Estudio del efecto del interferon b1a sobre la actividad de oxidorreducción en el tratamiento de la esclerosis múltiple remitente recidivante

Tesis descargada de TESEOEl Interferón ß (IFN) es la Droga Modificadora de la Enfermedad (DME) más ampliamente usada en la actualidad para el tratamiento de la esclerosis múltiple. Los principales beneficios de esta solo son vistos en aproximadamente del 30 al 50% de los pacientes. La determinación de la respuesta al tratamiento requiere una evaluación clínica del paciente durante un periodo de tiempo relativamente largo lo que puede significar la acumulación de discapacidad antes de que el paciente sea clasificado como no respondedor. Es por lo tanto importante que los no respondedores sean identificados de manera precoz y reciban una terapia alternativa tan pronto como sea posible. Un indicador precoz de la respuesta permitiría un uso racional de los fármacos y mejorarían el cuidado de los pacientes. Hipótesis.- Tenemos necesidad de métodos sencillos y fiables que nos indiquen, usando solo datos clínicos, si un paciente dudoso es buen respondedor o no. Desconocemos que influencia podrían tener tanto las variaciones en el ambiente de oxidorreducción como la variación de los niveles intra cerebrales in vivo de ciertas sustancias como el N Acetil Aspartato, la colina o el mioinositol tras el inicio de un tratamiento en la respuesta a largo plazo de este tratamiento así. También desconocemos la influencia de los polimorfismos genéticos en las diferentes respuestas al interferón beta que podrían suponer un instrumento de gran utilidad en la decisión de tratamiento de estos pacientes. Objetivos.- 1. Medir el efecto a largo plazo del tratamiento con interferón ß1a IM en la acumulación del daño axonal en pacientes con Esclerosis Múltiple Remitente Recidivante (EMRR) usando marcadores de oxidorreducción y Espectroscopia por Resonancia Magnética (ERM) 2. Validar los criterios clínicos de optimización de tratamiento de la Canadian Multiple Sclerosis Working Group (CMSWG) aplicándolos a una población española de pacientes con EMRR tratados inicialmente con interferón ß1a IM 3. Identificar un conjunto de genes ligados a las diferencias interindividuales en la eficacia a la terapia con Interferón Beta. Metodología.- Para responder a estas preguntas se han planteado tres estudios diferentes: 1. Estudio del efecto del interferón ß 1 a IM sobre marcadores de degeneración axonal y de oxido reducción. 2. Estudio de validación de los criterios de optimización del tratamiento de la CMSWG 3. Estudio de farmacogenómica de respuesta al Interferón ß. Conclusiones.- 1. Desde los primeros estadios de la enfermedad, los ratios NAA: Cr en SBAN determinados por ERM fueron menores en los pacientes con EM, es decir, el daño axonal es un fenomeno precoz. 2. La discapacidad de los pacientes (medida por la EDSS) se correlaciona con los niveles de NAA, un marcador de la pérdida axonal. 3. No hay correlación entre la discapacidad, cuando se utiliza el MSFC, y el NAA. 4. El hecho de que los brotes pudieran ser buenos marcadores subrrogados de la discapacidad clínica en EM sugiere que los pacientes con EM tienen probabilidades de obtener beneficio usando IFN-ß en lo que se refiere a la progresión de la discapacidad y apoya el uso de los cambios en estos marcadores como predictores de la evolución clínica durante los años siguientes. 5. El IFN beta 1 a IM no disminuyó el daño axonal en pacientes con EMRR. El ratio NAA / Cr en SBAN ha seguido disminuyendo durante el período de observación 6. Existe un grupo de pacientes que podríamos considerar buenos respondedores ya que, aunque globalmente los pacientes pierden NAA, el 30% no lo pierden o incluso lo recuperan. Este porcentaje es similar al que se comenta en estudios clínicos respecto a la respuesta del interferón. 7. Los niveles de oxidorreducción inmediatos a la introducción de la medicación inmuno moduladora pueden jugar un papel importante en la discapacidad desarrollada durante los primeros años de enfermedad y con su monitorización se podría pronosticar la respuesta al tratamiento 8. Los paciente que responden al tratamiento en las primeras etápas de la enfermedad disminuirán el estrés oxidativo con lo que dará tiempo a disminuir tanto el daño energético como el daño axonal y con la energía exedente se pondrían en marcha la remielinización y se evitaría la gliosis tardía. El fracaso de los tratamientos en la fase progresiva sería por el papel menos importante de la inflamación sino el mas preminente del daño difuso 9. Nuestros datos muestran que ROT, utilizando sólo la información clínica, son capaces de predecir si los pacientes tendran un alto nivel de actividad tanto por la tasa de brotes como en aumento de la discapacidad medida por la EDSS, con una alta sensibilidad y especificidad. Es decir, las ROT son una buena herramienta para el seguimiento de la respuesta a la DMD en pacientes con EM. 10. El programa desarrollado por nosotros es intuitivo, no requiere mucho tiempo y puede ayudar a los neurólogos a evaluar a los pacientes de manera objetiva y fácilmente. 11. Este estudio nos sugiere un grupo de marcadores que podrían estar relacionados con la respuesta al tratamiento con interferón beta en pacientes con esclerosis múltiple

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

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

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

Low-frequency atmospheric variability patterns and synoptic types linked to large floods in the lower Ebro River basin

This study analyzes the atmospheric variability that caused the largest floods affecting the town of Tortosa in the mouth of the Ebro River (northeast Iberian Peninsula). The Tortosa flood database and flood marks in the nearby town of Xerta are used to define the more relevant flooding episodes (discharges > 2900 m3s−1) of the 1600-2005 period. We explore the atmospheric variability based on low-frequency patterns and synoptic types applying a multivariable analysis to grids at sea-level pressure and geopotential at 500 hPa provided by the 20th Century V3 Reanalysis Project for the instrumental period (since 1836). Output from the Last Millennium Ensemble Project was used to analyze the sea-level pressure over the pre-instrumental period (before 1836). Our analysis includes 33 flood episodes. Four synoptic types are related to floods in Tortosa since 1836, characterized by low-pressure systems that interact with the Mediterranean warm air-mass and promote the atmosphere destabilization. Flooding in Tortosa is related to relative high values of solar activity, positive Northern Hemisphere temperature anomalies and NAO in positive phase. This indicates that the major floods are related to zonal atmospheric circulations (west to east cyclone transfer). During winter, the main impact of the floods is located at the western part of the basin, while the Pyrenean sub-basins are affected during autumn. The major finding is that similar flood behavior is detected since 1600, improving our understanding of past climates, enhancing the knowledge base for some aspects and impacts of climate change and reducing uncertainty about future outcomes

Peripheral Blood Mononuclear Cells (PBMC) Microbiome is Not Affected by Colon Microbiota in Healthy Goats

BACKGROUND: The knowledge about blood circulating microbiome and its functional relevance in healthy individuals remains limited. An assessment of changes in the circulating microbiome was performed by sequencing peripheral blood mononuclear cells (PBMC) bacterial DNA from goats supplemented or not in early life with rumen liquid transplantation. RESULTS: Most of the bacterial DNA associated to PBMC was identified predominantly as Proteobacteria (55%) followed by Firmicutes (24%), Bacteroidetes (11%) and Actinobacteria (8%). The predominant genera found in PBMC samples were Pseudomonas, Prevotella, Sphingomonas, Acinetobacter, Corynebacterium and Ruminococcus. Other genera such as Butyrivibrivio, Bifidobacterium, Dorea and Coprococcus were also present in lower proportions. Several species known as blood pathogens or others involved in gut homeostasis such as Faecalibacterium prausnitzii were also identified. However, the PBMC microbiome phylum composition differed from that in the colon of goats (P≤0.001), where Firmicutes was the predominant phylum (83%). Although, rumen liquid administration in early-life altered bacterial community structure and increased Tlr5 expression (P=0.020) in colon pointing to higher bacterial translocation, less than 8% of OTUs in colon were also observed in PBMCs. CONCLUSIONS: Data suggest that in physiological conditions, PBMC microbiome differs from and is not affected by colon gut microbiota in small ruminants. Although, further studies with larger number of animals and covering other animal tissues are required, results point to a common circulating bacterial profile on mammals being phylum Proteobacteria, and genera Pseudomonas and Prevotella the most abundants. All suggest that PBMC microbiome in healthy ruminants could be implicated in homeostatic condition. This study expands our knowledge about PBMC microbiome contribution to health in farm animals.This work was supported by grants from the Spanish Ministry of Science and Innovation (MCI) co-financed with FEDER funds [AGL2017-86757- to LA, AGL2017-86938-R to DRY]. Other contributions were SAF2015-65327-R to JA and SAF2015-73549-JIN to HR. LA is a Ramón y Cajal fellow [RYC-2013-13666] from the Spanish Ministry of Science and Innovation. APC is a recipient of a fellowship from the University of the Basque Country. We thank the MCI for the Severo Ochoa Excellence accreditation (SEV-2016-0644) and the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs

Mitochondrial complex I dysfunction alters the balance of soluble and membrane-bound TNF during chronic experimental colitis.

Inflammatory bowel disease (IBD) is a complex, chronic, relapsing and heterogeneous disease induced by environmental, genomic, microbial and immunological factors. MCJ is a mitochondrial protein that regulates the metabolic status of macrophages and their response to translocated bacteria. Previously, an acute murine model of DSS-induced colitis showed increased disease severity due to MCJ deficiency. Unexpectedly, we now show that MCJ-deficient mice have augmented tumor necrosis factor alpha converting enzyme (TACE) activity in the context of chronic inflammation. This adaptative change likely affects the balance between soluble and transmembrane TNF and supports the association of the soluble form and a milder phenotype. Interestingly, the general shifts in microbial composition previously observed during acute inflammation were absent in the chronic model of inflammation in MCJ-deficient mice. However, the lack of the mitochondrial protein resulted in increased alpha diversity and the reduction in critical microbial members associated with inflammation, such as Ruminococcus gnavus, which could be associated with TACE activity. These results provide evidence of the dynamic metabolic adaptation of the colon tissue to chronic inflammatory changes mediated by the control of mitochondrial function

Survival of patients receiving a liver transplant for hepatocellular carcinoma, and risk of tumor recurrence

Objective: the goal of this research has been to evaluate the survival, in long and short term, of the patient receiving liver transplant for hepatocellular carcinoma (HCC), the risk of posttransplant tumor relapse and factors related to this complication. Design: retrospective study of a consecutive series of patients having had liver transplant for HCC. Patients and methodology: transplant patients for HCC from 1989 to November 2003. Patients were selected due to general limitations of nodule size and quantity, which were subsequently published as Milan criteria. Also, criteria agreed in the Conference of Barcelona were followed in the pre-transplant diagnosis. Results: the survival of this 81 patients group was of the 80, 61 and 52% for 1, 5 and 10 years respectively. In the 32% of the cases the HCC was an incidental finding in the explant. In the 12.3%, the tumor relapse was verified. The multivariate research identified the size of the nodule (OR = 1,7944) (IC 95% = 1,1332-2,8413) and the vascular invasion (OR = 6,6346) (IC 95% = 1,4624-30,1003) as risk factors of relapse. Conclusions: the liver transplant in selected patients with HCC has good results in medium and long term. The risk of post-transplant tumor relapse becomes notably reduced and is associated with the size of the nodule and the microscopic vascular invasion

Incorporating Breast Asymmetry Studies into CADx Systems

Breast cancer is one of the global leading causes of death among women, and an early detection is of uttermost importance to reduce mortality rates. Screening mammograms, in which radiologists rely only on their eyesight, are one of the most used early detection methods. However, characteristics, such as the asymmetry between breasts, a feature that could be very difficult to visually quantize, is key to breast cancer detection. Due to the highly heterogeneous and deformable structure of the breast itself, incorporating asymmetry measurements into an automated detection system is still a challenge. In this study, we proposed the use of a bilateral registration algorithm as an effective way to automatically measure mirror asymmetry. Furthermore, this information was fed to a machine learning algorithm to improve the accuracy of the model. In this study, 449 subjects (197 with calcifications, 207 with masses, and 45 healthy subjects) from a public database were used to train and evaluate the proposed methodology. Using this procedure, we were able to independently identify subjects with calcifications (accuracy = 0.825, AUC = 0.882) and masses (accuracy = 0.698, AUC = 0.807) from healthy subjects

Genome-Wide Association Study of Multiple Sclerosis Confirms a Novel Locus at 5p13.1

Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80–0.89; p = 1.36×10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS