Feedback control of arm movements using Neuro-Muscular Electrical Stimulation (NMES) combined with a lockable, passive exoskeleton for gravity compensation

Within the European project MUNDUS, an assistive framework was developed for the support of arm and hand functions during daily life activities in severely impaired people. This contribution aims at designing a feedback control system for Neuro-Muscular Electrical Stimulation (NMES) to enable reaching functions in people with no residual voluntary control of the arm and shoulder due to high level spinal cord injury. NMES is applied to the deltoids and the biceps muscles and integrated with a three degrees of freedom (DoFs) passive exoskeleton, which partially compensates gravitational forces and allows to lock each DOF. The user is able to choose the target hand position and to trigger actions using an eyetracker system. The target position is selected by using the eyetracker and determined by a marker-based tracking system using Microsoft Kinect. A central controller, i.e., a finite state machine, issues a sequence of basic movement commands to the real-time arm controller. The NMES control algorithm sequentially controls each joint angle while locking the other DoFs. Daily activities, such as drinking, brushing hair, pushing an alarm button, etc., can be supported by the system. The robust and easily tunable control approach was evaluated with five healthy subjects during a drinking task. Subjects were asked to remain passive and to allow NMES to induce the movements. In all of them, the controller was able to perform the task, and a mean hand positioning error of less than five centimeters was achieved. The average total time duration for moving the hand from a rest position to a drinking cup, for moving the cup to the mouth and back, and for finally returning the arm to the rest position was 71 s.EC/FP7/248326/EU/MUltimodal Neuroprostesis for Daily Upper limb Support/MUNDU

Skin tolerant inactivation of multiresistant pathogens using far-UVC LEDs

Multiresistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) cause serious postoperative infections. A skin tolerant far-UVC (< 240 nm) irradiation system for their inactivation is presented here. It uses UVC LEDs in combination with a spectral filter and provides a peak wavelength of 233 nm, with a full width at half maximum of 12 nm, and an irradiance of 44 µW/cm2. MRSA bacteria in different concentrations on blood agar plates were inactivated with irradiation doses in the range of 15–40 mJ/cm2. Porcine skin irradiated with a dose of 40 mJ/cm2 at 233 nm showed only 3.7% CPD and 2.3% 6-4PP DNA damage. Corresponding irradiation at 254 nm caused 11–14 times higher damage. Thus, the skin damage caused by the disinfectant doses is so small that it can be expected to be compensated by the skin's natural repair mechanisms. LED-based far-UVC lamps could therefore soon be used in everyday clinical practice to eradicate multiresistant pathogens directly on humans

MUNDUS project : MUltimodal neuroprosthesis for daily upper limb support

Background: MUNDUS is an assistive framework for recovering direct interaction capability of severely motor impaired people based on arm reaching and hand functions. It aims at achieving personalization, modularity and maximization of the user’s direct involvement in assistive systems. To this, MUNDUS exploits any residual control of the end-user and can be adapted to the level of severity or to the progression of the disease allowing the user to voluntarily interact with the environment. MUNDUS target pathologies are high-level spinal cord injury (SCI) and neurodegenerative and genetic neuromuscular diseases, such as amyotrophic lateral sclerosis, Friedreich ataxia, and multiple sclerosis (MS). The system can be alternatively driven by residual voluntary muscular activation, head/eye motion, and brain signals. MUNDUS modularly combines an antigravity lightweight and non-cumbersome exoskeleton, closed-loop controlled Neuromuscular Electrical Stimulation for arm and hand motion, and potentially a motorized hand orthosis, for grasping interactive objects. Methods: The definition of the requirements and of the interaction tasks were designed by a focus group with experts and a questionnaire with 36 potential end-users. Five end-users (3 SCI and 2 MS) tested the system in the configuration suitable to their specific level of impairment. They performed two exemplary tasks: reaching different points in the working volume and drinking. Three experts evaluated over a 3-level score (from 0, unsuccessful, to 2, completely functional) the execution of each assisted sub-action. Results: The functionality of all modules has been successfully demonstrated. User’s intention was detected with a 100% success. Averaging all subjects and tasks, the minimum evaluation score obtained was 1.13 ± 0.99 for the release of the handle during the drinking task, whilst all the other sub-actions achieved a mean value above 1.6. All users, but one, subjectively perceived the usefulness of the assistance and could easily control the system. Donning time ranged from 6 to 65 minutes, scaled on the configuration complexity. Conclusions: The MUNDUS platform provides functional assistance to daily life activities; the modules integration depends on the user’s need, the functionality of the system have been demonstrated for all the possible configurations, and preliminary assessment of usability and acceptance is promising

Systemic Chemokine Levels with “Gut-Specific” Vedolizumab in Patients with Inflammatory Bowel Disease—A Pilot Study

Vedolizumab, a gut-specific biological treatment for inflammatory bowel disease (IBD), is an antibody that binds to the α4β7 integrin and blocks T-cell migration into intestinal mucosa. We aimed to investigate chemokine levels in serum of IBD-patients treated with vedolizumab. In this pilot study, we included 11 IBD patients (8 Crohn’s disease, 3 ulcerative colitis) previously non-respondent to anti-tumor necrosis factor (TNF)-agents. Patients received vedolizumab at week 0, 2 and 6 and were evaluated for clinical efficacy at week 10. Clinical characteristics and routine laboratory parameters were obtained and patients were classified as responders or non-responders. Expression of 21 chemokines in serum was measured using Proximity Extension Assay and related to clinical outcome. At week 10, 6 out of 11 patients had clinically responded. Overall expression of CCL13 increased after treatment. In non-responders, expression of CCL13 and CXCL8 increased after treatment, and CCL20 and CXCL1 expressions were higher compared to responders. In responders, CCL28 decreased after treatment. C-reactive protein (CRP) correlated negatively with 6 chemokines before therapy, but not after therapy. Systemic CCL13 expression increases in IBD-patients after vedolizumab therapy and several chemokine levels differ between responders and non-responders. An increased CCL13-level when starting vedolizumab treatment, might indicate potential prognostic value of measuring chemokine levels when starting therapy with vedolizumab. This study provides new information on modulation of systemic chemokine levels after vedolizumab treatment

Receptor-Type Protein-Tyrosine Phosphatase ζ and Colony Stimulating Factor-1 Receptor in the Intestine: Cellular Expression and Cytokine- and Chemokine Responses by Interleukin-34 and Colony Stimulating Factor-1

<div><p>Differential intestinal expression of the macrophage growth factors colony stimulating factor-1 (CSF-1), interleukin (IL)-34, and their shared CSF-1 receptor (CSF-1R) in inflammatory bowel disease (IBD) has been shown. Diverse expression between CSF-1 and IL-34, suggest that IL-34 may signal via an alternate receptor. Receptor-type protein-tyrosine phosphatase ζ (PTPRZ1, RPTP-ζ), an additional IL-34 receptor, was recently identified. Here, we aimed to assess <i>PTPRZ1</i> expression in IBD and non-IBD intestinal biopsies. Further, we aimed to investigate cellular PTPRZ1 and CSF-1R expression, and cytokine- and chemokine responses by IL-34 and CSF-1. The expression of <i>PTPRZ1</i> was higher in non-IBD colon compared to ileum. <i>PTPRZ1</i> expression was not altered with inflammation in IBD, however, correlated to <i>IL34</i>, <i>CSF1</i>, and <i>CSF1R</i>. The expression patterns of PTPRZ1 and CSF-1R differed in peripheral blood mononuclear cells (PBMCs), monocytes, macrophages, and intestinal epithelial cell line. PBMCs and monocytes of the same donors responded differently to IL-34 and CSF-1 with altered expression of tumor-necrosis factor α (TNF-α), IL-1β, interferon γ (IFN-γ), IL-13, IL-8, and monocyte chemotactic protein-1 (MCP-1) levels. This study shows that <i>PTPRZ1</i> was expressed in bowel tissue. Furthermore, CSF-1R protein was detected in an intestinal epithelial cell line and donor dependently in primary PBMCs, monocytes, and macrophages, and first hints also suggest an expression in these cells for PTPRZ1, which may mediate IL-34 and CSF-1 actions.</p></div

PTPRZ1 is differentially expressed in normal human ileum and colon but not regulated with inflammation.

<p><b>(A)</b><i>PTPRZ1</i> relative mRNA expression in ileum and colon, presented as the mean per colon sites for each non-IBD subjects. <b>(B)</b> <i>PTPRZ1</i> relative mRNA in different sites of the colon from non-IBD subjects. <i>PTPRZ1</i> relative mRNA expression in <b>(C)</b> colon and <b>(D)</b> ileum from non-IBD, IBD, UC and CD patients. Comparisons between ileum and colon were calculated using Mann–Whitney <i>U</i> tests, and between different sites of colon by ANOVA with post-hoc LSD tests. N = 18 for ileum, n = 24 for colon. Results are means ± SEM *P<0.05; **P<0.01; ***P<0.001. <b>(E)</b> <i>PTPRZ1</i> relative mRNA expression compared between non-inflamed and inflamed in IBD patients. <i>PTPRZ1</i> relative mRNA expression in colon presented as the mean per colon sites for each patient in IBD patients subdivided into CD and UC. Correlations of <i>PTPRZ1</i> with <b>(F)</b> <i>IL34</i>, <b>(G)</b> <i>CSF1</i>, <b>(H)</b> <i>CSF1R</i>, <b>(I)</b> <i>TNFA</i> and <b>(J)</b> <i>CD68</i> in IBD patients. Comparisons were evaluated using Mann–Whitney U tests. Correlations were assessed by Spearman’s correlation coefficients. N = 18 for non-inflamed IBD, n = 23 for inflamed IBD, n = 6 for non-inflamed CD, n = 6 for inflamed CD, n = 11 for non-inflamed UC, n = 16 for inflamed UC. Results are mean ± SEM *P<0.05; **P<0.01; ***P<0.001.</p

CSF-1R dependent regulation of pro-inflammatory cytokines and chemokines in PBMCs and monocytes <i>IL1B</i>, <i>TNFA</i>, <i>IFNG</i>, <i>IL8</i> and <i>MCP1</i> relative mRNA expression from PBMCs.

<p><b>(A, B)</b> and monocytes <b>(C, D)</b> stimulated with IL-34, PBMCs <b>(E, F)</b> and monocytes <b>(G, H)</b> stimulated with CSF-1, after blocking CSF-1R for 6 h. IgG1 was used as a control. Gene expression was analysed by q-PCR and normalized to <i>GAPDH</i>. Data represent mean + SEM, *P<0.05; **P<0.01; ***P<0.001, Student’s T-test, n = 5–6 donors. (<b>I-J</b>) Secreted MCP-1 in supernatants from PBMCs <b>(I)</b> and monocytes <b>(J)</b> stimulated with IL-34 or CSF-1 after blocking CSF-1R for 24 h, IgG1 was used as a control, were analysed by ELISA. Data represent mean + SEM, *P<0.05; **P<0.01; ***P<0.001, Student’s T-test, n = 6 donors.</p

Expression of CSF-1R and PTPRZ1 in PBMCs, monocytes, macrophages and colonic epithelial cells.

<p>Immunoblotting of lysates from PBMCs, monocytes, CSF-1 monocyte derived and non-polarized macrophages, Caco-2 and A549 cells analysed for <b>(A)</b> CSF-1R and <b>(B)</b> PTPRZ1. β-actin was used as a loading control (10 and 15 μg protein per lane, respectively).</p

Diverse regulation of IL-10, IL-1β, TNF-α and MCP-1 in macrophages differentiated in the presence of IL-34 and CSF-1.

<p><b>(A-C)</b><i>IL1B</i>, <i>TNFA</i> and <i>IL10</i> mRNA expression in IL-34 and/or CSF-1 differentiated macrophages and polarized to an M1-like phenotype, an M2-like phenotype or non-polarized were analysed by q-PCR and normalized to <i>GAPDH</i>. Data represent mean + SEM, *P<0.05; **P<0.01; ***P<0.001, ANOVA, n = 5–6 donors. <b>(D-F)</b> Secreted IL-10, MCP-1 and IL-1β in the supernatant from IL-34 and/or CSF-1 differentiated macrophages and polarized to an M1-like phenotype, an M2-like phenotype or non-polarized were analysed by ELISA. Data represent mean + SEM, *P<0.05; **P< 0.01; ***P<0.001, ANOVA, n = 9 donors.</p