Relationship between compression time and long-term hypoesthesia in primary trigeminal neuralgia treated with percutaneous balloon compression.

Percutaneous balloon compression is a surgical method for the treatment of trigeminal neuralgia, but one of the surgical parameters, compression time, is inconclusive. To investigate the effect of compression time during balloon compression on long-term postoperative hypoesthesia in patients with primary trigeminal neuralgia and to provide guidance on relevant parameters for balloon compression in the treatment of primary trigeminal neuralgia, we conducted a nested case-control study. Patients with primary trigeminal neuralgia treated by balloon compression from March 2013 to September 2013 were divided into case group and control group according to whether there were still symptoms of hypoesthesia at present. The relationship between the compression time of balloon compression and long-term hypoesthesia was analyzed. A total of 289 trigeminal neuralgia patients treated with percutaneous balloon compression were included in this study. Multivariate logistic regression showed that compression time was significantly correlated with long-term hypoesthesia (OR = 1.91, 95% CI = 1.13-3.23, P = 0.02), and compression time was greater than one. The risk of hypoesthesia in the long-term when the compression time is longer than 1 min is 1.93 times that of 1 min. PBC is a safe and effective surgical method, and the long-term hypoesthesia is related to the compression time during operation. The longer the compression time during operation, the greater the risk of long-term hypoesthesia.

Down-regulation of Beclin1 promotes direct cardiac reprogramming.

Direct reprogramming of fibroblasts to alternative cell fates by forced expression of transcription factors offers a platform to explore fundamental molecular events governing cell fate identity. The discovery and study of induced cardiomyocytes (iCMs) not only provides alternative therapeutic strategies for heart disease but also sheds lights on basic biology underlying CM fate determination. The iCM field has primarily focused on early transcriptome and epigenome repatterning, whereas little is known about how reprogramming iCMs remodel, erase, and exit the initial fibroblast lineage to acquire final cell identity. Here, we show that autophagy-related 5 (Atg5)-dependent autophagy, an evolutionarily conserved self-digestion process, was induced and required for iCM reprogramming. Unexpectedly, the autophagic factor Beclin1 (Becn1) was found to suppress iCM induction in an autophagy-independent manner. Depletion of Becn1 resulted in improved iCM induction from both murine and human fibroblasts. In a mouse genetic model, Becn1 haploinsufficiency further enhanced reprogramming factor-mediated heart function recovery and scar size reduction after myocardial infarction. Mechanistically, loss of Becn1 up-regulated Lef1 and down-regulated Wnt inhibitors, leading to activation of the canonical Wnt/ß-catenin signaling pathway. In addition, Becn1 physically interacts with other classical class III phosphatidylinositol 3-kinase (PI3K III) complex components, the knockdown of which phenocopied Becn1 depletion in cardiac reprogramming. Collectively, our study revealed an inductive role of Atg5-dependent autophagy as well as a previously unrecognized autophagy-independent inhibitory function of Becn1 in iCM reprogramming.

Isoform Specific Effects of Mef2C during Direct Cardiac Reprogramming.

Direct conversion of cardiac fibroblasts into induced cardiomyocytes (iCMs) by forced expression of defined factors holds great potential for regenerative medicine by offering an alternative strategy for treatment of heart disease. Successful iCM conversion can be achieved by minimally using three transcription factors, Mef2c (M), Gata4(G), and Tbx5 (T). Despite increasing interest in iCM mechanistic studies using MGT(polycistronic construct with optimal expression of M,G and T), the reprogramming efficiency varies among different laboratories. Two main Mef2c isoforms (isoform2, Mi2 and isoform4, Mi4) are present in heart and are used separately by different labs, for iCM reprogramming. It is currently unknown if differently spliced isoform of Mef2c contributes to varied reprogramming efficiency. Here, we used Mi2 and Mi4 together with Gata4 and Tbx5 in separate vectors or polycistronic vector, to convert fibroblasts to iCMs. We found that Mi2 can induce higher reprogramming efficiency than Mi4 in MEFs. Addition of Hand2 to MGT retroviral cocktail or polycistronic Mi2-GT retroviruses further enhanced the iCM conversion. Overall, this study demonstrated the isoform specific effects of Mef2c, during iCM reprogramming, clarified some discrepancy about varied efficiency among labs and might lead to future research into the role of alternative splicing and the consequent variants in cell fate determination.