Regulation of Erythropoietin Receptor Activity in Endothelial Cells by Different Erythropoietin (EPO) Derivatives: An in Vitro Study.

In endothelial cells, erythropoietin receptors (EPORs) mediate the protective, proliferative and angiogenic effects of EPO and its analogues, which act as EPOR agonists. Because hormonal receptors undergo functional changes upon chronic exposure to agonists and because erythropoiesis-stimulating agents (ESAs) are used for the long-term treatment of anemia, it is critical to determine the mechanism by which EPOR responsiveness is regulated at the vascular level after prolonged exposure to ESAs. Here, we investigated EPOR desensitization/resensitization in human umbilical vein endothelial cells (HUVECs) upon exposure to three ESAs with different pharmacokinetic profiles, epoetin alpha (EPOα), darbepoetin alpha (DarbEPO) and continuous EPOR activator (CERA). These agonists all induced activation of the transcription factor STAT-5, which is a component of the intracellular pathway associated with EPORs. STAT-5 activation occurred with either monophasic or biphasic kinetics for EPOα/DarbEPO and CERA, respectively. ESAs, likely through activation of the STAT-5 pathway, induced endothelial cell proliferation and stimulated angiogenesis in vitro, demonstrating a functional role for epoetins on endothelial cells. All epoetins induced EPOR desensitization with more rapid kinetics for CERA compared to EPOα and DarbEPO. However, the recovery of receptor responsiveness was strictly dependent on the type of epoetin, the agonist concentration and the time of exposure to the agonist. EPOR resensitization occurred with more rapid kinetics after exposure to low epoetin concentrations for a short period of desensitization. When the highest concentration of agonists was tested, the recovery of receptor responsiveness was more rapid with CERA compared to EPOα and was completely absent with DarbEPO. Our results demonstrate that these three ESAs regulate EPOR resensitization by very different mechanisms and that both the type of molecule and the length of EPOR stimulation are factors that are critical for the control of EPOR functioning in endothelial cells. The differences observed in receptor resensitization after stimulation with the structurally different ESAs are most likely due different control mechanisms of receptor turnover at the intracellular level

MOLECULAR NEUROGENETICS OF MITOCHONDRIAL DISEASES

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MOLECULAR NEUROGENETICS OF MITOCHONDRIAL DISEASES

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Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor

Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients

Does Observation of Postural Imbalance Induce a Postural Reaction?

Import JabRef | WosArea Life Sciences and Biomedicine - Other TopicsInternational audienceBackground: Several studies bring evidence that action observation elicits contagious responses during social interactions. However automatic imitative tendencies are generally inhibited and it remains unclear in which conditions mere action observation triggers motor behaviours. In this study, we addressed the question of contagious postural responses when observing human imbalance. Methodology/Principal Findings: We recorded participants' body sway while they observed a fixation cross (control condition), an upright point-light display of a gymnast balancing on a rope, and the same point-light display presented upside down. Our results showed that, when the upright stimulus was displayed prior to the inverted one, centre of pressure area and antero-posterior path length were significantly greater in the upright condition compared to the control and upside down conditions. Conclusions/Significance: These results demonstrate a contagious postural reaction suggesting a partial inefficiency of inhibitory processes. Further, kinematic information was sufficient to trigger this reaction. The difference recorded between the upright and upside down conditions indicates that the contagion effect was dependent on the integration of gravity constraints by body kinematics. Interestingly, the postural response was sensitive to habituation, and seemed to disappear when the observer was previously shown an inverted display. The motor contagion recorded here is consistent with previous work showing vegetative output during observation of an effortful movement and could indicate that lower level control facilitates contagion effects

An Ensemble Analysis of Electromyographic Activity during Whole Body Pointing with the Use of Support Vector Machines

We explored the use of support vector machines (SVM) in order to analyze the ensemble activities of 24 postural and focal muscles recorded during a whole body pointing task. Because of the large number of variables involved in motor control studies, such multivariate methods have much to offer over the standard univariate techniques that are currently employed in the field to detect modifications. The SVM was used to uncover the principle differences underlying several variations of the task. Five variants of the task were used. An unconstrained reaching, two constrained at the focal level and two at the postural level. Using the electromyographic (EMG) data, the SVM proved capable of distinguishing all the unconstrained from the constrained conditions with a success of approximately 80% or above. In all cases, including those with focal constraints, the collective postural muscle EMGs were as good as or better than those from focal muscles for discriminating between conditions. This was unexpected especially in the case with focal constraints. In trying to rank the importance of particular features of the postural EMGs we found the maximum amplitude rather than the moment at which it occurred to be more discriminative. A classification using the muscles one at a time permitted us to identify some of the postural muscles that are significantly altered between conditions. In this case, the use of a multivariate method also permitted the use of the entire muscle EMG waveform rather than the difficult process of defining and extracting any particular variable. The best accuracy was obtained from muscles of the leg rather than from the trunk. By identifying the features that are important in discrimination, the use of the SVM permitted us to identify some of the features that are adapted when constraints are placed on a complex motor task

Effects of Age on Optical Coherence Tomography Measurements of Healthy Retinal Nerve Fiber Layer, Macula, and Optic Nerve Head

Purpose—To determine the effects of age on global and sectoral peripapillary retinal nerve fiber layer (RNFL), macular thicknesses and optic nerve head (ONH) parameters in healthy subjects using optical coherence tomography (OCT). Design—Retrospective, cross-sectional observational study. Participants—226 eyes from 124 healthy subjects were included. Methods—Healthy subjects were scanned using the Fast RNFL, Fast Macula, and Fast ONH scan patterns on a Stratus OCT. All global and sectoral RNFL and macular parameters and global ONH parameters were modeled in terms of age using linear mixed effects models. Normalized slopes were also calculated by dividing the slopes by the mean value of the OCT parameter for inter-parameter comparison. Main Outcome Measures—Slope of each OCT parameter across age. Results—All global and sectoral RNFL thickness parameters statistically significantly decreased with increasing age, except for the temporal quadrant and clock hours 8-10, which were not statistically different from a slope of zero. Highest absolute slopes were in the inferior and superior quadrant RNFL and clock hour 1 (superior nasal). Normalized slopes showed similar rate in all sectors except for the temporal clock hours (8-10). All macular thickness parameters statistically significantly decreased with increasing age, except for the central fovea sector, which had a slight positive slope that was not statistically significant. The nasal outer sector had the greatest absolute slope. Normalized macular slope in the outer ring was similar to the normalized slopes in the RNFL. Normalized inner ring had shallower slope than the outer ring with similar rate in all quadrants. Disc area remained nearly constant across the ages, but cup area increased and rim area decreased with age, both of which were statistically significant. Conclusions—Global and regional changes due to the effects of age on RNFL, macula and ONH OCT measurements should be considered when assessing eyes over time.National Institutes of Health (U.S.) (R01-EY13178-09)National Institutes of Health (U.S.) (R01-EY11289-23)National Institutes of Health (U.S.) (P30-EY008098

Dual task interference during gait in patients with unilateral vestibular disorders

<p>Abstract</p> <p>Background</p> <p>Vestibular patients show slower and unsteady gait; they have also been shown to need greater cognitive resources when carrying out balance and cognitive dual tasks (DT). This study investigated DT interference during gait in a middle-aged group of subjects with dizziness and unsteadiness after unilateral vestibular neuronitis and in a healthy control group.</p> <p>Methods</p> <p>Fourteen individuals with subacute unilateral vestibular impairment after neuronitis and seventeen healthy subjects performed gait and cognitive tasks in single and DT conditions. A statistical gait analysis system was used and spatio-temporal parameters were considered. The cognitive task, consisting of backward counting by three, was tape recorded and the number of right figures was then calculated.</p> <p>Results</p> <p>Both patients and controls showed a more conservative gait during DT and between groups significant differences were not found. A significant decrease in cognitive performance during DT was found only in the vestibular group.</p> <p>Conclusions</p> <p>Results suggest that less attentional resources are available during gait in vestibular patients compared to controls, and that a priority is given in keeping up the motor task to the detriment of a decrease of the cognitive performance during DT.</p