Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study

Background Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures. Go to: Patients and methods In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded. Go to: Results Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy. Conclusion Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique

Retest reliability of individual alpha ERD topography assessed by human electroencephalography

Background Despite the immense literature related to diverse human electroencephalographic (EEG) parameters, very few studies have focused on the reliability of these measures. Some of the most studied components (i.e., P3 or MMN) have received more attention regarding the stability of their main parameters, such as latency, amplitude or topography. However, spectral modulations have not been as extensively evaluated considering that different analysis methods are available. The main aim of the present study is to assess the reliability of the latency, amplitude and topography of event-related desynchronization (ERD) for the alpha band (10–14 Hz) observed in a cognitive task (visual oddball). Topography reliability was analysed at different levels (for the group, within-subjects individually and between-subjects individually). Results The latency for alpha ERD showed stable behaviour between two sessions, and the amplitude exhibited an increment (more negative) in the second session. Alpha ERD topography exhibited a high correlation score between sessions at the group level (r = 0.903, p<0.001). The mean value for within-subject correlations was 0.750 (with a range from 0.391 to 0.954). Regarding between-subject topography comparisons, some subjects showed a highly specific topography, whereas other subjects showed topographies that were more similar to those of other subjects. Conclusion ERD was mainly stable between the two sessions with the exception of amplitude, which exhibited an increment in the second session. Topography exhibits excellent reliability at the group level; however, it exhibits highly heterogeneous behaviour at the individual level. Considering that the P3 was previously evaluated for this group of subjects, a direct comparison of the correlation scores was possible, and it showed that the ERD component is less reliable in individual topography than in the ERP component (P3).Ministerio de Economía y Competitividad (España) PSI2016-78133-PAsociación Sanitaria Virgen Macaren

Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS

Objective: Several factors influence the clinical course of autoimmune inflammatory diseases such as MS and inflammatory bowel disease. Only recently, the complex interaction between the gut microbiome, dietary factors, and metabolism has started to be appreciated with regard to its potential to modulate acute and chronic inflammation. One of the molecular sensors that mediates the effects of these environmental signals on the immune response is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with key functions in immune cells. Methods: In this study, we analyzed the levels of AHR agonists in serum samples from patients with MS and healthy controls in a case-control study. Results: We detected a global decrease of circulating AHR agonists in relapsing-remitting MS patients as compared to controls. However, during acute CNS inflammation in clinically isolated syndrome or active MS, we measured increased AHR agonistic activity. Moreover, AHR ligand levels in patients with benign MS with relatively mild clinical impairment despite longstanding disease were unaltered as compared to healthy controls. Conclusions: Collectively, these data suggest that AHR agonists in serum are dynamically modulated during the course of MS. These findings may guide the development of biomarkers to monitor disease activity as well as the design of novel therapeutic interventions for MSInstituto de Salud Carlos III, Unión Europea PT13/0010/004

Genotypic identification of an undescribed spotted fever group rickettsia in ixodes ricinus from southwestern Spain

An undescribed rickettsia was directly analyzed with specific rickettsial molecular biology tools on Ixodes ricinus L. collected in different localities of the province of Cadiz (southwestern Spain). On the basis of the results of the citrate synthase (glta) gene, 190 kD-outer membrane protein (rOmpA) gene, and 16S ribosomal RNA (16S rRNA) gene partial sequence data, it was found that this rickettsia is sufficiently genetically distinct from other Rickettsia to be considered a distinct taxonomic entity. The isolation and culture of this organism, as well as comparative antigenic analysis, are required to ensure its conclusive taxonomic placement among spotted fever rickettsiae. The epidemiologic role of this new rickettsial agent and its possible pathogenicity to wild and domestic animals or humans is still unknown and needs to be investigated

Effectiveness of Dry Needling versus Placebo on Gait Performance, Spasticity, Electromyographic Activity, Pain, Range-of-Movement and Quality of Life in Patients with Multiple Sclerosis: A Randomized Controlled Trial Protocol

Dry needling (DN) is an emerging technique commonly used in neurological and musculoskeletal pain conditions, but there have been no previous studies in patients with multiple sclerosis (pwMS). This trial aims to assess the efficacy of deep DN, compared with sham placebo DN, on gait performance, spasticity level, pain, electromyographic activity, range-of-movement (ROM) and quality of life in pwMS. Forty adults with MS were randomly assigned to one study group. The DN group will undergo 2 sessions (once per week) using DN over the rectus femoris (RF) and gastrocnemius medialis (GM) muscles at the lower extremity with higher spasticity. The placebo group will receive the same protocol using a sham placebo needle (Dong Bang needle). Outcome measures will include gait performance, using the GaitRite(R) system, spasticity level with the Modified Ashworth Scale, superficial electromyographic activity of RF and GM, pain (pressure algometer), ROM (goniometer), and quality of life (Musiqol). This study is the first investigating the short-term effect of DN, compared with placebo, in pwMS, and taking into account the possible changes in the electromyographic activity of the lower limb. Therefore, the results may help to understand the suitability of using this technique in the clinical setting for this population. Trial registration: ACTRN12619000880145

Neural correlates of alerting and orienting impairment in multiple sclerosis patients

Background A considerable percentage of multiple sclerosis patients have attentional impairment, but understanding its neurophysiological basis remains a challenge. The Attention Network Test allows 3 attentional networks to be studied. Previous behavioural studies using this test have shown that the alerting network is impaired in multiple sclerosis. The aim of this study was to identify neurophysiological indexes of the attention impairment in relapsing-remitting multiple sclerosis patients using this test. Results After general slowing had been removed in patients group to isolate the effects of each condition, some behavioral differences between them were obtained. About Contingent Negative Variation, a statistically significant decrement were found in the amplitude for Central and Spatial Cue Conditions for patient group (p<0.05). ANOVAs showed for the patient group a significant latency delay for P1 and N1 components (p<0.05) and a decrease of P3 amplitude for congruent and incongruent stimuli (p<0.01). With regard to correlation analysis, PASAT-3s and SDMT showed significant correlations with behavioral measures of the Attention Network Test (p<0.01) and an ERP parameter (CNV amplitude). Conclusions Behavioral data are highly correlated with the neuropsychological scores and show that the alerting and orienting mechanisms in the patient group were impaired. Reduced amplitude for the Contingent Negative Variation in the patient group suggests that this component could be a physiological marker related to the alerting and orienting impairment in relapsing-remitting multiple sclerosis. P1 and N1 delayed latencies are evidence of the demyelination process that causes impairment in the first steps of the visual sensory processing. Lastly, P3 amplitude shows a general decrease for the pathological group probably indexing a more central impairment. These results suggest that the Attention Network Test give evidence of multiple levels of attention impairment, which could help in the assessment and treatment of relapsing-remitting multiple sclerosis patients.Ministerio de Economía y Competitividad de España PSI2010-16825Asociación NeuroinvestAsociación Sanitaria Virgen Macaren

Retest reliability of individual P3 topography assessed by high density electroencephalography

Background Some controversy remains about the potential applicability of cognitive potentials for evaluating the cerebral activity associated with cognitive capacity. A fundamental requirement is that these neurophysiological parameters show a high level of stability over time. Previous studies have shown that the reliability of diverse parameters of the P3 component (latency and amplitude) ranges between moderate and high. However, few studies have paid attention to the retest reliability of the P3 topography in groups or individuals. Considering that changes in P3 topography have been related to different pathologies and healthy aging, the main objective of this article was to evaluate in a longitudinal study (two sessions) the reliability of P3 topography in a group and at the individual level. Results The correlation between sessions for P3 topography in the grand average of groups was high (r = 0.977, p<0.001). The within-subject correlation values ranged from 0.626 to 0.981 (mean: 0.888). In the between-subjects topography comparisons, the correlation was always lower for comparisons between different subjects than for within-subjects correlations in the first session but not in the second session. Conclusions The present study shows that P3 topography is highly reliable for group analysis (comprising the same subjects) in different sessions. The results also confirmed that retest reliability for individual P3 maps is suitable for follow-up studies for a particular subject. Moreover, P3 topography appears to be a specific marker considering that the between-subjects correlations were lower than the within-subject correlations. However, P3 topography appears more similar between subjects in the second session, demonstrating that is modulated by experience. Possible clinical applications of all these results are discussed.Ministerio de Economía de España SEJ2007-6534

Psychometric properties of a revised Spanish 20-item Toronto Alexithymia Scale adaptation in multiple sclerosis patients

There have been a small number of investigations of alexithymia in multiple sclerosis (MS) using the 20-item Toronto Alexithymia Scale (TAS-20). However, the TAS-20 factor structure has not yet been evaluated in a MS patient sample, and earlier Spanish translations of this instrument require some improvement. We aimed to evaluate the factorial validity and reliability of an improved Spanish translation of the TAS-20 (the TAS-20-S). The TAS-20-S was completed by 221 MS patients. Confirmatory factor analysis was used to compare the fit of six different factor models. Internal consistency and retest reliability coefficients were also computed. The correlated three-factor model and the higher-order factor model made up of Difficulty Identifying Feelings, Difficulty Describing Feelings, and Externally Oriented Thinking achieved the best fit. Alpha coefficients ranged between .87 and .67; mean inter-item correlations ranged between .48 and .20; and retest correlations after 6 months ranged between .61 and .52. A high degree of alexithymia was present in 18.1% of the sample. Reliability and the traditional three-factor structure were demonstrated for the TAS-20-S, which can now be recommended for assessing an aspect of emotional processing in MS patients.En la esclerosis múltiple (EM) son escasas las investigaciones centradas en evaluar la alexitimia con la Escala de Alexitimia de Toronto (TAS-20). A pesar de ello, no se ha evaluado aún su estructura factorial en dicha población y, además, las anteriores traducciones al español necesitan modificaciones. Los objetivos del presente estudio fueron evaluar la validez factorial y la fiabilidad de una traducción mejorada en español de la TAS-20 (la TAS-20-S), la cual fue administrada en una muestra de 221 pacientes con EM. Se realizaron análisis factoriales confirmatorios para comparar el ajuste de seis modelos factoriales. También se calcularon coeficientes de consistencia interna y de fiabilidad test-retest. Los modelos trifactorial correlacionado y el de orden superior conformados por Dificultad en Identificar Sentimientos, Dificultad en Describir Sentimientos y Pensamiento Externamente Orientado lograron el mejor ajuste. Los coeficientes alfa oscilaron entre 0,87 y 0,67; las correlaciones medias inter-ítem entre 0,48 y 0,20; y las correlaciones test-retest tras 6 meses oscilaron entre 0,61 y 0,52. El 18,10% de la muestra presentó niveles elevados de alexitimia. La TAS-20-S presentó una adecuada fiabilidad así como la tradicional estructura trifactorial, por lo que su uso es ahora recomendable para evaluar un aspecto del procesamiento emocional en EM.Ministerio de Educación, Cultura y Deporte de España Programa FPU (Formación del Profesorado Universitario

Disentangling the attention network test: behavioral, event related potentials, and neural source analyses

Background: The study of the attentional system remains a challenge for current neuroscience. The “Attention Network Test” (ANT) was designed to study simultaneously three different attentional networks (alerting, orienting, and executive) based in subtraction of different experimental conditions. However, some studies recommend caution with these calculations due to the interactions between the attentional networks. In particular, it is highly relevant that several interpretations about attentional impairment have arisen from these calculations in diverse pathologies. Event related potentials (ERPs) and neural source analysis can be applied to disentangle the relationships between these attentional networks not specifically shown by behavioral measures. Results: This study shows that there is a basic level of alerting (tonic alerting) in the no cue (NC) condition, represented by a slow negative trend in the ERP trace prior to the onset of the target stimuli. A progressive increase in the CNV amplitude related to the amount of information provided by the cue conditions is also shown. Neural source analysis reveals specific modulations of the CNV related to a task-related expectancy presented in the NC condition; a late modulation triggered by the central cue (CC) condition and probably representing a generic motor preparation; and an early and late modulation for spatial cue (SC) condition suggesting specific motor and sensory preactivation. Finally, the first component in the information processing of the target stimuli modulated by the interaction between orienting network and the executive system can be represented by N1. Conclusions: The ANT is useful as a paradigm to study specific attentional mechanisms and their interactions. However, calculation of network effects is based in subtractions with non-comparable experimental conditions, as evidenced by the present data, which can induce misinterpretations in the study of the attentional capacity in human subjects.Ministerio de Economía y Competitividad PSI2010- 1682