The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition.

The transcription factor Snail is a master regulator of cellular identity and epithelial-to-mesenchymal transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail-specific binding sites is unclear. Here we report that the long non-coding RNA (lncRNA) HOTAIR (for HOX Transcript Antisense Intergenic RNA) mediates a physical interaction between Snail and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2 and the main writer of chromatin-repressive marks. The Snail-repressive activity, here monitored on genes with a pivotal function in epithelial and hepatic morphogenesis, differentiation and cell-type identity, depends on the formation of a tripartite Snail/HOTAIR/EZH2 complex. These results demonstrate an lncRNA-mediated mechanism by which a transcriptional factor conveys a general chromatin modifier to specific genes, thereby allowing the execution of hepatocyte transdifferentiation; moreover, they highlight HOTAIR as a crucial player in the Snail-mediated EMT.

Efficacy and safety of dabigatran in a "real-life" population at high thromboembolic and hemorrhagic risk: data from MonaldiCare registry.

OBJECTIVE: Dabigatran is a novel target specific oral anticoagulant for stroke prevention in non valvular atrial fibrillation. Little is still known about its real-world effectiveness and safety in the italian population. Aim of our study was to evaluate the efficacy and safety of dabigatran in a large single-center cohort of "real-life" italian population with non-valvular AF and to compare the results with those obtained from the RE-LY trial and the Medicare study. PATIENTS AND METHODS: We studied a prospective cohort of 2108 patients (1119 male; mean age 69.4 ± 9.4 years) who started the oral anticoagulant treatment with dabigatran 110 mg twice-daily (DAB 110; N = 1075; 51%) or 150 mg twice-daily (DAB 150; N = 1033; 49%). Follow-up data were obtained trough outpatients visits each 3-6 months for assessing the clinical status, adherence to treatment, occurrence of side effects and major cardiovascular complications. RESULTS: In DAB 150 group the mean age was 64.9 ± 8.8 years, 56.8% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 94.3% and HAS-BLED was ≥ 3 in 59.7%. In DAB 110 group (N = 1075) the mean age was 73.9 ± 7.5 years; 49.5% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 73.4% and HAS-BLED was ≥ 3 in 87.4% of DAB 110 patients. One patient taking Dabigatran 110 mg bid had ischemic stroke without significantly neurological sequelae. In both groups, no patient experienced hemorrhagic stroke during the follow-up period. 147 patients (6.9%) of MonaldiCare population reported adverse effects from treatment with dabigatran, of whom 121 patients (5.7%) discontinued therapy. We reported one case of subarachnoid hemorrhage (0.05%) in a patient with high thrombo-embolic and high hemorrhagic risk score who was taking dabigatran 150 mg bid and one case (0.05%) of bladder bleeding in a patient who was taking dabigatran 110 mg bid. No major gastrointestinal bleeding was observed in the MonaldiCare population. CONCLUSIONS: MonaldiCare registry showed a safety profile of both dosages of dabigatran regarding major of fatal bleeding in a "real life" single center italian population at high thromboembolic and hemorrhagic risk. The majority of MonaldiCare patients tolerated dabigatran treatment without significant side effects. The efficacy of dabigatran was demonstrated by very low prevalence of ictus/TIA, also when patients underwent electrical AF cardioversion independently of the transesophageal examination.

Autophagy regulates hepatocyte identity and epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions promoting Snail degradation.

Epithelial-to-mesenchymal transition (EMT) and the reverse process mesenchymal-to-epithelial transition (MET) are events involved in development, wound healing and stem cell behaviour and contribute pathologically to cancer progression. The identification of the molecular mechanisms underlying these phenotypic conversions in hepatocytes are fundamental to design specific therapeutic strategies aimed at optimising liver repair. The role of autophagy in EMT/MET processes of hepatocytes was investigated in liver-specific autophagy-deficient mice (Alb-Cre;ATG7(fl/fl)) and using the nontumorigenic immortalised hepatocytes cell line MMH. Autophagy deficiency in vivo reduces epithelial markers' expression and increases the levels of mesenchymal markers. These alterations are associated with an increased protein level of the EMT master regulator Snail, without transcriptional induction. Interestingly, we found that autophagy degrades Snail in a p62/SQSTM1 (Sequestosome-1)-dependent manner. Moreover, accordingly to a pro-epithelial function, we observed that autophagy stimulation strongly affects EMT progression, whereas it is necessary for MET. Finally, we found that the EMT induced by TGFß affects the autophagy flux, indicating that these processes regulate each other. Overall, we found that autophagy regulates the phenotype plasticity of hepatocytes promoting their epithelial identity through the inhibition of the mesenchymal programme.

Monoclonal gammopathy of undetermined significance in pediatric kidney transplant: a possible role of Epstein-Barr virus.

MG is a common event of hematologic malignancies. There are many papers regarding kidney transplantation patients with MGUS in adults, while data in pediatrics are scarce. The etiology and clinical significance of MGUS are unclear both in adults and children. Immunosuppressive drugs, graft antigenicity, and viral infection could play a possible role. The viruses most frequently implicated seem to be EBV or CMV in particular, but their role has to be defined better. However, many investigators have emphasized an impaired balance between an adequate immune response and reactivation of viral infection.

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs.

Preservation of the epithelial state involves the stable repression of epithelial-to-mesenchymal transition program, whereas maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular mini-circuitry between master elements of these biological processes might provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4α, directly represses the expression of the epithelial microRNAs (miRs)-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4α, previously identified as a transcriptional repressor of Snail, induces the miRs-34a and -200a, b, c that, when silenced, causes epithelial dedifferentiation and reacquisition of stem traits. Altogether these data unveiled Snail, HNF4α and miRs-200a, b, c and -34a as epistatic elements controlling hepatic stem cell maintenance/differentiation.

[Electromagnetic interference of electronic devices in workers with AICD]. / Interferenze elettromagnetiche dei dispositivi elettronici in lavoratori portatori di AICD.

The Implantable Cardioverter Defibrillators and the Pacemakers are devices that produce electric signals and consequently they are touchy to the electromagnetic interferences. This touchiness may cause a temporary or permanent device's malfunction both for short, but of high intensity, and prolonged exposures. Considered the wide diffusion in the job's environments of the technologies based on the electromagnetic waves, the aim of the study is identify the presence of electronic equipment's electromagnetic interferences in AICD bearing workers. The last aim is give to the AICD bearing workers more detailed information about the prevention of inappropriate AICD shocks.

Superior vena cava thrombosis after intravascular AICD lead extraction: a case report.

Pacemaker lead extraction has been shown to be an effective and safe treatment in the case of infected per-manent pacemaker leads. However, it can lead to potentially serious complications, usually occurring during the ex-traction procedure. This report describes a case of a 74-year-old male with a persistent superior vena cava thrombo-sis related to an infected permanent pacemaker lead transvenous extraction. Clinical and surgical management are discussed.

Retrospective analysis of 300 cases of paroxysmal supraventicular tachycardia by electrophysiological transesophageal study.

AIM: Paroxysmal supraventricular tachycardia (PSVT) is a very frequent type of arrhythmia. Atrioventricular nodal reciprocating tachycardia (AVNRT) and atrioventricular reciprocating tachycardia through extranodal accessory pathways (AVRT) are the most common types of paroxysmal supraventricular tachycardia. We describe our experience in diagnosing these tachycardia by electrophysiological transesophageal study (ETS). METHODS: Three hundred patients, 155 men and 145 women, (mean age, 37.2 +/- 16 years), with a history of palpitations underwent clinical evaluation and ETS. The clinical features of those with AVNRT and those with AVRT were compared. RESULTS: Of a total of 300 patients, tachycardia was diagnosed only in 234, of which 136 (58%) had AVNRT and 98 (42%) had AVRT. AVNRT patients were older than those with AVRT (P = or < 0.004); patients with AVRT had palpitations earlier (P = or < 0.0001). Dyspnea and asthenia were the most frequent symptoms in the AVNRT patients (P = or < 0,02; P = or < 0.04). There were statistically significant differences between the two patient groups in Wencke-bach time (P = or < 0.05), ventricular-atrial (V-A) interval (P = or < 0.03) and period of induced tachycardia (P = or < 0.04). CONCLUSIONS: ETS revealed important clinical and electrophysiological differences between patients with AVRT and those with AVNRT.

Magnetic field exposure and arrythmic risk: evaluation in railway drivers.

Recent studies suggest that professional exposure to Extremely Low Frequency-Electro Magnetic Field (ELF-EMF) can increase the risk of sudden cardiac death. Aim of our work was to find predictive parameters of arrhythmic risk in a population of 28 railways drivers exposed to ELF-EMF. Our findings were that the exposure did not reduce HRV and did not increase the risk of arrhythmias.

Evaluation of the antioxidant response in the plasma of healthy or hypertensive subjects after short-term exercise.

Reactive oxygen species are produced during exercise. The antioxidants prevent or limit tissue damages by these species in physiological conditions. In particular, ascorbate and urate scavenge peroxynitrite, which can alter the function of many molecules, including the lecithin-cholesterol acyltransferase (LCAT) enzyme involved in reverse cholesterol transport. The aims of the present study were to compare the plasma antioxidant response to an ergometric test (ET) in hypertensive and healthy subjects, evaluate the exercise-dependent nitrosative stress in plasma, and assess whether the LCAT activity is altered by the exercise. Plasma samples, prepared before and after ET from hypertensive or healthy volunteers, were analysed for their levels of ascorbate, urate, alpha-tocopherol, retinol, nitrotyrosine, and LCAT activity. The alpha-tocopherol and retinol levels did not significantly change in both groups during exercise, while the ascorbate level changed displaying higher increase in controls (+38.8%) than in hypertensives (+17.2%). In these patients, during ET, the urate and nitrotyrosine levels changed more than in normotensives (+13.5 and +40.6% vs -3.1 and +25.2%, respectively). The antioxidants effectively prevented loss or reduction of LCAT activity, as it was similar in hypertensives and normotensives, and did not change after ET. The results demonstrate that exercise is associated with enhanced protein nitrosation, and suggest that the ascorbate or urate levels increase to limit oxidative damage.

[Treatment of ischemic cardiopathy in the elderly: risk and benefits]. / La terapia della cardiopatia ischemica nell'anziano: rischi e benefici.

Epidemiological data have shown a "demographic revolution" in our society which induced a progressive increase in the elderly population, and coronary heart disease occurs more frequently in this group of subjects. Moreover, the presence of other pathologies entails specific diagnostic and therapeutic aspects in the elderly. In acute coronary syndromes percutaneous coronary angioplasty and thrombolytic agents are ever more employed despite the higher morbidity and mortality rates in the elderly. Chronic ischemic heart disease therapy, even if not different from that in younger patients, requires careful evaluation of the risk/benefit ratio.

Ventricular tachyarrhythmias following coronary surgery: predisposing factors.

The perioperative factors potentially associated with post-coronary artery bypass grafting (CABG) ventricular tachyarrhythmias (VT) onset have not been deeply investigated. Monomorphic or polymorphic ventricular tachycardia and ventricular fibrillation represent the most dreadful arrhythmic events that can complicate the postoperative course of CABG. As a consequence, the aim of our paper was to identify which perioperative variables might predict post-CABG VT occurrence. One hundred and fifty-two consecutive patients who underwent CABG surgery at our Institution were included in the study. Post-CABG VT occurred in 13 out of 152 patients (8.5%, six cases of monomorphic ventricular tachycardia and seven cases of ventricular fibrillation). At univariate analysis, VT patients were significantly younger (54.8+/-6.6 vs. 60.1+/-8.8, P=0.038), exhibited a more severe coronary artery disease (CAD) (number of diseased vessels 2.92+/-0.3 vs. 2.45+/-0.7, P=0.023, and percentage of patients with three-vessel CAD 91.7% vs. 57.3%, P=0.043) and received a greater number of CABGs than those remaining in sinus rhythm (SR) (percentage of patients receiving three or more CABGs 76. 9% vs. 38.8%, P1000 76.9% vs. 38%, Pnormal range 72.7% vs. 30.7%, P=0.014), electrolyte derangement (84.6% vs. 45.6%, P=0.017) and a severe haemodynamic impairment (need for IABP 23% vs. 2.9%, P1000, postoperative electrolyte imbalance, the need for three or more CABGs and of IABP all were independent correlates for VT. In conclusion, post-CABG VT seem to be related to the preexistence of a severe underlying coronary artery disease along with perioperative triggering factors such as acute ischemia, electrolytic disorders and a sudden haemodynamic impairment.

Perioperative clinical predictors of atrial fibrillation occurrence following coronary artery surgery.

OBJECTIVE: Atrial fibrillation (AF) is the most frequently encountered arrhythmic complication associated with coronary surgery. The aim of this paper was then to identify the clinical predictors of post-CABG AF occurrence. METHODS: 150 consecutive patients were included in this study and divided into two groups according to the absence (SR group, 104 male and 22 female, age 58.4+/-8.8 years) or presence (AF group, 23 male and 1 female, age 65.4+/-6.3 years) of post-CABG AF. Forty-seven perioperative variables were considered. RESULTS: After univariate analysis, advanced age (SR vs. AF: 58.4+/-8.8 vs. 65.4+/-6.3, P < 0.001), an increased BMI (SR vs. AF: 26.1+/-2.7 vs. 27.4+/-2.5, P = 0.026), a prior history of paroxysmal AF (SR vs. AF: 3.2% vs. 16.7%, P = 0.028), left atrial enlargement (SR vs. AF: 21.1% vs. 70.8%, P < 0.001) and a more severe coronary artery disease (CAD) (SR vs. AF: no. of diseased vessels: 2.42+/-0.7 vs. 2.91+/-0.3, P = 0.001; three-vessel CAD (54.1% vs. 91.3%, P = 0.002) were the only factors that statistically differed between the groups. Multivariate logistic regression analysis identified left atrial enlargement (P < 0.0001), a prior history of paroxysmal AF (P = 0.007) and a more severe CAD (P = 0.0047) to be independent correlates for AF. CONCLUSIONS: Post-CABG AF seems to require a well definite anatomical and electrical substrate that is generated by increased left atrial dimensions, a greater extension of coronary lesions and a possible electrical remodeling consequent to prior repetitive episodes of paroxysmal AF.

[Idiopathic left fascicular ventricular tachycardia: the evidence for a "bystander" bundle of His participation]. / Tachicardia ventricolare fascicolare idiopatica sinistra: evidenza di una partecipazione hissiana "bystander".

Idiopathic left ventricular tachycardia is a rare arrhythmia whose electrophysiological basis is not yet well-defined. We report a case of idiopathic left ventricular tachycardia caused by a reentrant circuit limited exclusively to the two fascicles of the left bundle branch.

Perioperative correlates of malignant ventricular tachyarrhythmias complicating coronary surgery.

Sustained ventricular tachyarrhythmias (VT), such as monomorphic or polymorphic ventricular tachycardia, and ventricular fibrillation, represent the most serious arrhythmic events that can complicate the postoperative course of coronary artery bypass grafting (CABG). The perioperative factors potentially associated with post-CABG sustained VT onset have not been thoroughly investigated. As a consequence, the aim of our study was to identify which perioperative variables might predict post-CABG VT occurrence. One hundred and fifty-two consecutive patients who underwent CABG surgery at our Institute were included in the study. Post-CABG VT occurred in 13 out of 152 patients (8.5%, six cases of monomorphic ventricular tachycardia and seven cases of ventricular fibrillation). Univariate analysis revealed that VT patients were significantly younger (54.8 +/- 6.6 vs 60.1 +/- 8.8, P = 0.038), exhibited more severe coronary artery disease (CAD) (no. of diseased vessels, 2.92 +/- 0.3 vs 2.45 +/- 0.7, P = 0.023; and percentage of patients with three-vessel CAD, 91.7 vs 57.3%, P = 0.043), and received a greater number of CABGs than those remaining in sinus rhythm (SR) (percentage of patients receiving three or more CABGs, 76.9 vs 38.8%, P = 0.018) Moreover, VT patients more frequently developed intra- or postoperative myocardial infarction (total CK > 1,000, 76.9 vs 38%, P = 0.016; and MB-CK > normal range, 72.7 vs 30.7%, P = 0.014), electrolyte derangement (84.6 vs 45.6%, P = 0.017), and a severe hemodynamic impairment (need for intra-aortic balloon pump (IABP), 23 vs 2.9%, P = 0.009). On multivariate analysis, total CK > 1,000, postoperative electrolyte imbalance, the need for three or more CABGs, and for IABP all were independent correlates for VT. In conclusion, post-CABG VT seem to be related to the preexistence of a severe underlying coronary artery disease along with perioperative triggering factors, such as acute ischemia, electrolytic disorders, and sudden hemodynamic impairment.

Atrial fibrillation: what are the effects of drug therapy on the effectiveness and complications of electrical cardioversion?

Atrial fibrillation is the most common cardiac rhythm disorder associated with hospitalization. Two therapeutic options have been available: antiarrhythmic drug therapy, and external or internal electrical cardioversion. Electrical cardioversion of atrial fibrillation remains one of the most widely used and effective treatments for the restoration of normal sinus rhythm. However, many patients continue to receive an antiarrhythmic drug before and after cardioversion in an attempt either to cardiovert the arrhythmia chemically or to maintain sinus rhythm after successful cardioversion. Because some pharmacological agents can affect the cardioversion procedure for atrial fibrillation or flutter, and because many patients with such arrhythmias may require electrical cardioversion when they are taking antiarrhythmic drugs, the question of a possible effect of drug therapy on the efficacy and safety of electrical cardioversion of atrial fibrillation arises. Early reports of direct current cardioversion provoking potentially lethal ventricular arrhythmias raised suspicions of an arrhythmogenic role for digoxin antiarrhythmic therapy, and it is customary to withhold these drugs for 24 to 48 h before cardioversion is attempted. However, this complication is likely to arise only in patients who are close to, or actually manifesting, signs of drug toxicity. On the other hand, treatment with therapeutic concentrations of antiarrhythmic drugs before cardioversion may in some cases be associated with a significant reduction in the number of shocks and decreased energy required to restore sinus rhythm, a lower incidence of postshock arrhythmias and a reduced risk of early recurrence of atrial fibrillation.

Compared effects of sotalol, flecainide and propafenone on ventricular repolarization in patients free of underlying structural heart disease.

Antiarrhythmic drugs are known to affect the depolarization and repolarization time in a different fashion. The aim of the present study was to compare the effects of Sotalol, Flecainide and Propafenone on some common (QT, QTc, JT, JTc) or uncommon (QTc dispersion, T-peak to T-end interval) electrocardiographic parameters in order to evaluate the effects of these antiarrhythmic drugs on ventricular repolarization time both in terms of absolute values and of dispersion across the myocardium. The analysis of these antiarrhythmic drug effects was performed on the standard 12-lead electrocardiograms of 31 patients (17F and 14M, age 38.1+/-17 years, range 11-67 years) in the free-drug state and at the steady state after oral treatment with Sotalol (160 mg daily), Flecainide (200 mg daily) and Propafenone (450 mg daily). These drugs were prescribed, separately, to all the 31 patients, free of underlying structural heart disease, for the treatment of their atrio-ventricular nodal re-entry tachycardia. Data of the present study show that Sotalol, over the range prescribed, significantly prolongs ventricular repolarization index QT (P=0.001), JT (P=0.0001) and JTc (P=0.0001) values in an homogeneous fashion, as shown by the significant decrease in QTcD (P=0.019) and Tp-Te (P=0.01). On the contrary, Flecainide treatment was associated with an increase in QTcD (P=0.029), Tp-Te (0.0001), QT (P=0.001), QTc (P=0.0001) and QRS (P=0.0001), with no significant changes in JT and JTc. Propafenone, over the range prescribed, did not affect repolarization time, resulting only in a prolongation of depolarization time as expressed by the increase of QRS (P=0.0001).