Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis.

Objectives: Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities. Methods: We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (n=30; 23F/7M, 40 ± 8.14 years) or a relapse (n=30; 24F/6M, age 41 ± 10.74 years) and age/sex-matched controls (n=30; 23F/7M, 40 ± 8.38 years); ii) brain hemodynamic metrics at dynamic susceptibility contrast-enhanced 3T-MRI during relapse and remission, and iii) laboratory data with MRI perfusion metrics and clinical features of people with multiple sclerosis. Two models by Partial Least Squares Discriminant Analysis were performed using two groups as input: (1) multiple sclerosis vs. controls, and (2) relapsing vs. remitting multiple sclerosis. Results: Compared to controls, multiple sclerosis patients had a higher Body-Mass-Index, Protein-C and activated-C9; and a lower activated-C4. Levels of Tissue-Factor, Tie-2 and P-Selectin/CD62P were lower in relapse compared to remission and HC, whereas Angiopoietin-I was higher in relapsing vs. remitting multiple sclerosis. A lower number of total lymphocytes was found in relapsing multiple sclerosis vs. remitting multiple sclerosis and controls. Cerebral-Blood-Volume was lower in normal-appearing white matter and left caudatum while Cerebral-Blood-Flow was inferior in bilateral putamen in relapsing versus remitting multiple sclerosis. The mean-transit-time of gadolinium-enhancing lesions negatively correlated with Tissue-Factor. The top-5 discriminating variables for model (1) were: EBV-EBNA-1 IgG, Body-Mass-Index, Protein-C, activated-C4 and Tissue-Factor whereas for model (2) were: Tissue-Factor, Angiopoietin-I, MCHC, Vitamin A and T-CD3. Conclusion: Tissue-factor was one of the top-5 variables in the models discriminating either multiple sclerosis from controls or multiple sclerosis relapse from remission and correlated with mean-transit-time of gadolinium-enhancing lesions. Tissue-factor appears a promising pro-coagulative/vascular biomarker and a possible therapeutic target in relapsing-remitting multiple sclerosis. Clinical trial registration: ClinicalTrials.gov, identifier NCT04380220.

Shoulder Rehabilitation Exercises With Kinematic Biofeedback After Arthroscopic Rotator Cuff Repair: Protocol for a New Integrated Rehabilitation Program.

BACKGROUND: The recovery of scapular and humeral physiological kinematic parameters, as well as the sensorimotor control of movement, plays a primary role in the rehabilitation process after arthroscopic rotator cuff repair. A highly customized rehabilitation approach is required to achieve this aim. Biofeedback can be a useful tool, but there is poor evidence of its application in the rehabilitation after arthroscopic rotator cuff tear repair. OBJECTIVE: The aim of this paper is to outline an innovative exercise-based rehabilitation program exploiting visual biofeedback for the recovery of patients arthroscopically treated for rotator cuff repair. METHODS: For establishment of the innovative program, a multidisciplinary team involving experts in shoulder surgery, rehabilitation medicine, physical therapy, and biomedical and clinical engineering was formed. Starting from a conventional rehabilitation program, the team selected a set of exercises to be integrated with a biofeedback tool, named the INAIL (National Institute for Insurance against Accidents at Work) Shoulder and Elbow Outpatient program (ISEO program). ISEO is a motion analysis system based on inertial wearable sensors positioned over the thorax, scapula, humerus, and forearm. ISEO can return a visual biofeedback of humerus and scapula angles over time or of the scapula-humeral coordination, with possible overlap of patient-specific or asymptomatic reference values. A set of 12 progressive exercises was defined, divided into four groups based on humerus and scapula movements. Each group comprises 2-4 of the 12 exercises with an increasing level of complexity. Exercises can require the use of a ball, stick, rubber band, and/or towel. For each exercise, we present the starting position of the patient, the modality of execution, and the target position, together with notes about the critical factors to observe. The type of visual biofeedback to adopt is specified, such as the coordination between angles or the variation of a single angle over time. To guide the therapist in customizing the patient's rehabilitation program, a list of operative guidelines is provided. RESULTS: We describe various applications of the ISEO exercise program in terms of frequency and intensity. CONCLUSIONS: An innovative rehabilitation program to restore scapular and humeral kinematics after rotator cuff repair based on kinematic biofeedback is presented. Biofeedback is expected to increase patient awareness and self-correction under therapist supervision. Randomized controlled trials are needed to investigate the potential effect of the exercise-based biofeedback in comparison with conventional rehabilitation programs. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35757.

Home treatment against fatigue in multiple sclerosis by a personalized, bilateral whole-body somatosensory cortex stimulation.

BACKGROUND: Fatigue in multiple sclerosis (MS) is a highly invalidating symptom with no pharmacological efficacious therapies, which furthermore present frequent severe side effects. In two previous randomized controlled trials we observed the efficacy of a personalized neuromodulation treatment consisting of a personalized transcranial Direct Current Stimulation (tDCS) for 15 min per day for 5 days (Faremus). METHODS: By this medical-device phase II study, we aimed at assessing the feasibility, acceptance, safety and efficacy of Faremus treatment when applied at patients' home. We considered the efficacy as primary outcome assessed by a reduction of fatigue levels measured by Modified Fatigue Impact Scale (mFIS) scored before and after the treatment. Primary outcome determined the sample size estimate. Individual ad-hoc questionnaires quantified the acceptance, safety and side effects during the treatment. RESULTS: All 15 patients completed the treatment, reporting optimal acceptance and safety on using Faremus at their home without side-effects. The treatment ameliorated fatigue symptoms more than 20% of baseline in 10 out of the 15 patients and of 37% on average, with a corresponding effect size 1.21. CONCLUSIONS: Faremus personalized electroceutical intervention, a 5-days anodal tDCS over the bilateral whole-body somatosensory cortex, is well accepted and can be feasibly, safely, and efficaciously applied at patients' home, offering a comfortable treatment by reducing the need to travel when fatigue-related symptoms hamper the quality of life.

Reliability and construct validity of the Activities Scale for Kids in Italian children with cerebral palsy.

PURPOSE: To investigate internal consistency and construct validity of the of the Activities Scale for Kids performance (ASKp) in Italian children with cerebral palsy (CP). METHODS: This cross-sectional study was conducted from 2014 up to 2019 and consisted in the single self-administration of the Italian ASKp to 206 children aged 5-15, with unilateral or bilateral CP, classified on the basis of the Gross Motor Function Classification System (GMFCS). RESULTS: The ASKp showed good internal consistency (Chronbach's α 0.91, 95% CI 0.89-0.93). It distinguished between children and adolescents (70.3 ± 16.6 versus 83.0 ± 18.0, respectively; p < 0.001), unilateral and bilateral CP clinical manifestations (82.5 ± 13.6 versus 72.4 ± 19.0, respectively; p = 0.002), children with and without intellectual disability (60.3 ± 18.3 versus 77.2 ± 17.3, respectively; p < 0.001). It also distinguished children using assistive devices for indoor mobility from children who did not use devices or those who use devices only for outdoor mobility (66.1 ± 18.3 versus 83.6 ± 12.8 and versus 80.4 ± 17.4, respectively; both p < 0.001). CONCLUSIONS: The ASKp could help integrate the perspective of children with CP in their rehabilitation process. Trial registration: ClinicalTrials.gov Identifier: NCT03325842IMPLICATIONS FOR REHABILITATIONThe ASKp is a valid and widely used measure for several ICF domains of activities and participation in pediatrics.It has never been formally validated in children with CP, although this disorder causes restrictions in everyday activities.Recently, the culturally adapted Italian version of the ASKp has been tested in typically developing Italian children, confirming its high acceptability and providing evidence of construct validity.This study confirms the internal consistency reliability and the construct validity of the Italian ASKp when applied to the population with CP.The ASKp can support rehabilitation professionals in planning therapeutic intervention targeted to relevant goals.

A kinematic and electromyographic comparison of a Grammont-style reverse arthroplasty combined with a l'Episcopo transfer compared to a lateralized humeral component reverse for restoration of active external rotation.

PURPOSE: To assess kinematic and electromyographic findings of two designs of reverse total shoulder arthroplasty (RTSA). We tested two hypotheses: (H1) Grammont-style (RTSA) with l'Episcopo tendon transfer gains similar postoperative kinematic findings of a lateralized humeral component RTSA without a tendon transfer; (H2) RTSA with lateralized humeral component induces earlier shoulder muscle activation during shoulder motion compared with standard Grammont prosthesis with l'Episcopo transfer. METHODS: Twenty-five patients with a cuff tear arthropathy, pseudoparalysis, and a positive dropping sign were sequentially included. A Grammont-style RTSA with a l'Episcopo tendon transfer was implanted in 13 patients (medialized humerus and transfer group) and an on-lay curved-stem RTSA in 12 (lateralized humerus group). Constant score; the disabilities of the arm, shoulder, and hand (DASH) score; and active shoulder range of motion (flexion, abduction, external rotation, and internal rotation) were measured pre- and postoperatively. Upper limb kinematic and surface electromyography (EMG) (anterior and posterior deltoid; upper, middle, and lower trapezius; and the upper and lower latissimus dorsi muscles) were recorded during active range of motion. RESULTS: At > 24 months of follow-up, the Constant and DASH scores and active shoulder range of motion improved in both groups (p < 0.0001). Internal rotation was significantly higher in the lateralized humerus group than in the medialized humerus and transfer group (p = 0.004). The dropping sign was found in 0/12 patients in the lateralized humerus group and in 5/13 patients in the medialized humerus and transfer group (p < 0.001). Kinematic findings were similar between groups (p = 0.286). A pattern of earlier muscle activation in the lateralized humerus group was found as compared to the transfer group as follows: (i) posterior deltoid during external rotation (p = 0.004); (ii) upper latissimus dorsi and middle and lower trapezius during flexion (p = 0.004, p = 0.005, and p = 0.042, respectively); (iii) lower latissimus dorsi during abduction (p = 0.016). CONCLUSION: RTSA with a lateralized humeral component provided similar active external rotation restoration to a Grammont-style RTSA with a l'Episcopo procedure in patients with a dropping sign. The posterior deltoid muscle underwent earlier activation during active external rotation in the lateralized humerus RTSA group as compared to the tendon transfer group. Our findings demonstrated the H1 and only partially demonstrated the H2 of the study.

Effects on Motor Control of Personalized Neuromodulation Against Multiple Sclerosis Fatigue.

Fatigue is a hidden symptom of Multiple Sclerosis (MS) disease that nevertheless impacts severely on patients' everyday life. Evidence indicates the involvement of the sensorimotor network and its inter-nodes communication at the basis of this symptom. Two randomized controlled trials (RCTs) showed that the personalized neuromodulation called Fatigue Relief in Multiple Sclerosis (FaReMuS) efficaciously fights multiple sclerosis (MS) fatigue. By this Proof of Concept study, we tested whether FaReMuS reverts the alteration of the brain-muscular synchronization previously observed occurring with fatigue. The cortico muscular coherence (CMC) was studied in 11 patients before and after FaReMuS, a 5-day tDCS (1.5 mA, 15 min per day) anodal over the whole body's somatosensory representation (S1) via a personalized MRI-based electrode (35 cm2) against the occipital cathode (70 cm2). Before FaReMuS, the CMC was observed at a mean frequency of 31.5 ± 1.6 Hz (gamma-band) and positively correlated with the level of fatigue (p = .027). After FaReMuS, fatigue reduced in average of 28% ± 33% the baseline level, and the CMC frequency reduced to 26.6 ± 1.5 Hz (p = .022), thus forthcoming the physiological beta-band as observed in healthy people. The personalized S1 neuromodulation treatment, ameliorating the central-peripheral communication that subtends simple everyday movements, supports the appropriateness of neuromodulations aiming at increasing the parietal excitability in fighting MS fatigue. The relationship between central-peripheral features and fatigue profile strengthens a central more than peripheral origin of the symptom.

Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study.

OBJECTIVE: To identify baseline factors associated with disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) under teriflunomide treatment. METHODS: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment. RESULTS: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0-4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007). CONCLUSIONS: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern.

Exit strategies for "needle fatigue" in multiple sclerosis: a propensity score-matched comparison study.

Patients with multiple sclerosis on long-term injectable therapies may suffer from the so-called "needle fatigue", i.e., a waning commitment to continue with the prescribed injectable treatment. Therefore, alternative treatment strategies to enhance patients' adherence are warranted. In this independent, multicentre post-marketing study, we sought to directly compare switching to either teriflunomide (TFN), dimethyl fumarate (DMF), or pegylated interferon (PEG) on treatment persistence and time to first relapse over a 12-month follow-up. We analyzed a total of 621 patients who were free of relapses and gadolinium-enhancing lesions in the year prior to switching to DMF (n = 265), TFN (n = 160), or PEG (n = 196). Time to discontinuation and time to first relapse were explored in the whole population by Cox regression models adjusted for baseline variables and after a 1:1:1 ratio propensity score (PS)-based matching procedure. Treatment discontinuation was more frequent after switching to PEG (28.6%) than DMF (14.7%; hazard ratio [HR] = 0.25, p < 0.001) and TFN (16.9%; HR = 0.27, p < 0.001). We found similar results even in the re-sampled cohort of 222 patients (74 per group) derived by the PS-based matching procedure. The highest discontinuation rate observed in PEG recipient was mainly due to poor tolerability (p = 0.005) and pregnancy planning (p = 0.04). The low number of patients who relapsed over the 12-month follow-up (25 out of 621, approximately 4%) prevented any analysis on the short-term risk of relapse. This real-world study suggests that oral drugs are a better switching option than low-frequency interferon for promoting the short-term treatment persistence in stable patients who do not tolerate injectable drugs.

Oxidative Stress Related to Iron Metabolism in Relapsing Remitting Multiple Sclerosis Patients With Low Disability.

Oxidative status may play a role in chronic inflammation and neurodegeneration which are considered critical etiopathogenetic factors in Multiple Sclerosis (MS), both in the early phase of the disease and in the progressive one. The aim of this study is to explore oxidative status related to iron metabolism in peripheral blood of stable Relapsing-Remitting MS with low disability. We studied 60 Relapsing-Remitting MS patients (age 37.2 ± 9.06, EDSS median 1.0), and 40 healthy controls (age 40.3 ± 10.86). We measured total hydroperoxides (dROMs test) and Total Antioxidant Status (TAS), along with the iron metabolism biomarkers: Iron (Fe), ferritin (Ferr), transferrin (Tf), transferrin saturation (Tfsat), and ceruloplasmin (Cp) panel biomarkers [concentration (iCp) and enzymatic activity (eCp), copper (Cu), ceruloplasmin specific activity (eCp:iCp), copper to ceruloplasmin ratio (Cu:Cp), non-ceruloplasmin copper (nCp-Cu)]. We computed also the Cp:Tf ratio as an index of oxidative stress related to iron metabolism. We found lower TAS levels in MS patients than in healthy controls (CTRL) and normal reference level and higher dROMs and Cp:Tf ratio in MS than in healthy controls. Cp and Cu were higher in MS while biomarkers of iron metabolism were not different between patients and controls. Both in controls and MS, dROMs correlated with iCp (CTRL r = 0.821, p < 0.001; MS r = 0.775 p < 0.001) and eCp (CTRL r = 0.734, p < 0.001; MS r = 0.820 p < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat (r = -0.257, p = 0.047). Dividing MS patients in "untreated" group and "treated" group, we found a significant difference in Fe values [F(2, 97) = 10.136, p < 0.001]; in particular "MS untreated" showed higher mean values (mean = 114.5, SD = 39.37 µg/dL) than CTRL (mean 78.6, SD = 27.55 µg/dL p = 0.001) and "MS treated" (mean = 72.4, SD = 38.08 µg/dL; p < 0.001). Moreover, "MS untreated" showed significantly higher values of Cp:Tf (mean = 10.19, SD = 1.77∗10-2; p = 0.015), than CTRL (mean = 9.03, SD = 1.46 ∗10-2). These results suggest that chronic oxidative stress is relevant also in the remitting phase of the disease in patients with low disability and short disease duration. Therefore, treatment with antioxidants may be beneficial also in the early stage of the disease to preserve neuronal reserve.

Assessment of anatomical and reverse total shoulder arthroplasty with the scapula-weighted Constant-Murley score.

AIM OF THE STUDY: To evaluate total (TSA) and reverse total shoulder arthroplasty (RTSA) using the Constant-Murley score (CMS) and the scapula-weighted (SW) CMS, an integrated outcome measure that takes into account the compensatory movements of the scapula. METHODS: Twenty-five consecutive patients, 12 with TSA and 13 with RTSA, underwent kinematic analysis before and after shoulder replacement. Measurements included flexion (FLEX) and abduction (ABD) for the humerus and Protraction-Retraction (PR-RE), Medio-Lateral rotation (ME-LA), and Posterior-Anterior tilting (P-A) for the scapula. They were recorded at baseline (T0) and at six (T1) and 12 months (T2). Reference data were obtained from 31 control shoulders. RESULTS: At T1, differences in CMS and SW-CMS were not significant in either group, whereas values at T2 were significantly lower in RTSA patients (p = 0.310 and p = 0.327, respectively). In TSA shoulders, the compensatory scapular movements in FLEX were all reduced from T0 to T2, whereas P-A was increased in ABD. In RTSA patients, the compensatory scapular movements in FLEX showed a general reduction at T1, with an increase in P-A at T2, whereas in ABD, all increased at T1 and decreased at T2 except for P-A, which did not decrease. DISCUSSION: The SW-CMS showed that the physiological scapulothoracic motion was not restored in TSA and RTSA patients; it may be used as a reference for the gradual progression of deltoid and scapular muscle rehabilitation. CONCLUSIONS: The worse CMS and SW-CMS scores found in RTSA patients at six months may be due to the biomechanics of the reverse prosthesis and to the weakness of deltoid and periscapular muscles.

Evaluation of hand function in patients with unilateral cerebral palsy who underwent multilevel functional surgery: a retrospective observational study.

BACKGROUND: Hemiplegia is the most common form of cerebral palsy. Upper limb is generally more affected than lower one. Indeed, hemiplegic children can spontaneously acquire standing and walking ability, while manipulation remains uncertain, with severe limitations in activity and participation, which define a child's functional status (International Classification of Functioning [ICF]). Several non-surgical tools are currently available to approach upper limb impairments. Studies regarding upper limb multilevel surgery in Hemiplegic Cerebral Palsy are relatively few and inhomogeneous. AIM: The aim of this study is to propose a surgical approach based on upper limb functional level and manipulation strategy and establish whether multilevel surgery can improve segmental alignment, performance and capacity, that ICF defines as activities and participation qualifiers. DESIGN: This study is an observational retrospective study. SETTING: This study involves patients who referred to the Unit of Children Rehabilitation of S. Maria Nuova Institute for Research and Care, in Reggio Emilia (Italy), over a four-year period. POPULATION: Children affected by hemiplegic cerebral palsy who underwent upper limb multilevel surgery. METHODS: For each patient, we previously defined functional use of affected upper limb applying the House classification and the Ferrari one of manipulation pattern. Patients are divided into three groups: synergic hand (House 4, 5), imprisoned hand (House 3), excluded hand (House 0). We recorded goals achievement through Goal Attainment Scale and unimanual and bimanual abilities through Melbourne Assessment of Unilateral Upper Limb Function and through Assisting Hand Assessment respectively. RESULTS: We recorded 16 upper limb multilevel surgical interventions in 13 children and report their results. CONCLUSIONS: This study suggests that surgery can induce a segmental and/or aesthetic and/or a functional change depending on manipulation pattern. It also underlines the importance to analyze results in term of spontaneous manipulation abilities and daily use. CLINICAL REHABILITATION IMPACT: This study provides a preliminary guide to plan surgery in relation to segmental deformities and overall manipulation pattern and describes their feasible improvement measures. It also suggests the most useful tools to record goal achievements in modifying manipulation function. Further controlled, randomized and prospective studies are required to support this idea.

Executive functioning in relapsing-remitting multiple sclerosis patients without cognitive impairment: A task-switching protocol.

BACKGROUND: Cognitive dysfunction affects 40%-65% of multiple sclerosis (MS) patients, most often affecting information processing speed and working memory, mediated by the pre-frontal cortex (PFC). OBJECTIVE: Our study aimed to investigate PFC functioning through a task-switching protocol in relapsing-remitting multiple sclerosis (RRMS) patients without cognitive impairment. METHODS: A total of 24 RRMS patients and 25 controls were enrolled. Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called switch cost (SC). RESULTS: Patients had worse performance than controls only in the switch trials, as indicated by increased SC and reaction times. Moreover, patients showed a reduced ability to reconfigure the task-set for the execution of a new task and to disengage from the previous one. CONCLUSION: Our results showed a primary deficit in executive control processes involved in the task-switching performance in RRMS patients without cognitive impairment. This deficit may depend on the functional impairment of the PFC, which is essential to adjust behaviour rapidly and flexibly in response to environmental changes, representing one of the most sophisticated human abilities.

Personalized, bilateral whole-body somatosensory cortex stimulation to relieve fatigue in multiple sclerosis.

BACKGROUND: The patients suffering from multiple sclerosis (MS) often consider fatigue the most debilitating symptom they experience, but conventional medicine currently offers poorly efficacious therapies. OBJECTIVE: We executed a replication study of an innovative approach for relieving MS fatigue. METHODS: According to the sample size estimate, we recruited 10 fatigued MS patients who received 5-day transcranial direct current stimulation (tDCS) in a randomized, double-blind, Sham-controlled, crossover study, with modified Fatigue Impact Scale (mFIS) score reduction at the end of the treatment as primary outcome. A personalized anodal electrode, shaped on the magnetic resonance imaging (MRI)-derived individual cortical folding, targeted the bilateral whole-body primary somatosensory cortex (S1) with an occipital cathode. RESULTS: The amelioration of fatigue symptoms after Real stimulation (40% of baseline) was significantly larger than after Sham stimulation (14%, p = 0.012). Anodal whole body S1 induced a significant fatigue reduction in mildly disabled MS patients when the fatigue-related symptoms severely hampered their quality of life. CONCLUSION: This second result in an independent group of patients supports the idea that neuromodulation interventions that properly select a personalized target might be a suitable non-pharmacological treatment for MS fatigue.

Electrocardiogram Alterations Associated With Psychotropic Drug Use and CACNA1C Gene Variants in Three Independent Samples.

Several antipsychotics and antidepressants have been associated with QTc prolongation or other electrocardiogram (ECG) alterations, but their impact is still debated and other risk factors are known to affect QTc. We investigated the effect of antidepressants and antipsychotics on QTc and other ECG intervals/waves in three samples. Two discovery samples (cross-sectional sample n = 145 and prospective sample n = 68, naturalistic treatment) and a replication prospective sample (Clinical Antipsychotic Trials of Intervention Effectiveness, n = 515, randomized treatment) were analysed. In both prospective samples, baseline/follow-up changes in ECG parameters were analysed in relation to the number of psychotropic drugs stratified according to their known cardiovascular risk. In the cross-sectional sample, ECG parameters were compared among drugs with different risk profile. The possible effect of single nucleotide polymorphisms (SNPs) in the CACNA1C gene on QTc was also investigated. There was no evidence of mean QTc prolongation or increased risk of clinically relevant QTc prolongation (≥20 msec.) in association with psychotropic drugs stratified according to their known cardiovascular risk. The prescription of drugs with cardiovascular risk was less common in older individuals or individuals with cardiovascular comorbidities. Other factors (gender, baseline QTc, renal function) affected QTc. rs1006737 and SNPs in linkage disequilibrium with it modulated QTc duration/changes in all samples. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not observed. A number of factors other than psychotropic drugs may influence QTc. CACNA1C rs1006737 may modulate QTc in patients treated with psychotropic drugs.

Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS) in the Italian population.

Cognitive dysfunction involves 40-65 % of multiple sclerosis (MS) patients. It can be detected in all MS phenotypes from the early stages of the disease, and it tends to progress over time. Minimal Assessment of Cognitive Function in MS (MACFIMS) has been proved to be the most sensitive and comprehensive battery available for MS cognitive assessment in the English population. In Italy, MACFIMS applicability is limited in everyday clinical practice since the overall validity of this battery in the Italian MS population has never been demonstrated. The aim of this study was to translate/cross-culturally adapt and validate an Italian version of the MACFIMS. A total of 130 MS patients and 60 healthy controls (HCs) were enrolled and evaluated with an Italian version of the MACFIMS. All tests discriminated MS patients from HCs; according to the literature, approximately more than half of MS patients (70.8 %) exhibit cognitive impairment. Principal component analysis showed four distinct components: visual-spatial memory/processing speed, working memory, executive functions and verbal memory. Our study is the first to validate an Italian version of the MACFIMS. Several aspects of validity have been demonstrated: criterion and, partially, construct. Future work will investigate the longitudinal course of neuropsychological dysfunction in Italian MS patients using these measures.

Brain Plasticity Effects of Neuromodulation Against Multiple Sclerosis Fatigue.

RATIONALE: We recently reported on the efficacy of a personalized transcranial direct current stimulation (tDCS) treatment in reducing multiple sclerosis (MS) fatigue. The result supports the notion that interventions targeted at modifying abnormal excitability within the sensorimotor network could represent valid non-pharmacological treatments. OBJECTIVE: The present work aimed at assessing whether the mentioned intervention also induces changes in the excitability of sensorimotor cortical areas. METHOD: Two separate groups of fatigued MS patients were given a 5-day tDCS treatments targeting, respectively, the whole body somatosensory areas (S1wb) and the hand sensorimotor areas (SM1hand). The study had a double blind, sham-controlled, randomized, cross-over (Real vs. Sham) design. Before and after each treatment, we measured fatigue levels (by the modified fatigue impact scale, mFIS), motor evoked potentials (MEPs) in response to transcranial magnetic stimulation and somatosensory evoked potentials (SEPs) in response to median nerve stimulation. We took MEPs and SEPs as measures of the excitability of the primary motor area (M1) and the primary somatosensory area (S1), respectively. RESULTS: The Real S1wb treatment produced a 27% reduction of the mFIS baseline level, while the SM1hand treatment showed no difference between Real and Sham stimulations. M1 excitability increased on average 6% of the baseline in the S1wb group and 40% in the SM1hand group. Observed SEP changes were not significant and we found no association between M1 excitability changes and mFIS decrease. CONCLUSION: The tDCS treatment was more effective against MS fatigue when the electrode was focused on the bilateral whole body somatosensory area. Changes in S1 and M1 excitability did not correlate with symptoms amelioration. SIGNIFICANCE: The neuromodulation treatment that proved effective against MS fatigue induced only minor variations of the motor cortex excitability, not enough to explain the beneficial effects of the intervention.

Assessment of the ability of wheelchair subjects with spinal cord injury to perform a specific protocol of shoulder training: a pilot study.

BACKGROUND: a regular program of exercises in subjects with spinal cord injury (SCI) can contribute to reduce the risk of upper extremities injuries. METHODS: in this prospective laboratory study we tested the hypothesis that a training machine developed for able-body users is suitable for a shoulder training protocol in 11 paraplegic subjects with SCI. Overall subjects were assessed with the SCIM III, CS, DASH and standard shoulder examination. We set a protocol of shoulder exercises performed with a training machine. Overall subjects were able to perform the protocol but 2 did not complete the exercises n° 6 and 7. The position of the wheelchair during each exercise was recorded. Wheelchair position/loading level were significantly correlated with the protocol n° 2, 3 and 5 as well as BMI/loading level for the exercises n° 5 and 9 and age/loading level for the exercise n° 7. Clinical scores were neither correlated with loading nor with anthropometric data. RESULTS/CONCLUSIONS: FROM THE ANALYSIS OF DATA COLLECTED IN THIS STUDY ARISED THAT: 1) the training machine needs some adjustments for paraplegic subjects, 2) the training protocol was appropriate except for the exercises needing a torso-rotation and 3) the template for wheelchair position may be a valid guide for an optimal paraplegic shoulder training.

Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation.

Multiple sclerosis-related fatigue is highly common and often refractory to medical therapy. Ten fatigued multiple sclerosis patients received two blocks of 5-day anodal bilateral primary somatosensory areas transcranial direct current stimulation in a randomized, double-blind sham-controlled, cross-over study. The real neuromodulation by a personalized electrode, shaped on the MR-derived primary somatosensory cortical strip, reduced fatigue in all patients, by 26 % in average (p = 0.002), which did not change after sham (p = 0.901). Anodal tDCS over bilateral somatosensory areas was able to relief fatigue in mildly disabled MS patients, when the fatigue-related symptoms severely hamper their quality of life. These small-scale study results support the concept that interventions modifying the sensorimotor network activity balances could be a suitable non-pharmacological treatment for multiple sclerosis fatigue.

Thalamocortical sensorimotor circuit in multiple sclerosis: an integrated structural and electrophysiological assessment.

Demyelination and axonal damage are pathologic hallmarks of multiple sclerosis (MS), leading to loss of neuronal synchronization, functional disconnection amongst brain relays, and clinical sequelae. To investigate these properties, the primary component of the sensorimotor network was analyzed in mildly disabled Relapsing-Remitting MS patients without sensory symptoms at the time of the investigation. By magnetoencephalography (MEG), the recruitment pattern within the primary sensory (S1) and motor (M1) areas was estimated through the morphology of the early components of somatosensory evoked magnetic fields (SEFs), after evaluating the S1 responsiveness to sensory inputs from the contralateral arm. In each hemisphere, network recruitment properties were correlated with ispilateral thalamus volume, estimated by morphometric techniques upon high-resolution 3D structural magnetic resonance images (MRI). S1 activation was preserved, whereas SEF morphology was strikingly distorted in MS patients, marking a disruption of primary somatosensory network patterning. An unbalance of S1-M1 dynamic recruitment was documented and correlated with the thalamic volume reduction in the left hemisphere. These findings support the model of MS as a disconnection syndrome, with major susceptibility to damage experienced by nodes belonging to more frequently recruited and highly specialized networks.

Inter-operator reliability and prediction bands of a novel protocol to measure the coordinated movements of shoulder-girdle and humerus in clinical settings.

A clinical motion analysis protocol was developed to measure the coordinated movements of shoulder-girdle and humerus (girdle-humeral rhythm--GD-H-R) during humerus flexion-extension (HFE) and ab-adduction (HAA), through an optoelectronic system. In particular, the protocol describes the GD-H-R with 2 angle-angle plots for each movement: girdle elevation-depression and protraction-retraction vs HFE, and vs HAA. Each of these plots is further divided in two subplots, one for the upward and one for the downward phases of the movement. By involving 11 participants and 2 operators, we measured the protocol's inter-operator reliability which ranged from very-good to excellent depending on the angle-angle plot (median values of the inter-operator coefficient of multiple correlation for the angle-angle plots higher than 0.94). We then computed the subjects' average control patterns, together with statistically meaningful prediction bands. +/-1SD confidence bands were also computed and their width ranged from +/-0.5 degrees to +/-4.6 degrees. Based on these results we could conclude that the method is robust and able to identify even limited differences in the GD-H-R.