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1. The ultimate aim of this research was to find an inexpensive biochemical method for the production of Normal Butyric Acid from Blackstrap. 2. A native organism was found and isolated in pure culture which proved admirably adapted to this purpose. 3. Difficulties experienced by previous investigators were obviated in the course of the above described work. 4. The process is simple, inexpensive, and merits further efforts towards its industrial application and commercial exploitation. 5. The main end product of fermentation (Normal Butyric Acid) is obtained in nearly theoretical yield, and of a splendid degree of purity: 99 percent or better. 6. It is the writer's intention to apply for patent rights protection for his discovery and process.

Objectives1. To analyze the prevalence and levels of anti-EBNA-1 and anti-VCA IgG antibodies of Epstein-Barr virus (EBV) in a Spanish cohort of multiple sclerosis (MS) patients and their interactions with other environmental and genetic risk factors. 2. To analyze the association of the evolution of these antibodies with the clinical response to different disease modifying therapies (DMTs) after two-years of follow-up. 3. To assess their possible correlation with the class II HLA alleles as well as with several SNPs identified in GWAS related to disease susceptibility.Materials and methodsWe recruited 325 MS patients without DMT (serum samples were collected 1-3 months before starting a therapy) and 295 healthy controls (HC). For each patient we also collected serum samples 6, 12, 18 and 24 months after starting the DMT. EBNA-1 and VCA IgG titers were analyzed by ELISA; 25(OH)D levels were analyzed by immunoassay; HLA DRB1*15:01 allelic variant was analyzed by Taqman technology.Results1. 97.8% (318/325) vs. 87.1% (257/295) positives for EBNA-1 in MS patients and HC, respectively (pConclusionsThese results confirm that MS occurs rarely in absence of EBV. An intriguing association between genetic burden and lower EBNA-1 IgG titers was associated with an earlier age of disease onset. Similar studies with B-cell–targeted therapies should be performed.

Background Patient-reported outcomes are increasingly used in the management of patients with multiple sclerosis to understand the patient's perspective of disease and treatment. These measures provide insights into important factors including treatment satisfaction, physical and psychological function, and quality of life. Objective To present results from the real-world PRO-ACT study in patients with multiple sclerosis who switched to alemtuzumab from another disease-modifying therapy. Methods This 24-month, prospective, multicenter, observational study had a primary endpoint of change in overall satisfaction, measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4. Secondary endpoints included the Multiple Sclerosis Impact Scale-29 (MSIS-29), Modified Fatigue Impact Scale-5 (MFIS-5), and the Patient-Determined Disease Steps (PDDS). Safety was monitored with adverse events (AEs). Results Of 199 enrolled patients, improvements were observed in mean TSQM scores for overall satisfaction (baseline, 50.3; year 2, + 13.2; p Conclusions The primary endpoint was met; the safety of alemtuzumab was consistent with pivotal studies.

En los últimos años comunidades ubicadas en zonas rurales de Colombia han establecido acciones encaminadas a la conservación de recursos naturales que han servido de manera indirecta como una estrategia para reducir los efectos de cambio climático a nivel local. El presente documento da a conocer algunas acciones que han realizado las comunidades de Bahía Málaga ubicadas en el Distrito de Buenaventura para reducir los niveles de deforestación en su territorio y de esta manera contribuir a la conservación y reducción de los efectos de invernadero, además de las acciones de adaptación y mitigación de dichos cambios.

Resumen: Se revisa la relación entre las teorías de Freud y Lacan, a propósito de recientes investigaciones que encuentran notables diferencias entre ellas. A través de la reflexión sobre diversos aspectos del trabajo público en salud mental, y varios ejemplos clínicos, se propone que la enseñanza de Lacan permite un psicoanálisis más acorde a la práctica actual, que en buena parte se ejerce sin las condiciones para las que Freud diseñó su método.

We developed an ELISA assay demonstrating the high prevalence of serum IgM to phosphatidylcholine (IgM-PC) in the first stages of multiple sclerosis (MS). We aimed to analyze the role of serum IgM-PC as a biomarker of response to treatment. Paired serum samples from 95 MS patients were obtained before (b.t) and after (a.t) treatment with disease modifying therapies. Patients were classified as non-responders or responders to treatment, according to classical criteria. Serum IgM-PC concentration was analyzed using our house ELISA assay. The level of serum IgM-PC b.t was higher in patients treated later with natalizumab than in those treated with Copaxone (p = 0.011) or interferon-β (p = 0.009). Responders to natalizumab showed higher concentration of serum IgM-PC b.t than those who did not respond to it (p = 0.019). The 73.3% of patients with the highest level of serum IgM-PC b.t responded to natalizumab. IgM-PC level decreased a.t in both cases, non-responders and responders to natalizumab. IgM-PC levels a.t did not decrease in non-responders to interferon-β, but in responders to it the IgM-PC level decreased (p = 0.007). Serum IgM-PC could be a biomarker of response to natalizumab or interferon-β treatment. Further studies would be necessary to validate these results.

Introduction: The detection of intrathecal IgA synthesis (IAS) in multiple sclerosis (MS) is cumbersome, for this reason, we developed a highly sensitive assay to assess it in MS. Methods: 151 MS patients and 22 controls with different neurological diseases were recruited. IgA concentration was analyzed by ELISA. Oligoclonal IgA bands to detect IAS were determined by a new ultrasensitive assay based on isoelectrofocusing (IEF). Results: Most individuals showed an IgA concentration within normal range in serum samples (95.95%) but 38.41% of individuals had a low IgA concentration in the cerebrospinal fluid (CSF), with no significant differences observed between MS and control groups, neither in CSF nor in serum. The new IEF was more sensitive than those previously described (0.01 mg/dl of IgA), and clearly identified patients with and without IAS, that was not related with IgA concentration. MS patients showed higher percentage of IAS (43.00%) than the control group (18.20) (p = 0.035), because the incidence was especially higher in MS patients with clinically isolated syndrome (CIS, 66.00%). Conclusions: Intrathecal IgA synthesis is observed more frequently in MS patients than in other neurological diseases, and with higher incidence than assumed in the past.

[Introduction] Limited information is available on people’s experiences of living with Alzheimer’s disease (AD) at earlier stages. This study assessed awareness of diagnosis among people with early-stage AD and its impact on different person-centered outcome measures., [Methods] We conducted an observational, cross-sectional study in 21 memory clinics in Spain. Persons aged 50–90 years, diagnosed with prodromal or mild AD (NIA/AA criteria), a Mini Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5 or 1.0 were recruited. The Representations and Adjustment to Dementia Index (RADIX) was used to assess participants’ beliefs about their condition and its consequences., [Results] A total of 149 persons with early-stage AD were studied. Mean (SD) age was 72.3 (7.0) years and 50.3% were female. Mean duration of AD was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1) and 87.2% had a CDR-GS score of 0.5. Most participants (n = 84, 57.5%) used a descriptive term related to specific AD symptoms (e.g., memory difficulties) when asked what they called their condition. Participants aware of their diagnosis using the term AD (n = 66, 45.2%) were younger, had more depressive symptoms, and poorer life satisfaction and quality of life compared to those without awareness of their specific diagnosis. Practical and emotional consequences RADIX scores showed a significant negative correlation with Quality of Life in Alzheimer’s Disease score (rho = − 0.389 and − 0.413, respectively; p, [Conclusions] Awareness of diagnosis was a common phenomenon in persons with early-stage AD negatively impacting their quality of life. Understanding illness representations in earlier stages may facilitate implementing optimized care that supports improved quality of life and well-being., This study was funded by the Medical Department of Roche Farma Spain (ML42346); funding sources with Life Molecular Imaging, Bioiberica, and Schwabe; and grants from CIBERNED, EU/EFPIA, Instituto de Salud Carlos III (ISCIII), Fundación La Caixa, and Grífols.

El autor expone el sistema de partidos políticos peruano que se configura a partir del gobierno de Piérola, no sin antes realizar un panorama previo al sistema entre los años 1821 y 1895. Por lo demás, se describen los esfuerzos realizados para reconstruir una alternativa con la progresiva desarticulación del civilismo y la desaparición de los grandes líderes políticos de la posguerra.

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

Background: In CARE-MS II (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved health-related quality of life (HRQL) outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients over 2 years. Patients completing CARE-MS II could enter a 4-year extension study (NCT00930553). Objective: The aim of this study is to assess 6-year HRQL outcomes in alemtuzumab-treated CARE-MS II patients, including those with highly active disease (HAD). Methods: During extension, patients could receive additional alemtuzumab for clinical/magnetic resonance imaging (MRI) activity or other disease-modifying therapies per investigator’s discretion. Assessments include Functional Assessment of Multiple Sclerosis (FAMS), 36-Item Short-Form Health Survey (SF-36), and EQ-5D visual analog scale (EQ-VAS). Results: Alemtuzumab-treated patients improved or stabilized all HRQL measures over 6 years with significant improvements from baseline at all time points on EQ-VAS and for up to 5 years on FAMS, SF-36 MCS, and SF-36 PCS. Alemtuzumab-treated patients with HAD showed significant improvements versus baseline at Year 2 on all HRQL measures, and significant improvements versus SC IFNB-1a on SF-36 PCS and EQ-VAS; however, the improvements did not reach the threshold for clinical relevance. Conclusion: Alemtuzumab-treated CARE-MS II patients improved or stabilized HRQL versus baseline over 6 years. This is the first study to show long-term HRQL benefits in patients with HAD.

Although impaired mitochondrial function has been proposed as a hallmark of multiple sclerosis (MS) disease, few studies focus on the mitochondria of immune cells. We aimed to compare the mitochondrial function of the peripheral blood mononuclear cells (PBMCs) from MS patients with (M+) and without (M−) lipid-specific oligoclonal immunoglobulin M bands (LS-OCMB), and healthydonors (HD). We conducted an exploratory cross-sectional study with 19 untreated MS patients (M+ = 9 and M− = 10) and 17 HDs. Mitochondrial superoxide anion production and mitochondrial mass in PBMCs were assessed without and with phytohemagglutinin by flow cytometry. The PBMCs’ mitochondrial function was analyzed using Seahorse technology. Superoxide anion production corrected by the mitochondrial mass was higher in MS patients compared with HDs (p = 0.011). Mitochondrial function from M+ patients showed some impairments compared with M− patients. Without stimulus, we observed higher proton leak (p = 0.041) but lower coupling efficiency (p = 0.041) in M+ patients; and under stimulation, lower metabolic potential ECAR (p = 0.011), and lower stressed OCR/ECAR in the same patients. Exclusively among M+ patients, we described a higher mitochondrial dysfunction in the oldest ones. The mitochondrial impairments found in the PBMCs from MS patients, specifically in M+ patients, could help to better understand the disease’s physiopathology.

Epstein–Barr virus (EBV), human herpesvirus 6A/B (HHV-6A/B) and multiple sclerosis (MS)-associated retrovirus (MSRV) have been described as possible MS triggers. We analysed antibody titres against EBV and HHV-6, and MSRV envelope (env) mRNA expression, in the serum of pregnant multiple sclerosis patients (P-MS) to study their possible link to the clinical activity of MS during pregnancy and postpartum and their possible role as relapse predictors. For that purpose, serum samples were collected from 71 pregnant women (50 pregnant MS and 21 pregnant healthy controls—P-HC) during pregnancy and postpartum. Relating to antibody titres, IgM antibody titres against HHV-6A/B were significantly higher in P-MS than in P-HC both in each pregnancy trimester and in the postpartum period. Moreover, IgM antibody titres against HHV-6A/B were higher in P-MS who suffered a relapse during the postpartum. Regarding MSRV env mRNA expression, the prevalence in the first trimester of pregnancy was significantly higher in P-MS who suffered relapses during pregnancy. Summing it up, high IgM antibody titres against HHV-6A/B and MSRV env mRNA expression during the first trimester of pregnancy could act as relapse predictors for the gestation/postpartum periods.

Introduction: Amimia is one of the most typical features of Parkinson's disease (PD). However, its significance and correlation with motor and nonmotor symptoms is unknown. The aim of this study is to evaluate the association between amimia and motor and nonmotor symptoms, including cognitive status, depression, and quality of life in PD patients. We also tested the blink rate as a potential tool for objectively measuring upper facial bradykinesia.Methods: We prospectively studied amimia in PD patients. Clinical evaluation was performed using the Unified Parkinson's Disease Rating Scale (UPDRS) and timed tests. Cognitive status, depression, and quality of life were assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS), the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR16), and the PDQ-39, respectively. Amimia was clinically evaluated according to item 19 of UPDRS III. Finally, we studied upper facial amimia by measuring resting blink frequency and blink rate during spontaneous conversation.Results: We included 75 patients. Amimia (item 19 UPDRS III) correlated with motor and total UPDRS (r: 0.529 and 0.551 Spearman), and its rigidity, distal bradykinesia, and motor axial subscores (r: 0.472; r: 0.252, and r: 0.508, respectively); Hoehn and Yahr scale (r: 0.392), timed tests, gait freezing, cognitive status (r: 0.29), and quality of life (r: 0.268) correlated with amimia. Blinking frequency correlated with amimia (measured with item 19 UPDRS), motor and total UPDRS.Conclusion: Amimia correlates with motor (especially axial symptoms) and cognitive situations in PD. Amimia could be a useful global marker of overall disease severity, including cognitive decline.

Oxidative stress (OS) and inflammation have been related to colorectal cancer (CRC), but the influence of the Mediterranean diet (MD) on these parameters is unknown. Therefore, the aim of this study was to determine the association between adherence to the MD and markers of OS and DNA damage in CRC patients and to study the influence of adherence to the MD on metabolic and tumor-related factors. This prospective observational study included a total of 80 patients diagnosed with CRC. Adherence to the MD was estimated by the 14-item Mediterranean Diet Adherence Screener (MEDAS) questionnaire. The levels of OS markers (catalase, glutathione peroxidase, and glutathione system in serum; 8-oxo-7′8-dihydro-2′-deoxyguanosine and F2-isoprotanes in urine) and tumor and metabolic factors were determined. A total of 51.2% of our CRC patients showed a high adherence to the MD. These patients presented decreased levels of 8-oxodG, increased GPX and HDL–cholesterol levels, and a downward trend in the GSSG/GSH ratio with respect to patients with low adherence to the MD. In addition, a high adherence to the MD was associated with a lower histological grade of the tumor and a lower presence of synchronous adenomas. We conclude that a high adherence to the MD has a protective role against metabolic and oxidative DNA damage and improves antioxidant systems in CRC patients.

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from, This study was supported by grants PI15/00513, PI18/00572, and RD17/0015 (Red Espanola de Esclerosis Multiple) from Instituto de Salud Carlos III, Ministerio de Economia y Empresa, Spain.

There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years. We analyzed the following variables at recruitment: sex, current age, age at disease onset, disease duration, EDSS, number of T2 and Gd + lesions, IgG and IgM oligoclonal bands, HLA class II (DR, DRB, DQA, DQB, and DRB1*15:01), IgG and IgM antibody titers against human herpesvirus 6 (HHV-6) and the antibody response to Epstein–Barr virus (EBV) through the measurement of the anti-EBNA-1 and anti-VCA IgG titers, in relation to clinical response (no relapses or disability progression), and to NEDA-3 (no evidence of disease activity in terms of clinical response and no changes in MRI scans either) after 2-years follow-up. Baseline EDSS score, baseline EBNA-1 IgG titers and percentage change of HHV6 IgG titers between baseline and 6 month visits were significantly different in clinical responders and in NEDA-3 status (all of them remained significant in the multivariate analysis). We identified three variables for the early identification of natalizumab optimal responders in a rapid and cost-effective approach.

Syncytin-1 is the envelope protein of the human endogenous retrovirus W (HERV-W). It has been related to multiple sclerosis (MS) but its role in cellular immunity and its pathogenic mechanism in the autoimmune context are not fully understood. We analyzed syncytin-1 levels in peripheral blood mononuclear cells (PBMC) subsets from healthy donors, MS patients in relapse or remission, and patients with acute infections by flow cytometry. PBMC cultures were also prepared to analyze protein expression kinetics. MS patients had higher levels of syncytin-1 levels than controls. We found that syncytin-1 is elevated in monocytes during MS relapses and infections. Cells expressing syncytin-1, including monocytes, T and B lymphocytes, and NKs presented mainly an activated phenotype and, upon stimulation with LPS, its levels increased rapidly on antigen-presenting cells. Syncytin-1 ligation promoted the activation of monocytes, as demonstrated by the upregulation of CD80 and the nonclassical subset CD14low CD16+ . Our results suggest an important role for syncytin-1 in the activation of leukocytes. Given that the expression of syncytin-1 is upregulated in MS patients, this protein might be contributing to the autoimmune cascade in the disease.

Background Low levels of 25-hydroxyvitamin D (25(OH)D) have been described as one of the possible environmental factors involved in multiple sclerosis (MS) etiopathogenesis. Objectives To study epidemiology of MS and 25(OH)D serum levels of patients in Lanzarote (29°02′06″N), a region with high ultraviolet radiation values during the whole year which is located far apart from Iberian Peninsula (36°–43°N), but without genetic/ethnic differences with it. Methods Incidence in Lanzarote was assessed according to McDonald 2005 criteria between January 2008 and December 2015 and prevalence date was 12/31/15. For 25(OH)D serum levels analyses, samples from 60 MS patients and 60 healthy donors (HD) were collected monthly in a one-year prospective study. Results The prevalence of MS in Lanzarote was 50.0/100,000 and the incidence per year was 2.5/100,000. Median 25(OH)D levels values were 29.1 ng/ml for MS patients (maximum = 36.1 ng/ml, minimum = 22.5 ng/ml) and 27.1 ng/ml for HD (maximum = 34.8 ng/ml, minimum = 22.8 ng/ml). There were no significant differences between 25(OH)D serum levels between MS patients and HD. Conclusions Lanzarote possesses lower prevalence and incidence values than peninsular Spain. Moreover, 25(OH)D serum levels do not differ between MS patients and HD.

Background One of the risk factor to develop progressive multifocal leukoencephalopathy (PML) among natalizumab-treated patients is the presence and high levels of anti-JCV antibodies. Our purpose was to test the association of different clinical and demographic variables with the presence and levels of anti-JCV antibodies in a Spanish cohort of multiple sclerosis (MS) patients during natalizumab treatment Materials and methods All MS patients from two hospitals with at least one measure of the anti-JCV antibodies levels (2011-2014) were recruited, among them two PML cases. Anti-JCV antibody levels were assessed using two-step ELISA Results 1061 patients (16.3% natalizumab-treated) participated in this study. The seropositivity rate of anti-JCV antibodies was 58.2%. It increased with age (pcorrected=0.00005) and was lower among HLA-DRB1*15:01 carriers (pcorrected=0.049). The two PML patients were HLA-DRB1*15:01carriers. We had at least 3 quarterly anti-JCV antibody measurements (index value) from 137 patients, whose levels did not increase during natalizumab treatment. However, 5.8% of these patients had an increase of the index value higher of one point in a maximum of 6 months, something that was more frequently observed (p=0.054) among patients treated with immunosuppressant prior to natalizumab onset Conclusions Old age and HLA-DRB1*15:01 were the factors that influence positively and negatively respectively our anti-JCV antibody prevalence, although our both PML cases were HLA-DRB1*15:01carriers. Most of our patients showed a stable anti-JCV antibody index values during natalizumab treatment. This article is protected by copyright. All rights reserved.

Although the etiology of multiple sclerosis (MS) is still unknown, it is commonly accepted that environmental factors could contribute to the disease. The objective of this study was to analyze the humoral response to Epstein-Barr virus, human herpesvirus 6A/B and cytomegalovirus, and the levels of 25-hydroxyvitamin D (25(OH)D) and the three main short-chain fatty acids (SCFA), propionate (PA), butyrate (BA) and acetate (AA), in MS patients and healthy controls (HC) to understand how they could contribute to the pathogenesis of the disease. With this purpose, we analyzed the correlations among them and with different clinical variables and a wide panel of cell subsets. We found statistically significant differences for most of the environmental factors analyzed when we compared MS patients and HC, supporting their possible involvement in the disease. The strongest correlations with the clinical variables and the cell subsets analyzed were found for 25(OH)D and SCFAs levels. A correlation was also found between 25(OH)D and PA/AA ratio, and the interaction between these factors negatively correlated with interleukin 17 (IL-17)-producing CD4+ and CD8+ T cells in untreated MS patients. Therapies that simultaneously increase vitamin D levels and modify the proportion of SCFA could be evaluated in the future.

Background Gut microbiota has been related to multiple sclerosis (MS) etiopathogenesis. Short-chain fatty acids (SCFA) are compounds derived from microbial metabolism that have a role in gut-brain axis. Objectives To analyse SCFA levels in plasma of MS patients and healthy donors (HD), and the possible link between these levels and both clinical data and immune cell populations. Methods Ninety-five MS patients and 54 HD were recruited. Patients were selected according to their score in the Expanded Disability Status Scale (EDSS) (49 EDSS ≤ 1.5, 46 EDSS ≥ 5.0). SCFA were studied in plasma samples by liquid chromatography-mass spectrometry. Peripheral blood mononuclear cells were studied by flow cytometry. Gender, age, treatments, EDSS and Multiple Sclerosis Severity Score (MSSS) were evaluated at the recruitment. Results Plasma acetate levels were higher in patients than in HD (p = 0.003). Patients with EDSS ≥ 5.0 had higher acetate levels than those with EDSS≤ 1.5 (p = 0.029), and HD (p = 2.97e–4). Acetate levels correlated with EDSS (r = 0.387; p = 1.08e–4) and MSSS (r = 0.265; p = 0.011). In untreated MS patients, acetate levels correlated inversely with CD4+ naïve T cells (r = − 0.550, p = 0.001) and directly with CD8+ IL-17+ cells (r = 0.557; p = 0.001). Conclusions Plasma acetate levels are higher in MS patients than in HD. In MS there exists a correlation between plasma acetate levels, EDSS and increased IL-17+ T cells. Future studies will elucidate the role of SCFA in the disease.

Background Gadolinium-perfusion magnetic resonance (MR) identifies gray matter abnormalities in early multiple sclerosis (MS), even in the absence of structural differences. These perfusion changes could be related to the cognitive disability of these patients, especially in the working memory. Arterial spin labeling (ASL) is a relatively recent perfusion technique that does not require intravenous contrast, making the technique especially attractive for clinical research. Purpose To verify the perfusion alterations in early MS, even in the absence of cerebral volume changes. To introduce the ASL sequence as a suitable non-invasive method in the monitoring of these patients. Material and Methods Nineteen healthy controls and 28 patients were included. The neuropsychological test EDSS and SDMT were evaluated. Cerebral blood flow and bolus arrival time were collected from the ASL study. Cerebral volume and cortical thickness were obtained from the volumetric T1 sequence. Spearman’s correlation analyzed the correlation between EDSS and SDMT tests and perfusion data. Differences were considered significant at a level of P

Multiple sclerosis (MS) is a complex disease with a heterogeneous and unpredictable clinical course. Mobility impairment after progressive paralyses and muscle tone spasticity is common. Areas covered: The prevalence, assessment, and pharmacological management of gait impairment and spasticity in MS and their effects on health-related quality of life (HRQoL) are discussed. The roles of oral and intrathecal baclofen and of delta-9-tetrahydrocannabinol/cannabidiol (THC:CBD) oromucosal spray in treating MS spasticity-related gait impairment are reviewed. Expert commentary: Mobility impairment and spasticity are experienced by approximately 90% and 80% of MS patients, respectively, during the disease course. Prevalence and severity of gait impairment and spasticity increase as disease progresses. The symptoms are related and both impact negatively on HRQoL. Oral baclofen and tizanidine are generally used for first-line treatment of MS spasticity but are ineffective in approximately 40% of cases. Second-line therapy includes add-on THC:CBD spray for patients with resistant MS spasticity. Results of studies evaluating baclofen for treating MS spasticity gait impairment are equivocal. In studies of patients with resistant MS spasticity, THC:CBD spray consistently improved the timed 10-meter walk test and significantly improved multiple spatial-temporal and kinematic gait parameters. THC:CBD oromucosal spray warrants further investigation as a treatment for MS spasticity-related gait impairment.

Objective Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti–John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML. Methods We studied 24 MS patients who developed PML and another 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited at 25 university hospitals. IgM bands were studied by isoelectric focusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited at Ramon y Cajal Hospital in Madrid, Spain. Results IgM bands were independently associated with decreased PML risk (odds ratio [OR] = 45.9, 95% confidence interval [CI] = 5.9–339.3, p

Until the mid 1990s, with the appearance of interferon beta and glatiramer acetate, there was no treatment for multiple sclerosis (MS). However, due to their moderate therapeutic potential in some patients, a broad search was continued to find new and more effective treatment strategies, largely concentrated on monoclonal antibodies (MOAB). Natalizumab, the first MOAB for the treatment of MS, was approved at the end of 2004, representing a major advance in the field of neuroimmunology. Today, there is broad experience with natalizumab and other MOAB (alemtuzumab, daclizumab, rituximab, ocrelizumab, ofatumumab and anti-lingo-1) that are pending commercialization or are under phase II or III of development with promising results. The present review analyzes the efficacy and safety results of all these drugs.

Objective To identify a biomarker distinguishing patients who, despite a primary progressive multiple sclerosis (PPMS) clinical course, may nonetheless benefit from immune therapy. Methods The presence or absence of both immunoglobulin (Ig) G and IgM oligoclonal bands (OCB) was blindly examined in paired cerebrospinal fluid (CSF) and serum samples from a large PPMS patient cohort, and related to clinical and imaging evidence of focal inflammatory disease activity. Results Using both cross-sectional samples and serial sampling in a subgroup of patients followed prospectively as part of the placebo-controlled OLYMPUS study of rituximab in PPMS, we found that the presence of CSF-restricted IgM OCB (but not of IgG OCB) is associated with an active inflammatory disease phenotype in PPMS patients. This finding was confirmed in an independent, multicenter validation cohort. Interpretation The presence of CSF IgM OCB may be a biomarker for a subset of PPMS patients with more active inflammatory disease, who may benefit from immune-directed treatments. Ann Neurol 2014;76:231–240

Background Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with a low incidence in the paediatric population; cortical atrophy is often striking, even in the early stages of the disease. Evidence of cortical thinning in childhood MS is scant. Aims This study aimed to assess cortical thickness in paediatric patients during the initial attack of remitting–relapsing MS. Methods We report two cases of remitting–relapsing MS, with initial attacks at 12 and 16 years of age. We analysed brain cortical thickness (CTh) in these patients and compared these data to the CTh of a control group comprised of six 12-year-old females and six 16-year-old males. Results Both cases exhibited a total brain CTh significantly below that of the control group. This difference was also observed when analysing the CTh of all lobes except the left parietal lobe in one of the cases. Conclusions Cortical atrophy is already present at the time of onset of MS. Studies with larger patient populations that have a more homogenous clinical presentation could identify the time of onset of cortical atrophy and use this parameter as a prognostic and/or treatment marker of MS.

BACKGROUND Balance and postural control (PC) disorders are frequent motor disorder symptoms associated with multiple sclerosis (MS). OBJECTIVE To demonstrate the potential improvements in balance and PC among patients with MS who complete a virtual reality telerehabilitation program that represents a feasible alternative to physical therapy for situations in which conventional treatment is not available. METHODS 50 patients was recruited. Control group (n = 25) received physiotherapy treatment twice a week (40 min per session). Experimental group (n = 25) received telerehabilitation treatment using the Xbox 360® console monitored via videoconference. Experimental group attended 40 sessions, four sessions per week (20 min per session). The treatment schedule lasted 10 weeks for both groups. A computerised dynamic posturography and clinical outcomes (Berg Balance and Tinettti scales) were used at baseline and at the end of the treatment. RESULTS Results showed an improvement over general balance in both groups. Visual preference, the contribution of vestibular information, mean response time and Tinetti test yielded significant differences in the experimental group. An ANOVA revealed significant between-group post-treatment differences in the composite equilibrium score, Berg and Tinetti scales in the experimental group. CONCLUSION We suggest that our virtual reality program enables anticipatory PC and response mechanisms and might serve as a successful therapeutic alternative in situations in which conventional therapy is not readily available.

Spasticity is a common symptom in multiple sclerosis (MS) that increases the burden of disease. This study investigated the relationship between the degree of spasticity and patients' health-related quality of life (QoL).Epidemiological, multicentre, cross-sectional study in patients with MS spasticity. The SF-12 questionnaire was used to assess QoL. The modified Ashworth scale and a 0-10 Numerical Rating Scale (NRS) were used to assess spasticity severity.Data were analysed for 409 MS patients with spasticity from 53 neurology clinics in Spain. Mean age was 46.4 (±11.0) years; 62.4% were women. Most patients had relapsing-remitting MS (42.1%) or secondary progressive MS (43.9%). Mean time since MS diagnosis was 12.5 (±7.4) years and mean time since first spasticity symptoms was 6.1 (±4.8) years. A total of 71.3% of patients were being treated pharmacologically for spasticity. Moderate to severe spasticity was measured in 59.2% of patients according to the modified Ashworth scale and in 83.4% according to the NRS. Mean scores for the 0-100 Physical Component Summary and Mental Component Summary subscales of the SF-12 questionnaire were 31.0 (±9.3) and 45.4 (±12.0), respectively. Scores on the SF-12 correlated significantly with scores on both spasticity scales ( p ≤ 0.002) but the correlation was stronger with the NRS across all domains.The results confirm an association between spasticity severity and QoL in patients with MS. The correlation between 0-10 NRS scores and QoL was stronger than that between modified Ashworth scale scores and QoL.

Objective: To assess patients ` preferences for a range of disease-modifying therapy (DMT) attributes in multiple sclerosis (MS). Design: A cross-sectional observational study. Setting: The data reported were from 17 MS units throughout Spain. Participants: Adult patients with relapsingremitting MS. Main outcome: A conjoint analysis was applied to assess preferences. A total of 221 patients completed a survey with 10 hypothetical DMT profiles developed using an orthogonal design and rating preferences from 1 (most acceptable) to 10 (least acceptable). Medication attributes included preventing relapse, preventing disease progression, side effect risk, route and frequency of administration. Results: Patients placed the greatest relative importance on the side effect risk domain (32.9%), followed by route of administration (26.1%), frequency of administration (22.7%), prevention of disease progression (10.0%) and prevention of relapse (8.3%). These results were independent of the Expanded Disability Status Scale score. The importance assigned to side effect risk was highest for patients with a recent diagnosis. Patients who had previously received more than one DMT gave a higher importance to relapse rate reduction than patients receiving their first DMT. Conclusions: Patient DMT preferences were mainly driven by risk minimisation, route of administration and treatment schedule. The risk-benefit spectrum of available DMT for MS is becoming increasingly complicated. Understanding which treatment characteristics are meaningful to patients may help to tailor information for them and facilitate shared decision-making in clinical practice.

Background: Alemtuzumab was superior on clinical and magnetic resonance imaging (MRI) outcomes versus subcutaneous interferon beta-1a in phase 3 trials in patients with relapsing-remitting multiple sclerosis. Objective: To examine quality-of-life (QoL) outcomes in the alemtuzumab phase 3 trials. Methods: Patients who were treatment naive (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36). Results: Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS. Conclusion: Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.

OBJECTIVE To assess the effectiveness and safety of fingolimod use in a Spanish clinical practice setting. METHODS Retrospective study with multiple sclerosis patients who received at least 1 fingolimod dose between January 2004 and January 2015. Effectiveness and safety data were collected during the entire treatment of each patient. Analysis was performed for the total population and stratified according to prior treatment, sex, and age at treatment initiation. RESULTS A total of 167 patients were included, 50.9% had prior immunomodulator use, 33.5% natalizumab use, and 15.6% were naive patients. The annual relapse rate (ARR) decreased for the total population at month 12 (62%) and month 24 (84%) (P < 0.0001, in both cases); for naive patients (P < 0.05) and patients with prior immunomodulator use (P < 0.0001); for patients with prior natalizumab use, the ARR kept low after treatment initiation (0.23). After 24 months, the proportion of relapse-free patients was 70% or greater and disability progression-free patients was 80% or greater. No significant differences were observed when the results were compared by prior treatment, sex, or age. Thirty-two patients (19.2%) reported adverse drug reactions and 9.6% discontinued: 4.8% due to adverse drug reactions and 4.8% for lack of effectiveness. CONCLUSIONS The results support fingolimod use due to clinical effectiveness, tolerability, and ease of administration.

The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.Genzyme (Sanofi) and Bayer Schering Pharma.

Objective: The aim of this study was to assess cost-effectiveness of the different Disease Modifying Drugs (DMD) used as first-line treatments (interferons IM IFNβ-1a, SC IFNβ-1a, SC IFNβ-1b, and glatiramer acetate, GA) in Remitting-Relapsing Multiple Sclerosis (RRMS) in Spain.A Markov model was developed to simulate the progression of a cohort of patients with RRMS, during a period of 10 years. Seven health states, defined by the Expanded Disability Status Scale (EDSS), were considered in the model. Patients with an EDSS score less than 6.0 were assumed to be treated with one of the DMD. In addition, all patients were assumed to receive symptomatic treatment. The monthly transition probabilities of the model were obtained from the literature. The analysis was performed from the societal perspective, in which both direct and indirect (losses in productivity) healthcare costs (€, 2010) were included. A discount rate of 3% was applied to both costs and efficacy results.GA was the less costly strategy (€322,510), followed by IM IFNβ-1a (€329,595), SC IFNβ-1b (€ 333,925), and SC IFNβ-1a (€348,208). IM IFNβ-1a has shown the best efficacy results, with 4.176 quality-adjusted life years (QALY), followed by SC IFNβ-1a (4.158 QALY), SC IFNβ-1b (4.157 QALY), and GA (4.117 QALY). Incremental costs per QALY gained with IM IFNβ-1a were €-1,005,194/QALY, €-223,397/QALY, and €117,914/QALY in comparison to SC IFNβ-1a, SC IFNβ-1b, and GA, respectively.First-line treatment with GA is the less costly strategy for the treatment of patients with RRMS. Treatment with IM IFNβ-1a is a dominant strategy (lower cost and higher QALY) compared with SC IFNβ-1a and SC IFNβ-1b. However, IM IFNβ-1a is not a cost-effective strategy vs GA, because incremental cost per QALY gained with IM IFNβ-1a exceeds the €30,000 per QALY threshold commonly used in Spain.The highly-restrictive inclusion criteria of clinical trials limits generalization of the results on efficacy to all patients with multiple sclerosis. Availability of data for head-to-head comparisons is associated with the use of information from clinical trials.

Although the etiology of multiple sclerosis (MS) is unknown, it is generally believed that genetic, immunologic, and environmental factors are involved. The objectives of this study were: 1. to analyze if a genetic control could explain why HHV-6 would be able to actively replicate in a subset of MS patients but not in controls; 2. to study if MS patients with HHV-6 active replication are clinically different from those without HHV-6 active replication. A total of 195 MS patients and 195 controls were analyzed for two SNPs at the MHC2TA locus and two SNPs at the CD46 locus. Furthermore, the MS cohort was analyzed by PCR for the detection of HHV-6 genomes in five serum samples collected every six months along two-year follow-up. We found that 59/195 (30.2%) MS patients had at least one HHV-6 positive serum sample. No statistical significant difference was found for the two genes when the comparison was made between MS patients and controls; however, a statistical significance was found for the two polymorphisms of MHC2TA when we compared MS patients with active replication and controls (p=0.0000004 for rs4774C and p=0.011 for rs3087456G). Furthermore, increased significant differences were found for MHC2TA and CD46 when we compared interferon beta responders and non-responders within MS patients. In conclusion, we describe a gene-environment interaction in MS patients between HHV-6 and MHC2TA and CD46 that should be further studied to clarify if that interaction could be a genetic control. The results show that MS patients without HHV-6 active replication are better responders to interferon beta treatment than those with HHV-6 active replication.

Much attention has been paid in recent years to the role of prenatal exposure to alcohol. Fetal alcohol syndrome is one of the most severe afflictions resulting from such exposure. The present report documents the cases of adopted children diagnosed with fetal alcohol syndrome who developed both Tourette syndrome and attention deficit-hyperactivity disorder. Out of a population of 138 adopted children with behavior issues whose clinical histories were reviewed retrospectively, 9 children (6.5%) presented this constellation. Epidemiologic data, clinical data, neurologic examination findings, complementary testing, and developmental data were recorded. All nine patients studied had initial psychomotor retardation, despite the frequent case of subsequent intelligence quotient normalization. From a behavioral perspective, half of the cases presented obsessive-compulsive disorder and problems with social relations. Aggressive behavior was common. These cases also presented a high degree of severity of both tics and hyperactivity. The most common drug treatment was methylphenidate. This constellation of fetal alcohol syndrome, Tourette syndrome, and attention deficit-hyperactivity disorder is scantly reported in the literature and is likely underdiagnosed. This particular constellation poses its own prognosis and requires its own treatment.

Interleukin (IL)-2/IL-2R signalling promotes proliferation and survival of activated T cells and has an essential non-redundant role in the production of regulatory T cells. Associations with different autoimmune diseases of polymorphisms in a linkage disequilibrium block in which the IL2/IL21 genes map (4q27), and also in genes encoding the IL2RA and IL2RB subunits (located in 10p15 and 22q13, respectively), were identified through genome-wide studies. Polymorphisms in these three genes were studied in 430 multiple sclerosis (MS) patients and in 550 ethnically matched controls from Madrid (Spain). Replication and meta-analysis with results from an independent cohort of 771 MS patients and 759 controls from Andalucía (Spain) confirmed the association of polymorphisms in the IL2RA gene (PMantel-Haenszel, odds ratio (OR) M-H (95% confidence interval, CI) for rs2104286: 0.0001, 0.75 (0.65-0.87); for rs11594656/rs35285258: 0.004, 1.19 (1.06-1.34); for rs41295061: 0.03, 0.77 (0.60-0.98)); showed a trend for association of the IL2/IL21 rs6822844 (P M-H 0.07, OR M-H (95% CI)0.86 (0.73-1.01)), but did not corroborate the association for IL2RB. Regression analyses of the combined Spanish cohort revealed the independence of two IL2RA association signals: rs2104286 and rs11594656/rs35285258. The relevant role of the IL2RA gene on MS susceptibility adds support to its common effect on autoimmune risk and the suggestive association of IL2/IL21 warrants further investigation. © 2010 Macmillan Publishers Limited All rights reserved., Concepción Núñez holds a research contract from Fondo Investigaciones Sanitarias (CA06/0163) and Elena Urcelay works for the Fundación para la Investigación Biomédica-Hospital Clínico San Carlos. This study was supported by grants from: Alfonso Martín Escudero Foundation and Fondo Investigaciones Sanitarias FIS PI07/0353, FIS PI07/0369, PI08/1636 and Plan Nacional PN-SAF2006-02023.

The beneficial effects of interferon beta-1a (IFNbeta-1a) in multiple sclerosis (MS) remain only partially understood. CD8(+) T cells are key cells in MS pathogenesis that contribute to axonal damage in MS, whereas CD4(+) regulatory T cells (T(Reg)) and CD8(+) regulatory/suppressor T cells (Ts) play an important role in protecting against subsequent MS activity. We analysed ex vivo changes on T(Reg) and on the different subsets of CD4(+) and CD8(+) T lymphocytes, before IFNbeta-1a (Rebif) therapy and at 3, 6, and 12 months after treatment, in 23 MS patients and in 26 healthy controls. IFNbeta-1a significantly increased the proportions of CD4(+) T(Reg) and regulatory CD8(+) T cells (Tr). Memory CD8(+) T cells were significantly decreased after 1 year of treatment, maybe reflecting down-regulation of abnormally persistent systemic activation in MS patients. After 1 year of IFNbeta-1a, a direct correlation was observed between plasmacytoid dendritic cells and effector CD8(+) T cells.

Background: The objective of this study was to correlate the detection of neutralizing antibodies (NAbs) by the cytopathic effect (CPE) assay, with the expression of myxovirus resistance protein A (MxA), and the ratio between matrix metalloproteinase 9 (MMP-9) and its tissular inhibitor (TIMP-1), in order to evaluate their usefulness as markers of interferon beta (IFN-beta) bioavailability. Methods: Pairs of blood and serum samples were collected from 50 patients with multiple sclerosis (MS) during 2 years of IFN-beta treatment. Expression of MxA, MMP-9 and TIMP-1 were analysed by quantitative PCR, and NAbs were measured by CPE assay. Results: During the study, 60% of patients presented NAbs. The number of serum samples that were NAbs+ was significantly increased amongst patients with relapses (41/92 vs. 33/108, P = 0.04). With one serum sample and with a NAb titre >100 tenfold reduction unit (TRU), 66.7% of patients with MS suffered from relapses, 41.7% suffered from progression, and 75% was not an optimal clinical responder. We did not find any significant difference in MxA. We found that 62.5% of patients with MS patients whose ratio was increased twofold after 2 years suffered from relapses, 37.5% suffered from progression, and 68.7% was not an optimal clinical responder. Conclusion: The early detection of NAbs by CPE assay and the finding of only one serum sample with a NAb titre >100 TRU seem to be markers of low bioavailability of IFN-beta, whilst a twofold decrease in the MMP-9/TIMP-1 ratio by quantitative PCR assay seems to be a marker of high bioavailability of IFN-beta.

Objectives – The aim of this study was to investigate the possible association between the levels of the CD46 expression, and the presence and viral load of HHV-6 in patients with multiple sclerosis (MS). Methods – We collected blood and serum samples of 103 patients with MS and the same number of healthy blood donors (HBD); total DNA and RNA was extracted from peripheral blood mononuclear cells (PBMCs) and serum, and then analyzed using quantitative real-time PCR for the detection of CD46 transcripts and HHV-6 genomes; the expression of rRNA18s was used for the calculation of the relative expression of CD46. Results – Almost 80% of patients with MS had increased levels of CD46 in comparison with HBD, and a positive correlation was also found between the over-expression of CD46 in patients with MS and the HHV-6 DNA prevalence and viral load in the blood and serum. Discussion – Therefore, the up-regulation of CD46 expression in patients with MS with HHV-6 infection could constitute an immunopathogenic factor that should be further investigated to elucidate its role in MS.

Many variables with association with better response to interferon-beta-1a (IFNbeta-1a) have been described, but none has yet been shown to be predictive of clinical response. In this real-life observational 1-year longitudinal study of 23 relapsing-remitting multiple sclerosis (RRMS) patients treated with subcutaneous IFNbeta-1a, we have shown a lower proportion of circulating myeloid dendritic cells (mDCs) than in healthy controls at baseline. Both univariate (Kaplan-Meier) and multivariate (Cox regression) analyses were conducted to determine which variables (age, sex, baseline EDSS, MS relapse rates 1 year and 2 years before initiating IFNbeta-1a, mDCs and plasmacytoid (pDCs) subsets, activated and regulatory CD4(+) T-cells (T(Reg))) were associated with clinical response to IFNbeta-1a. During 1 year of treatment, we observed a shift towards lower proportions of CD123(+) pDCs expression and higher numbers and function of the T(Reg). Univariate analysis disclosed that MS activity was significantly associated with baseline BDCA1(+) mDCs below < or = 0.4% (p

Recent studies have shown association of the IL23R gene with inflammatory bowel disease, psoriasis and ankylosing spondylitis. We aimed at studying the involvement of IL23R in celiac disease (CD) and multiple sclerosis (MS). We performed a case-control study including 598 patients with CD, 414 with MS and 546 healthy controls, all of them white Spaniards. All samples were genotyped for two single nucleotide polymorphisms: rs7517847 and rs11209026 (Arg381Gln). Statistical analyses were performed using chi(2-)tests or the Fisher's exact test. The minor allele (Gln) of the coding variant Arg381Gln was significantly increased in CD and MS patients when compared to controls (8% in CD vs 6% in controls, P=0.02; 9% in MS, P=0.006). In MS, a stronger effect was observed in patients showing primary-progressive disease (16%, P=0.004). Moreover, heterozygotes for rs7517847 were significantly increased in this group of MS patients (81% in MS vs 48% in controls, P=0.0002). In conclusion, contrary to what has been described previously, the less frequent allele of the functional polymorphism Arg381Gln (rs11209026) seems to be increasing susceptibility to CD and MS, although in this last group of patients a stronger effect is observed in patients affected of a primary-progressive form.

Our aim in the present study is to evaluate the variation present in the TLR4 gene and its relationship with multiple sclerosis susceptibility in the Spanish population. Three hundred and sixty-two multiple sclerosis patients and 467 healthy controls from the Spanish population were included in the present study. Twelve single nucleotide polymorphisms (SNPs) were selected, and analyzed by the TaqMan technique. No statistically significant differences for any polymorphism or haplotypes were observed when patients were compared with controls. In conclusion, TLR4 does not play a major role in the predisposition to suffer from multiple sclerosis in our population.

Objective To evaluate the possible involvement of JC virus (JCV) in the aetiology of multiple sclerosis (MS), through the comparison of DNA prevalences and viral loads of JCV in cerebrospinal fluid (CSF) of MS patients at the first demyelinating event and subjects suffering from other neurological diseases (OND). Methods Seventy-three CSF samples (43 from MS patients at the first demyelinating event, and 30 from patients with OND) were collected; all MS cases were followed up from 1 to 6.7 years after they were diagnosed with clinically definite MS. DNA was extracted and analysed by real-time PCR for the detection of JCV genomes. Results We found JCV DNA in the CSF of two MS patients (4.7%) with a mean viral load of 2.1 and 6.7 copies/mL of CSF. Among the patients of the OND group we did not find any positive sample. We did not find any difference in the course of the disease between MS patients with and without JCV genomes in their CSF along the follow up. Conclusion JCV seems to be only a bystander in the pathology of MS, and the presence of cell-free viral particles could be related to the immunological activation of the disease, mainly during relapses. Multiple Sclerosis 2007; 13: 590-595. http://msj.sagepub.com