Effect of lead design and pacing vector on electrical parameters of quadripolar coronary sinus leads: The RALLY-X4 study

Abstract Background Various lead designs have been developed to accommodate different coronary sinus anatomies. Our objectives were to compare electrical parameters of straight and spiral left ventricular leads, to evaluate capture thresholds and impedances using different pacing vectors, and to study evolution of thresholds over time. Methods The RALLY-X4 study enrolled patients implanted with a lead from the Acuity X4 family (Straight, Spiral Short or Spiral Long). Electrical parameters (including capture thresholds from all 17 vectors) were measured at baseline and follow-up. Results Data from 795 patients who were successfully implanted were analysed. Straight and spiral leads had similar proportions of patients with thresholds 80% of patients. Pacing vectors significantly affect electrical parameters, with higher thresholds in more proximal electrodes and lower thresholds with unipolar and extended bipolar configurations. Capture thresholds slightly decreased over a mean follow-up of one year. This article is protected by copyright. All rights reservedPeer reviewe

Cardiac resynchronization therapy-defibrillator improves long-term survival compared with cardiac resynchronization therapy-pacemaker in patients with a class IA indication for cardiac resynchronization therapy: Data from the Contak Italian Registry

Aims In candidates for cardiac resynchronization therapy (CRT), the choice between pacemaker (CRT-P) and defibrillator (CRT-D) implantation is still debated. We compared the long-term prognosis of patients who received CRT-D or CRT-P according to class IA recommendations of the European Society of Cardiology (ESC) and who were enrolled in a multicentre prospective registry. Methods and results A total of 620 heart failure patients underwent successful implantation of a CRT device and were enrolled in the Contak Italian Registry. This analysis included 266 patients who received a CRT-D and 108 who received a CRT-P according to class IA ESC indications. Their survival status was verified after a median follow-up of 55 months. During follow-up, 73 CRT-D and 44 CRT-P patients died (rate 6.6 vs. 10.4%/year; log-rank test, P = 0.020). Patients receiving CRT-P were predominantly older, female, had no history of life-threatening ventricular arrhythmias, and more frequently presented non-ischaemic aetiology of heart failure, longer QRS durations, and worse renal function. However, the only independent predictor of death from any cause was the use of CRT-P (hazard ratio, 1.97; 95% confidence interval, 1.21–3.16; P = 0.007). Conclusion The implantation of CRT-D, rather than CRT-P, may be preferable in patients presenting with current class IA ESC indications for CRT. Indeed, CRT-D resulted in greater long-term survival and was independently associated with a better prognosis

Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease

CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5−/− mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments.Peer reviewe

Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease

CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5−/− mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments

Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease

CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5−/− mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments

Nonalcoholic Fatty Liver Disease Is Associated With Ventricular Arrhythmias in Patients With Type 2 Diabetes Referred for Clinically Indicated 24-Hour Holter Monitoring

Recent studies have suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of heart rate-corrected QT interval prolongation and atrial fibrillation in patients with type 2 diabetes. Currently, no data exist regarding the relationship between NAFLD and ventricular arrhythmias in this patient population

Linguistica generale

The book offers a new perspective in the scientific study of language. After considering the role of different abstraction levels in science, a non-deterministic point of view is proposed in which language structures are seen as characterized by semantic vagueness and indeterminacy of meaning. This makes it possible to develop a functional point of view in which language units and language processes are described in the model as "conceptual schemes" associated with patterns of manifestation. This point of view is useful in the description of the phonological, morphological and syntactical levels

Linguistica generale

This is the second, revised edition of a book that appeared in 2010. A functional approach to language is proposed in which both the synchronic and diachronic viewpoints are considered. Synchronic description and diachronic explanation relative to Indo-European are considered on the basis of empirical data from Romance, Germanic and Slavic languages as well as from Latin and Greek

Safety and efficacy of a cardiologist-only approach to deep sedation for electrical cardioversion

Electrical cardioversion is still the preferred method to restore sinus rhythm in patients with atrial fibrillation. The main disadvantage is that electrical cardioversion requires deep sedation, generally administered by anaesthesiologists, for safety concern. An exclusively cardiologic management of deep sedation should have the advantage to reduce resources and time consumed