Predictors of CNS Injury as Measured by Proton Magnetic Resonance Spectroscopy in the Setting of Chronic HIV infection and CART

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS) Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr and Glx/Cr) were measured in the basal ganglia, the frontal white matter and grey matter and the best predictive models were selected using a bootstrap-enhanced Akaike Information Criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease

Physical activity mass media campaigns and their evaluation: a systematic review of the literature 2003–2010

Internationally, mass media campaigns to promote regular moderate-intensity physical activity have increased recently. Evidence of mass media campaign effectiveness exists in other health areas, however the evidence for physical activity is limited. The purpose was to systematically review the literature on physical activity mass media campaigns, 2003–2010. A focus was on reviewing evaluation designs, theory used, formative evaluation, campaign effects and outcomes. Literature was searched resulting in 18 individual adult mass media campaigns, mostly in high-income regions and two in middle-income regions. Designs included: quasi experimental (n = 5); non experimental (n = 12); a mixed methods design (n = 1). One half used formative research. Awareness levels ranged from 17 to 95%. Seven campaigns reported significant increases in physical activity levels. The review found that beyond awareness raising, changes in other outcomes were measured, assessed but reported in varying ways. It highlighted improvements in evaluation, although limited evidence of campaign effects remain. It provides an update on the evaluation methodologies used in the adult literature. We recommend optimal evaluation design should include: (1) formative research to inform theories/frameworks, campaign content and evaluation design; (2) cohort study design with multiple data collection points; (3) sufficient duration; (4) use of validated measures; (5) sufficient evaluation resources

Conduction in ulnar nerve bundles that innervate the proximal and distal muscles: a clinical trial

<p>Abstract</p> <p>Background</p> <p>This study aims to investigate and compare the conduction parameters of nerve bundles in the ulnar nerve that innervates the forearm muscles and hand muscles; routine electromyography study merely evaluates the nerve segment of distal (hand) muscles.</p> <p>Methods</p> <p>An electrophysiological evaluation, consisting of velocities, amplitudes, and durations of ulnar nerve bundles to 2 forearm muscles and the hypothenar muscles was performed on the same humeral segment.</p> <p>Results</p> <p>The velocities and durations of the compound muscle action potential (CMAP) of the ulnar nerve bundle to the proximal muscles were greater than to distal muscles, but the amplitudes were smaller.</p> <p>Conclusions</p> <p>Bundles in the ulnar nerve of proximal muscles have larger neuronal bodies and thicker nerve fibers than those in the same nerve in distal muscles, and their conduction velocities are higher. The CMAPs of proximal muscles also have smaller amplitudes and greater durations. These findings can be attributed to the desynchronization that is caused by a wider range of distribution in nerve fiber diameters.</p> <p>Conduction parameters of nerve fibers with different diameters in the same peripheral nerve can be estimated.</p

Disrupted cerebral metabolite levels and lower nadir CD4+ counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatmentpatients on stable treatment

AbstractCognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV+ patients scanned with whole-brain MRI at 1.5T (mean age: 48.6±8.4years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4+ count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4+. Even so, brain volume measured by TBM showed no detectable association with current CD4+ count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage

Comparative Analysis of Cas9 Activators Across Multiple Species

Several groups have generated programmable transcription factors based on the versatile Cas9 protein, yet their relative potency and effectiveness across various cell types and species remain unexplored. Here, we compare Cas9 activator systems and examine their ability to induce robust gene expression in several human, mouse, and fly cell lines. We also explore the potential for improved activation through the combination of the most potent activator systems and assess the role of cooperativity in maximizing gene expression

Cas9 gRNA engineering for genome editing, activation and repression

We demonstrate that by altering the length of Cas9-associated guide RNA(gRNA) we were able to control Cas9 nuclease activity and simultaneously perform genome editing and transcriptional regulation with a single Cas9 protein. We exploited these principles to engineer mammalian synthetic circuits with combined transcriptional regulation and kill functions governed by a single multifunctional Cas9 protein.National Human Genome Research Institute (U.S.) (P50 HG005550)United States. Department of Energy (DE-FG02-02ER63445)Wyss Institute for Biologically Inspired EngineeringUnited States. Army Research Office (DARPA W911NF-11-2-0054)National Science Foundation (U.S.)United States. National Institutes of Health (5R01CA155320-04)United States. National Institutes of Health (P50 GM098792)National Cancer Institute (U.S.) (5T32CA009216-34)Massachusetts Institute of Technology. Department of Biological EngineeringHarvard Medical School. Department of GeneticsDefense Threat Reduction Agency (DTRA) (HDTRA1-14-1-0006

Behaviour of motor unit action potential rate, estimated from surface EMG, as a measure of muscle activation level

BACKGROUND: Surface electromyography (EMG) parameters such as root-mean-square value (RMS) are commonly used to assess the muscle activation level that is imposed by the central nervous system (CNS). However, RMS is influenced not only by motor control aspects, but also by peripheral properties of the muscle and recording setup. To assess motor control separately, the number of motor unit action potentials (MUAPs) per second, or MUAP Rate (MR) is a potentially useful measure. MR is the sum of the firing rates of the contributing MUs and as such reflects the two parameters that the CNS uses for motor control: number of MUs and firing rate. MR can be estimated from multi-channel surface EMG recordings. The objective of this study was to explore the behaviour of estimated MR (eMR) in relation to number of active MUs and firing rate. Furthermore, the influence of parameters related to peripheral muscle properties and recording setup (number of fibers per MU, fiber diameter, thickness of the subcutaneous layer, signal-to-noise-ratio) on eMR was compared with their influence on RMS. METHODS: Physiological parameters were varied in a simulation model that generated multi-channel EMG signals. The behaviour of eMR in simulated conditions was compared with its behaviour in experimental conditions. Experimental data was obtained from the upper trapezius muscle during a shoulder elevation task (20–100 N). RESULTS: The simulations showed strong, monotonously increasing relations between eMR and number of active MUs and firing rate (r(2 )> 0.95). Because of unrecognized superimpositions of MUAPs, eMR was substantially lower than the actual MUAP Rate (aMR). The percentage of detected MUAPs decreased with aMR, but the relation between eMR and aMR was rather stable in all simulated conditions. In contrast to RMS, eMR was not affected by number of fibers per MU, fiber diameter and thickness of the subcutaneous layer. Experimental data showed a strong relation between eMR and force (individual second order polynomial regression: 0.96 < r(2 )< 0.99). CONCLUSION: Although the actual number of MUAPs in the signal cannot be accurately extracted with the present method, the stability of the relation between eMR and aMR and its independence of muscle properties make eMR a suitable parameter to assess the input from the CNS to the muscle at low contraction levels non-invasively

Modulation in voluntary neural drive in relation to muscle soreness

The aim of this study was to investigate whether (1) spinal modulation would change after non-exhausting eccentric exercise of the plantar flexor muscles that produced muscle soreness and (2) central modulation of the motor command would be linked to the development of muscle soreness. Ten healthy subjects volunteered to perform a single bout of backward downhill walking exercise (duration 30 min, velocity 1 ms−1, negative grade −25%, load 12% of body weight). Neuromuscular test sessions [H-reflex, M-wave, maximal voluntary torque (MVT)] were performed before, immediately after, as well as 1–3 days after the exercise bout. Immediately after exercise there was a −15% decrease in MVT of the plantar flexors partly attributable to an alteration in contractile properties (−23% in electrically evoked mechanical twitch). However, MVT failed to recover before the third day whereas the contractile properties had significantly recovered within the first day. This delayed recovery of MVT was likely related to a decrement in voluntary muscle drive. The decrease in voluntary activation occurred in the absence of any variation in spinal modulation estimated from the H-reflex. Our findings suggest the development of a supraspinal modulation perhaps linked to the presence of muscle soreness