Ubiquitous classical (typical) calpains, calpain-1 and calpain-2, are Ca+2-dependent cysteine proteases, which have been associated with numerous physiological and pathological cellular functions. However, a clear understanding of the role of calpains in the CNS has been hampered by the lack of appropriate deletion paradigms in the brain. In this study, we describe a unique model of conditional deletion of both calpain-1 and calpain-2 activities in mouse brain, which more definitively assesses the role of these ubiquitous proteases in brain development/function and pathology. Surprisingly, we show that these calpains are not critical for gross CNS development. However, calpain-1/calpain-2 loss leads to reduced dendritic branching complexity and spine density deficits associated with major deterioration in hippocampal long-term potentiation and spatial memory. Moreover, calpain-1/calpain-2-deficient neurons were significantly resistant to injury induced by excitotoxic stress or mitochondrial toxicity. Examination of downstream target showed that the conversion of the Cdk5 activator, p35, to pathogenic p25 form, occurred only in the presence of calpain and that it played a major role in calpain-mediated neuronal death. These findings unequivocally establish two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.
A 75-year-old male with a previous orthotopic heart transplantation performed 28 years ago was incidentally discovered to have an asymptomatic chronic type A aortic dissection. Catheter-induced dissection during coronary angiography was believed to be the culprit factor. Aortic root replacement and aortic valve reconstruction were successfully performed.
OBJECTIVES The impact of coaptation length on recurrent mitral regurgitation following degenerative mitral repair is not fully understood. METHODS Between May 2008 and February 2021, 386 consecutive patients underwent mitral repair for degenerative mitral regurgitation at a single centre. We compared patients with a post-repair coaptation length >11 mm (long-coaptation group, n = 230) and ≤11 mm (short-coaptation group, n = 156). The coaptation length cutoff was selected based on published postoperative transesophageal echocardiographic measurement of mitral repair patients and healthy controls. Propensity score with inverse probability of treatment weighting (IPTW) analyses were performed. The median duration of clinical follow-up was 41 months and follow-up was complete in the entire cohort. RESULTS The long-coaptation patients underwent more neochord implantation (89% vs 65%, P < 0.001) and less leaflet resection (11% vs 29%, P < 0.001). Overall in-hospital/30-day mortality and mitral reintervention occurred in 3 (1%) and 4 (1%) patients, respectively, and freedom from recurrent mitral regurgitation was 98% at 1 year and 94% at 5 years. Freedom from recurrent mitral regurgitation moderate or greater was significantly higher in the long-coaptation patients (IPTW-adjusted difference in average time to recurrent mitral regurgitation: 31 months, 95% confidence interval 9–53, P = 0.006). However, there was no difference in intermediate-term survival between both groups (IPTW-adjusted difference in average time to death: 9.5 months, 95% confidence interval −27 to 46, P = 0.61). Stratified analysis and pairwise comparison of different coaptation intervals also appeared to support the protective effect of longer coaptation on repair durability. CONCLUSIONS Longer coaptation length appears to be associated with improved intermediate-term durability after mitral repair.
Objective The safety of minimally invasive mitral valve surgery (MIMVS) in elderly patients is still debated. Our objective was to perform a systematic review and meta-analysis of studies comparing MIMVS with conventional sternotomy (CS) in elderly patients (≥65 years old). Methods We searched PubMed, EMBASE, Web of Science, clinicaltrials.gov, and Cochrane Central Register of Controlled Trials for trials and observational studies comparing MIMVS with CS in patients ≥65 years old presenting for mitral valve surgery. We performed a random-effects meta-analysis of all outcomes. Results The MIMVS group had lower odds of acute renal failure (odds ratio [OR] 0.27; 95% CI 0.10 to 0.78), prolonged intubation (>48 h; OR 0.47; 95% CI 0.31 to 0.70), less blood product transfusion (weighted mean difference [WMD] −0.82 units; 95% CI −1.29 to −0.34 units), shorter ICU length of stay (LOS; WMD −2.57 days; 95% CI −3.24 to −1.90 days) and hospital LOS (WMD −4.06 days; 95% CI −5.19 to −2.94 days). There were no significant differences in the odds of mortality, stroke, respiratory infection, reoperation for bleeding, and postoperative atrial fibrillation. MIMVS was associated with longer cross-clamp (WMD 11.8 min; 95% CI 3.5 to 20.1 min) and cardiopulmonary bypass times (WMD 23.0 min; 95% CI 10.4 to 35.6 min). Conclusions MIMVS in elderly patients is associated with lower postoperative complications, blood transfusion, shorter ICU, and hospital LOS, and longer cross-clamp and bypass times.
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