Locomotor adaptation is influenced by the interaction between perturbation and baseline asymmetry after stroke.

Stroke survivors without cerebellar involvement retain the ability to adapt to the split-belt treadmill; however it has been suggested that their rate of adaptation may be slowed compared to those who are neurologically intact. Depending on limb placement, the split-belt treadmill can be configured to either exaggerate baseline asymmetry, or reduce it, which may affect the behavior of adaptation or de-adaptation. The objectives of this study were to characterize the rate and magnitude of locomotor (de)adaptation in chronic stroke survivors compared to healthy matched subjects, and to evaluate whether exaggeration or reduction of baseline asymmetry impact the responses. Seventeen stroke survivors and healthy subjects completed 10min of split-belt treadmill walking, then 5min of tied-belt walking. Stroke survivors completed this once with each leg on the fast belt. Magnitude and rate of (de)adaptation were evaluated for step length and limb phase asymmetry. There were no differences between the groups with the exception of the reduced step length asymmetry configuration, in which case there was a significantly reduced magnitude (p≤0.000) and rate (p=0.011) of adaptation when compared to controls. There was a similar trend observed during post-adaptation for the exaggerated asymmetry group. The rate and magnitude of locomotor (de)adaptation is similar between chronic stroke survivors and neurologically intact controls, except when the adaptation or de-adaptation response would take the stroke survivors away from a symmetric step length pattern. This suggests that there may be some benefit to symmetry that is recognized by the system

Does high-intensity exercise better improve ambulation in the population with chronic stroke, as compared to standard care?: A Systematic Review of the Literature

Purpose: To assess the effectiveness of high-intensity exercise on the improvement of gait deficits in survivors of chronic stroke as compared to standard care.https://jdc.jefferson.edu/dptcapstones/1006/thumbnail.jp

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Influence of Systematic Increases in Treadmill Walking Speed on Gait Kinematics After Stroke

Background. Fast treadmill training improves walking speed to a greater extent than training at a self-selected speed after stroke. It is unclear whether fast treadmill walking facilitates a more normal gait pattern after stroke, as has been suggested for treadmill training at self-selected speeds. Given the massed stepping practice that occurs during treadmill training, it is important for therapists to understand how the treadmill speed selected influences the gait pattern that is practiced on the treadmill. Objective. The purpose of this study was to characterize the effect of systematic increases in treadmill speed on common gait deviations observed after stroke. Design. A repeated-measures design was used. Methods. Twenty patients with stroke walked on a treadmill at their self-selected walking speed, their fastest speed, and 2 speeds in between. Using a motion capture system, spatiotemporal gait parameters and kinematic gait compensations were measured. Results. Significant improvements in paretic- and nonparetic-limb step length and in single- and double-limb support were found. Asymmetry of these measure

Senescent Phenotype Induced by p90RSK-NRF2 Signaling Sensitizes Monocytes and Macrophages to Oxidative Stress in HIV-Positive Individuals: Implications for Atherogenesis

Background: The incidence of cardiovascular disease is higher in HIV-positive (HIV ) patients than it is in the average population, and combination antiretroviral therapy (cART) is a recognized risk factor for cardiovascular disease. However, the molecular mechanisms that link cART and cardiovascular disease are currently unknown. Our study explores the role of the activation of p90RSK, a reactive oxygen species-sensitive kinase, in engendering senescent phenotype in macrophages and accelerating atherogenesis in patients undergoing cART. Methods: Peripheral whole blood from cART-treated HIV individuals and nontreated HIV-negative individuals was treated with H O (200 μmol/L) for 4 minutes, and p90RSK activity in CD14 monocytes was measured. Plaque formation in the carotids was also analyzed in these individuals. Macrophage senescence was determined by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. The involvement of p90RSK-NRF2 signaling in cART-induced senescence was assessed by p90RSK-specific inhibitor (FMK-MEA) or dominant-negative p90RSK (DN-p90RSK) and NRF2 activator (NRF2A). Further, the severity of atherosclerosis was determined in myeloid cell-specific wild-type and DN-p90RSK transgenic mice. Results: Monocytes from HIV patients exhibited higher levels of p90RSK activity and were also more sensitive to reactive oxygen species than monocytes from HIV-negative individuals. A multiple linear regression analysis involving cART, Reynolds cardiovascular risk score, and basal p90RSK activity revealed that cART and basal p90RSK activity were the 2 significant determinants of plaque formation. Many of the antiretroviral drugs individually activated p90RSK, which simultaneously triggered all components of the macrophage senescent phenotype. cART inhibited antioxidant response element reporter activity via ERK5 S496 phosphorylation. NRF2A reversed the H O -induced overactivation of p90RSK in cART-treated macrophages by countering the induction of senescent phenotype. Last, the data obtained from our gain- or loss-of-function mice conclusively showed the crucial role of p90RSK in inducing senescent phenotype in macrophages and atherogenesis. Conclusions: cART increased monocyte/macrophage sensitivity to reactive oxygen species- in HIV individuals by suppressing NRF2-ARE activity via p90RSK-mediated ERK5 S496 phosphorylation, which coordinately elicited senescent phenotypes and proinflammatory responses. As such, our report underscores the importance of p90RSK regulation in monocytes/macrophages as a viable biomarker and therapeutic target for preventing cardiovascular disease, especially in HIV patients treated with cART. + + 2 2 + + 2 2 +

Multiple loci on 8q24 associated with prostate cancer susceptibility

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility