Numerical Simulation of Concussive-Generated Cortical Spreading Depolarization to Optimize DC-EEG Electrode Spacing for Noninvasive Visual Detection.

BACKGROUND: Cortical spreading depolarization (SD) is a propagating depolarization wave of neurons and glial cells in the cerebral gray matter. SD occurs in all forms of severe acute brain injury, as documented by using invasive detection methods. Based on many experimental studies of mechanical brain deformation and concussion, the occurrence of SDs in human concussion has often been hypothesized. However, this hypothesis cannot be confirmed in humans, as SDs can only be detected with invasive detection methods that would require either a craniotomy or a burr hole to be performed on athletes. Typical electroencephalography electrodes, placed on the scalp, can help detect the possible presence of SD but have not been able to accurately and reliably identify SDs. METHODS: To explore the possibility of a noninvasive method to resolve this hurdle, we developed a finite element numerical model that simulates scalp voltage changes that are induced by a brain surface SD. We then compared our simulation results with retrospectively evaluated data in patients with aneurysmal subarachnoid hemorrhage from Drenckhahn et al. (Brain 135:853, 2012). RESULTS: The ratio of peak scalp to simulated peak cortical voltage, Vscalp/Vcortex, was 0.0735, whereas the ratio from the retrospectively evaluated data was 0.0316 (0.0221, 0.0527) (median [1st quartile, 3rd quartile], n = 161, p < 0.001, one sample Wilcoxon signed-rank test). These differing values provide validation because their differences can be attributed to differences in shape between concussive SDs and aneurysmal subarachnoid hemorrhage SDs, as well as the inherent limitations in human study voltage measurements. This simulated scalp surface potential was used to design a virtual scalp detection array. Error analysis and visual reconstruction showed that 1 cm is the optimal electrode spacing to visually identify the propagating scalp voltage from a cortical SD. Electrode spacings of 2 cm and above produce distorted images and high errors in the reconstructed image. CONCLUSIONS: Our analysis suggests that concussive (and other) SDs can be detected from the scalp, which could confirm SD occurrence in human concussion, provide concussion diagnosis on the basis of an underlying physiological mechanism, and lead to noninvasive SD detection in the setting of severe acute brain injury.

Transcriptional mechanism of vascular endothelial growth factor-induced expression of protein kinase CßII in chronic lymphocytic leukaemia cells.

A key feature of chronic lymphocytic leukaemia (CLL) cells is overexpressed protein kinase CßII (PKCßII), an S/T kinase important in the pathogenesis of this and other B cell malignancies. The mechanisms contributing to enhanced transcription of the gene coding for PKCßII, PRKCB, in CLL cells remain poorly described, but could be important because of potential insight into how the phenotype of these cells is regulated. Here, we show that SP1 is the major driver of PKCßII expression in CLL cells where enhanced association of this transcription factor with the PRKCB promoter is likely because of the presence of histone marks permissive of gene activation. We also show how vascular endothelial growth factor (VEGF) regulates PRKCB promoter function in CLL cells, stimulating PKCß gene transcription via increased association of SP1 and decreased association of STAT3. Taken together, these results are the first to demonstrate a clear role for SP1 in the up regulation of PKCßII expression in CLL cells, and the first to link SP1 with the pathogenesis of this and potentially other B cell malignancies where PKCßII is overexpressed.

Epigenetic biomarkers in lung cancer.

Lung cancer mortality is strongly associated with the predominant diagnosis of late stage lesions that hampers effective therapy. Molecular biomarkers for early lung cancer detection is an unmet public health need and the lung cancer research community worldwide is putting a lot of effort to utilise major lung cancer population programmes in order to develop such molecular tools. The study of cancer epigenetics in the last decade has radically altered our views in cancer pathogenesis, providing new insights in biomarker development for risk assessment, early detection and therapeutic stratification. DNA methylation and miRNAs have rapidly emerged as potential biomarkers in body fluids showing promise to assist the clinical management of lung cancer. These new developments are exemplified in this review, demonstrating the huge potential of clinical cancer epigenetics, but also critically discussing the necessary validation steps to bring epigenetic biomarkers towards clinical implementation and the weaknesses of current biomarker studies.

Evidence of galaxy cluster motions with the kinematic Sunyaev-Zel'dovich effect.

Using high-resolution microwave sky maps made by the Atacama Cosmology Telescope, we for the first time present strong evidence for motions of galaxy clusters and groups via microwave background temperature distortions due to the kinematic Sunyaev-Zel'dovich effect. Galaxy clusters are identified by their constituent luminous galaxies observed by the Baryon Oscillation Spectroscopic Survey, part of the Sloan Digital Sky Survey III. We measure the mean pairwise momentum of clusters, with a probability of the signal being due to random errors of 0.002, and the signal is consistent with the growth of cosmic structure in the standard model of cosmology.

Vascular endothelial growth factor stimulates protein kinase CbetaII expression in chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia (CLL) is a malignant disease of mature B lymphocytes. We have previously shown that a characteristic feature of CLL cells are high levels of expression and activity of protein kinase CbetaII (PKCbetaII), and that this might influence disease progression by modulating signaling in response to B-cell receptor engagement. The aim of the present work was to investigate the factors involved in stimulating PKCbetaII expression in CLL cells. Here we show that the activation of PKCbetaII in CLL cells stimulated with vascular endothelial growth factor (VEGF) can drive expression of the gene for PKCbeta, PRKCB1. We found that this effect of VEGF on PRKCB1 transcription is paralleled by high expression of PKCbetaII protein and therefore probably contributes to the malignant phenotype of CLL cells. Taken together, the data presented in this study demonstrate that VEGF, in addition to its role in providing prosurvival signals, also plays a role in overexpression of PKCbetaII, an enzyme with a specific pathophysiologic role in CLL.

Heterogeneous response of cerebral blood flow to hypotension demonstrated by laser speckle imaging flowmetry in rats.

The response of cerebral blood flow (CBF) to mild hypotension shows great variability. CBF changes in different cortical regions at a mean arterial blood pressure (MABP) of 70 mmHg (near the lower limit of CBF-pressure autoregulation) were analyzed using laser speckle imaging flowmetry (LSIF). We hypothesize that variations in CBF autoregulation might be due to differences between regions within the cortex of each animal, regional heterogeneity, as opposed to differences between animals. Different responses of local CBF to hypotension in each rat were demonstrated as %CBF(70), the ratio of CBF at a MABP of 70 mmHg to CBF at a MABP of 100 mmHg. Regional heterogeneity ranged from 12 to 51%, expressed as the coefficient of variation of %CBF(70). At the same time LSIF revealed distinctly different patterns of CBF-pressure autoregulation between animals. Between-animal heterogeneity represents a continuous distribution, spread between animals with predominantly decreased CBF (%CBF(70) < 85%, rat #3) and animals with a high proportion of increased flow responses (%CBF(70) > 115%, rat #2). There are approximately equal contributions to the heterogeneity of %CBF(70) from within-animal (57 +/- 5%, percent variance +/- standard error) and between-animal (43 +/- 26%) variations. Within-animal variations could be due to heterogeneity of vascular anatomy, while the diversity of vascular control mechanisms might contribute to between-animal variations.