N-methyl-d-aspartate Receptor-mediated Preconditioning Mitigates Excitotoxicity in Human Induced Pluripotent Stem Cell-derived Brain Organoids.

Studies in rodent models of acute and chronic neurodegenerative disorders have uncovered that glutamate-induced excitotoxic cell death is mediated primarily by extrasynaptic N-methyl-d-aspartate receptors (NMDARs). Rodent neurons can also build up in an activity-dependent manner a protective shield against excitotoxicity. This form of acquired neuroprotection is induced by preconditioning with low doses of NMDA or by activation of synaptic NMDARs triggered by bursts of action potentials. Whether NMDARs in human neurons have similar dichotomous actions in cell death and survival is unknown. To investigate this, we established an induced pluripotent stem cell (iPSC)-derived forebrain organoid model for excitotoxic cell death and explored conditions of NMDAR activation that promote neuronal survival when applied prior to a toxic insult. We found that glutamate-induced excitotoxicity in human iPSC-derived neurons is mediated by NMDARs. Treatment of organoids with high concentrations of glutamate or NMDA caused the typical excitotoxicity pathology, comprising structural disintegration, neurite blebbing, shut-off of the transcription factor CRE binding protein (CREB), and cell death. In contrast, bath-applied low doses of NMDA elicited synaptic activity, a robust and sustained increase in CREB phosphorylation as well as function, and upregulation of immediate-early genes, including neuroprotective genes. Moreover, we found that conditions of enhanced synaptic activity increased survival of human iPSC-derived neurons if applied as pre-treatment before toxic NMDA application. These results revealed that both toxic and protective actions of NMDARs are preserved in human neurons. The experimental platform described in this study may prove useful for the validation of neuroprotective gene products and drugs in human neurons.

Evaluation of the Behavior of Carbon Short Fiber Reinforced Concrete (CSFRC) Based on a Multi-Sensory Experimental Investigation and a Numerical Multiscale Approach.

Carbon fiber reinforcement used in concrete has become a remarkable alternative to steel fibers. Admixing short fibers to fresh concrete and processing the material with a 3D printer leads to an orientation of fibers and a material with high uniaxial strength properties, which offers an economic use of fibers. To investigate its mechanical behavior, the material is subjected to flexural and tensional tests, combining several measuring techniques. Numerical analysis complements this research. Computed tomography is used with several post-processing algorithms for separating matrix and fibers. This helps to validate fiber alignment and serves as input data for numerical analysis with representative volume elements concatenating real fiber position and orientation with the three-dimensional stress tensor. Flexural and uniaxial tensional tests are performed combining multiple measuring techniques. Next to conventional displacement and strain measuring methods, sound emission analysis, in terms of quantitative event analysis and amplitude appraisal, and also high-resolution digital image correlation accompany the tests. Due to the electrical conductibility of carbon fibers, the material's resistivity could be measured during testing. All sensors detect the material's degradation behavior comparably, showing a strain-hardening effect, which results from multiple, yet locally restricted and distributed, microcracks arising in combination with plastic deformation.

Nasally delivered VEGFD mimetics mitigate stroke-induced dendrite loss and brain damage.

In the adult brain, vascular endothelial growth factor D (VEGFD) is required for structural integrity of dendrites and cognitive abilities. Alterations of dendritic architectures are hallmarks of many neurologic disorders, including stroke-induced damage caused by toxic extrasynaptic NMDA receptor (eNMDAR) signaling. Here we show that stimulation of eNMDARs causes a rapid shutoff of VEGFD expression, leading to a dramatic loss of dendritic structures. Using the mouse middle cerebral artery occlusion (MCAO) stroke model, we have established the therapeutic potential of recombinant mouse VEGFD delivered intraventricularly to preserve dendritic architecture, reduce stroke-induced brain damage, and facilitate functional recovery. An easy-to-use therapeutic intervention for stroke was developed that uses a new class of VEGFD-derived peptide mimetics and postinjury nose-to-brain delivery.

Post-injury Nose-to-Brain Delivery of Activin A and SerpinB2 Reduces Brain Damage in a Mouse Stroke Model.

Synaptic NMDA receptors activating nuclear calcium-driven adaptogenomics control a potent body-own neuroprotective mechanism, referred to as acquired neuroprotection. Viral vector-mediated gene transfer in conjunction with stereotactic surgery has previously demonstrated the proficiency of several nuclear calcium-regulated genes to protect in vivo against brain damage caused by toxic extrasynaptic NMDA receptor signaling following seizures or stroke. Here we used noninvasive nose-to-brain administration of Activin A and SerpinB2, two secreted nuclear calcium-regulated neuroprotectants, for post-injury treatment of brain damage following middle cerebral artery occlusion (MCAO) in C57BL/6N mice. The observed reduction of the infarct volume was comparable to the protection obtained by intracerebroventricular injection of recombinant Activin A or SerpinB2 or by stereotactic delivery 3 weeks prior to the injury of a recombinant adeno-associated virus containing an expression cassette for the potent neuroprotective transcription factor Npas4. These results establish post-injury, nose-to-brain delivery of Activin A and SerpinB2 as effective and possibly clinically applicable treatments of acute and chronic neurodegenerative conditions.

Isolated and concomitant minimally invasive minithoracotomy aortic valve surgery.

OBJECTIVE: To evaluate whether the outcomes of minimally invasive aortic valve surgery were similar in younger versus older patient groups, as well as whether concomitant minimally invasive aortic valve replacement (AVR) surgeries added significant risks in these populations. METHODS: We performed a single-institution retrospective analysis of 1018 patients undergoing isolated AVR and 378 patients undergoing concomitant AVR procedures over a 6-year period. All surgeries were via a right minithoracotomy approach, and patients who underwent reoperation were excluded. RESULTS: Mortality was 1.3% in the isolated AVR group and 3.2% in the concomitant AVR group. The incidence of permanent stroke was low in both the isolated and concomitant AVR groups (0.8% and 1.1%, respectively). In both groups, femoral cannulation was associated with equally low stroke rates (0.8% and 0.6%, respectively). When analyzing operative outcomes by age, mortality was similar for the isolated AVR group (age <80 vs ≥80 years, 0.9% vs 2.2%; P = .07) and the concomitant AVR group (<80 vs ≥80 years, 3.2% vs 3.2%; P = .99), whereas transfusion requirements, intensive care unit and hospital lengths of stay, and atrial fibrillation rates were greater in the older subsets of both AVR groups. CONCLUSIONS: Minimally invasive right thoracotomy AVR surgery was associated with low stroke and mortality rates in all age groups within 30 days of surgery. Similarly, minithoracotomy concomitant AVR surgery demonstrated excellent results and is deemed feasible in patients with multiple pathologies.

Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture.

Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines.

Minimally invasive aortic valve replacement in octogenarians performed via a right anterior thoracotomy approach.

BACKGROUND AND AIM OF THE STUDY: A significant number of patients aged > or =80 years are denied aortic valve surgery due to the assumption of poor outcomes with surgery. The study aim was to evaluate the outcomes of minimally invasive aortic valve replacement (AVR), performed via a right anterior thoracotomy approach, in octogenarians. METHODS: A retrospective review was conducted of all minimally invasive isolated AVRs in patients aged > or =80 years performed at the authors' institution between February 2009 and April 2014. The operative times, postoperative complications, hospital length of stay and mortality were analyzed. RESULTS: A total of 255 consecutive patients (133 males, 122 females; mean age 83.5 +/- 3 years) was identified. The mean left ventricular ejection fraction was 57 +/- 10%, and 31 patients (12.2%) had prior cardiac surgery. The median predicted Society of Thoracic Surgeons mortality score was 3.2% (IQR 2.4-4.4%). Postoperatively, four patients (1.6%) had cerebrovascular accidents, 38 (14.9%) had prolonged ventilation, four (1.6%) required reoperation for bleeding, and eight (3.1%) had acute kidney injury. The median intensive care unit length of stay was 48.5 h (IQR 27-92 h) and the postoperative length of stay was 7 days (IQR 5-9 days). The 30-day mortality was 3.1% (n=8), and the combined end point of morbidity and mortality was 19.2% (n=49). The all-cause mortality at one and three years was 6.7%, and 10.2%, respectively. CONCLUSION: Minimally invasive AVR in octogenarians, performed via a right anterior thoracotomy approach, is associated with a low morbidity and mortality. This applies to both primary or reoperative surgery.

Left-ventricular hypertrophy and renal outcome in hypertensive patients in primary-care.

BACKGROUND: Subclinical cardiac damage has recently emerged as a potential predictor of adverse renal outcome. We therefore retrospectively evaluated the effect of left-ventricular hypertrophy (LVH), diagnosed electrocardiographically, on the renal outcome of hypertensive patients managed in primary care. METHODS: From a historical cohort of 39,525 hypertensive individuals evaluated in 2005, we retrieved 5-year data of the 18,510 surviving subjects for whom renal follow-up was available. RESULTS: The baseline prevalences of chronic kidney disease (CKD) and LVH in the study cohort were 25.6% and 5.6%, respectively. During the 5-year follow-up, 1.4% of patients with LVH and 0.5% of those without LVH progressed to end-stage renal disease (ESRD) requiring dialysis (P < 0.01). Moreover, 25.6% of patients with LVH and 17% without LVH progressed from each stage of CKD to a more advanced stage (P < 0.01), whereas 0.9% of patients with LVH and 0.4% without LVH reached stage 5 CKD (P < 0.01). Multivariate Cox regression analysis showed that besides estimated glomerular filtration rate (eGFR) and male gender, LVH was the most significant modifiable predictor of progression to dialysis (hazard ratio (HR), 1.82; 95% CI, 1.05-3.17; P = 0.03). Multivariate logistic regression analysis also revealed LVH as a significant predictor of the risk of progression from each stage of CKD to a more advanced stage (OR, 1.24; 95% CI, 1.07-1.45; P < 0.01), as well as of progression to stage 5 CKD (OR, 1.86; 95% CI, 1.17-2.95; P < 0.01). CONCLUSIONS: Left-ventricular hypertrophy proved to be a significant predictor of adverse renal outcome in hypertensive patients managed with primary care, and systematic screening for LVH should be adopted for assessing renal risk in these patients.