Machine learning -based decision support framework for CBRN protection.

Detecting chemical, biological, radiological and nuclear (CBRN) incidents is a high priority task and has been a topic of intensive research for decades. Ongoing technological, data processing, and automation developments are opening up new potentials in CBRN protection, which has become a complex, interdisciplinary field of science. According to it, chemists, physicists, meteorologists, military experts, programmers, and data scientists are all involved in the research. The key to effectively enhancing CBRN defence capabilities is continuous and targeted development along a well-structured concept. Our study highlights the importance of predictive analytics by providing an overview of the main components of modern CBRN defence technologies, including a summary of the conceptual requirements for CBRN reconnaissance and decision support steps, and by presenting the role and recent opportunities of information management in these processes.

Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci.

Spreading depolarizations (SDs) indicate injury progression and predict worse clinical outcome in acute brain injury. We demonstrate in rodents that acute brain swelling upon cerebral ischemia impairs astroglial glutamate clearance and increases the tissue area invaded by SD. The cytotoxic extracellular glutamate accumulation (>15 µM) predisposes an extensive bulk of tissue (4-5 mm2) for a yet undescribed simultaneous depolarization (SiD). We confirm in rat brain slices exposed to osmotic stress that SiD is the pathological expansion of prior punctual SD foci (0.5-1 mm2), is associated with astrocyte swelling, and triggers oncotic neuron death. The blockade of astrocytic aquaporin-4 channels and Na+/K+/Cl- co-transporters, or volume-regulated anion channels mitigated slice edema, extracellular glutamate accumulation (<10 µM) and SiD occurrence. Reversal of slice swelling by hyperosmotic mannitol counteracted glutamate accumulation and prevented SiD. In contrast, inhibition of glial metabolism or inhibition of astrocyte glutamate transporters reproduced the SiD phenotype. Finally, we show in the rodent water intoxication model of cytotoxic edema that astrocyte swelling and altered astrocyte calcium waves are central in the evolution of SiD. We discuss our results in the light of evidence for SiD in the human cortex. Our results emphasize the need of preventive osmotherapy in acute brain injury.

Managing Alternative Patient Appointments Using P-Graph Methodology.

BACKGROUND: Patient appointment scheduling is one of the main challenging tasks in the healthcare administration and is constantly in the focus of theoretical researches. OBJECTIVES: The aim of this study was to investigate the applicability of the P-graph (Process graph) methodology to find the n-best alternative for patient's scheduling. METHODS: The patient appointment scheduling task was formalised as an integer linear programming problem and was considered as a process network synthesis problem. The optimal and n-best alternative solutions were determined by an efficient branch and bound algorithm implemented in a decision support system. RESULTS: Experimental results show, that the P-graph methodology can be effectively applied to produce the optimal scheduling for the examinations and to find the alternatives of the best scheduling.

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).

Advancing age and ischemia elevate the electric threshold to elicit spreading depolarization in the cerebral cortex of young adult rats.

Spreading depolarizations of long cumulative duration have been implicated in lesion development and progression in patients with stroke and traumatic brain injury. Spreading depolarizations evolve less likely in the aged brain, but it remains to be determined at what age the susceptibility to spreading depolarizations starts to decline, especially in ischemia. Spreading depolarizations were triggered by epidural electric stimulation prior and after ischemia induction in the cortex of 7-30 weeks old anesthetized rats ( n = 38). Cerebral ischemia was achieved by occlusion of both common carotid arteries. Spreading depolarization occurrence was confirmed by the acquisition of DC potential and electrocorticogram. Cerebral blood flow variations were recorded by laser-Doppler flowmetry. Dendritic spine density in the cortex was determined in Golgi-COX stained sections. Spreading depolarization initiation required increasingly greater electric charge with older age, a potential outcome of consolidation of cortical connections, indicated by altered dendritic spine distribution. The threshold of spreading depolarization elicitation increased with ischemia in all age groups, which may be caused by tissue acidosis and increased K+ conductance, among other factors. In conclusion, the brain appears to be the most susceptible to spreading depolarizations at adolescent age; therefore, spreading depolarizations may occur in young patients of ischemic or traumatic brain injury at the highest probability.

Capillary injury in the ischemic brain of hyperlipidemic, apolipoprotein B-100 transgenic mice.

AIMS: Apolipoprotein B-100 (apoB-100) has been implicated in hyperlipidemia, which contributes to the pathogenesis of vascular disorders. Our aim was to investigate whether the expression of human apoB-100 in transgenic mice and/or a high-cholesterol diet cause cerebral microvascular lesions, and whether these conditions augment ischemia-related capillary damage. MAIN METHODS: Human apoB-100 overexpressing transgenic (Tg(apoB-100), n=23) and wild-type mice (C5/B6, Wt, n=26) were supplied with standard or 2% cholesterol-enriched diet for 17-19 weeks. Cerebral ischemia was induced by unilateral common carotid artery occlusion. Cortical samples were embedded for electron microscopy. Microvascular density (number of microvascular profiles/examined area), lumen diameter, the swelling of astrocytic endfeet, the occurrence of endothelial microvilli (affected capillaries expressed as ratio of all capillaries encountered), and the ratio of intact capillaries (devoid of all the above pathology) were calculated. KEY FINDINGS: The expression of apoB-100 coincided with decreased cortical microvascular density (195+/-7 vs. 223+/-8 vessels/mm(2), vs. Wt; P<0.008) and increased capillary lumen diameter (3.16+/-0.5 vs. 2.88+/-0.6 microm, vs. Wt; P<0.001). Cerebral ischemia promoted the swelling of perivascular astrocytes (62.1+/-4.2 vs. 36.5+/-4.0%, vs. contralateral, Wt; P<0.001), and reduced the ratio of intact capillaries (32.1+/-5.6 vs. 65.2+/-3.7%, vs. contralateral, Wt; P<0.001). Hyperlipidemia did not exacerbate the injury. SIGNIFICANCE: The overexpression of human apoB-100 alters the density of the microvascular network and the diameter of capillaries, which may compromise cerebrovascular reactivity during ischemia.

Effects of cyclooxygenase (COX) inhibition on memory impairment and hippocampal damage in the early period of cerebral hypoperfusion in rats.

Chronic cerebral hypoperfusion is related to neurological disorders and contributes to a cognitive decline. Its experimental model in rats is permanent, bilateral common carotid artery occlusion. The cyclooxygenase (COX) system plays a pivotal role in the evolution of ischemic brain damage. Several COX inhibitors have proved to be neuroprotective in stroke models. We set out to characterize the effects of COX inhibitors in rats with permanent cerebral hypoperfusion. Some of the animals were exposed to two-vessel occlusion (n=72), while the others served as sham-operated controls (n=54). This was followed by a 3-day post-treatment with the nonselective COX inhibitor indomethacin (3 mg/kg) or with the selective COX-2 inhibitor NS-398 (15 mg/kg) or with the solvent. Some groups of the animals were sacrificed after 3 days, while the remainder were tested in the Morris watermaze for 5 days, and were sacrificed after 2 weeks. Neurons in the hippocampus were subjected to immunocytochemical labeling with cresyl violet, the dendrites with microtubule-associated protein-2, astrocytes with glial fibrillary acidic protein and microglia activation with OX-42 antibody. Two-vessel occlusion induced a learning impairment, mild neuronal damage, marked dendritic injury and moderate astrocytic reaction in the hippocampus. NS-398, but not indomethacin improved the survival rate and abolished the learning disability. However, both drugs increased the proportion of animals displaying neuronal damage. Glial markers revealed a time-dependent elevation in both the sham and the two-vessel occluded group, and were unaffected by the treatments. In summary, NS-398 prevented the hypoperfusion-induced memory impairment, but not by protecting the hippocampal neurons.

Pre-treatment and post-treatment with alpha-tocopherol attenuates hippocampal neuronal damage in experimental cerebral hypoperfusion.

Alpha-tocopherol, a potent antioxidant, has been widely investigated as a dietary supplement with which to reduce the risk of atherosclerosis, and has recently been considered as a potential supplement to moderate oxidative neuronal damage in Alzheimer's disease patients. Since alpha-tocopherol appears beneficial in vascular and neurodegenerative disorders, we set out to identify its neuroprotective action in a rat model of chronic cerebral hypoperfusion-induced brain injury. The bilateral common carotid arteries of male Wistar rats were permanently occluded (2VO). Sham-operated animals served as controls. Half of the animals were pre- or post-treated repeatedly with alpha-tocopherol (5x100 mg/kg daily, i.p.), the other half receiving only soybean oil, the alpha-tocopherol vehicle. One week after the onset of 2VO, the spatial learning capacity of the animals was assessed in the Morris water maze. After testing, hippocampal slices were stained with cresyl violet in order to examine the pyramidal cell layer integrity. The density of microtubule-associated protein-2 (MAP-2)-positive dendrites and the OX-42-labeled microglial activation level were determined immunocytochemically. Finally, alpha-tocopherol was determined in the peripheral tissues, blood and brain. Alpha-tocopherol moderated the 2VO-induced learning impairment. The various forms of alpha-tocopherol treatment, and particularly the post-treatment, prevented the 2VO-induced pyramidal cell death and the activation of microglia in the hippocampus CA1 region, and the degeneration of MAP-2-positive dendrites in the CA3 region. The alpha-tocopherol concentration was elevated in the peripheral tissues and the blood, but not in the brain. The data indicate that alpha-tocopherol, particularly when administered as post-treatment, is neuroprotective in chronic cerebral hypoperfusion.

Tumor necrosis factor-alpha increases cerebral blood flow and ultrastructural capillary damage through the release of nitric oxide in the rat brain.

Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine implicated in cerebrovascular pathology. The aim of the present study was to characterize the simultaneous effects of an intracarotid administration of TNFalpha on cerebral blood flow (CBF) and the ultrastructure of the blood-brain barrier (BBB) and to determine whether nitric oxide (NO) is a mediator of the TNFalpha-induced alterations in CBF and BBB. TNFalpha (2.5 microg/kg) or saline was infused into the right common carotid artery of male Wistar rats (n = 70). NO production was inhibited with L-NAME (20 mg/kg, i.v.). CBF was monitored for 2 h with laser-Doppler flowmetry. Tissue samples were taken from the unilateral frontoparietal cortex and prepared for electron microscopy. The proportion of capillaries with swollen astrocytic endfeet and the lumen diameter of the capillaries were measured. TNFalpha significantly increased CBF, which reached a maximum of 190% of the baseline 1 h after the cessation of TNFalpha infusion. L-NAME completely prevented the increase in CBF. TNFalpha elevated the swelling of the astrocytic endfeet from a baseline value of 22.4 +/- 9.35% to 64.9 +/- 3.16%. The administration of L-NAME before TNFalpha infusion prevented the astrocytic swelling. These results demonstrate that TNFalpha increases CBF and the swelling of astrocytes through the production of NO. Our data additionally demonstrate that the breakdown of the BBB by circulating TNFalpha may involve the astrocytic endfeet.