An Abnormal Nitric Oxide Metabolism Contributes to Brain Oxidative Stress in the Mouse Model for the Fragile X Syndrome, a Possible Role in Intellectual Disability

Background. Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF-κB-p65 subunit in different brain areas on the fragile X mouse model. Methods. This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF-κBp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas. Results. Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF-κB-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes. Conclusions. These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial

BACKGROUND: Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, phisical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms. Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment. Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children–Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. METHODS/DESIGN: A phase II randomized, double-blind pilot clinical trial. Scope: male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. Instrumentation: clinical data, blood analysis, Wechsler Intelligence Scale for Children–Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. DISCUSSION: A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011

Efectividad de la combinación de antioxidantes, ácido ascórbico y alfa-tocoferol, en los problemas cognitivos y de comportamiento asociados al síndrome X-fragil

Resumen del póster presentado al I Congreso Interdisciplinar en Genética Humana, celebrado en Madrid del 25 al 28 de abril de 2017.-- et al.[Objetivos]: Síndrome X Frágil (SXF) es un trastorno genético del neurodesarrollo infantil que afecta a la inteligencia y el comportamiento, puede causar autismo y epilepsia. La fisiopatología incluye aumento del estrés oxidativo en el cerebro del ratón modelo del síndrome, que se ha revertido con el tratamiento crónico con antioxidantes así como las características fenotípicas. Comprobaremos si el tratamiento antioxidante mejora la sintomatología cognitiva y comportamiento de pacientes jovenes con el Síndrome. [Material y Método]: 100 pacientes SXF a doble ciego aleatorizados, 50 tratamiento (10mg/kg/dia ácido ascórbico y alfatocoferol hasta maximo de 800 y 600mg/dia) y 50 placebo agrupados por edad: A:18 años (N=17 adultos). Las pruebas neuropsicológicas se realizaron al inicio (T0) y después de 12 semanas (T1). Variables: porcentaje de cambio en las subescalas manipulativas y verbales de (WISC-R) en el grupo B (n = 64), para los estudios cognitivos. Test Peabody para las evaluaciones del lenguaje receptivo (n=100). Análisis de los porcentajes de cambio por el test U de Mann Whitney (p <0,05). Ensayo código EudraCT:2009-017837-23. [Resultados]: Mejora significativa en las Escala Verbal WISC-R: 30,8 en el grupo tratado frente a 13,7 en el placebo (p <0,05). Mejora muy significativa en la escala manipulativa WISC-R: 35,4 en el grupo tratado y 10,9 en placebo, (P = 0,01). Mejora significativa en lenguaje: 24,4 en tratamiento frente a 6,8 en placebo (P <0,05). Fue bien tolerado en general, no se han descrito efectos adversos significativos. [Conclusiones]: La cognición mejora con una potencia de 65% y el lenguaje en un 45% después de 12 semanas de tratamiento con ácido ascórbico y alfa-tocoferol, una combinación sinérgica de vitaminas con una potente capacidad antioxidante. Ahora los ensayos clínicos con antioxidantes deben probar la eficacia en niños menores de 6 años con FXS.Proyectos PI2009-0507, EC10-191, EC11-434, PI10-CTS-05704, Fondos FEDER.Peer reviewe

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0).[Background]: Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, phisical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment. Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. [Methods/Design]: A phase II randomized, double-blind pilot clinical trial. Scope: male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. Instrumentation: clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. [Discussion]: A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. [Trial registration]: ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).The trial protocol is approved and funded by the Spanish Ministry of Health, Research Funds from FEDER-EU (TRA152, EC10-191 and EC11-434), the Health Department of the Andalusian Regional Government (PI09-0507), the Economic Innovation and Science Regional Government (CTS546 and P10-CTS-05704) and the Jerome Lejeune Foundation (Paris, France). YDDO is the recipient of a Nicolas Monarde contract from the Servicio Andaluz de Salud. Consejería de Salud. Junta de Andalucía.Peer Reviewe

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial.

Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't;BACKGROUND Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, physical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. METHODS/DESIGN A phase II randomized, double-blind pilot clinical trial. SCOPE male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. INSTRUMENTATION clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. DISCUSSION A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).the Spanish Ministry of Health, Research Funds from FEDER-EU (TRA152, EC10-191 and EC11-434), the Health Department of the Andalusian Regional Government (PI09-0507), the Economic Innovation and Science Regional Government (CTS546 and P10-CTS-05704) and the Jerome Lejeune Foundation (Paris, France).Ye

Libro digital Proyectos Posgrados 2016-10

MaestríaDoctoradoDoctor en Ingeniería Eléctrica y ElectrónicaDoctor en Ingeniería CivilDoctor en Ingeniería de Sistemas y ComputaciónDoctor en Ingeniería IndustrialDoctor en Ingeniería MecánicaMagister en Ingeniería AdministrativaMagister en Ingeniería AmbientalMagister en Ingeniería CivilMagister en Ingeniería de Sistemas y ComputaciónMagister en Ingeniería EléctricaMagister en Ingeniería ElectrónicaMagister en Ingeniería IndustrialMagister en Ingeniería Mecánic