transcriptional functions and antiproliferative effects, each of them appears to play a distinct role in development and tumor suppression. One of the principal regulators of p53 activity is the MDM2 protein. The interaction of MDM2 with p53 inhibits p53 transcriptional activity and targets p53 for ubiquitin-dependent degradation. The ability of MDM2 to inhibit p53 functions is antagonized by the ARF oncosuppressor protein. We show here that like p53, the p63alpha and p63gamma isoforms are able to associate with human MDM2 (HDM2). Overexpression of HDM2 increased the steady-state level of intracellular p63 and enhanced its transcriptional activity. Both effects appeared to be counteracted by ARF coexpression. These data indicate that p63 can be activated by HDM2 under conditions in which p53 is inhibited. Therefore, HDM2 expression could support p63-specific transcriptional functions on a common set of genes, keeping interference by p53 at a minimum

Heart rate variability analysis in postural orthostatic tachycardia syndrome: a case report

The authors present a case of 36 year old male patient with idiopathic postural orthostatic tachycardia syndrome (POTS) diagnosed during head-up tilt testing. Power spectral analysis of heart rate variability (HRV) during the tilt test revealed that the ratio of low and high frequency powers (LF/HF) increased with the onset of orthostatic intolerance. This analysis confirmed in our patient a strong activation in sympathetic tone

Pathophysiological mechanisms and clinical evidence of relationship between Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease

Evidence suggests a close connection between Nonalcoholic Fatty Liver Disease (NAFLD) and increased cardiovascular (CV) risk. Several cross-sectional studies report that NAFLD is related to preclinical atherosclerotic damage, and to coronary, cerebral and peripheral vascular events. Similar results have been showed by prospective studies and also by meta-analyzes on observational studies. The pathophysiological mechanisms of NAFLD are related to insulin resistance, which causes a dysfunction in adipokine production, especially adiponectin, from adipose tissue. A proinflammatory state and an increase in oxidative stress, due to increased reacting oxygen species (ROS) formation with consequent oxidation of free fatty acids and increased de novo lipogenesis with accumulation of triglycerides, are observed. These mechanisms may have an impact on atherosclerotic plaque formation and progression, and they can lead to increased cardiovascular risk in subjects with NAFLD. This review extensively discusses and comments current and developing NAFLD therapies and their possible impact on cardiovascular outcome

High current and low q95 scenario studies for FAST in the view of ITER and DEMO

The Fusion Advanced Study Torus (FAST) has been proposed as a possible European satellite, in view of ITER and DEMO, in order to: a) explore plasma wall interaction in reactor relevant conditions b) test tools and scenarios for safe and reliable tokamak operation up to the border of stability c) address fusion plasmas with a significant population of fast particles. A new FAST scenario has been designed focusing on low-q operation, at plasma current IP=10 MA, toroidal field BT=8.5T, with a q95=2.3 that would correspond to IP=20 MA in ITER. The flat-top of the discharge can last a couple of seconds (i.e. half the diffusive resistive time and twice the energy confinement time), and is limited by the heating of the toroidal field coils. A preliminary evaluation of the end-of-pulse temperatures and of the electromagnetic forces acting on the central solenoid pack and poloidal field coils has been performed. Moreover, a VDE plasma disruption has been simulated and the maximum total vertical force applied on the vacuum vessel has been estimated

An atypical assessment of Ebstein’s anomaly in an 86-year-old man

We present the echocardiographic analysis of an 86- year-old man affected by Ebstein’s anomaly. In the natural history of this congenital disease only 5% of patients survive beyond the fifth decade. The patient presented severe right atrial dilatation and right heart failure, and he was referred to our institution for supraventricular tachycardia

pathogenesis of takotsubo syndrome

Takotsubo syndrome (TTS) is an enigmatic disease with a multifactorial and still unresolved pathogenesis. Postulated mechanisms include catecholamine excess, coronary artery spasm, and microvascular dysfunction, however catecholamines seem to play a central role in the pathophysiology of TTS. In facts catecholamines have relevant effects on the vasculature and myocardium. Toxic direct effects of catecholamine on myocardium are mediated by multiple pathway including functional hypoxia, metabolic changes and changes in membrane permeability leading to various electrolytic imbalances. Recently report of familial cases has suggested a genetic component. Further research is required to help clarify the proposed hypotheses and to increase our understanding of the cardiovascular responses to acute stress and the pathophysiology underpinning TTS

Alcohol Septal Ablation in Patients with Hypertrophic Obstructive Cardiomyopathy: A Contemporary Perspective

Alcohol septal ablation is a minimally invasive procedure for the treatment of left ventricular outflow tract (LVOT) obstruction in patients with hypertrophic obstructive cardiomyopathy (HOCM) who remain symptomatic despite optimal medical therapy. The procedure causes a controlled myocardial infarction of the basal portion of the interventricular septum by the injection of absolute alcohol with the aim of reducing LVOT obstruction and improving the patient's hemodynamics and symptoms. Numerous observations have demonstrated the efficacy and safety of the procedure, making it a valid alternative to surgical myectomy. In particular, the success of alcohol septal ablation depends on appropriate patient selection and the experience of the institution where the procedure is performed. In this review, we summarize the current evidence on alcohol septal ablation and highlight the importance of a multidisciplinary approach involving a team of clinical and interventional cardiologists and cardiac surgeons with high expertise in the management of HOCM patients-the Cardiomyopathy Team

Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry

Background: The inflammatory response occurring in acute myocardial infarction (AMI) has been proposed as a potential pharmacological target. Sodium-glucose co-transporter 2 inhibitors (SGLT2-I) currently receive intense clinical interest in patients with and without diabetes mellitus (DM) for their pleiotropic beneficial effects. We tested the hypothesis that SGLT2-I have anti-inflammatory effects along with glucose-lowering properties. Therefore, we investigated the link between stress hyperglycemia, inflammatory burden, and infarct size in a cohort of type 2 diabetic patients presenting with AMI treated with SGLT2-I versus other oral anti-diabetic (OAD) agents. Methods: In this multicenter international observational registry, consecutive diabetic AMI patients undergoing percutaneous coronary intervention (PCI) between 2018 and 2021 were enrolled. Based on the presence of anti-diabetic therapy at the admission, patients were divided into those receiving SGLT2-I (SGLT-I users) versus other OAD agents (non-SGLT2-I users). The following inflammatory markers were evaluated at different time points: white-blood-cell count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-platelet ratio (NPR), and C-reactive protein. Infarct size was assessed by echocardiography and by peak troponin levels. Results: The study population consisted of 583 AMI patients (with or without ST-segment elevation): 98 SGLT2-I users and 485 non-SGLT-I users. Hyperglycemia at admission was less prevalent in the SGLT2-I group. Smaller infarct size was observed in patients treated with SGLT2-I compared to non-SGLT2-I group. On admission and at 24 h, inflammatory indices were significantly higher in non-SGLT2-I users compared to SGLT2-I patients, with a significant increase in neutrophil levels at 24 h. At multivariable analysis, the use of SGLT2-I was a significant predictor of reduced inflammatory response (OR 0.457, 95% CI 0.275-0.758, p = 0.002), independently of age, admission creatinine values, and admission glycemia. Conversely, peak troponin values and NSTEMI occurrence were independent predictors of a higher inflammatory status. Conclusions: Type 2 diabetic AMI patients receiving SGLT2-I exhibited significantly reduced inflammatory response and smaller infarct size compared to those receiving other OAD agents, independently of glucose-metabolic control. Our findings are hypothesis generating and provide new insights on the cardioprotective effects of SGLT2-I in the setting of coronary artery disease. Trial registration: Data are part of the ongoing observational registry: SGLT2-I AMI PROTECT. Clinicaltrials: gov Identifier: NCT05261867

Right atrial mass following transcatheter radiofrequency ablation for recurrent atrial fibrillation: thrombus, endocarditis or mixoma?

We report a case of an asymptomatic patient in whom a right atrial mass was fortuitously documented by echocardiography few months after a transcatheter radiofrequency catheter ablation for recurrent AF. No masses were seen in the cardiac chambers before the ablative procedure, raising important diagnostic and decision-making issues. The patient was referred to the surgeon and a diagnosis of right atrial myxoma was made