Pericardiectomy for constrictive pericarditis: a risk factor analysis for early and late failure

Predictors of early and late failure of pericardiectomy for constrictive pericarditis (CP) have not been established. Early and late outcomes of a cumulative series of 81 (mean age 60\ua0years; mean EuroSCORE II, 3.3%) consecutive patients from three European cardiac surgery centers were reviewed. Predictors of a combined endpoint comprising in-hospital death or major complications (including multiple transfusion) were identified with binary logistic regression. Non-parametric estimates of survival were obtained with the Kaplan\u2013Meier method. Predictors of poor late outcomes were established using Cox proportional hazard regression. There were 4 (4.9%) in-hospital deaths. Preoperative central venous pressure > 15\ua0mmHg (p = 0.005) and the use of cardiopulmonary bypass (p = 0.016) were independent predictors of complicated in-hospital course, which occurred in 29 (35.8%) patients. During follow-up (median, 5.4\ua0years), preoperative renal impairment was a predictor of all-cause death (p = 0.0041), cardiac death (p = 0.0008), as well as hospital readmission due to congestive heart failure (p = 0.0037); while partial pericardiectomy predicted all-cause death (p = 0.028) and concomitant cardiac operation predicted cardiac death (p = 0.026), postoperative central venous pressure < 10\ua0mmHg was associated with a low risk both of all-cause and cardiac death (p < 0.0001 for both). Ten-year adjusted survival free of all-cause death, cardiac death, and hospital readmission were 76.9%, 94.7%, and 90.6%, respectively. In high-risk patients with CP, performing pericardiectomy before severe constriction develops and avoiding cardiopulmonary bypass (when possible) could contribute to improving immediate outcomes post-surgery. Complete removal of cardiac constriction could enhance long-term outcomes

Persistent left ventricular dysfunction after acute lymphocytic myocarditis: Frequency and predictors.

BACKGROUND: Persistent left ventricular (LV) systolic dysfunction in patients with acute lymphocytic myocarditis (LM) is widely unexplored. OBJECTIVES: To assess the frequency and predictors of persistent LV dysfunction in patients with LM and reduced LVEF at admission. METHODS AND RESULTS: We retrospectively evaluated 89 consecutive patients with histologically-proven acute myocarditis enrolled at three Italian referral hospitals. A subgroup of 48 patients with LM, baseline systolic impairment and an available echocardiographic assessment at 12 months (6-18) from discharge constituted the study population. The primary study end-point was persistent LV dysfunction, defined as LVEF <50% at 1-year, and was observed in 27/48 patients (56.3%). Higher LV end-diastolic diameter at admission (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.04-1.43, p = 0.002), non-fulminant presentation (OR 8.46, 95% CI 1.28-55.75, p = 0.013) and presence of a poor lymphocytic infiltrate (OR 12.40, 95% CI 1.23-124.97, p = 0.010) emerged as independent predictors of persistent LV dysfunction at multivariate analysis (area under the curve 0.91, 95% CI 0.82-0.99). Pre-discharge LVEF was lower in patients with persistent LV dysfunction compared to the others (32%±8 vs. 53%±8, p <0.001), and this single variable showed the best accuracy in predicting the study end-point (area under the curve 0.95, 95% CI 0.89-1.00). CONCLUSIONS: More than half of patients presenting with acute LM and LVEF <50% who survive the acute phase show persistent LV dysfunction after 1-year from hospital discharge. Features of subacute inflammatory process and of established myocardial damage at initial hospitalization emerged as predictors of this end-point

NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease.

Disarrangement in functions and quality control of mitochondria at synapses are early events in Alzheimer's disease (AD) pathobiology. We reported that a 20-22 kDa NH2-tau fragment mapping between 26 and 230 amino acids of the longest human tau isoform (aka NH2htau): (i) is detectable in cellular and animal AD models, as well in synaptic mitochondria and cerebrospinal fluids (CSF) from human AD subjects; (ii) is neurotoxic in primary hippocampal neurons; (iii) compromises the mitochondrial biology both directly, by inhibiting the ANT-1-dependent ADP/ATP exchange, and indirectly, by impairing their selective autophagic clearance (mitophagy). Here, we show that the extensive Parkin-dependent turnover of mitochondria occurring in NH2htau-expressing post-mitotic neurons plays a pro-death role and that UCHL-1, the cytosolic Ubiquitin-C-terminal hydrolase L1 which directs the physiological remodeling of synapses by controlling ubiquitin homeostasis, critically contributes to mitochondrial and synaptic failure in this in vitro AD model. Pharmacological or genetic suppression of improper mitophagy, either by inhibition of mitochondrial targeting to autophagosomes or by shRNA-mediated silencing of Parkin or UCHL-1 gene expression, restores synaptic and mitochondrial content providing partial but significant protection against the NH2htau-induced neuronal death. Moreover, in mitochondria from human AD synapses, the endogenous NH2htau is stably associated with Parkin and with UCHL-1. Taken together, our studies show a causative link between the excessive mitochondrial turnover and the NH2htau-induced in vitro neuronal death, suggesting that pathogenetic tau truncation may contribute to synaptic deterioration in AD by aberrant recruitment of Parkin and UCHL-1 to mitochondria making them more prone to detrimental autophagic clearance

AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons

Functional as well as structural alterations in mitochondria size, shape and distribution are precipitating, early events in progression of Alzheimer's Disease (AD). We reported that a 20\u201322 kDa NH2-tau fragment (aka NH2htau), mapping between 26 and 230 amino acids of the longest human tau isoform, is detected in cellular and animal AD models and is neurotoxic in hippocampal neurons. The NH2htau \u2013but not the physiological full-length protein\u2013 interacts with A\u3b2 at human AD synapses and cooperates with it in inhibiting the mitochondrial ANT-1-dependent ADP/ATP exchange. Here we show that the NH2htau also adversely affects the interplay between the mitochondria dynamics and their selective autophagic clear- ance. Fragmentation and perinuclear mislocalization of mitochondria with smaller size and density are early found in dying NH2htau-expressing neurons. The specific effect of NH2htau on quality control of mitochondria is accompanied by (i) net reduction in their mass in correlation with a general Parkin- mediated remodeling of membrane proteome; (ii) their extensive association with LC3 and LAMP1 autoph- agic markers; (iii) bioenergetic deficits and (iv) in vitro synaptic pathology. These results suggest that NH2htau can compromise the mitochondrial biology thereby contributing to AD synaptic deficits not only by ANT-1 inactivation but also, indirectly, by impairing the quality control mechanism of these organelles

AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons

Functional as well as structural alterations in mitochondria size, shape and distribution are precipitating, early events in progression of Alzheimer's Disease (AD). We reported that a 20\u201322 kDa NH2-tau fragment (aka NH2htau), mapping between 26 and 230 amino acids of the longest human tau isoform, is detected in cellular and animal AD models and is neurotoxic in hippocampal neurons. The NH2htau \u2013but not the physiological full-length protein\u2013 interacts with A\u3b2 at human AD synapses and cooperates with it in inhibiting the mitochondrial ANT-1-dependent ADP/ATP exchange. Here we show that the NH2htau also adversely affects the interplay between the mitochondria dynamics and their selective autophagic clear- ance. Fragmentation and perinuclear mislocalization of mitochondria with smaller size and density are early found in dying NH2htau-expressing neurons. The specific effect of NH2htau on quality control of mitochondria is accompanied by (i) net reduction in their mass in correlation with a general Parkin- mediated remodeling of membrane proteome; (ii) their extensive association with LC3 and LAMP1 autoph- agic markers; (iii) bioenergetic deficits and (iv) in vitro synaptic pathology. These results suggest that NH2htau can compromise the mitochondrial biology thereby contributing to AD synaptic deficits not only by ANT-1 inactivation but also, indirectly, by impairing the quality control mechanism of these organelles

Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation

Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

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Asymptomatic papillary fibroelastoma of the Aortic valve in a young woman - a case report

Echocardiography represents an invaluable diagnostic tool for the detection of intracardiac masses while simultaneously provides information about their size, location, mobility and attachment site as well as the presence and extent of any consequent hemodynamic derangement

SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence