Polymorphisms CYP2R1 rs10766197 and CYP27B1 rs10877012 in Multiple Sclerosis: A Case-Control Study.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Low vitamin D levels have been reported to be a risk factor for MS, and genetic variances could be implicated. The aim of this study was to evaluate the association of MS with rs10766197 polymorphism of CYP2R1 gene and rs10877012 polymorphism of CYP27B1 gene. The second aim was to analyse whether these polymorphisms are associated with the severity of the progression of MS. Material and Methods. In a case-control study, we included 116 MS patients and 226 controls, all of whom were Mexican Mestizo. MS was diagnosed by McDonald criteria (2017). A complete neurological evaluation was performed to evaluate the severity of disease progression. Serum 25-hydroxyvitamin D [25(OH) vitamin D] levels were measured by ELISA. Single nucleotide polymorphisms rs10766197 of CYP2R1 gene and rs10877012 SNP of CYP27B1 gene were genotyped by real-time PCR. RESULTS: Serum 25(OH) vitamin D levels were lower in MS patients than in controls (p = 0.009). No differences were observed between serum 25(OH) vitamin D levels of MS patients with severe progression compared to low progression (p = 0.88). A higher frequency of the A allele of CYP2R1 rs10766197 was observed between MS patients and controls (p = 0.05). No differences were observed in the frequency of T allele of CYP27B1 rs10877012 (p = 0.65). In subanalysis, patients with GA + AA genotypes of CYP2R1 rs10766197 had an increased risk of MS compared to controls (p = 0.03). No increased risk was observed in GT + TT genotypes of CYP27B1 rs10877012 (p = 0.63). No differences were observed in allele frequencies of either polymorphism between patients with severe vs. low disease progression. CONCLUSION: Lower serum 25(OH) vitamin D levels were observed in MS patients than in controls, although these levels were not associated with disease progression. Carriers of GA + AA genotypes of CYP2R1 rs10766197 had an increased risk of MS. None of these polymorphisms was associated with severe progression of MS.

Effect of melatonin administration on the PER1 and BMAL1 clock genes in patients with Parkinson's disease.

Sleep disorders are a widespread condition in patients with Parkinson's disease (PD), which has been linked to a deregulation of the circadian cycle and therefore of the clock genes. The aim of this study was to evaluate the effect of melatonin (MEL) on the PER1 and BMAL1 clock genes in patients with PD. A double-blind, cross-over, placebo-controlled randomized clinical trial pilot study was conducted in 26 patients with stage 1-3 PD according to the Hoehn & Yahr scale, who received either 25 mg of MEL or a placebo at noon and 30 min before bedtime for three months. The relative expression of the PER1 and BMAL1 genes was measured, as well as the presence of daytime, nocturnal, and global sleepiness, and the progression of PD. The levels of the PER1 and BMAL1 genes at baseline were 0.9 (0.1-3) vs. 0.56 (0.1-2.5), respectively; while after the intervention with MEL or placebo the BMAL1 levels increased to 2.5 (0-3.70) vs. 2.2 (0.10-3.30), respectively (d = 0.387). Fifty percent (50 %) of patients had daytime sleepiness and sixty-five percent (65 %) had abnormal nighttime sleepiness, yet neither group showed changes after the intervention. Patients with PD exhibited an alteration in the levels of the clock genes: MEL increased the levels of BMAL1, but the PER1 levels remained unchanged.

MIF functional polymorphisms (-794 CATT5-8 and -173 G>C) are associated with MIF serum levels, severity and progression in male multiple sclerosis from western Mexican population.

Macrophage migration inhibitory factor (MIF) is a cytokine associated with tissue damage in multiple autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and psoriatic arthritis. The role of MIF in multiple sclerosis (MS) and the contribution of its polymorphisms are unknown in our population. Therefore, we decided to investigate the genetic association of -794 CATT5-8 (rs5844572) and -173 G>C (rs755622) MIF polymorphisms with MS, clinical variables and MIF serum levels in the population of western Mexico. 230 MS patients diagnosed according to McDonald criteria and 248 control subjects (CS) were recruited for this study, both polymorphisms were genotyped by PCR and PCR-RFLP and MIF serum levels were measured by ELISA kit. Severity and progression of MS were evaluated by EDSS and MSSS scores, respectively. Genotypes carrying the 5 repeats alleles of -794 CATT5-8MIF polymorphism present higher MIF serum levels in comparison with no carriers, and the presence of 5,7 heterozygous genotype contribute to the increase of disease severity and damage progression in MS patients. Notably when we stratified by sex, an effect of risk alleles (7 repeats and -173*C) of both MIF polymorphisms on EDSS and MSSS scores on males was found (p < 0.01). This study suggests that polymorphic alleles of MIF polymorphisms could act as sex-specific disease modifiers that increase the severity and progression of MS in male Mexican-Mestizo western population.

Absence of the tag polymorphism for the risk haplotype HLA-DR2 for multiple sclerosis in Wixárika subjects from Mexico.

The HLA-DRB1*15:01 allele has a demonstrated risk for the development of multiple sclerosis (MS) in most populations around the world. The single nucleotide polymorphism (SNP) rs3129934 is found in linkage disequilibrium with the risk haplotype formed by the HLA-DRB1*15:01 and HLA-DQB1*06:02 alleles, and it is considered a reliable marker of the presence of this haplotype. Native Americans have a null or low prevalence of MS. In this study, we sought to identify the frequency of rs3129934 in the Wixárika ethnic group as well as in Mestizo (mixed race) patients with MS and in controls from western Mexico. Through real-time polymerase chain reaction (PCR) using TaqMan probes, we analyzed the allele and genotype frequencies of rs3129934 in Mestizo individuals with and without MS and in 73 Wixárika subjects from the state of Jalisco, Mexico. The Wixárika subjects were homozygote for the C allele of rs3129934. The allele and genotype frequency in Mestizos with MS was similar to that of other MS populations with Caucasian ancestry. The absence of the T risk allele rs3129934 (associated with the haplotype HLA-DRB1*15:01, HLA-DQ1*06:02) in this sample of Wixárika subjects is consistent with the unreported MS in this Amerindian group, related to absence of such paramount genetic risk factor.

Effect of melatonin administration on cyclooxygenase-2 activity, serum levels of nitric oxide metabolites, lipoperoxides and glutathione peroxidase activity in patients with Parkinson's disease / Efecto de la administración de melatonina sobre la actividad de la ciclooxigenasa-2, la concentración sérica de metabolitos del óxido nítrico, los lipoperóxidos y la actividad de la glutatión peroxidasa en pacientes con enfermedad de Parkinson.

Objective: To determine the effect of melatonin (MEL) administration on ciclooxigenase 2 (COX-2) activity and serum concentration of nitric oxide metabolites, lipoperoxides and glutathione peroxidase (GPx) activity in patients with Parkinson's disease. Methods: Prospective double-blind randomized clinical pilot trial. 13 patients were included and two groups were formed: MEL at doses of 25 mg orally every 12 hours for 12 months and placebo with corn starch. Patients were assessed using the Unified Parkinson's Disease Scale. A blood sample was taken at baseline and every 3 months until 12 months. Results: COX-2 activity decreased as did nitrates/nitrites (3, 6 and 9 months) and lipoperoxides (9 and 12 months); GPx exhibited no significant differences.

Efficacy of fish oil on serum of TNF α , IL-1 ß , and IL-6 oxidative stress markers in multiple sclerosis treated with interferon beta-1b.

UNLABELLED: Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the central nervous system. Oxidative stress is also thought to promote tissue damage in multiple sclerosis. Current research findings suggest that omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapenta-enoic acid (EPA) and docosahexaenoic acid (DHA) contained in fish oil may have anti-inflammatory, antioxidant, and neuroprotective effects. The aim of the present work was to evaluate the efficacy of fish oil supplementation on serum proinflammatory cytokine levels, oxidative stress markers, and disease progression in MS. 50 patients with relapsing-remitting MS were enrolled. The experimental group received orally 4 g/day of fish oil for 12 months. The primary outcome was serum TNF α levels; secondary outcomes were IL-1 ß 1b, IL-6, nitric oxide catabolites, lipoperoxides, progression on the expanded disability status scale (EDSS), and annualized relapses rate (ARR). Fish oil treatment decreased the serum levels of TNF α , IL-1 ß , IL-6, and nitric oxide metabolites compared with placebo group (P ≤ 0.001). There was no significant difference in serum lipoperoxide levels during the study. No differences in EDSS and ARR were found. CONCLUSION: Fish oil supplementation is highly effective in reducing the levels of cytokines and nitric oxide catabolites in patients with relapsing-remitting MS.

Detection of membrane fluidity in submitochondrial particles of platelets and erythrocyte membranes from Mexican patients with Alzheimer disease by intramolecular excimer formation of 1,3 dipyrenylpropane.

It has been suggested that mitochondrial dysfunction and defects in membrane structure could be implied in AD pathogenesis. The aim of the present work was the study of membrane fluidity in submitochondrial platelet particles and erythrocyte membranes from Mexican patients. Blood samples were obtained from 30 patients with Alzheimer disease and 30 aged-matched control subjects. Membrane fluidity determinations were done using a very low concentration of the fluorescent dipyrenylpropane probe incorporated in both types of membranes. This probe is able to give excimer and monomer fluorescence, therefore it can be used to monitor fluidity changes in biological membranes. The data obtained showed that in submitochondrial particles from AD patients, the excimer to monomer fluorescent intensity ratio was lower (0.231 +/- 0.008) than aged-matched control subjects (0.363 +/- 0.014). Therefore, membrane fluidity was lower in AD samples. On the other hand, we found similar membrane fluidity in erythrocytes from AD patients and aged-matched controls: the fluorescent intensity ratios were 0.312 +/- 0.03 and 0.305 +/- 0.033, respectively. In addition, lipid peroxidation in submitochondrial particles and erythrocyte membranes was higher in AD samples than in aged-matched controls. These data suggest that submitochondrial platelet particles are more sensitive to oxidative stress than erythrocyte membranes.

[Recommendations for optimising the treatment of multiple sclerosis in Latin America]. / Recomendaciones para la optimización del tratamiento de la esclerosis múltiple en Latinoamérica.

INTRODUCTION: Multiple sclerosis (MS) is the most common primary demyelinating disease affecting the central nervous system. In recent years the development of new drugs that have been shown to modify the natural history of MS have had a substantial impact on the treatment of the disease. AIMS: To harmonise and integrate the evidence available on optimising the treatment of patients with MS. DEVELOPMENT: In order to fulfil our main aim, a group of experts from different Latin American countries drew up a list of statements related to the use of immunomodulatory agents in the different clinical forms of the disease and the strategies that should be considered in cases in which the therapeutic response was suboptimal. Each of the participants used a structured scale to express the extent to which he or she agreed or disagreed, and a consensus was considered to have been reached when acceptance of each of the statements was equal to or higher than 80%. CONCLUSIONS: These recommendations will provide neurologists with the tools needed to make decisions that optimise the treatment of MS patients.

Recomendaciones para la optimización del tratamiento de la esclerosis múltiple en Latinoamérica / Recommendations for optimising the treatment of multiple sclerosis in Latin America

Introducción. La esclerosis múltiple (EM) es la enfermedad desmielinizante primaria más común que afecta al sistema nervioso central. Durante los últimos años ha impactado sustancialmente en el tratamiento de la EM el desarrollo de nuevos fármacos que han demostrado modificar la evolución natural de la enfermedad. Objetivo. Armonizar e integrar la evidencia disponible en la actualidad respecto a la optimización del tratamiento de los pacientes con EM. Desarrollo. A fin de cumplir con el objetivo propuesto, un grupo de expertos pertenecientes a diferentes países de Latinoamérica confeccionó una lista de enunciados relacionados con el uso de agentes inmunomoduladores en las distintas formas clínicas de la enfermedad y las estrategias que se deben considerar en aquellos casos en los que la respuesta terapéutica fuera subóptima. Utilizando una escala estructurada, cada uno de los participantes expresó su grado de acuerdo o desacuerdo, pudiendo alcanzarse un consenso cuando la aceptación para cada uno de los enunciados era igual o mayor al 80%. Conclusión. Estas recomendaciones proporcionarán al médico neurólogo las herramientas necesarias para la toma de decisiones que optimicen el tratamiento de los pacientes con EM

Introduction. Multiple sclerosis (MS) is the most common primary demyelinating disease affecting the central nervous system. In recent years the development of new drugs that have been shown to modify the natural history of MS have had a substantial impact on the treatment of the disease. Aims. To harmonise and integrate the evidence available on optimising the treatment of patients with MS. Development. In order to fulfil our main aim, a group of experts from different Latin American countries drew up a list of statements related to the use of immunomodulatory agents in the different clinical forms of the disease and the strategies that should be considered in cases in which the therapeutic response was suboptimal. Each of the participants used a structured scale to express the extent to which he or she agreed or disagreed, and a consensus was considered to have been reached when acceptance of each of the statements was equal to or higher than 80%. Conclusions. These recommendations will provide neurologists with the tools needed to make decisions that optimise the treatment of MS patients

Altered beta-amyloid precursor protein isoforms in Mexican Alzheimer's Disease patients.

OBJECTIVE: To determine the beta-amyloid precursor protein (betaAPP) isoforms ratio as a risk factor for Alzheimer's Disease and to assess its relationship with demographic and genetic variables of the disease. METHODS: Blood samples from 26 patients fulfilling NINCDS-ADRDA diagnostic criteria for AD and 46 healthy control subjects were collected for Western blotting for betaAPP. A ratio of betaAPP isoforms, in optical densities, between the upper band (130 Kd) and the lower bands (106-110 Kd) was obtained. Odds ratios were obtained to determine risk factor of this component. RESULTS: betaAPP ratio on AD subjects was lower than that of control subjects: 0.3662 +/- 0.1891 vs. 0.6769 +/- 0.1021 (mean +/- SD, p<0.05). A low betaAPP ratio (<0.6) showed an OR of 4.63 (95% CI 1.45-15.33). When onset of disease was taken into account, a betaAPP ratio on EOAD subjects of 0.3965 +/- 0.1916 was found vs. 0.3445 +/- 0.1965 on LOAD subjects (p>0.05). CONCLUSIONS: Altered betaAPP isoforms is a high risk factor for Alzheimer's disease, although it has no influence on the time of onset of the disease.

Neuropsychological function in nondemented carriers of presenilin-1 mutations.

BACKGROUND: Prospective and case-control studies have demonstrated that memory loss and executive dysfunction occur early in Alzheimer disease (AD). OBJECTIVE: To investigate these observations by the study of persons at risk for autosomal dominant forms of AD. METHODS: Neuropsychological and genetic tests were performed on 51 nondemented at-risk members of 10 Mexican families with two distinct presenilin-1 (PS1) mutations. Test scores were compared between PS1 mutation carriers (MCs; n = 30) and noncarriers (NCs; n = 21) by analyses of variance, co-varying for family and specific mutation. Regression analyses were performed, taking into account age relative to the median age at dementia diagnosis in the family (adjusted age), gender, Beck Depression Inventory (BDI) scores, education, and number of APOE epsilon4 alleles. Subjects were divided into age tertiles and scores compared within these groups. Composite scores for Verbal Memory, Executive Function/Working Memory, Language, and Visuospatial Function were created, and these scores compared between MCs and NCs. RESULTS: MCs performed worse than NCs on the Mini-Mental State Examination, Trails Making Tests A and B, Delayed Recall of a 10-Word List, and Wechsler Adult Intelligence Scale WAIS Block Design. In multiple linear regression analyses, BDI score, gender, and number of APOE epsilon4 alleles did not consistently affect test scores. The differences seen between MCs and NCs were due to differences in the oldest tertile. MCs had lower Visuospatial and Executive Function/Working Memory but not Verbal Memory or Language composite scores. CONCLUSIONS: This study is consistent with findings in sporadic Alzheimer disease of early problems with memory, visuospatial function, and particularly with executive function in PS1 mutation carriers. Depression, gender, and presence of an APOE epsilon4 allele did not demonstrate large influences on neuropsychological performance.

[Functional disorders of FOF1-ATPase in submitochondrial particles obtained from platelets of patients with a diagnosis of probable Alzheimer's disease]. / Alteración funcional de la F0F1-ATPasa en partículas submitocondriales obtenidas de plaquetas de pacientes con diagnóstico de enfermedad de Alzheimer probable.

INTRODUCTION: Recent studies indicate that decreased energy generation by mitochondria is a feature that is common across neurodegenerative diseases. PATIENTS AND METHODS: In order to obtain direct evidence that mitochondrial functioning is altered, we measured the hydrolytic activity of F0F1-ATPase and its capacity to generate a stable proton gradient in submitochondrial particles in 29 patients diagnosed with probable Alzheimer's disease (AD). Submitochondrial particles were obtained from platelets of patients with a diagnosis of probable AD and from clinically healthy controls. RESULTS: Data revealed that the hydrolytic activity of F0F1-ATPase increases significantly in patients with probable AD (41.7+/-4.3 nmol PO4 min-1[mg protein]-1, n=29) as compared to the control subjects (29.1+/-1.9 nmol PO4 min-1 [mg protein]-1, n=29). It is important to note that, in the male population with probable AD, we found that hydrolytic activity of F0F1-ATPase increased as cerebral deterioration progressed. We also detected a lower pH gradient in the submitochondrial particles of patients with probable AD (0.28+/-0.08 pH units, n=25) as compared to the controls (0.5+/-0.1 pH units, n=20). CONCLUSIONS: Overall, these data point to an alteration in the functioning of the enzyme.

[Multiple sclerosis in Mexico: a multicentre study]. / Esclerosis múltiple en México: un estudio multicéntrico.

INTRODUCTION: Multiple sclerosis (MS) is considered to be a low prevalence disease in Mexico; its characteristics have been described in isolated studies in small populations concentrated in a single region of the country and using heterogeneous methodological tools. AIMS. In this study, our aim was define the clinical profile and some socio demographic aspects of MS in Mexico using validated homogeneous criteria and tools. PATIENTS AND METHODS: Eight hospitals representing the five most densely populated regions of the country, the north, centre and south of Mexico, took part in the study. Data were obtained through a survey created, validated and published in Spanish (k interobserver 0.73 and k intraobserver 0.76), which consisted of 142 questions arranged in 10 sections and which was applied by 12 neurologists. The procedure was verified with 50 randomly selected surveys. A total of 337 surveys were applied, which were analysed by descriptive statistics using the EPI INFO, version 6.04b, software application. All the patients presented MS that had been clinically defined with the help of paraclinical studies according to Schumaher and Poser's criteria. RESULTS: A sample of 337 patients was studied; 99.1% were mestizos, with an average age of 37 9 years, 69.7% were females and 30.3% males. 95% had access to the Social Security system and 96% had been born in Mexico to Mexican parents. No cases were found among native Mexicans. The clinical profile of the disease did not differ to that reported in other countries; the pattern observed corresponded to that found in northern latitudes. CONCLUSION: This is the first multicentre study carried out in Mexico with a population that is highly representative of the whole country and with a homogeneous methodology.

Esclerosis múltiple en México: un estudio multicéntrico / Multiple sclerosis in Mexico: a multicentre study

Introducción. La esclerosis múltiple (EM) se considera una enfermedad de baja prevalencia en México; sus características se han descrito en estudios aislados en poblaciones pequeñas, concentradas en una sola región del país y utilizando herramientas metodológicas heterogéneas. Objetivo. En este estudio se propone definir el perfil clínico y algunos aspectos sociodemográficos de la EM en México, empleando criterios y herramientas homogéneas validadas. Pacientes y métodos. Participaron ocho centros hospitalarios representativos de las cinco regiones más pobladas del país, zonas norte, centro y sur de México. Los datos se obtuvieron a través de una encuesta creada y validada en español, publicada (k-interobservador, 0.73 yk-intraobservador, 0.76), que consta de 142 preguntas agrupadas en 10 secciones, aplicada por 12 neurólogos. El procedimiento se verificó con 50 encuestas seleccionadas en forma aleatoria. Se aplicaron 337 encuestas, que se analizaron estadísticamente de un modo descriptivo con el programa EPI INFO versión 6.04b. Todos los pacientes presentaban EM clínicamente definida y con apoyo de estudios paraclínicos según los criterios de Schumaher y Poser. Resultados. Se estudiaron 337 pacientes, 99,1 por ciento de raza mestiza, con una edad promedio de 37ñ9 años, 69,7 por ciento mujeres y 30,3 por ciento hombres. El 95 por ciento tuvo acceso al sistema de seguridad social. Un 96 por ciento correspondió a nacidos en México de padres mexicanos. No se encontró ningún caso en indígenas. El perfil clínico de la enfermedad no difiere del publicado en otros países; se conserva un patrón latitudinal norte. Conclusión. Este es el primer estudio multicéntrico realizado en México con una población altamente representativa del país y con una metodología homogénea (AU)