Distinct effects of cardiac mitochondrial calcium uniporter inactivation via EMRE deletion in the short and long term.

Transport of Ca2+ into mitochondria is thought to stimulate the production of ATP, a critical process in the heart's fight or flight response, but excess Ca2+ can trigger cell death. The mitochondrial Ca2+ uniporter complex is the primary route of Ca2+ transport into mitochondria, in which the channel-forming protein MCU and the regulatory protein EMRE are essential for activity. In previous studies, chronic Mcu or Emre deletion differed from acute cardiac Mcu deletion in response to adrenergic stimulation and ischemia/reperfusion (I/R) injury, despite equivalent inactivation of rapid mitochondrial Ca2+ uptake. To explore this discrepancy between chronic and acute loss of uniporter activity, we compared short-term and long-term Emre deletion using a novel conditional cardiac-specific, tamoxifen-inducible mouse model. After short-term Emre deletion (3 weeks post-tamoxifen) in adult mice, cardiac mitochondria were unable to take up Ca2+, had lower basal mitochondrial Ca2+ levels, and displayed attenuated Ca2+-induced ATP production and mPTP opening. Moreover, short-term EMRE loss blunted cardiac response to adrenergic stimulation and improved maintenance of cardiac function in an ex vivo I/R model. We then tested whether the long-term absence of EMRE (3 months post-tamoxifen) in adulthood would lead to distinct outcomes. After long-term Emre deletion, mitochondrial Ca2+ handling and function, as well as cardiac response to adrenergic stimulation, were similarly impaired as in short-term deletion. Interestingly, however, protection from I/R injury was lost in the long-term. These data suggest that several months without uniporter function are insufficient to restore bioenergetic response but are sufficient to restore susceptibility to I/R.

Sagittal balance in sitting and standing positions: A systematic review of radiographic measures.

Background: Sagittal imbalance can be caused by various etiologies and is among the most important indicators of spinal deformity. Sagittal balance can be restored through surgical intervention based on several radiographic measures. The purpose of this study is to review the normal parameters in the sitting position, which are not well understood and could have significant implications for non-ambulatory patients. Methods: A systematic review was performed adhering to PRISMA Guidelines. Using R-software, the weighted means and 95% confidence intervals of the radiographic findings were calculated using a random effect model and significance testing using unpaired t-tests. Results: 10 articles with a total of 1066 subjects reported radiographic measures of subjects with no spinal deformity in the sitting and standing position. In the healthy individual, standing sagittal vertical axis -16.8°was significantly less than sitting 28.4° (p < 0.0001), while standing lumbar lordosis 43.3°is significantly greater than sitting 21.3° (p < 0.0001). Thoracic kyphosis was not significantly different between the two groups (p = 0.368). Standing sacral slope 34.3° was significantly greater than sitting 19.5° (p < 0.0001) and standing pelvic tilt 14.0° was significantly less than sitting 33.9° (p < 0.0001). Conclusions: There are key differences between standing and sitting postures, which could lead to undue stress on surgical implants and poor outcomes, especially for non-ambulatory populations. There is a need for more studies reporting sitting and standing radiographic measures in different postures and spinal conditions.

Frequency settings of subthalamic nucleus DBS for Parkinson's disease: A systematic review and network meta-analysis.

INTRODUCTION: Deep Brain Stimulation (DBS) is an effective treatment for the motor symptoms of Parkinson's Disease. The targeted physiological structure for lead location is commonly the subthalamic nucleus (STN). The efficacy of DBS for improving motor symptoms is assessed via the Unified Parkinson's Disease Rating III Scale (UPDRS-III). In this study, we sought to compare the efficacy of frequency settings utilized for STN-DBS. METHODS: Following PRISMA Guidelines, a search on PUBMED and MEDLINE was performed to include full-length randomized controlled trials evaluating STN-DBS. The frequency stimulation parameters and Unified Parkinson's Disease Rating Scale (UPDRS-III) outcomes were extracted in the search. High-frequency stimulation (HFS) was defined as ≥100 Hz and low-frequency stimulation (LFS) was defined as <100 Hz. A frequentist network meta-analysis was performed with odds ratios (OR) and pooling performed using the Mantel-Haenszel method. Statistics are presented as OR [95% CI]. RESULTS: 15 studies consisting of 298 patients were included for analysis. Bilateral HFS -0.68 [-0.89; -0.46] was associated with better UPDRS-III scores compared to bilateral LFS. On the other hand, bilateral LFS with medications (MEDS) was favored over HFS with MEDS (-0.28 [-0.63; 0.07]). Bilateral LFS and MEDS, HFS and MEDS, stimulation (STIM) OFF MEDS ON, HFS, LFS, STIM OFF MEDS OFF UPDRS outcomes were ranked from best to worst outcomes. DISCUSSION: The outcomes of this study suggest that bilateral HFS has better utility for those with no response to medication, while LFS has additive benefits to medication by improving unique symptoms via different neurophysiological mechanisms.

WITHDRAWN: Laterality and frequency settings of subthalamic nucleus DBS for Parkinson's disease: A systematic review and network meta-analysis.

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