3D gait assessment in young and elderly subjects using foot-worn inertial sensors.

This study describes the validation of a new wearable system for assessment of 3D spatial parameters of gait. The new method is based on the detection of temporal parameters, coupled to optimized fusion and de-drifted integration of inertial signals. Composed of two wirelesses inertial modules attached on feet, the system provides stride length, stride velocity, foot clearance, and turning angle parameters at each gait cycle, based on the computation of 3D foot kinematics. Accuracy and precision of the proposed system were compared to an optical motion capture system as reference. Its repeatability across measurements (test-retest reliability) was also evaluated. Measurements were performed in 10 young (mean age 26.1±2.8 years) and 10 elderly volunteers (mean age 71.6±4.6 years) who were asked to perform U-shaped and 8-shaped walking trials, and then a 6-min walking test (6MWT). A total of 974 gait cycles were used to compare gait parameters with the reference system. Mean accuracy±precision was 1.5±6.8cm for stride length, 1.4±5.6cm/s for stride velocity, 1.9±2.0cm for foot clearance, and 1.6±6.1° for turning angle. Difference in gait performance was observed between young and elderly volunteers during the 6MWT particularly in foot clearance. The proposed method allows to analyze various aspects of gait, including turns, gait initiation and termination, or inter-cycle variability. The system is lightweight, easy to wear and use, and suitable for clinical application requiring objective evaluation of gait outside of the lab environment.

Hydrogeophysical data integration at larger scales: Application of Bayesian sequential simulation for the characterization of heterogeneous alluvial aquifers

Knowledge of the spatial distribution of hydraulic conductivity (K) within an aquifer is critical for reliable predictions of solute transport and the development of effective groundwater management and/or remediation strategies. While core analyses and hydraulic logging can provide highly detailed information, such information is inherently localized around boreholes that tend to be sparsely distributed throughout the aquifer volume. Conversely, larger-scale hydraulic experiments like pumping and tracer tests provide relatively low-resolution estimates of K in the investigated subsurface region. As a result, traditional hydrogeological measurement techniques contain a gap in terms of spatial resolution and coverage, and they are often alone inadequate for characterizing heterogeneous aquifers. Geophysical methods have the potential to bridge this gap. The recent increased interest in the application of geophysical methods to hydrogeological problems is clearly evidenced by the formation and rapid growth of the domain of hydrogeophysics over the past decade (e.g., Rubin and Hubbard, 2005).

Objective analysis of gait coordination for total knee arthroplasty outcome

Introduction: Coordination is a strategy chosen by the central nervous system to control the movements and maintain stability during gait. Coordinated multi-joint movements require a complex interaction between nervous outputs, biomechanical constraints, and pro-prioception. Quantitatively understanding and modeling gait coordination still remain a challenge. Surgeons lack a way to model and appreciate the coordination of patients before and after surgery of the lower limbs. Patients alter their gait patterns and their kinematic synergies when they walk faster or slower than normal speed to maintain their stability and minimize the energy cost of locomotion. The goal of this study was to provide a dynamical system approach to quantitatively describe human gait coordination and apply it to patients before and after total knee arthroplasty. Methods: A new method of quantitative analysis of interjoint coordination during gait was designed, providing a general model to capture the whole dynamics and showing the kinematic synergies at various walking speeds. The proposed model imposed a relationship among lower limb joint angles (hips and knees) to parameterize the dynamics of locomotion of each individual. An integration of different analysis tools such as Harmonic analysis, Principal Component Analysis, and Artificial Neural Network helped overcome high-dimensionality, temporal dependence, and non-linear relationships of the gait patterns. Ten patients were studied using an ambulatory gait device (Physilog®). Each participant was asked to perform two walking trials of 30m long at 3 different speeds and to complete an EQ-5D questionnaire, a WOMAC and Knee Society Score. Lower limbs rotations were measured by four miniature angular rate sensors mounted respectively, on each shank and thigh. The outcomes of the eight patients undergoing total knee arthroplasty, recorded pre-operatively and post-operatively at 6 weeks, 3 months, 6 months and 1 year were compared to 2 age-matched healthy subjects. Results: The new method provided coordination scores at various walking speeds, ranged between 0 and 10. It determined the overall coordination of the lower limbs as well as the contribution of each joint to the total coordination. The difference between the pre-operative and post-operative coordination values were correlated with the improvements of the subjective outcome scores. Although the study group was small, the results showed a new way to objectively quantify gait coordination of patients undergoing total knee arthroplasty, using only portable body-fixed sensors. Conclusion: A new method for objective gait coordination analysis has been developed with very encouraging results regarding the objective outcome of lower limb surgery.

A gene knockout approach in mice to identify glucose sensors controlling glucose homeostasis.

A key aspect of glucose homeostasis is the constant monitoring of blood glucose concentrations by specific glucose sensing units. These sensors, via stimulation of hormone secretion and activation of the autonomic nervous system (ANS), regulate tissue glucose uptake, utilization or production. The best described glucose detection system is that of the pancreatic beta-cells which controls insulin secretion. Secretion of other hormones, in particular glucagon, and activation of the ANS, are regulated by glucose through sensing mechanisms which are much less well characterized. Here I review some of the studies we have performed over the recent years on a mouse model of impaired glucose sensing generated by inactivation of the gene for the glucose transporter GLUT2. This transporter catalyzes glucose uptake by pancreatic beta-cells, the first step in the signaling cascade leading to glucose-stimulated insulin secretion. Inactivation of its gene leads to a loss of glucose sensing and impaired insulin secretion. Transgenic reexpression of the transporter in GLUT2/beta-cells restores their normal secretory function and rescues the mice from early death. As GLUT2 is also expressed in other tissues, these mice were then studied for the presence of other physiological defects due to absence of this transporter. These studies led to the identification of extra-pancreatic, GLUT2-dependent, glucose sensors controlling glucagon secretion and glucose utilization by peripheral tissues, in part through a control of the autonomic nervous system.

Directed integration of new insulated lentiviral vectors to heterochromatin towards safer gene transfer to stem cells

The need for better gene transfer systems towards improved risk=benefit balance for patients remains a major challenge in the clinical translation of gene therapy (GT). We have investigated the improvement of integrating vectors safety in combining (i) new short synthetic genetic insulator elements (GIE) and (ii) directing genetic integration to heterochromatin. We have designed SIN-insulated retrovectors with two candidate GIEs and could identify a specific combination of insulator 2 repeats which translates into best functional activity, high titers and boundary effect in both gammaretro (p20) and lentivectors (DCaro4) (see Duros et al, abstract ibid). Since GIEs are believed to shield the transgenic cassette from inhibitory effects and silencing, DCaro4 has been further tested with chimeric HIV-1 derived integrases which comprise C-ter chromodomains targeting heterochromatin through either histone H3 (ML6chimera) or methylatedCpGislands (ML10). With DCaro4 only and both chimeras, a homogeneous expression is evidenced in over 20% of the cells which is sustained over time. With control lentivectors, less than 2% of cells express GFP as compared to background using a control double-mutant in both catalytic and ledgf binding-sites; in addition, a two-times increase of expression can be induced with histone deacetylase inhibitors. Our approach could significantly reduce integration into open chromatin sensitive sites in stem cells at the time of transduction, a feature which might significantly decrease subsequent genotoxicity, according to X-SCIDs patients data.Work performed with the support of EC-DG research within the FP6-Network of Excellence, CLINIGENE: LSHB-CT-2006-018933

Sex biased spatial strategies relying on the integration of multimodal cues in a rat model of schizophrenia: impairment in predicting future context?

Male and female Wistar rats were treated postnatally (PND 5-16) with BSO (l-buthionine-(S,R)-sulfoximine) to provide a rat model of schizophrenia based on transient glutathione deficit. In the watermaze, BSO-treated male rats perform very efficiently in conditions where a diversity of visual information is continuously available during orientation trajectories [1]. Our hypothesis is that the treatment impairs proactive strategies anticipating future sensory information, while supporting a tight visual adjustment on memorized snapshots, i.e. compensatory reactive strategies. To test this hypothesis, BSO rats' performance was assessed in two conditions using an 8-arm radial maze task: a semi-transparent maze with no available view on the environment from maze centre [2], and a modified 2-parallel maze known to induce a neglect of the parallel pair in normal rats [3-5]. Male rats, but not females, were affected by the BSO treatment. In the semi-transparent maze, BSO males expressed a higher error rate, especially in completing the maze after an interruption. In the 2-parallel maze shape, BSO males, unlike controls, expressed no neglect of the parallel arms. This second result was in accord with a reactive strategy using accurate memory images of the contextual environment instead of a representation based on integrating relative directions. These results are coherent with a treatment-induced deficit in proactive decision strategy based on multimodal cognitive maps, compensated by accurate reactive adaptations based on the memory of local configurations. Control females did not express an efficient proactive capacity in the semi-transparent maze, neither did they show the significant neglect of the parallel arms, which might have masked the BSO induced effect. Their reduced sensitivity to BSO treatment is discussed with regard to a sex biased basal cognitive style.

Looming signals reveal synergistic principles of multisensory integration.

Multisensory interactions are a fundamental feature of brain organization. Principles governing multisensory processing have been established by varying stimulus location, timing and efficacy independently. Determining whether and how such principles operate when stimuli vary dynamically in their perceived distance (as when looming/receding) provides an assay for synergy among the above principles and also means for linking multisensory interactions between rudimentary stimuli with higher-order signals used for communication and motor planning. Human participants indicated movement of looming or receding versus static stimuli that were visual, auditory, or multisensory combinations while 160-channel EEG was recorded. Multivariate EEG analyses and distributed source estimations were performed. Nonlinear interactions between looming signals were observed at early poststimulus latencies (∼75 ms) in analyses of voltage waveforms, global field power, and source estimations. These looming-specific interactions positively correlated with reaction time facilitation, providing direct links between neural and performance metrics of multisensory integration. Statistical analyses of source estimations identified looming-specific interactions within the right claustrum/insula extending inferiorly into the amygdala and also within the bilateral cuneus extending into the inferior and lateral occipital cortices. Multisensory effects common to all conditions, regardless of perceived distance and congruity, followed (∼115 ms) and manifested as faster transition between temporally stable brain networks (vs summed responses to unisensory conditions). We demonstrate the early-latency, synergistic interplay between existing principles of multisensory interactions. Such findings change the manner in which to model multisensory interactions at neural and behavioral/perceptual levels. We also provide neurophysiologic backing for the notion that looming signals receive preferential treatment during perception.

Foot worn inertial sensors for gait assessment and rehabilitation based on motorized shoes.

Fall prevention in elderly subjects is often based on training and rehabilitation programs that include mostly traditional balance and strength exercises. By applying such conventional interventions to improve gait performance and decrease fall risk, some important factors are neglected such as the dynamics of the gait and the motor learning processes. The EU project "Self Mobility Improvement in the eLderly by counteractING falls" (SMILING project) aimed to improve age-related gait and balance performance by using unpredicted external perturbations during walking through motorized shoes that change insole inclination at each stance. This paper describes the shoe-worn inertial module and the gait analysis method needed to control in real-time the shoe insole inclination during training, as well as gait spatio-temporal parameters obtained during long distance walking before and after the 8-week training program that assessed the efficacy of training with these motorized shoes.

Rapid detection of bacterial resistance to antibiotics using AFM cantilevers as nanomechanical sensors.

The widespread misuse of drugs has increased the number of multiresistant bacteria, and this means that tools that can rapidly detect and characterize bacterial response to antibiotics are much needed in the management of infections. Various techniques, such as the resazurin-reduction assays, the mycobacterial growth indicator tube or polymerase chain reaction-based methods, have been used to investigate bacterial metabolism and its response to drugs. However, many are relatively expensive or unable to distinguish between living and dead bacteria. Here we show that the fluctuations of highly sensitive atomic force microscope cantilevers can be used to detect low concentrations of bacteria, characterize their metabolism and quantitatively screen (within minutes) their response to antibiotics. We applied this methodology to Escherichia coli and Staphylococcus aureus, showing that live bacteria produced larger cantilever fluctuations than bacteria exposed to antibiotics. Our preliminary experiments suggest that the fluctuation is associated with bacterial metabolism.

Esophagogastric cancer: integration of targeted therapies into systemic chemotherapy.

Although combination chemotherapy has been shown to be more effective than single agents in advanced esophagogastric cancer, the better response rates have not fulfilled their promise as overall survival times from best combination still range between 8 to 11 months. So far, the development of targeted therapies stays somewhat behind their integration into treatment concepts compared to other gastrointestinal diseases. Thus, the review summarizes the recent advances in the development of targeted therapies in advanced esophagogastric cancer. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors EGFR1 and HER2. For trastuzumab and bevacizumab, phase III trial results have been presented recently. While addition of trastuzumab to cisplatin/5-fluoropyrimidine-based chemotherapy results in a clinically relevant and statistically significant survival benefit in HER 2+ patients, the benefit of the addition of bevacizumab to chemotherapy was not significant. Thus, all patients with metastatic disease should be tested for HER-2 status in the tumor. Trastuzumab in combination with cisplatin/5-fluoropyrimidine-based chemotherapy is the new standard of care for patients with HER2-positive advanced gastric cancer.