Many neurodegenerative conditions are characterized by the deposition of protein aggregates (mainly amyloid-like) in the central nervous system (CNS). In post-mitotic CNS cells protein aggregation ...causes cytotoxicity by interfering with various cellular functions. Mutations in different genes may directly cause protein aggregation. However, genetic factors together with aging may contribute to the onset of protein aggregation also by affecting cellular degradative functions, in particular the autophagy-lysosomal pathway (ALP). Increasing body of evidence show that ALP dysfunction and protein aggregation are functionally interconnected and induce each other during neurodegenerative processes. We will summarize the findings supporting these concepts by focusing on lysosomal storage diseases (LSDs), a class of metabolic inherited conditions characterized by global lysosomal dysfunction and often associated to a severe neurodegenerative course. We propose a model by which the inherited lysosomal defects initiate aggregate-prone protein deposition, which, in turns, worsen ALP degradation function, thus generating a vicious cycle, which boost neurodegenerative cascades.
Abstract
Background
Pulsed field ablation (PFA) is a novel, largely nonthermal ablative modality that, by virtue of its putative preferential action on myocardial tissue through the process of ...irreversible electroporation (IRE), may replace conventional thermal ablation for atrial fibrillation (AF). The recent inspIRE study confirmed safety and effectiveness of a fully integrated biphasic PFA system with a variable loop circular catheter for the treatment of paroxysmal AF. The majority of PFA procedures were performed using general anesthesia. However, due to the risks of general anesthesia we report the data regarding our sedation protocol used during inspIRE study.
Methods
A total of 29 patients (mean age 55±9 years; 72% male) were enrolled as part of this analysis within the inspIRE trial. The sedation protocol is reported in the manuscript. The Richmond Agitation-Sedation Scale (RASS), the Visual Analogue Scale (VAS) and the Patient State Index were collected during sedation. Each patient was monitored using the Masimo Sedline. At the end of ablation, the Likert Scale Questionnaire (LSQ) was used to assess the patients' satisfaction with intraoperative analgesia-sedation.
Results
No procedural complications were documented. Sufficient oxygen saturation was maintained in all patients during procedure. Non-invasive ventilation or tracheal intubation were not required for any patient. The RAAS score between -1 to -5 was obtained in 27 patients (93%) while the value 0 was obtained in 2 patients (7%). The VAS score between 0 to 2 was obtained in 24 patients (83%); the VAS score 3 in 3 patients (10%) and the VAS score 4 in 2 patients (7%). The PSI score <50 was achieved in 16 patients (55%) while the PSI between 50 and 70 was achieved in 9 patients (31%). Positive answers to LSQ were obtained in most patients.
Conclusion
During PFA ablation procedures with the variable-loop circular catheter and its accompanying biphasic pulse, our deep sedation protocol is a valid alternative to general anesthesia.
Graphical Abstract
Graphical abstract
Background:Not all heart failure (HF) patients benefit from cardiac resynchronization therapy (CRT). We assessed whether choosing the site of left ventricular (LV) pacing by a quadripolar lead may ...improve response to CRT.Methods and Results:We prospectively randomized 23 patients with HF (67±11 years; 21 males) to CRT with a quadripolar LV lead (group 1, with the LV pacing site chosen on the basis of QRS shortening using simultaneous biventricular pacing), and 20 patients (71±6 years; 16 males) to a bipolar LV lead (group 2, with devices programmed with a conventional tip-to-ring configuration). New York Heart Association (NYHA) class and LV ejection fraction (EF) by 2D echocardiography were assessed at baseline and after 3 months. The baseline EF was not different between the 2 groups (25±6% group 1 vs. 27±3% group 2; P=0.22), but after 3 months EF was higher in group 1 (35±13% group 1 vs. 31±4% group 2; P<0.001). A reduction in at least 1 NYHA class at 3 months was observed in 22 (96%) and 12 (60%) of group 1 and group 2 patients, respectively (P<0.05).Conclusions:CRT with a quadripolar LV lead was associated with an improvement of EF greater than that observed in patients receiving a bipolar LV lead. In devices with a quadripolar lead, CRT programming based on the best QRS shortening is reliable and effective. (Circ J 2016; 80: 613–618)
Patients with microvascular angina (MVA) often have persistence of symptoms despite full classical anti-ischemic therapy. In this study, we assessed the effect of ivabradine and ranolazine in MVA ...patients. We randomized 46 patients with stable MVA (effort angina, positive exercise stress test EST, normal coronary angiography, coronary flow reserve <2.5), who had symptoms inadequately controlled by standard anti-ischemic therapy, to ivabradine (5 mg twice daily), ranolazine (375 mg twice daily), or placebo for 4 weeks. The Seattle Angina Questionnaire (SAQ), EuroQoL scale, and EST were assessed at baseline and after treatment. Coronary microvascular dilation in response to adenosine and to cold pressor test and peripheral endothelial function (by flow-mediated dilation) were also assessed. Both drugs improved SAQ items and EuroQoL scale compared with placebo (p <0.01 for all), with ranolazine showing some more significant effects compared with ivabradine, on some SAQ items and EuroQoL scale (p <0.05). Time to 1-mm ST-segment depression and EST duration were improved by ranolazine compared with placebo. No effects on coronary microvascular function and on flow-mediated dilation were observed with drugs or placebo. In conclusion, ranolazine and ivabradine may have a therapeutic role in MVA patients with inadequate control of symptoms in combination with usual anti-ischemic therapy.
•Before cardiac ablation or cardioversion of atrial fibrillation, anticoagulation is recommended for patient safety.•In patients with atrial fibrillation, transesophageal echocardiography is accurate ...in detecting left atrial thrombosis.•A meta-analysis of atrial thrombosis prevalence in 50 studies and 30,762 patients was performed.•Prevalence of left atrial thrombosis by transesophageal echocardiography is smaller in direct oral anticoagulants than in vitamin K antagonists.
Left atrial or left atrial appendage thrombosis (LAT) is contraindicated for cardiac ablation (CA) or cardioversion (CV) of atrial fibrillation (AF). This study was aimed to compare the frequency of LAT detected by transesophageal echocardiography (TEE) before CA or CV in patients with AF treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs). We searched PubMed, Scopus, Web of Science, and Cochran Library databases from inception through July 13, 2023 to select studies reporting data on LAT identification before CA or CV using TEE in patients with AF treated with DOACs or VKAs. Pooled odds ratios (ORs) with 95% confidence interval were calculated with a random-effects model. Studies retrieved were 50 (38 observational), 29 on CA, 15 on CV, and 6 on both procedures (17,096 patients on DOACs and 13,666 on VKAs). The overall prevalence of LAT was smaller in DOACs than in VKAs, with an OR of 0.66 (0.52 to 0.84), confirmed at sensitivity analysis and in most subgroups. This finding was consistent for the 3 most reported DOACs: the pooled OR for LAT was 0.68 (0.50 to 0.90) in apixaban, 0.67 (0.51 to 0.88) in dabigatran, 0.61 (0.43 to 0.89) in rivaroxaban, and 1.10 (0.74 to 1.64) in edoxaban (not significant). In conclusion, in this large meta-analysis in patients with AF, the prevalence of LAT by TEE evaluation performed before CV or CA appears lower in those treated with DOACs than in those on VKAs. Additional research may help in better understanding differences between these classes of anticoagulant drugs in the setting of protection against AF-related left atrial thrombotic formation.
Cadmium is a biologically non-essential metal. It is also toxic to many organs including the brain. The aim of this study was to analyse the neurodegenerative effects of this metal in embryos and ...adults of zebrafish exposed to sub-lethal concentrations of cadmium. The study was performed by cytochemical stainings. Six hours after fertilisation (hpf) zebrafish embryos were treated for 24 hours with 9 μM of cadmium and subsequently stained with Acridine orange in whole mount to detect apoptosis in the brain. Adult zebrafish were treated for 16 days with the same concentration of cadmium, and cell death in the brain was detected by Fluoro-Jade B staining at 2, 7 and 16 days of treatment. An increase in cell death was observed only at 16 days of treatment in adults, while an increase in apoptotic events was revealed in the brain of embryos after 24 h of treatment. This evidence is indicative that cadmium, even at a sub-lethal concentration, induces cell death in the brain of embryos but also in adults of zebrafish in which the phenomenon appears time-dependent.Â.
Aim
Stereotactic ablative radiation therapy (SABR) is used in non-oncologic indications, recently even for cardiac arrhythmias. Thus, aim of this analysis is to review preclinical, early clinical ...evidences and future direction of the latter new treatment approach.
Method
A collection of available data regarding SABR and cardiac arrhythmias was made, by Pubmed research and 2 independent researchers, including preclinical and clinical data. A review of ongoing trials was conducted on ClinicalTrials.gov.
Results
Preclinical research conducted in animal models showed that a safe and effective noninvasive treatment approach for cardiac arrhythmias could be represented by SABR with a median time of response around 2–3 months. The treatment dose plays a crucial role: the atrioventricular node would seem more radiosensitive than the other cardiac electric zones. Clinical data, such as published case series, case reports and early prospective studies, have already suggested the feasibility, efficacy and safety of SABR (25 Gy in one session) for refractory ventricular arrhythmias.
Conclusion
Considering the ongoing trials of SABR and new technological improvements in radiotherapy (e.g. hybrid magnetic resonance) and in arrhythmias noninvasive mapping systems, the future analyses will improve the reliability of those preliminary results.
Mammals have evolved to occupy spatial and temporal niches in order to optimize resource utilization and minimize predation risk or competition. Subsequently, niche partitioning may be influenced by ...phylogenetic associations, which could have substantial consequences for ecosystem structure and function. We use the output from occupancy models based on camera trapping data to construct a tri-partite network describing the environmental and temporal partitioning of activity among twelve sympatric mammals in the Apennine Mountains of central Italy. We further evaluate if there were any effects of phylogenetic associations on the contributions of species to the properties of this spatio-temporal network. The Apennines form a pristine region in central Italy with a relatively intact Mediterranean mammal fauna. The mammal community in our study consisted of species ranging in size from 300 gs to over 200 kg, and included herbivores, omnivores and predators. There was limited structuring of the network describing environmental and temporal niche use. Furthermore, we did not find any phylogenetic signal in species contributions to network structures, and phylogenetic relatedness among species was not associated with their similarities in environmental or spatial niche use. However, animals appeared to have partitioned environmental niches more than temporal ones, suggesting that spatial variation in resource availability may have been more important than temporal avoidance of predation risk or competition in shaping activity within this mammal community. Our study highlights the need to evaluate under which conditions evolutionary history is influencing contemporary ecological processes.
Objectives The goal of this study was to compare transesophageal echocardiography (TEE) and intracardiac echocardiography (ICE) for the diagnosis of cardiac device–related endocarditis (CDI). ...Background The diagnosis of infective endocarditis (IE) was established by using the modified Duke criteria based mainly on echocardiography and blood culture results. No previous studies have compared ICE with TEE for the diagnosis of IE. Methods We prospectively enrolled 162 patients (age 72 ± 11 years; 125 male) who underwent transvenous lead extraction: 152 with CDI and 10 with lead malfunction (control group). Using the modified Duke criteria, we divided the patients with infection into 3 groups: 44 with a “definite” diagnosis of IE (group 1), 52 with a “possible” diagnosis of IE (group 2), and 56 with a “rejected” diagnosis of IE (group 3). TEE and ICE were performed before the procedure. Results In group 1, ICE identified intracardiac masses (ICM) in all 44 patients; TEE identified ICM in 32 patients (73%). In group 2, 6 patients (11%) had ICE and TEE both positive for ICM, 8 patients (15%) had a negative TEE but a positive ICE, and 38 patients (73%) had ICE and TEE both negative. In group 3, 2 patients (3%) had ICM both at ICE and TEE, 1 patient (2%) had an ICM at ICE and a negative TEE, and 53 patients (95%) had no ICM at ICE and TEE. ICE and TEE were both negative in the control group. Conclusions ICE represents a useful technique for the diagnosis of ICM, thus providing improved imaging of right-sided leads and increasing the diagnostic yield compared with TEE.
Hepatocellular carcinoma (HCC) is the third cause of cancer-related deaths worldwide. Sorafenib is the only approved drug for patients with advanced HCC but has shown limited activity. microRNAs ...(miRs) have been involved in several neoplasms including HCC suggesting their use or targeting as good tools for HCC treatment. The purpose of this study was to identify novel approaches to sensitize HCC cells to sorafenib through miRs. miR-423-5p was validated as positive regulator of autophagy in HCC cell lines by transient transfection of miR and anti-miR molecules. miR-423-5p expression level was evaluated by real-time polymerase chain reaction (PCR) in sera collected from 39 HCC patients before and after treatment with sorafenib. HCC cells were cotreated with sorafenib and miR-423-5p and the effects on cell cycle, apoptosis, and autophagy were evaluated. Secretory miR-423-5p was upregulated both in vitro and in vivo by sorafenib treatment and its increase was correlated with response to therapy since 75% of patients in which an increase of secretory miR423-5p was found were in partial remission or stable disease after 6 moths from the beginning of therapy. HCC cells transfected with miR-423-5p showed an increase of cell percentage in S-phase of cell cycle paralleled by a similar increase of autophagic cells evaluated at both fluorescence activated cell sorter (FACS) and transmission electron microscopy. Our results suggest the miR423-5p can be used as a useful tool to predict response to sorafenib in HCC patients and is involved in autophagy regulation in HCC cells.
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