Kinect-based assessment of proximal arm non-use after a stroke.

BACKGROUND: After a stroke, during seated reaching with their paretic upper limb, many patients spontaneously replace the use of their arm by trunk compensation movements, even though they are able to use their arm when forced to do so. We previously quantified this proximal arm non-use (PANU) with a motion capture system (Zebris, CMS20s). The aim of this study was to validate a low-cost Microsoft Kinect-based system against the CMS20s reference system to diagnose PANU. METHODS: In 19 hemiparetic stroke individuals, the PANU score, reach length, trunk length, and proximal arm use (PAU) were measured during seated reaching simultaneously by the Kinect (v2) and the CMS20s over two testing sessions separated by two hours. RESULTS: Intraclass correlation coefficients (ICC) and linear regression analysis showed that the PANU score (ICC = 0.96, r2 = 0.92), reach length (ICC = 0.81, r2 = 0.68), trunk length (ICC = 0.97, r2 = 0.94) and PAU (ICC = 0.97, r2 = 0.94) measured using the Kinect were strongly related to those measured using the CMS20s. The PANU scores showed good test-retest reliability for both the Kinect (ICC = 0.76) and CMS20s (ICC = 0.72). Bland and Altman plots showed slightly reduced PANU scores in the re-test session for both systems (Kinect: - 4.25 ± 6.76; CMS20s: - 4.71 ± 7.88), which suggests a practice effect. CONCLUSION: We showed that the Kinect could accurately and reliably assess PANU, reach length, trunk length and PAU during seated reaching in post stroke individuals. We conclude that the Kinect can offer a low-cost and widely available solution to clinically assess PANU for individualised rehabilitation and to monitor the progress of paretic arm recovery. TRIAL REGISTRATION: The study was approved by The Ethics Committee of Montpellier, France (N°ID-RCB: 2014-A00395-42) and registered in Clinical Trial (N° NCT02326688, Registered on 15 December 2014, https://clinicaltrials.gov/ct2/show/results/NCT02326688 ).

Kinematics in the brain: unmasking motor control strategies?

In rhythmical movement performance, our brain has to sustain movement while correcting for biological noise-induced variability. Here, we explored the functional anatomy of brain networks during voluntary rhythmical elbow flexion/extension using kinematic movement regressors in fMRI analysis to verify the interest of method to address motor control in a neurological population. We found the expected systematic activation of the primary sensorimotor network that is suggested to generate the rhythmical movement. By adding the kinematic regressors to the model, we demonstrated the potential involvement of cerebellar-frontal circuits as a function of the irregularity of the variability of the movement and the primary sensory cortex in relation to the trajectory length during task execution. We suggested that different functional brain networks were related to two different aspects of rhythmical performance: rhythmicity and error control. Concerning the latter, the partitioning between more automatic control involving cerebellar-frontal circuits versus less automatic control involving the sensory cortex seemed thereby crucial for optimal performance. Our results highlight the potential of using co-registered fine-grained kinematics and fMRI measures to interpret functional MRI activations and to potentially unmask the organisation of neural correlates during motor control.

Aging effects on electrical and hemodynamic responses in the sensorimotor network during unilateral proximal upper limb functional tasks.

Healthy aging leads to poorer performance in upper limb (UL) daily living movements. Understanding the neural correlates linked with UL functional movements may help to better understand how healthy aging affects motor control. Two non-invasive neuroimaging methods allow for monitoring the movement-related brain activity: functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG), respectively based on the hemodynamic response and electrical activity of brain regions. Coupled, they provide a better spatiotemporal mapping. The aim of this study was to evaluate the effect of healthy aging on the bilateral sensorimotor (SM1) activation patterns of functional proximal UL movements. Twenty-one young and 21 old healthy participants realized two unilateral proximal UL movements during: i) a paced reaching target task and ii) a circular steering task to capture the speed-accuracy trade-off. Combined fNIRS-EEG system was synchronised with movement capture system to record SM1 activation while moving. The circular steering task performance was significantly lower for the older group. The rate of increase in hemodynamic response was longer in the older group with no difference on the amplitude of fNIRS signal for the two tasks. The EEG results showed aging related reduction of the alpha-beta rhythms synchronisation but no desynchronisation modification. In conclusion, this study uncovers the age-related changes in brain electrical and hemodynamic response patterns in the bilateral sensorimotor network during two functional proximal UL movements using two complementary neuroimaging methods. This opens up the possibility to utilise combined fNIRS-EEG for monitoring the movement-related neuroplasticity in clinical practice.

Systematic study of liposomes composition towards efficient delivery of plasmid DNA as potential application of dermal fibroblasts targeting.

The use of non-viral DNA vectors to topically treat skin diseases has demonstrated a high potential. However, vectors applied on the skin face extracellular barriers including the stratum corneum and intracellular barriers such as the endosomal escape and the nuclear targeting of the plasmid DNA. The aim of this study was to develop a formulation suitable for dermal application and effective for delivering plasmid DNA into cells. Different formulations were prepared using different cationic lipids (DOTAP, DC-Chol, DOTMA) and co-lipids (DOPE, DSPE). Lipoplexes were produced by complexing liposomes with plasmid DNA at different pDNA/CL (w/w) ratios. Our results showed that appropriate pDNA/CL ratios allowing total complexation of plasmid DNA differed depending on the structure of the lipid used. The transfection rates showed that (i) higher rates were obtained with DOTMA lipoplexes, (ii) DC-Chol lipoplexes provided a transfection twice as important as DOTAP lipoplexes and (iii) when DSPE was added, the cytotoxicity decreased while transfection rates were similar. We found that formulations composed of DC-Chol:DOPE:DSPE or DOTMA:DOPE were appropriate to complex plasmid DNA and to transfect human primary dermal fibroblasts with efficacy and limited cytotoxicity. Therefore, these formulations are highly promising in the context of gene therapy to treat skin diseases.

In vitro skin penetration enhancement techniques: A combined approach of ethosomes and microneedles.

Dermal administration of different macromolecules, such as nucleic acids, remains a real challenge because of the difficulty of crossing the main skin barrier, the stratum corneum (SC). To overcome this barrier, the use of deformable lipid-based nanovectors were developed to increase topical penetration through the SC and to promote the intercellular delivery of drugs. The purpose of this study is to compare the skin penetration of different liposome formulations according to their composition. In vitro and ex vivo experiments using Franz diffusion cells were performed to highlight the effect of (i) lipid charge, (ii) edge activators (EA) and (iii) ethanol on the diffusion properties of nanovectors. We showed that all formulations were not able to cross the SC. However, on a tape stripped skin, we showed that cationic formulations containing an EA and ethanol improved the skin penetration. The use of microneedles was considered to bypass the SC. We have shown that sodium cholate and ethanol were necessary to ensure an appropriate diffusion of liposomes into the dermis when applied by means of microneedles. This could be a promising approach to further deliver efficiently macromolecules such as genes into the skin.

Proximal arm non-use when reaching after a stroke.

After a stroke, many people "cannot and do not" use their paretic upper limb. With recovery, some people "can but do not" use their paretic upper limb and this non-use should be counteracted with specific rehabilitation. The aim of the study was to quantify one aspect of the non-use: proximal arm non-use when reaching within one's arm length in 45 post-stroke and 45 age matched controls. Arm use refers to the contribution of the shoulder and elbow motion to the hand movement towards the target. Proximal arm non-use is calculated as the ratio of the difference between spontaneous arm use and maximal arm use. We found that proximal arm non-use has very good test-retest reliability, does not depend on time since stroke, increases with impairment (Fugl-Meyer) and loss of function (Box & Block), and most importantly, that 61% of patients with lower impairment (Fugl-Meyer >28/42) exhibit proximal arm non-use. We conclude that quantifying proximal arm non-use in post-stroke individuals provides novel information that complements routine clinical measures. It is likely that proximal arm non-use quantifies one aspect of the motor reserve that therapists can target in patient specific rehabilitation programs.

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition.

The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.

Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation.

Hypoxia-Inducible Factor-1 (HIF-1) is a transcription factor which is activated by hypoxia and involved in the adaptative response of the cell to oxygen deprivation. During hypoxic stress, HIF-1 triggers the overexpression of genes coding for glycolytic enzymes and angiogenic factors. To be active HIF-1 must be phosphorylated. HIF-1 is a substrate for various kinase pathways including PI-3K and the MAP kinases ERK and p38. Several transduction pathways have been proposed which act downstream of putative oxygen sensors and lead to the activation of these kinases. In this review, we summarize some of the latest advances describing the possible signaling pathways leading to HIF-1 phosphorylation and subsequent activation. The physiological relevance of these regulations is also discussed.

ERK activation upon hypoxia: involvement in HIF-1 activation.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor activated by hypoxia. The HIF-1 activation transduction pathway is poorly understood. In this report, we investigated the activation of extracellular regulated kinases (ERK) in hypoxia and their involvement in HIF-1 activation. We demonstrated that in human microvascular endothelial cells-1 (HMEC-1), ERK kinases are activated during hypoxia. Using dominant negative mutants, we showed that ERK1 is needed for hypoxia-induced HIF-1 transactivation activity. Moreover, using a kinase assay and Western blot experiments, we showed that HIF-1alpha is phosphorylated in hypoxia by an ERK-dependent pathway. These results evidence the role of mitogen-activated protein kinase in the transcriptional response to hypoxia.

Hypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction.

The protein chaperone heat shock protein 90 (Hsp90) is a major regulator of different transcription factors such as MyoD, a basic helix loop helix (bHLH) protein, and the bHLH-Per-aryl hydrocarbon nuclear translocator (ARNT)-Sim (PAS) factors Sim and aryl hydrocarbon receptor (Ahr). The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), involved in the response to hypoxia, also belongs to the bHLH-PAS family. This work was aimed to investigate the putative role of Hsp90 in HIF-1 activation by hypoxia. Using a EGFP-HIF-1alpha fusion protein, co-immunoprecipitation experiments evidenced that the chimeric protein expressed in COS-7 cells interacts with Hsp90 in normoxia but not in hypoxia. We also demonstrated that Hsp90 interacts with the bHLH-PAS domain of HIF-1alpha. Moreover, Hsp90 is not co-translocated with HIF-1alpha into the nucleus. At last, we showed that Hsp90 activity is essential for HIF-1 activation in hypoxia since it is inhibited in the presence of geldanamycin. These results indicate that Hsp90 is a major regulator in HIF-1alpha activation.

The dynamics of human isometric pointing movements under varying accuracy requirements.

The goal of the present study was to explore the relation between speed-accuracy trade-off phenomena and action kinematics in the case of pointing under isometric conditions. Increasing task difficulty resulted in a linear increase in movement time (as predicted by Fitts' law) and in systematic changes in the spatio-temporal patterning of force production. The observed changes in motion topology were similar to those reported for isotonic tasks and adequately captured by a limit cycle model derived for the latter type of task. These results indicate that, for isometric force control as for isotonic position control, the reasons underlying the emergence of Fitts' law might be sought in dynamic trajectory formation processes.

Stability and phase locking in human soccer juggling.

We explored a variant of juggling in which human adults were asked to rhythmically bounce a soccer ball with their dominant foot while standing on the other foot. Eight subjects performed the task at three prescribed heights and one free height condition. Kinematic analyses of foot movement at ball-foot impact showed that, for the smallest height, foot acceleration was positive or zero at impact, which indicates an active stabilization regime. Increasing juggling height resulted in foot acceleration becoming increasingly negative at impact, which is required for a passive dynamical stability regime. These results show that skilled soccer jugglers exploit the passive stability regime afforded by the task, but that similar stability can be achieved with an active stabilization strategy.

Two-handed performance of a rhythmical fitts task by individuals and dyads.

The authors investigated 4 variants of a reciprocal Fitts task in which the pointer was moved to a stationary target, the target was moved to a stationary pointer, or both the pointer and the target were moved to each other bimanually; the bimanual task was carried out either by a single person or by a dyad. Fitts's law held in all 4 conditions, with only minor parametric changes. The kinematic organization varied with task difficulty but remained invariant in task space (i.e., in the mutual frame of reference of the pointer-target system) whatever the pointing condition. In the bimanual conditions, the 2 effectors were coordinated in antiphase with compensatory variability. The authors suggest that the observed chronometric and kinematic patterns emerge from an interplay between simple harmonic motion and the stabilizing influence of the informational flow generated by the closing of the gap between the pointer and the target interval.

The dynamics of rhythmical aiming in 2D task space: relation between geometry and kinematics under examination.

We explored a two-dimensional task space variant of the classical rhythmical Fitts' task in which participants were asked to sequentially cross four targets arranged around the extreme points of the major axes of an ellipse. Fitts' law was found to adequately describe the changes in movement time with the variations in task difficulty (ID), but the 1/3 power-law relating curvature and tangential velocity of the trajectory did not resist the increase in ID. Kinematic analyses showed that the behavioral adaptation to the ID resulted in an increase in the contribution of non-linear terms to the kinematics along the two axes of task space. Moreover, a limit cycle model (combining Rayleigh damping and Duffing stiffness, as in one-dimensional Fitts' task) captured such a behavior. In such a context, Fitts' law and the 1/3 power law appear as surface relations that emerge from parametric changes in a dynamical structure that captures the nature of Fitts' task.

A note on data smoothing for movement analysis: the relevance of a nonlinear method.

The goal of this experiment was to test a potentially useful nonlinear method for smoothing noisy position data, which often is encountered in the analysis of data. This algorithm (7RY) uses a nonlinear smoothing function and behaves like a low-pass filter, automatically removing aberrant points; it is used prior to differentiation of time series so that usable acceleration information can be obtained. The experimental procedure comprises position data collection along with direct accelerometric data recording. From the position-time data, (a) 7RY and (b) Butterworth algorithms have been used to compute twice-differentiated acceleration curves. The directly recorded acceleration measurements were then compared with the acceleration computed from the original position data. Although the results indicated an overall good fit between the recorded and the calculated acceleration curves, only the nonlinear method led to reliable acceleration curves when aberrant points were present in the position data.

[Training in motor skills and psychopathology. Climbing with psychotic children]. / Apprentissages moteurs et psychopathologie. Pratique de l'escalade chez l'enfant psychotique.

The author investigates learning skills in psychotic and borderline children through the physical activity of climbing. Motor skills are considered as an interaction between the subject and his/her environment. Motor learning skills have been studied throughout 6 training sessions in rock-climbing. Etho-clinical methods of investigation allow to assess behaviors and the meaning given by the subject to different forms of action. The author emphasizes here the pleasure/anxiety dimensions of this activity. Results show remarkable learning skills in these children. Significant increase in motor activity and in the height reached point to an obvious integrity of the mechanisms necessary to motor acquisitions. These results are closely linked with the characteristics of rock climbing, a sport involving clinging behaviors and leading to a mastering of the primary anxiety of loosing support.

[Prevention of thromboembolism using low molecular weight heparin and hemodilution in traumatologic geriatric surgery of the femur neck]. / Prophylaxie thrombo-embolique par héparine de bas poids moléculaire et hémodilution en chirurgie traumatologique gériatrique du col du fémur.

A routine method of prophylaxis of thromboembolic disease is evaluated on 181 elderly patients undergoing post-traumatic hip surgery. A low incidence of proximal thrombosis and fatal embolism is noted and rated as a beneficial effect of the association of low molecular weight heparin therapy and moderate hemodilution; it is also connected with a precocious diagnosis of the thrombotic complications--before the proximal extension of silent thromboses--by the measurement of specific fibrin derivatives used as a screening technique in order to select the patients who will have to undergo venographical examination.

Innovative technologies applied to sensorimotor rehabilitation after stroke.

Innovative technologies for sensorimotor rehabilitation after stroke have dramatically increased these past 20 years. Based on a review of the literature on "Medline" and "Web of Science" between 1990 and 2013, we offer an overview of available tools and their current level of validation. Neuromuscular electric stimulation and/or functional electric stimulation are widely used and highly suspected of being effective in upper or lower limb stroke rehabilitation. Robotic rehabilitation has yielded various results in the literature. It seems to have some effect on functional capacities when used for the upper limb. Its effectiveness in gait training is more controversial. Virtual reality is widely used in the rehabilitation of cognitive and motor impairments, as well as posture, with admitted benefits. Non-invasive brain stimulation (rTMS and TDCS) are promising in this indication but clinical evidence of their effectiveness is still lacking. In the same manner, these past five years, neurofeedback techniques based on brain signal recordings have emerged with a special focus on their therapeutic relevance in rehabilitation. Technological devices applied to rehabilitation are revolutionizing our clinical practices. Most of them are based on advances in neurosciences allowing us to better understand the phenomenon of brain plasticity, which underlies the effectiveness of rehabilitation. The acceptation and "real use" of those devices is still an issue since most of them are not easily available in current practice.

HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells.

Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we further investigated the biological function of HDAC5 in cancer cells. We found HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. We demonstrated that specific depletion of HDAC5 by RNA interference resulted in profound changes in the heterochromatin structure and slowed down ongoing replication forks. This defect in heterochromatin maintenance and assembly are sensed by DNA damage checkpoint pathways, which triggered cancer cells to autophagy and apoptosis, and arrested their growth both in vitro and in vivo. Finally, we also demonstrated that HDAC5 depletion led to enhanced sensitivity of DNA to DNA-damaging agents, suggesting that heterochromatin de-condensation induced by histone HDAC5 silencing may enhance the efficacy of cytotoxic agents that act by targeting DNA in vitro. Together, these results highlighted for the first time an unrecognized link between HDAC5 and the maintenance/assembly of heterochromatin structure, and demonstrated that its specific inhibition might contribute to increase the efficacy of DNA alteration-based cancer therapies in clinic.

Isokinetic muscle strengthening after acquired cerebral damage: a literature review.

OBJECTIVE: Isokinetic strengthening is a rehabilitation technique rarely used in stroke patients. However, the potential benefits of force and endurance training in this population are strongly suspected. METHOD: This literature review synthesizes the results of clinical trials on this topic. The research was conducted on PubMed, using "Stroke", "rehabilitation", "isokinetic", "upper limb" and "training" as keywords. RESULTS: Seventeen studies focusing on the use of isokinetics in assessment or rehabilitation (six studies) following stroke were reviewed. For the lower limb, muscle strength and walking ability improved after isokinetic rehabilitation programs. For the upper limb, the only two studies found in the literature suggest improvement in the strength of the trained muscles, of grip force, of the Fugl-Meyer motor score and of global functional capacities. This review does not reveal any consensus on the protocols to be implemented: type of muscle contraction, velocities…. CONCLUSION: While isokinetic strengthening has not proven its efficiency in rehabilitation of the upper limb following stroke, its interest with regard to rehabilitation of the lower limbs has been recognized. Randomized controlled trials in this field are necessary to confirm its efficiency, especially concerning upper arm rehabilitation.