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Background: Adequate cerebral perfusion is crucial for a positive neurological outcome in trauma; however, it is difficult to characterize in the acute setting with noninvasive methods. Intra-arterial computed tomography perfusion may offer a solution. The aim of this study was to develop an intra-arterial computed tomography perfusion protocol for resuscitation research., Methods: The study examined intra-arterial contrast administration for computed tomography perfusion (CTP) acquisition. It consisted of three phases: intra-arterial contrast dose finding, evaluation of reproducibility, and evaluation during hypotension. Blood pressure and laser Doppler flow data were collected. In phase 1, animals underwent CTPs using several intra-arterial contrast injection protocols. In phase 2, animals underwent two CTPs 7 hours apart using the 2.5 mL/s for 3-second protocol. In phase 3, animals underwent CTPs at several pressures following a computer-controlled bleed including euvolemia and at systolic pressures of 60, 40, and 20 mm Hg. Phase 1 CTPs were evaluated for contrast-to-noise ratio. In phase 2, CTPs were compared within each animal and with laser Doppler flow using linear regression. Phase 3 CTPs were graphed against systolic pressure and fitted with a nonlinear fit., Results: The protocol using 2.5mL/s for 3 seconds was optimal, demonstrating a contrast-to-noise ratio of 40.1 and a superior arterial input function curve compared with the 1 mL/s bolus. Cerebral blood flow demonstrated high concordance between baseline and end of study CTPs (R2 = 0.82, p < 0.001). Cerebral blood flow also compared moderately well against laser Doppler flow during 8 (R2 = 0.53, p = 0.03); however, laser Doppler flow did not perform well during hypovolemia, and the favorable concordance was not maintained (R2 = 0.45, p = 0.06). Cerebral blood flow was graphed against systolic blood pressure and fitted with a nonlinear fit (R2 = 0.95, p = 0.003)., Conclusion: Computed tomography perfusion using intra-arterial contrast injection may offer a novel alternative to traditional CTP protocols that could prove a useful additional tool in the setting of resuscitation research., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Less than 1.5% of the human genome encodes protein. However, vast portions of the human genome are subject to transcriptional and epigenetic regulation, and many noncoding regulatory DNA elements are thought to regulate the spatial organization of interphase chromosomes. For example, chromosomal "loopings" are pivotal for the orderly process of gene expression, by enabling distal regulatory enhancer or silencer elements to directly interact with proximal promoter and transcription start sites, potentially bypassing hundreds of kilobases of interspersed sequence on the linear genome. To date, however, epigenetic studies in the human brain are mostly limited to the exploration of DNA methylation and posttranslational modifications of the nucleosome core histones. In contrast, very little is known about the regulation of supranucleosomal structures. Here, we show that chromosome conformation capture, a widely used approach to study higher-order chromatin, is applicable to tissue collected postmortem, thereby informing about genome organization in the human brain. We introduce chromosome conformation capture protocols for brain and compare higher-order chromatin structures at the chromosome 6p22.2-22.1 schizophrenia and bipolar disorder susceptibility locus, and additional neurodevelopmental risk genes, (DPP10, MCPH1) in adult prefrontal cortex and various cell culture systems, including neurons derived from reprogrammed skin cells. We predict that the exploration of three-dimensional genome architectures and function will open up new frontiers in human brain research and psychiatric genetics and provide novel insights into the epigenetic risk architectures of regulatory noncoding DNA., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Expression of tight junction proteins between brain microvascular endothelial cells (BMECs) of the blood-brain barrier (BBB) is lost during development of human immunodeficiency virus (HIV) encephalitis (HIVE). Although many studies have focused on the strains of virus that induce neurological sequelae or on the macrophages/microglia that are associated with development of encephalitis, the molecular signaling pathways within the BMECs involved have yet to be resolved. We have previously shown that there is activation and disruption of an in vitro BBB model using lentivirus-infected CEMx174 cells. We and others have shown similar disruption in vivo. Therefore, it was of interest to determine if the presence of infected cells could disrupt intact cerebral microvessels immediately ex vivo, and if so, which signaling pathways were involved. The present data demonstrate that disruption of tight junctions between BMECs is mediated through activation of focal adhesion kinase (FAK) by phosphorylation at TYR-397. Inhibition of FAK activation is sufficient to prevent tight junction disruption. Thus, it may be possible to inhibit the development of HIVE by using inhibitors of FAK.

Background: The 21-aminosteroids are a series of compounds designed to inhibit lipid peroxidation in the cell, and, as such, may have cerebral protective effects. The current study was performed to evaluate the effect of a 21-aminosteroid, tirilazad mesylate (U74006F), on cerebral blood flow, metabolism, and carbon dioxide reactivity., Methods: Using a double-blind study design, eight volunteers received tirilazad mesylate, and eight others received only vehicle. The cerebral blood flow was measured by single photon emission computerized tomography using 133Xe inhalation in the resting condition at the beginning of the study and after infusion of tirilazad mesylate (1.5 mg/kg) or vehicle. Cerebral oxygen metabolism was calculated from the cerebral blood flow and the measured cerebral arteriovenous oxygen content difference. After both of the above cerebral blood flow measurements, arterial carbon dioxide tension was decreased by voluntary hyperventilation, and, later, increased by breathing an air/carbon dioxide mixture. The relative changes in cerebral blood flow induced by the PaCO2 variations were estimated from the changes in the arteriovenous oxygen content difference., Results: Blood pressure, pulse rate, and PaCO2 were similar before and after the infusion of tirilazad mesylate in both groups, and there was no difference between the groups. The cerebral blood flow and oxygen metabolism did not change after the tirilazad mesylate infusion. The slope of the regression line of relative change of estimated cerebral blood flow and PaCO2 (regression coefficients in both groups, > 0.90) was unchanged after infusion., Conclusions: Tirilazad mesylate has no effect on cerebral blood flow, cerebral oxygen metabolism, or reactivity of cerebral blood flow to carbon dioxide in healthy volunteers.

Functional hemispherectomy, indicated for the control of pharmacologically refractory seizures, has been used at the Montreal Neurological Hospital since 1974. We have used this technique in 18 children suffering from intractable seizures secondary to conditions such as infantile hemiplegia, chronic encephalitis, head trauma, cerebrovascular accident, brain dysplasia and Sturge-Weber angiomatosis. None has developed superficial cerebral hemosiderosis often seen following the classical anatomical hemispherectomy. Eighty-two per cent (82%) of patients have been seizure-free since hospital discharge while another 11.5% have had at least 80% reduction in their seizure frequency. Most patients have shown an improvement in their intellectual capacity and sociability.

We reviewed the prognostic significance of preoperative EEG findings in 25 patients who underwent functional hemispherectomy. Bilateral independent epileptogenic foci, found in five patients, generally indicate a less satisfactory outcome, with only three of the five patients becoming seizure free following hemispherectomy. In contrast, abnormalities of background activity over the "good" hemisphere, multifocal epileptic activity confined to the side of operation, or bilaterally synchronous discharges were associated with a good outcome and should not be considered as contraindications to operation. Postoperatively, discharges may occur in the functionally isolated frontal and occipital cortex, which are benign, with no other clinical significance than showing that the isolated cortex remains viable and continues to generate epileptogenic potentials.

The serious, late complication of superficial cerebral hemosiderosis, which appears after several years in 1/4-1/3 of patients who have undergone hemispherectomy, has resulted in recent years in a considerable reluctance to carry out this operation despite the fact it has proved to be highly effective in patients with medically refractory seizures associated with hemiplegia. Preservation of a small portion of the hemisphere, usually the frontal or occipital pole, has proved to be effective in preventing this late complication, but at the cost of a significant reduction in the effectiveness of the operation in reducing the patients' seizure tendency. Preserving the frontal and occipital poles but disconnecting them from the rest of the brain, resulting in a functional complete but anatomical subtotal hemispherectomy, retains the therapeutic effectiveness of a complete hemispherectomy while still protecting adequately against the serious late postoperative complication of superficial cerebral hemosiderosis and its associated neurologic deterioration, hydrocephalus and sometimes death.

The risk-benefit ratio of this functionally complete but anatomically subtotal hemispherectomy is strongly in favor of its more widespread and early use for the small group of unfortunate seizure patients who have maximal or near maximal hemiplegia and a complete or high-grade hemianopsia, and whose seizures constitute a significant handicap in regard to schooling and psychosocial development despite an adequate trial of appropriate antiepileptic medication. The earlier the "good" hemisphere and the upper brain are spared the nociferous effect of continual bombardment by wide-spread high-amplitude epileptiform discharges, the more effectively motor, sensory, intellectual, and psychosocial development can take place in the remainder of the nervous system.