Ibutilide for the Cardioversion of Paroxysmal Atrial Fibrillation during Radiofrequency Ablation of Supraventricular Tachycardias

Direct current electrical cardioversion (DC-ECV) is the preferred treatment for the termination of paroxysmal atrial fibrillation (AF) that occurs during radiofrequency ablation (RFA) of supraventricular tachycardias (SVT). Intravenous Ibutilide may be an alternative option in this setting. Thirty-four out of 386 patients who underwent SVT-RFA presented paroxysmal AF during the procedure and were randomized into receiving ibutilide or DC-ECV. Ibutilide infusion successfully cardioverted 16 out of 17 patients (94%) within 17.37 ± 7.87  min. DC-ECV was successful in all patients (100%) within 17.29 ± 3.04  min. Efficacy and total time to cardioversion did not differ between the study groups. No adverse events were observed. RFA was successfully performed in 16 patients (94%) in the ibutilide arm and in all patients (100%) in the DC-ECV arm, p = NS. In conclusion, ibutilide is a safe and effective alternative treatment for restoring sinus rhythm in cases of paroxysmal AF complicating SVT-RFA

Assessment of α-Synuclein Secretion in Mouse and Human Brain Parenchyma

Genetic, biochemical, and animal model studies strongly suggest a central role for α-synuclein in the pathogenesis of Parkinson's disease. α-synuclein lacks a signal peptide sequence and has thus been considered a cytosolic protein. Recent data has suggested that the protein may be released from cells via a non-classical secretory pathway and may therefore exert paracrine effects in the extracellular environment. However, proof that α-synuclein is actually secreted into the brain extracellular space in vivo has not been obtained. We developed a novel highly sensitive ELISA in conjugation with an in vivo microdialysis technique to measure α-synuclein in brain interstitial fluid. We show for the first time that α-synuclein is readily detected in the interstitial fluid of both α-synuclein transgenic mice and human patients with traumatic brain injury. Our data suggest that α-synuclein is physiologically secreted by neurons in vivo. This interstitial fluid pool of the protein may have a role in the propagation of synuclein pathology and progression of Parkinson's disease

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Direct current electrical cardioversion (DC-ECV) is the preferred treatment for the termination of paroxysmal atrial fibrillation (AF) that occurs during radiofrequency ablation (RFA) of supraventricular tachycardias (SVT). Intravenous Ibutilide may be an alternative option in this setting. Thirty-four out of 386 patients who underwent SVT-RFA presented paroxysmal AF during the procedure and were randomized into receiving ibutilide or DC-ECV. Ibutilide infusion successfully cardioverted 16 out of 17 patients (94%) within 17.37 ± 7.87 min. DC-ECV was successful in all patients (100%) within 17.29 ± 3.04 min. Efficacy and total time to cardioversion did not differ between the study groups. No adverse events were observed. RFA was successfully performed in 16 patients (94%) in the ibutilide arm and in all patients (100%) in the DC-ECV arm, p = NS. In conclusion, ibutilide is a safe and effective alternative treatment for restoring sinus rhythm in cases of paroxysmal AF complicating SVT-RFA

Wild Type α-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells*S⃞

α-Synuclein (ASYN) is crucial in Parkinson disease (PD) pathogenesis. Increased levels of wild type (WT) ASYN expression are sufficient to cause PD in humans. The manner of post-transcriptional regulation of ASYN levels is controversial. Previously, we had shown that WT ASYN can be degraded by chaperone-mediated autophagy (CMA) in isolated liver lysosomes. Whether this occurs in a cellular and, in particular, in a neuronal cell context is unclear. Using a mutant ASYN form that lacks the CMA recognition motif and RNA interference against the rate-limiting step in the CMA pathway, Lamp2a, we show here that CMA is indeed involved in WT ASYN degradation in PC12 and SH-SY5Y cells, and in primary cortical and midbrain neurons. However, the extent of involvement varies between cell types, potentially because of differences in compensatory mechanisms. CMA inhibition leads to an accumulation of soluble high molecular weight and detergent-insoluble species of ASYN, suggesting that CMA dysfunction may play a role in the generation of such aberrant species in PD. ASYN and Lamp2a are developmentally regulated in parallel in cortical neuron cultures and in vivo in the central nervous system, and they physically interact as indicated by co-immunoprecipitation. In contrast to previous reports, inhibition of macroautophagy, but not the proteasome, also leads to WT ASYN accumulation, suggesting that this lysosomal pathway is also involved in normal ASYN turnover. These results indicate that CMA and macroautophagy are important pathways for WT ASYN degradation in neurons and underline the importance of CMA as degradation machinery in the nervous system