Efficacy of Transcranial Direct Current Stimulation (tDCS) on Balance and Gait in Multiple Sclerosis Patients: A Machine Learning Approach.

Transcranial direct current stimulation (tDCS) has emerged as an appealing rehabilitative approach to improve brain function, with promising data on gait and balance in people with multiple sclerosis (MS). However, single variable weights have not yet been adequately assessed. Hence, the aim of this pilot randomized controlled trial was to evaluate the tDCS effects on balance and gait in patients with MS through a machine learning approach. In this pilot randomized controlled trial (RCT), we included people with relapsing−remitting MS and an Expanded Disability Status Scale >1 and <5 that were randomly allocated to two groups­a study group, undergoing a 10-session anodal motor cortex tDCS, and a control group, undergoing a sham treatment. Both groups underwent a specific balance and gait rehabilitative program. We assessed as outcome measures the Berg Balance Scale (BBS), Fall Risk Index and timed up-and-go and 6-min-walking tests at baseline (T0), the end of intervention (T1) and 4 (T2) and 6 weeks after the intervention (T3) with an inertial motion unit. At each time point, we performed a multiple factor analysis through a machine learning approach to allow the analysis of the influence of the balance and gait variables, grouping the participants based on the results. Seventeen MS patients (aged 40.6 ± 14.4 years), 9 in the study group and 8 in the sham group, were included. We reported a significant repeated measures difference between groups for distances covered (6MWT (meters), p < 0.03). At T1, we showed a significant increase in distance (m) with a mean difference (MD) of 37.0 [−59.0, 17.0] (p = 0.003), and in BBS with a MD of 2.0 [−4.0, 3.0] (p = 0.03). At T2, these improvements did not seem to be significantly maintained; however, considering the machine learning analysis, the Silhouette Index of 0.34, with a low cluster overlap trend, confirmed the possible short-term effects (T2), even at 6 weeks. Therefore, this pilot RCT showed that tDCS may provide non-sustained improvements in gait and balance in MS patients. In this scenario, machine learning could suggest evidence of prolonged beneficial effects.

The synergic use of the High Power Laser Therapy and Glucosamine sulfate in Knee osteoarthritis: A Randomized Controlled Trial.

BACKGROUND AND AIM: To determine the efficacy of the synergistic use of High Power Laser Therapy (HPLT) with glucosamine sulfate (GS) in knee osteoarthritis. METHODS: This 2-arm randomized controlled trial (RCT) enrolled 90 subjects (M=53, F=37, y= 55±11.2) and randomly allocated using a stratified sampling method in experimental group (A) with HPLT+GS 1500mg (GS - Dona®, Rottapharm, Monza, Italy) (n=45) or in a control group (B) with HPLT + placebo (n=45).  Results: VAS score in Activities of day Living (ADL), Standardized stair climb test (SSCT), Zohlen's sign (RASPING) and Rabot test were used, to evaluate patients at the beginning of the study (T0), at 2 months (T1) and at 6 months (T2). In the mean scores for VAS in ADL, SSCT, RABOT and RASPING at T1, no significant differences were found between the experimental and the control group with paired T and ANOVA test. But significant differences between groups (p<0.05) in all outcomes were observed at 6 months (T2). CONCLUSIONS: HPLT is useful in treating knee osteoarthritis, but when combined with Glucosamine Sulfate, thanks to the synergy of two interventions, can achieve a long-term effect up to 6 months after treatment.

Role of Physical Exercise and Nutraceuticals in Modulating Molecular Pathways of Osteoarthritis.

Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression.

Synergic use of botulinum toxin injection and radial extracorporeal shockwave therapy in Multiple Sclerosis spasticity.

BACKGROUND AND AIM: In Multiple Sclerosis (MS) spasticity worsen patient's quality of life. Botulinum NeuroToxin TypeA (BoNT-A) is extensively used in focal spasticity, frequently combined with physical therapies. Radial extracorporeal shock waves (rESW) were already used in association with BoNT-A.  Considering that loss of efficacy and adverse events are determinants of BoNT-A treatment interruption, this study aimed to evaluate the possibility to prolong BoNT-A's effect by using rESW in MS focal spasticity. METHODS: Sixteen MS patients with spasticity of triceps surae muscles were first subjected to BoNT-A therapy and, four months later, to 4 sections of rESWT. Patients were evaluated before, 30, 90 days after the end of the treatments, by using Modified Ashworth Scale (MAS), Modified Tardieu Scale (MTS) and kinematic analysis of passive and active ankle ROM.   Results: BoNT-A determined a significant reduction of spasticity evaluated by MAS with a reduction of positive effects after 4months (p<0.05); MTS highlighted the efficacy only 90 days after injection (p<0.05). rESWT decreased MAS values at the end and 30 days later the treatment (p<0.01); MTS values showed instead a prolonged effect (p<0.01). BoNT-A determined a gain of passive and active ankle ROM, persisting along with treatment and peaking the maximum value after rESWT (p<0.05).  Conclusions: rESWT can prolong BoNT-A effect inducing significant reduction of spasticity and improvement in passive and active ankle ROM in MS patients. The use of rESWT following BoNT-A injection is useful to avoid some limitations and to prolong the therapeutic effects of BoNT-A therapy.

Comparative Effectiveness of Orthoses for Thumb Osteoarthritis: A Systematic Review and Network Meta-analysis.

OBJECTIVE: To evaluate the best option among orthoses for carpometacarpal (CMC) osteoarthritis (OA) of the thumb, using a network meta-analysis. DATA SOURCES: Medline, Embase, Cochrane, and ClinicalTrials.gov registry databases were used. PubMed, Embase, Cochrane Controlled Trials Register, Cochrane, and other databases were used without language restrictions. STUDY SELECTION: We searched randomized controlled trials (RCTs) on adults with OA of the thumb by studying any orthosis from the beginning to March 10, 2020. DATA EXTRACTION: Data were extracted and checked for accuracy and completeness by pairs of reviewers. Outcomes were pain and function. Comparative treatment effects were analyzed by random-effects model for direct pairwise comparisons and Bayesian network meta-analyses to integrate direct and indirect evidence. DATA SYNTHESIS: Eleven RCTs involving 619 patients were included. We evaluated 5 groups, for 4 different orthoses: short thermoplastic CMC splint (rigid CMC) (n=5), long thermoplastic carpometacarpal-metacarpophalangeal splint (rigid CMC-MCP) (n=7), short neoprene CMC splint (soft CMC) (n=1), long neoprene CMC-MCP splint (soft CMC-MCP) (n=5), and one as a control group (n=5). Our results show that all splints were superior to placebo to reduce pain intensity and the top-ranked intervention was the rigid CMC-MCP (surface under the cumulative ranking curve analysis [SUCRA], score: 65.4). In function evaluation, we report a 71.6 SUCRA for rigid CMC. CONCLUSIONS: Although the current evidence is unclear on the use of the splint in OA of the thumb, it is not known which orthosis is more effective and whether the orthosis is more effective than other interventions. The network meta-analysis shows that a long thermoplastic splint it is the best choice for pain relief and the short thermoplastic CMC splint is the best treatment to increase function. These results may suggest initial treatment with a long rigid orthosis and then a short rigid orthosis.

Rehabilitation in primary lateral sclerosis mimicking parkinsonism: A case report.

BACKGROUND: Primary lateral sclerosis (PLS) is an upper motor neurons disease that on rare occasions may determine bradykinesia and motor fatigue. To date, no rehabilitative treatment has been described as useful for these patients. CASE PRESENTATION: A 68-year-old male developed dysarthria, spastic laugh, impairments of handwriting and fine motor, gait and dysphagia disorders for both solids and liquids over the period from 2015 to December 2018, with normal DaT scans and no clinical benefits from therapy with levodopa, pramipexole and baclofen. The patient underwent exercises for gait training and balance control with sensory treadmill and stabilometric platform and kinesiotherapy to improve fine motor skills of both hands and postural changes, five days a week for two weeks. Based on our data, the patient showed an improvement in balance and gait parameters in T2 compared to T1. CONCLUSION: Thanks to the synergistic action of a combined treatment of physical and instrumental therapy, despite the rare pathology and complex disability, the patient had important benefits in terms of performance and independence in daily activity.

Comparative effectiveness of breathing exercises in patients with chronic obstructive pulmonary disease.

BACKGROUND AND PURPOSE: This study aims to determine the best choice of breathing exercises (BE) for patients with chronic obstructive pulmonary disease (COPD) via a network meta-analysis. METHODS: We searched randomized controlled trials (RCTs) of adults with COPD investigating any BEs in MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov databases. The effects of comparative treatment on the St. George Respiratory Questionnaire as the outcome were analysed and ranked according to a surface under the cumulative classification curve (SUCRA) analysis. RESULTS: The network meta-analysis included six RCTs involving 280 patients with four intervention groups, comprising control, diaphragmatic breathing training (DBT), yoga, and singing course. Performing SUCRA, we reported that yoga is 75% likely to be the best treatment available as DBT with 66%, instead of 35% for singing and 21% for control. CONCLUSION: DBT and yoga seem to be the best choices for breathing exercises in people with COPD.

International Classification of Functioning, Disability and Health (ICF) and correlation between disability and finance assets in chronic stroke patients.

BACKGROUND: Stroke is the third cause of long term disability worldwide and its rehabilitation program must to have into account all aspects of disability. International research and politics increasingly study the relationship between disability and the direct costs associated with living with a disability. OBJECTIVE: Using the ICF, this article provides a correlation between financial assets and disability in participation and activities, in a context such as the Italian one where there is a twenty-year decentralization of the national health system Methods. At the University of Catanzaro, in southern Italy, n=130 ICF checklists of stroke patients were analyzed at 6 months from the end of the rehabilitation treatment. Financial assets domains in environment and nine domains in participation and activities were correlated, in order to evaluate the relationship between familiar economic condition and disability. RESULTS: Pearson's r test (t = -6.6515, df = 25, p-value<0.05) showed a significant correlation of 0.79. Multiple R-squared was 0.639 and an we reported an Adjusted R-squared of 0.6245 (p<0.05). Thus, about 62% of the increase of the all considered disability qualifiers in participation and activities in ICF checklist can be explained by a lower financial income. CONCLUSIONS: In a regional context (Calabria) of an European country (Italy) with a national health system, thanks to the ICF it can be assumed that with the decrease of the financial income, the gap in participation of activities increases.

Identification of copy number alterations in colon cancer from analysis of amplicon-based next generation sequencing data.

The objective of this study was to determine the feasibility to detect copy number alterations in colon cancer samples using Next Generation Sequencing data and to elucidate the association between copy number alterations in specific genes and the development of cancer in different colon segments. We report the successful detection of somatic changes in gene copy number in 37 colon cancer patients by analysis of sequencing data through Amplicon CNA Algorithm. Overall, we have found a total of 748 significant copy number alterations in 230 significant genes, of which 143 showed CN losses and 87 showed CN gains. Validation of results was performed on 20 representative genes by quantitative qPCR and/or immunostaining. By this analysis, we have identified 4 genes that were subjected to copy number alterations in tumors arising in all colon segments (defined "common genes") and the presence of copy number alterations in 14 genes that were significantly associated to one specific site (defined "site-associated genes"). Finally, copy number alterations in ASXL1, TSC1 and IL7R turned out to be clinically relevant since the loss of TSC1 and IL7R was associated with advanced stages and/or reduced survival whereas copy number gain of ASXL1 was associated with good prognosis.

Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients.

Background: Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients. Methods: Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade. Results: We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients. Conclusion: This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.

Circulating non-hematological cells during cardiopulmonary bypass: new findings in cardiac surgery procedures.

BACKGROUND: Several factors have been historically advocated to explain the coagulative and inflammatory disorders following cardiopulmonary bypass (CPB). In this paper, we describe the presence of circulating non-hematological cells, introduced within the bloodstream during CPB. We defined the origin of the cells and tested their impact on coagulation. METHODS: We collected peripheral arterial blood samples in twenty consecutive coronary artery bypass graft cases at four different surgical moments and assessed the presence and nature of circulating cells with the use of the CELLSEARCH® Test, immunocytochemistry and immunofluorescence, evaluating the expression of cytokeratin and calretinin. The effect of the circulating non-hematological cells on coagulation was tested in vitro, using the ROTEM assay. RESULTS: A mean of 263.85 ± 57.5 (median 258.5) cells were present in the samples following the suction of blood from the surgical field while all the other samples were negative (zero cells) (p<0.00001). Immunologic tests confirmed the mesothelial origin of the cells. The ROTEM® assay of the blood samples contaminated by the mesothelial cells presented longer clotting times (53.4 ± 8.2 secs 48.3 ± 8.9 sec, p=0.05), longer clot formation times (137.1 ± 31.5 sec vs 111.9 ± 25.2 sec, p=0.009), smaller alfa angle amplitudes (66.7 ± 9.1° vs 71.1 ± 5.1°, p=0.04) and maximum clot firmness times (59.0 ± 5.4 sec vs 61.9 ±4.6 sec, p=0.004) than the controls. CONCLUSION: The presence of circulating non-hematological cells during CPB with a mesothelial immunophenotype alters in vitro coagulation assays. This finding can help to further understand the pathophysiology of CPB.

Wnt signaling has opposing roles in the developing and the adult brain that are modulated by Hipk1.

The canonical Wnt/Wingless pathway is implicated in regulating cell proliferation and cell differentiation of neural stem/progenitor cells. Depending on the context, ß-Catenin, a key mediator of the Wnt signaling pathway, may regulate either cell proliferation or differentiation. Here, we show that ß-Catenin signaling regulates the differentiation of neural stem/progenitor cells in the presence of the ß-Catenin interactor Homeodomain interacting protein kinase-1 gene (Hipk1). On one hand, Hipk1 is expressed at low levels during the entire embryonic forebrain development, allowing ß-Catenin to foster proliferation and to inhibit differentiation of neural stem/progenitor cells. On the other hand, Hipk1 expression dramatically increases in neural stem/progenitor cells, residing within the subventricular zone (SVZ), at the time when the canonical Wnt signaling induces cell differentiation. Analysis of mouse brains electroporated with Hipk1, and the active form of ß-Catenin reveals that coexpression of both genes induces proliferating neural stem/progenitor cells to escape the cell cycle. Moreover, in SVZ derive neurospheres cultures, the overexpression of both genes increases the expression of the cell-cycle inhibitor P16Ink4. Therefore, our data confirm that the ß-Catenin signaling plays a dual role in controlling cell proliferation/differentiation in the brain and indicate that Hipk1 is the crucial interactor able to revert the outcome of ß-Catenin signaling in neural stem/progenitor cells of adult germinal niches.

In vivo fate analysis reveals the multipotent and self-renewal features of embryonic AspM expressing cells.

Radial Glia (RG) cells constitute the major population of neural progenitors of the mouse developing brain. These cells are located in the ventricular zone (VZ) of the cerebral cortex and during neurogenesis they support the generation of cortical neurons. Later on, during brain maturation, RG cells give raise to glial cells and supply the adult mouse brain of Neural Stem Cells (NSC). Here we used a novel transgenic mouse line expressing the CreER(T2) under the control of AspM promoter to monitor the progeny of an early cohort of RG cells during neurogenesis and in the post natal brain. Long term fate mapping experiments demonstrated that AspM-expressing RG cells are multi-potent, as they can generate neurons, astrocytes and oligodendrocytes of the adult mouse brain. Furthermore, AspM descendants give also rise to proliferating progenitors in germinal niches of both developing and post natal brains. In the latter--i.e. the Sub Ventricular Zone--AspM descendants acquired several feature of neural stem cells, including the capability to generate neurospheres in vitro. We also performed the selective killing of these early progenitors by using a Nestin-GFP(flox)-TK allele. The forebrain specific loss of early AspM expressing cells caused the elimination of most of the proliferating cells of brain, a severe derangement of the ventricular zone architecture, and the impairment of the cortical lamination. We further demonstrated that AspM is expressed by proliferating cells of the adult mouse SVZ that can generate neuroblasts fated to become olfactory bulb neurons.

Cxcl10 enhances blood cells migration in the sub-ventricular zone of mice affected by experimental autoimmune encephalomyelitis.

The peri-ventricular area of the forebrain constitutes a preferential site of inflammation in multiple sclerosis, and the sub-ventricular zone (SvZ) is functionally altered in its animal model experimental autoimmune encephalomyelitis (EAE). The reasons for this preferential localization are still poorly understood. We show here that, in EAE mice, blood-derived macrophages, T and B cells and microglia (Mg) from the surrounding parenchyma preferentially accumulate within the SvZ, deranging its cytoarchitecture. We found that the chemokine Cxcl10 is constitutively expressed by a subset of cells within the SvZ, constituting a primary chemo-attractant signal for activated T cells. During EAE, T cells and macrophages infiltrating the SvZ in turn secrete pro-inflammatory cytokines such as TNFalpha and IFNgamma capable to induce Mg cells accumulation and SvZ derangement. Accordingly, lentiviral-mediated over-expression of IFNgamma or TNFalpha in the healthy SvZ mimics Mg/microglia recruitment occurring during EAE, while Cxcl10 over-expression in the SvZ is able to increase the frequency of peri-ventricular inflammatory lesions only in EAE mice. Finally, we show, by RT-PCR and in situ hybridization, that Cxcl10 is expressed also in the healthy human SvZ, suggesting a possible molecular parallelism between multiple sclerosis and EAE.

RFX-1, a putative alpha Adducin interacting protein in a human kidney library.

Adducin regulates tubular absorption of sodium by modulating the expression levels of the sodium-potassium-ATPase in renal tubular cells. Adducin is a candidate gene in the pathogenesis of hypertension. Yeast two hybrid screen showed a specific interaction between human alpha Adducin and the regulatory factor for X box (RFX-1), a nuclear protein that down regulates the expression of several proteins in non neuronal cells. The interaction was confirmed in cells through co-immunoprecipitation and colocalization experiments. The binding of alpha Adducin to RFX-I and their nuclear co-localization suggests that Adducin can have a role in modulating the transcriptional regulating activity of RFX-I.