Risk Acceptance in Multiple Sclerosis Patients on Natalizumab Treatment

Objective: We aimed to investigate the ability of natalizumab (NTZ)-treated patients to assume treatment-associated risks and the factors involved in such risk acceptance.Methods: From a total of 185 patients, 114 patients on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits' scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ patients were split into subgroups (A-E), depending on their individual PML risk. Some 22 MS patients on first-line drugs (DMD) acted as controls.Results: No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p<0.01). Perception of the own disease as a more severe condition tended to predict higher RAS (p=0.07). Higher neuroticism scores predicted higher RAS in the NTZ group as a whole (p=0.04), and in high PML-risk subgroups (A-B) (p=0.02). in low PML-risk subgroups (C-E), higher RAS were associated with a JCV+ status (p=0.01). Neither disability scores nor pre-treatment relapse rate predicted RAS in either group.Conclusions: Risk acceptance is a multifactorial phenomenon, which might be partly explained by an adaptive process, in light of the higher risk acceptance amongst NTZ-treated patients and, especially, amongst those who are JCV seropositive but still have low PML risk, but which seems also intimately related to personality traits.Bayer Health CareMerck SeronoTEVAVall dHebron Univ Hosp, Dept Neurol Neuroimmunol, Multiple Sclerosis Ctr Catalonia Cemcat, Barcelona, SpainUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, São Paulo, BrazilUniv Hosp Principe de Asturias, Dept Neurol, Madrid, SpainUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, São Paulo, BrazilWeb of Scienc

Assessment of automatic decision-support systems for detecting active T2 lesions in multiple sclerosis patients

Active (new/enlarging) T2 lesion counts are routinely used in the clinical management of multiple sclerosis. Thus, automated tools able to accurately identify active T2 lesions would be of high interest to neuroradiologists for assisting in their clinical activity. To compare the accuracy in detecting active T2 lesions and of radiologically active patients based on different visual and automated methods.Postprint (author's final draft

Joint QTL mapping and gene expression analysis identify positional candidate genes influencing pork quality traits

Meat quality traits have an increasing importance in the pig industry because of their strong impact on consumer acceptance. Herewith, we have combined phenotypic and microarray expression data to map loci with potential effects on five meat quality traits recorded in the longissimus dorsi (LD) and gluteus medius (GM) muscles of 350 Duroc pigs, i. e. pH at 24 hours post-mortem (pH24), electric conductivity (CE) and muscle redness (a*), lightness (L*) and yellowness (b*). We have found significant genome-wide associations for CE of LD on SSC4 (-104 Mb), SSC5 (-15 Mb) and SSC13 (-137 Mb), while several additional regions were signifcantly associated with meat quality traits at the chromosome-wide level. There was a low positional concordance between the associatlons found for LD and GM traits, a feature that refiects the existence of differences in the genetic determinism of meat quality phenotypes in these two muscles. The performance of an eQTL search for SNPs mapping to the regions associated with meat quality traits demonstrated that the GM a* SSC3 and pH24 SSC17 QTL display positional concordance with cis-eQTL regulating the expression of several genes with a potential role on muscle metabolism

Expression patterns and genetic variation of the ovine skeletal muscle transcriptome of sheep from five Spanish meat breeds

The goal of the current study is to analyse the gene expression profile of the ovine skeletal muscle as well as to characterize the genetic variation of transcripts expressed in such tissue. This aim has been achieved by sequencing the longissimus dorsi transcriptomes of 50 sheep distributed in five pools representing the Canaria de Pelo, Roja Mallorquina, Gallega, Xisqueta and Ripollesa Spanish autochthonous breeds. Approximately, 363 million reads per pool have been produced and 71.9-82.9% have been successfully mapped to the ovine genome in a paired-end mode (2 X 75 bp). The 200 most expressed muscle transcripts (-1% of the total transcript count) account for 51% (Canaria de Pelo) to 67% (Gallega) of the total ovine skeletal muscle mRNA expression. These highly expressed genes play key roles in pathways related with striated muscle contraction, gluconeogenesis, glycolysis, citric acid cycle and respiratory electron transport. RNA-Sequencing of muscle transcripts has also revealed that -72% of the SNPs detected with this approach are shared by at least two pools, and 10% of them segregate in the five pools under analysis. Most of the substitutions detected by RNA-Seq are synonymous or missense and only a minority are predicted to have consequences on protein function

Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course

BACKGROUND: It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients. METHODS: MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies. RESULTS: By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0.05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0.05). In addition, a trend for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes and macrophages/microglial cells, and expression of CPXM2 and NLRP9 restricted to brain macrophages/microglia. CONCLUSIONS: Genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis

Estudio del efecto de pseudoatrofia cerebral en pacientes con esclerosis múltiple remitente-recurrente

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018La esclerosis múltiple (EM) es una enfermedad crónica, inmunomediada y degenerativa que afecta principalmente a adulto jóvenes, siendo la segunda causa de discapacidad neurológica en esas edades. De forma temprana, los pacientes con EM presentan una pérdida de volumen cerebral (VC) que se ha relacionado con el grado de discapacidad concurrente así como con el que ocurrirá durante el seguimiento. La mayoría de los tratamientos aprobados hoy en día para el manejo de la enfermedad, han demostrado poseer un efecto beneficioso sobre la pérdida de VC. Sin embargo, en algunos casos no se han podido demostrar diferencias significativas, especialmente durante los primeros meses tras el inicio del tratamiento. En este sentido, es importante tener en cuenta que la presencia de inflamación debida a la enfermedad, tiene un impacto sobre la medida de VC. Los pacientes que inician un tratamiento, ya sea en contexto de un ensayo clínico o en la práctica clínica habitual, suelen ser pacientes con importante actividad clínica (en forma de brotes) y radiológica (con lesiones que realzan tras la administración de gadolinio en la RM cerebral). La resolución de esta inflamación dará lugar una pérdida de VC inicial más acelerada durante los primeros meses de tratamiento; este fenómeno se ha descrito como el efecto de pseudoatrofia. Este proyecto de tesis doctoral se centra en el estudio y conocimiento del efecto de pseudoatrofia cerebral en los pacientes que inician tratamiento con natalizumab e interferón beta, con el objetivo último de comprender mejor la dinámica del cambio de VC en estas circunstancias y poder ofrecer mejores herramientas de monitorización clínica y radiológica a nuestros pacientes. La principal hipótesis de trabajo de la tesis doctoral fue que el cambio de VC que ocurre durante el primer año de tratamiento con natalizumab e interferón beta se relacionará con la presencia de actividad inflamatoria basal o pre-tratamiento. Además, el cambio de volumen cerebral observado durante el primer año de tratamiento con natalizumab e interferón beta, afectará de forma diferente a la sustancia gris y sustancia blanca cerebral, especialmente en los pacientes con presencia de actividad inflamatoria basal o pre-tratamiento. Con estas hipótesis de trabajo estudiamos dos cohortes de pacientes que iniciaron tratamiento en nuestro centro y de los que disponíamos de resonancia magnéticas (RM) previas y un año después del inicio de tratamiento con natalizumab e interferón beta. Mediante el programa informático Statistical Parametric Mapping (SPM) y Structural Image Evaluation, using Normalization, of Atrophy (SIENA) obtuvimos medidas de cambio de VC global, cambio de sustancia gris y cambio de sustancia blanca cerebral. Analizamos las asociaciones entre la presencia de actividad inflamatoria basal (definida por el número de lesiones que realzan con gadolinio en la RM cerebral basal) mediante las pruebas estadísticos apropiados. Los principales hallazgos de esta tesis doctoral se pueden resumir de la siguiente manera: la pérdida de VC global y de sustancia blanca cerebral, pero no de sustancia gris cerebral, durante el primer año de tratamiento se ve afectada por la presencia de actividad inflamatoria previa al inicio del tratamiento con natalizumab e interferón beta. Esta tesis doctoral pone de manifiesto por tanto, que parte de la pérdida de VC que ocurre durante los primeros meses tras el inicio de tratamiento inmunomodulador con natalizumab e interferón beta es debida a una resolución de la inflamación que está presente en el momento del inicio del tratamiento y que ocurre principalmente por una pérdida de sustancia blanca cerebral. Por tanto, la presencia de actividad inflamatoria a nivel basal debe tomarse en cuenta en los estudios que quieran evaluar asociaciones clínico-radiológicas en pacientes con EM que inician tratamiento inmunomodulador.Multiple sclerosis (MS) is a chronic, immune-mediated and degenerative disease that primarily affects young adults. It is the second cause of neurological disability in this age group. Brain volume (BV) loss is known to occur since very early stages of the disease and it has been related to relevant clinical outcomes such as neurological disability. Most of the treatments currently approved for the management of the disease, have demonstrated a beneficial effect on BV loss. However, in some cases significant differences could have not been demonstrated, especially during the first few months after treatment onset. In this regard, it is important to note that the presence of inflammation due to the disease could have an impact on the extent of BV loss. Patients starting treatment usually present with significant clinical (relapses) and radiological (gadolinium-enhancing lesions) disease activity. The resolution of this inflammation will result in a more rapid loss of initial BV during the first months of treatment; this phenomenon has been described as the pseudoatrophy effect. This doctoral thesis focuses on the study and knowledge of the pseudoatrophy effect in patients starting treatment with natalizumab and interferon beta, in order to better understand the dynamics of BV loss in these circumstances and to offer better tools for monitoring our patients. The main hypothesis was that the BV loss occurring during the first year of treatment with natalizumab and interferon beta would relate with baseline inflammatory disease activity. In addition, BV loss occurring during the first year of treatment with natalizumab and interferon beta, will affect differently grey and white matter, especially in patients with baseline inflammatory disease activity. With these assumptions we studied two cohorts of patients who started treatment in our centre and that had amenable brain magnetic resonance imaging (MRI) at baseline and one year after treatment onset with natalizumab and interferon beta for volumetric analysis. Statistical Parametric Mapping software (SPM) and Structural Image Evaluation, using Normalization, of Atrophy (SIENA) were used to obtain measures of global BV change, grey matter change, and white matter change. We analysed the associations between the presence of baseline inflammatory disease activity (defined by the number of gadolinium-enhancing lesions) using the appropriate statistical tests. The main findings of this thesis can be summarized as follows: global BV loss and white matter change during the first year of treatment is related to the presence of baseline disease activity. Grey matter volume loss during the first year of treatment is independent of baseline disease activity. This doctoral thesis shows that part of the BV loss occurring during the first months after natalizumab and interferon beta treatment onset is due to a resolution of baseline inflammation and that it is mainly due a white matter volume loss. The presence of baseline disease activity should be taken into account when clinic-radiological associations want to be studied in these setting

CSF Chitinase 3–Like 2 Is Associated With Long-term Disability Progression in Patients With Progressive Multiple Sclerosis

Objective: This study aimed to identify long-term prognostic protein biomarkers associated with disease progression in patients with progressive multiple sclerosis (MS). Methods: CSF samples were collected from a discovery cohort of 28 patients with progressive MS who participated in a clinical trial with interferon beta. Patients were classified into high and low disability progression phenotypes according to numeric progression rates (NPR) and step-based progression rates (SPR) after a mean follow-up time of 12 years. Protein abundance was measured by shotgun proteomics. Selected proteins from the discovery cohort were quantified by parallel reaction monitoring in CSF samples from an independent validation cohort of 41 patients with progressive MS classified also into high and low disability progression phenotypes after a mean follow-up time of 7 years. Results: Of 2,548 CSF proteins identified in the discovery cohort, 10 were selected for validation based on their association with long-term disability progression: SPATS2-like protein, chitinase 3-like 2 (CHI3L2), plasma serine protease inhibitor, metallothionein-3, phospholipase D4, beta-hexosaminidase, neurexophilin-1, adipocyte enhancer-binding protein 1, cathepsin L1, and lipopolysaccharide-binding protein. Only CHI3L2 was validated, and patients with high disability progression exhibited significantly higher CSF protein levels compared with patients with low disability progression (p = 0.03 for NPR and p = 0.02 for SPR). CHI3L2 levels showed good performance to discriminate between high and low disability progression in patients with progressive MS (area under the curve 0.73; sensitivity 90% and specificity 63%). Conclusions: Although further confirmatory studies are needed, we propose CSF CHI3L2 as a prognostic protein biomarker associated with long-term disability progression in patients with progressive MS

Cognitive impairment in multiple sclerosis: diagnosis and monitoring.

Cognitive impairment (CI) has a prevalence of 45-70% in people with multiple sclerosis (MS), producing a negative impact on their quality of life, personal life, and work. Early detection of CI has become an important aspect to be considered for an adequate follow-up, to optimize social adaptation and to implement specific cognitive rehabilitation strategies. The aim of this work is to propose a suitable cognitive evaluation of patients with MS based on available and efficient tools for diagnosis and monitoring purposes well supported by literature review and clinical experience. A multidisciplinary panel of professionals from the field of neurology, neuropsychology, and neuroimaging performed a literature review of the topic of cognitive impairment assessment. This was combined and completed with their clinical experience to produce a set of recommendations. Some limitations to cognitive evaluation are described: shortage of time and resources during the neurology consultation, scarceness or absence of specialized professionals' availability, importance of tests adaptation, and doubts about its use to define therapeutic efficiency. We recommend a baseline and annual screening evaluation, and we suggest a baseline and periodic neuropsychological assessment. The latter ought to change to a recommendation with the presence of either positive screening test, or subjective to cognitive complaints, screening-test results and patient or family report mismatch, or in specific social/work situations. Cognitive evaluation should be performed on all patients diagnosed with MS and throughout follow-up. It is necessary to support the creation of multidisciplinary MS teams to optimize the evaluation and follow-up of MS patients

Joint QTL mapping and gene expression analysis identify positional candidate genes influencing pork quality traits

Meat quality traits have an increasing importance in the pig industry because of their strong impact on consumer acceptance. Herewith, we have combined phenotypic and microarray expression data to map loci with potential effects on five meat quality traits recorded in the longissimus dorsi (LD) and gluteus medius (GM) muscles of 350 Duroc pigs, i. e. pH at 24 hours post-mortem (pH24), electric conductivity (CE) and muscle redness (a*), lightness (L*) and yellowness (b*). We have found significant genome-wide associations for CE of LD on SSC4 (-104 Mb), SSC5 (-15 Mb) and SSC13 (-137 Mb), while several additional regions were signifcantly associated with meat quality traits at the chromosome-wide level. There was a low positional concordance between the associatlons found for LD and GM traits, a feature that refiects the existence of differences in the genetic determinism of meat quality phenotypes in these two muscles. The performance of an eQTL search for SNPs mapping to the regions associated with meat quality traits demonstrated that the GM a* SSC3 and pH24 SSC17 QTL display positional concordance with cis-eQTL regulating the expression of several genes with a potential role on muscle metabolism