Pigment epithelium-derived factor (PEDF) and PEDF-receptor in the adult mouse brain: Differential spatial/temporal localization pattern.

Pigment epithelium-derived factor (PEDF) is a multifunctional protein which was initially described in the retina, although it is also present in other tissues. It functions as an antioxidant agent promoting neuronal survival. Recently, a PEDF receptor has shown an elevated binding affinity for PEDF. There are no relevant data regarding the distribution of both proteins in the brain, therefore the main goal of this work was to investigate the spatiotemporal presence of PEDF and PEDFR in the adult mouse brain, and to determine the PEDF blood level in mouse and human. The localization of both proteins was analyzed by different experimental methods such as immunohistochemistry, western-blotting, and also by enzyme-linked immunosorbent assay. Differential expression was found in some telencephalic structures and positive signals for both proteins were detected in the cerebellum. The magnitude of the PEDFR labeling pattern was higher than PEDF and included some cortical and subventricular areas. Age-dependent changes in intensity of both protein immunoreactions were found in the cortical and hippocampal areas with greater reactivity between 4 and 8 months of age, whilst others, like the subventricular zones, these differences were more evident for PEDFR. Although ubiquitous presence was not found in the brain for these two proteins, their relevant functions must not be underestimated. It has been described that PEDF plays an important role in neuroprotection and data provided in the present work represents the first extensive study to understand the relevance of these two proteins in specific brain areas.

Estado epiléptico en pacientes pediátricos: consecuencias evolutivas y actualización epidemiológica / Epileptic status in paediatric patients: its developmental consequences and an epidemiological update

INTRODUCCIÓN: El estado epiléptico representa la emergencia neurológica más frecuente en pediatría. Las convulsiones febriles prolongadas representan la etiología más frecuente. Nuestro objetivo es actualizar su epidemiología y analizar sus consecuencias evolutivas. PACIENTES Y MÉTODOS: Estudio observacional analítico de cohortes retrospectivas de niños atendidos en urgencias con estado epiléptico entre enero de 2014 y diciembre de 2018. Se recogieron las variables demográficas, los antecedentes personales, las características clínicas, las pruebas complementarias y la etiología de los estados epilépticos seguidos en nuestro hospital. Se analizaron las consecuencias evolutivas en cuanto a neurodesarrollo y epilepsia ulterior. RESULTADOS: De un total de 525.000 urgencias atendidas durante el estudio, los casos de estado epiléptico fueron 79 en 68 pacientes (16 casos/100.000 niños/año). La etiología sintomática fue la más frecuente (35,4%). El 20,6% de los pacientes presentaba antecedente de prematuridad; el 30,8%, un déficit del neurodesarrollo previo, más frecuente en caso de etiología sintomática, y el 44% estaba diagnosticado de epilepsia. La duración mediana de las crisis fue de 50 minutos. En siete pacientes se identificó un desencadenante cerebral agudo. El déficit del neurodesarrollo ulterior achacable al estado epiléptico fue del 9,1%, y se relacionó con la etiología sintomática o antecedentes de prematuridad. El desarrollo de epilepsia ocurrió en el 10,7%. CONCLUSIONES: La alteración del neurodesarrollo achacable al estado epiléptico afecta a uno de cada 11 casos. La prematuridad fue un factor de riesgo por sí misma. La epilepsia posterior a un estado epiléptico se desarrolló en uno de cada 10 casos

INTRODUCTION: Epileptic status represents the most frequent neurological emergency in pediatrics. Prolonged febrile seizures represent the most common etiology. Our objective is to update its epidemiology and analyze its evolutionary consequences. PATIENTS AND METHODS: Observational analytical study of retrospective cohorts of children seen in the emergency department with epileptic status between January-2014 and December-2018. Demographic variables, personal history, clinical characteristics, complementary tests and the etiology of the epileptic status followed in our hospital were collected. The evolutionary consequences in terms of neurodevelopment and subsequent epilepsy were analyzed. RESULTS: Of a total of 525,000 emergencies attended during the study, epileptic status cases were 79 in 68 patients (16 cases/100,000 children/year). The symptomatic etiology was the most frequent (35.4%). 20.6% of the patients had a history of prematurity, 30.8% had a deficit of previous neurodevelopment, this being more frequent in case of symptomatic etiology, and 44% were diagnosed with epilepsy. The median duration of seizures was 50 minutes. An acute brain trigger was identified in seven patients. The subsequent neurodevelopmental deficit attributable to epileptic status was 9.1% of patients related to symptomatic etiology and/or a history of prematurity. The development of epilepsy occurred in 10.7%. CONCLUSIONS: The neurodevelopmental disorder attributable to epileptic status affects one in 11 cases. Prematurity was a risk factor per se. Post-epileptic status epilepsy developed in one in 10 cases

Discinesia asociada a ADCY5 en la infancia: a propósito de una familia y revisión actualizada / ADCY5-associated dyskinesia in young children: a case report of a family and an updated review

INTRODUCCIÓN: La discinesia de la mutación ADCY5 es un raro trastorno del movimiento de inicio en la infancia. Se caracteriza por movimientos coreicos aislados o asociados a mioclonías y distonías que afectan a las extremidades, el cuello y la cara. El escaso número de pacientes y familias no permite aún una adecuada relación genotipo-fenotipo. OBJETIVOS: Presentar el caso de un niño con trastornos del movimiento de inicio precoz en el seno de una familia con tres generaciones de afectados, y realizar una revisión actualizada de la casuística y el tratamiento de esta rara enfermedad. CASO CLÍNICO: Varón de 6 años, remitido por retraso del lenguaje e hiperactividad. Tras seis meses de seguimiento, comenzó a presentar movimientos coreicos de predominio facial y de la raíz de los miembros, especialmente al despertar. Al año de seguimiento, se evidenció corea generalizado en reposo con afectación orofacial y torpeza en la marcha. Como antecedentes familiares destacaban su madre, abuelo, tío y prima maternos, que fueron diagnosticados de síndrome de Meige (distonía oromandibular y músculos periorbitarios) con trastornos del movimiento de tipo coreiforme sin filiar desde la infancia. El estudio cerebral por resonancia magnética no presentó alteraciones. Se realizó un exoma clínico dirigido a trastornos del movimiento que descubrió la mutación patógena en el gen ADCY5 causante de la discinesia familiar autosómica. CONCLUSIÓN: La mutación c.1126G > A p.A376T muestra una historia natural con un fenotipo clínico no progresivo en tres generaciones de afectados, con inicio en la infancia y respuesta al tratamiento con guanfacina

INTRODUCTION. Dyskinesia of the ADCY5 mutation is a rare movement-onset disorder in childhood. It is characterized by isolated chorea movements or associated with myoclonus and dystonia affecting the limbs, neck and face. The low number of patients and families still does not allow an adequate genotype-phenotype relationship. AIMS. The case of a child with movement disorders of early onset is presented in a family with three generations of affected members. An updated review of the casuistry and management of this rare disease is made. CASE REPORT: A 6-year-old boy referred for language delay and hyperactivity. After six months of follow-up he begins to show chorea movements of predominantly facial and limb roots, especially when waking up. At one year of follow-up, generalized chorea at rest with orofacial involvement and awkward gait begins to show. His family history includes his mother, grandfather, maternal uncle and cousin, who were diagnosed with Meige's syndrome (oromandibular dystonia and periorbital muscles) with choreiform-like movement disorders without affiliation since childhood. The brain study by MRI showed no alterations. A clinical exome targeting movement disorders was performed that discovered the pathogenic mutation in the ADCY5 gene causing autosomal familial dyskinesia. CONCLUSION: The c.1126G>A p.A376T mutation shows a natural history with a non-progressive clinical phenotype in three generations of affected members, with childhood debut and response to guanfacine treatment

Síndrome de Aicardi-Goutières: espectro fenotípico y genético en una serie de 3 casos / Aicardi-Goutières syndrome: Phenotypic and genetic spectrum in a series of three cases

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Hipertensión intracraneal idiopática: casuística y revisión de la bibliografía / Idiopathic intracranial hypertension: epidemiology and current literature review

Introducción: se analizan las características de la hipertensión intracraneal idiopática; clínica al inicio, pruebas realizadas, tratamiento y evolución que presentaron. Material y métodos: estudio descriptivo retrospectivo de los pacientes diagnosticados de hipertensión intracraneal idiopática en los últimos siete años (2011-2017) en un hospital de tercer nivel. Resultados: se estudiaron 40 pacientes (55% mujeres) con una edad media de 9,6 años. Como factores asociados, el 5% seguían tratamiento con hormona del crecimiento. Solo el 25% presentaban sobrepeso u obesidad. El síntoma principal fue cefalea opresiva, asociando vómitos (27,5%) o alteraciones visuales (22%). Tres pacientes presentaron hallazgo casual de papiledema bilateral. La exploración física fue anodina (65%), se observó estrabismo por parálisis del VI par craneal (35%). Presentaron papiledema el 62,5%. La campimetría solo se realizó en el 55% de los pacientes y estaba alterada en el 50% de estos. El tiempo hasta el diagnóstico fue 44,8 días. Obtuvimos una presión de apertura media 29,7 cm H2O (± 8,2). Se realizó tomografía computarizada al 85% de los pacientes y fue normal en el 88,2% de estos. Se hizo resonancia magnética craneal al 7,5%, y fue normal en el 70% de estos. Se practico angio-RM al 5%, y fue normal en todos los casos. Se solicitó analítica, con función renal y hepática (62,5%, todos normal), hormonal (65%), estudio de trombofilias y autoinmunidad (10% y 20% respectivamente, anodinas). Se inició tratamiento con acetazolamida (95%), y hubo que añadir corticoterapia por falta de respuesta en el 24% de los casos. En el 5% se autolimitó espontáneamente. Como último escalón, el 7,5% requirió válvula de derivación lumboperitoneal. Evolucionaron favorablemente el 95%, con recidivas en el 15% de los casos. El tiempo medio hasta la resolución fue de 3,9 meses. Conclusión: el diagnóstico y tratamiento precoz de la hipertensión intracraneal idiopática es importante para evitar posibles secuelas irreversibles. El estudio oftalmológico, especialmente la campimetría, es esencial para el diagnóstico, seguimiento y determinación de la agresividad del tratamiento

Introduction: the characteristics of idiopathic intracranial hypertension are analyzed; epidemiology, clinic at the beginning, tests performed, treatment and evolution that presented the analyzed cases. Material and methods: a retrospective descriptive study was conducted on patients with idiopathic intracra­nial hypertension in the last seven years (2011-2017), in a third level hospital. Results: forty patients (55% women) were studied, with a mean age of 9.6 years. As associated factors, 5% had a treatment with growth hormone. It is important to note that only 25% were overweight or obese. The main symptom was oppressive headache, without predominance hours, associating vomiting (27.5%), or visual alterations (22%). Three asymptomatic patients presented a chance finding of bilateral papilledema. The physical examination was anodyne (65%), showing strabismus due to cranial nerve palsy VI (35%). 62,5% presented papilledema, and the campimetry was only performed in 55% of the patients, altered in 50% of them. The time to diagnosis was 44.8 days. We obtained an average opening pressure of 29.7 cm H2O (± 8.2). CT was performed (85%), being normal (88.2%). MRI of the skull (7.5%), normal (70%). Angio-NMR (5%), all normal. Analytical was requested, with renal and hepatic function (62.5%, all normal), hormonal (65%), thrombophilic study and autoimmunity (10% and 20% respectively, anodyne). Treatment was started with acetazolamide (95%), requiring the addition of corticotherapy due to lack of response 24%. In 5%, it spontaneously self-limited. As a last step, 7.5% required a lumboperitoneal bypass valve. They evolved favora­bly 95%, relapsing 15%. Redialing the average time to resolution was 3.9 months. Conclusion: idiopathic intracranial hypertension is rare, but its diagnosis and early treatment is essential to avoid possible irreversible sequelae. The ophthalmological study, by fundus and especially campimetry, is es­sential for the diagnosis, monitoring and determination of the aggressiveness of the treatment

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.

Distrofia muscular de Duchenne: Presentación atípica y diagnóstico precoz / Duchenne muscular dystrophy: Case of atypical presentation and early diagnosis

Introducción. La distrofia muscular de Duchenne es la forma más habitual de distrofia muscular, con una incidencia de 1/3300 nacimientos de niños vivos de sexo masculino y una tasa de prevalencia en la población total de 3/100 000 individuos. Suele ser hereditaria (recesiva Ligada al X), aunque también son frecuentes los casos esporádicos. La edad media de diagnóstico es de 4,83 años, sin embargo, es posible un diagnóstico precoz. Caso clínico. Varón de 18 meses en estudio ambulatorio por fallo en el crecimiento y desnutrición, que ingresa por cuadro respiratorio. En la analítica, se destaca hipertransaminasemia sin otros datos de hepatopatía. La presencia de hipotonía detectada en la exploración orientó al diagnóstico de miopatía, confirmada mediante creatina quinasa elevada y electromiograma. El estudio genético inicial para distrofia muscular de Duchenne fue negativo. La biopsia muscular mostró ausencia completa de distrofina. Una ampliación del estudio genético evidenció una mutación no descrita previamente.

Introduction. Duchenne muscular dystrophy is the most common form of muscular dystrophy, with an incidence of 1/3300 male live births and a prevalence rate in the total population of 3/100000 individuals. It is often hereditary (X-linked recessive) but sporadic cases are also frequent. The average age at diagnosis is 4.83 years but an early diagnosis is possible. Clinical case. An 18-month male infant in ambulatory study for failure to thrive and malnutrition was admitted in our hospital for respiratory problems. Hypertransaminasemia without other data of hepatic involvement in addition to hypotonia detected in the examination oriented diagnosis towards myopathy, confirmed by elevated creatine kinase and electromyogram. The genetic study for Duchenne muscular dystrophy was negative. Mutations were not detected. Muscle biopsy showed complete absence of dystrophin. A more sensitive genetic study showed a previously undescribed mutation.

Distrofia muscular de Duchenne: Presentación atípica y diagnóstico precoz / Duchenne muscular dystrophy: Case of atypical presentation and early diagnosis

Introducción. La distrofia muscular de Duchenne es la forma más habitual de distrofia muscular, con una incidencia de 1/3300 nacimientos de niños vivos de sexo masculino y una tasa de prevalencia en la población total de 3/100 000 individuos. Suele ser hereditaria (recesiva Ligada al X), aunque también son frecuentes los casos esporádicos. La edad media de diagnóstico es de 4,83 años, sin embargo, es posible un diagnóstico precoz. Caso clínico. Varón de 18 meses en estudio ambulatorio por fallo en el crecimiento y desnutrición, que ingresa por cuadro respiratorio. En la analítica, se destaca hipertransaminasemia sin otros datos de hepatopatía. La presencia de hipotonía detectada en la exploración orientó al diagnóstico de miopatía, confirmada mediante creatina quinasa elevada y electromiograma. El estudio genético inicial para distrofia muscular de Duchenne fue negativo. La biopsia muscular mostró ausencia completa de distrofina. Una ampliación del estudio genético evidenció una mutación no descrita previamente.(AU)

Introduction. Duchenne muscular dystrophy is the most common form of muscular dystrophy, with an incidence of 1/3300 male live births and a prevalence rate in the total population of 3/100000 individuals. It is often hereditary (X-linked recessive) but sporadic cases are also frequent. The average age at diagnosis is 4.83 years but an early diagnosis is possible. Clinical case. An 18-month male infant in ambulatory study for failure to thrive and malnutrition was admitted in our hospital for respiratory problems. Hypertransaminasemia without other data of hepatic involvement in addition to hypotonia detected in the examination oriented diagnosis towards myopathy, confirmed by elevated creatine kinase and electromyogram. The genetic study for Duchenne muscular dystrophy was negative. Mutations were not detected. Muscle biopsy showed complete absence of dystrophin. A more sensitive genetic study showed a previously undescribed mutation.(AU)

[Duchenne muscular dystrophy: Case of atypical presentation and early diagnosis]. / Distrofia muscular de Duchenne: Presentación atípica y diagnóstico precoz.

INTRODUCTION: Duchenne muscular dystrophy is the most common form of muscular dystrophy, with an incidence of 1/3300 male live births and a prevalence rate in the total population of 3/100000 individuals. It is often hereditary (X-linked recessive) but sporadic cases are also frequent. The average age at diagnosis is 4.83 years but an early diagnosis is possible. CLINICAL CASE: An 18-month male infant in ambulatory study for failure to thrive and malnutrition was admitted in our hospital for respiratory problems. Hypertransaminasemia without other data of hepatic involvement in addition to hypotonia detected in the examination oriented diagnosis towards myopathy, confirmed by elevated creatine kinase and electromyogram. The genetic study for Duchenne muscular dystrophy was negative. Mutations were not detected. Muscle biopsy showed complete absence of dystrophin. A more sensitive genetic study showed a previously undescribed mutation.

Estado epiléptico en pediatría: estudio retrospectivo y revisión de la bibliografía / Status epilepticus in paediatrics: a retrospective study and review of the literature

Introducción. El estado epiléptico (EE) es la emergencia neurológica más frecuente en pediatría. Dada la posibilidad de secuelas neurológicas y mortalidad asociadas, requiere un tratamiento agresivo precoz. Pacientes y métodos. Estudio descriptivo retrospectivo a través de la revisión de historias clínicas de pacientes ingresados en nuestro hospital entre 2010-2013 con diagnóstico de EE. El objetivo fue describir las características epidemiológicas y el manejo de estos pacientes, así como revisar la bibliografía disponible sobre este tema. Resultados. Hemos recogido 39 pacientes (25 varones) y 51 episodios de EE. Edad media: 4,8 años. Tenían enfermedad de base 22 pacientes. Dieciocho eran epilépticos conocidos y cinco tuvieron un EE previo. De los 51 episodios de EE, 33 fueron sintomáticos, 15 febriles y tres criptogénicos. Los tipos de EE fueron: 25 parciales (de ellos, 16 complejos) y 26 generalizados. El tratamiento de primera elección fue benzodiacepinas en 47 pacientes (40, diacepam), fenitoína en tres y ácido valproico en uno. Veintisiete pacientes precisaron fármacos de segunda línea: 16, ácido valproico; ocho, fenitoína; dos, fenobarbital; y uno, levetiracetam. Diez pacientes precisaron fármacos de tercera línea para la inducción del coma: el midazolam fue el más utilizado en nuestro centro, seguido del tiopental y el propofol. Dos EE superrefractarios requirieron inmunoglobulinas y corticoides sistémicos por presentarse en el curso de encefalitis autoinmunes. Conclusiones. Debe plantearse el esquema terapéutico del EE desde el inicio de cualquier crisis convulsiva. El tratamiento es escalonado, con benzodiacepinas en la primera etapa, antiepilépticos de amplio espectro y disponibilidad intravenosa en la segunda (ácido valproico, levetiracetam en el EE generalizado y fenitoína en el EE focal), mientras que el tercer nivel varía en función de la experiencia de cada equipo (AU)

Introduction. Status epilepticus (SE) is the most common neurological emergency on pediatric. Given the possibility of neurological sequelae and mortality associated, it requires an early aggressive treatment. Patients and methods. Retrospective descriptive study based on the review of medical histories of patients admitted to our hospital from 2010 to 2013 with a diagnosis of SE. The objective was to describe the epidemiology characteristics and the management of these patients, and to review the available literature on this topic. Results. We collected 39 patients (25 males) and 51 episodes of SE. Average age: 4.8 years. Twenty-two patients had an underlying disease, 18 were known epileptic and 5 had a previous SE. With a total of 51 SE, 33 were symptomatic, 15 were febrile and 3 were cryptogenic. Types of SE: 25 were partial (16 of them complex) and 26 were generalized. Treatment: 47 benzodiazepines as treatment of choice (40 diazepam), 3 phenytoin and 1 valproic acid. Twenty-seven patients required second-line drugs: 16 valproic acid, 8 phenytoin, 2 phenobarbital and 1 levetiracetam. Ten patients required third-line drugs for the induction of barbiturate-induced coma: midazolam was the most used in our center, followed by thiopental and propofol. Two super-refractory SE required immunoglobulins and systemic corticosteroids for appearing on the course of autoimmune encephalitis. Conclusions. The therapeutic scheme of SE should be considered since the start of any seizure. The treatment is staggered with benzodiazepines in the first stage, broad spectrum antiepileptic drugs, and intravenous availability in the second (valproic acid, levetiracetam in the generalized SE and phenytoin in the focal), while the third level varies depending on the experience of each team (AU)

[Status epilepticus in paediatrics: a retrospective study and review of the literature]. / Estado epileptico en pediatria: estudio retrospectivo y revision de la bibliografia.

INTRODUCTION: Status epilepticus (SE) is the most common neurological emergency on pediatric. Given the possibility of neurological sequelae and mortality associated, it requires an early aggressive treatment. PATIENTS AND METHODS: Retrospective descriptive study based on the review of medical histories of patients admitted to our hospital from 2010 to 2013 with a diagnosis of SE. The objective was to describe the epidemiology characteristics and the management of these patients, and to review the available literature on this topic. RESULTS: We collected 39 patients (25 males) and 51 episodes of SE. Average age: 4.8 years. Twenty-two patients had an underlying disease, 18 were known epileptic and 5 had a previous SE. With a total of 51 SE, 33 were symptomatic, 15 were febrile and 3 were cryptogenic. Types of SE: 25 were partial (16 of them complex) and 26 were generalized. TREATMENT: 47 benzodiazepines as treatment of choice (40 diazepam), 3 phenytoin and 1 valproic acid. Twenty-seven patients required second-line drugs: 16 valproic acid, 8 phenytoin, 2 phenobarbital and 1 levetiracetam. Ten patients required third-line drugs for the induction of barbiturate-induced coma: midazolam was the most used in our center, followed by thiopental and propofol. Two super-refractory SE required immunoglobulins and systemic corticosteroids for appearing on the course of autoimmune encephalitis. CONCLUSIONS: The therapeutic scheme of SE should be considered since the start of any seizure. The treatment is staggered with benzodiazepines in the first stage, broad spectrum antiepileptic drugs, and intravenous availability in the second (valproic acid, levetiracetam in the generalized SE and phenytoin in the focal), while the third level varies depending on the experience of each team.

TITLE: Estado epileptico en pediatria: estudio retrospectivo y revision de la bibliografia.Introduccion. El estado epileptico (EE) es la emergencia neurologica mas frecuente en pediatria. Dada la posibilidad de secuelas neurologicas y mortalidad asociadas, requiere un tratamiento agresivo precoz. Pacientes y metodos. Estudio descriptivo retrospectivo a traves de la revision de historias clinicas de pacientes ingresados en nuestro hospital entre 2010-2013 con diagnostico de EE. El objetivo fue describir las caracteristicas epidemiologicas y el manejo de estos pacientes, asi como revisar la bibliografia disponible sobre este tema. Resultados. Hemos recogido 39 pacientes (25 varones) y 51 episodios de EE. Edad media: 4,8 años. Tenian enfermedad de base 22 pacientes. Dieciocho eran epilepticos conocidos y cinco tuvieron un EE previo. De los 51 episodios de EE, 33 fueron sintomaticos, 15 febriles y tres criptogenicos. Los tipos de EE fueron: 25 parciales (de ellos, 16 complejos) y 26 generalizados. El tratamiento de primera eleccion fue benzodiacepinas en 47 pacientes (40, diacepam), fenitoina en tres y acido valproico en uno. Veintisiete pacientes precisaron farmacos de segunda linea: 16, acido valproico; ocho, fenitoina; dos, fenobarbital; y uno, levetiracetam. Diez pacientes precisaron farmacos de tercera linea para la induccion del coma: el midazolam fue el mas utilizado en nuestro centro, seguido del tiopental y el propofol. Dos EE superrefractarios requirieron inmunoglobulinas y corticoides sistemicos por presentarse en el curso de encefalitis autoinmunes. Conclusiones. Debe plantearse el esquema terapeutico del EE desde el inicio de cualquier crisis convulsiva. El tratamiento es escalonado, con benzodiacepinas en la primera etapa, antiepilepticos de amplio espectro y disponibilidad intravenosa en la segunda (acido valproico, levetiracetam en el EE generalizado y fenitoina en el EE focal), mientras que el tercer nivel varia en funcion de la experiencia de cada equipo.

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, 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).

[Embryology and genetics of primary vesicoureteral reflux and associated renal dysplasia]. / Embriología y genética del reflujo vesicoureteral primario y de la displasia renal asociada.

OBJECTIVES: The main reasons of this review are: To determine some of the embryological and genetic mechanisms of vesicoureteral reflux (VUR) and associated congenital reflux nephropathy (NR); recognize different patterns of familiar clustering and identify appropriate cases where genetic counselling and investigations might be indicated; and finally, to establish the association of these phenomena (VUR and NR). METHODS: Bibliographic search of related articles until June 2007. RESULTS: There are two kinds of primary VUR: isolated VUR and syndromic VUR; the last one has an inherited Mendelian transmission and we know the mechanisms. Epidemiological studies seem to demonstrate that isolated VUR also presents familiar clustering and its inheritance pattern is the main object of interest in some studies; most authors support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. There are lots of candidate implicated genes. The characteristics of VUR (incomplete penetrance, variability of expression, spontaneous resolution...) make difficult to configure a selection of patients subsidiary of genetic study. Despite different treatment options, the incidence of renal chronic failure secondary to VUR has not decreased. Some of the candidate genes identified regulate the position of ureteral budding, a critical step in both kidney and urinary tract development. Analysis of data from humans and mice suggests that some of the renal damage associated with VUR is congenital and is due to a kidney malformation. Therefore, in these cases, the association of VUR and renal failure may be caused by a genetic defect affecting the formation of the kidney and the urinary tract and not by evolution of VUR. Investigation in animals is fundamental to know more about this issue (candidate genes and VUR-NR association). CONCLUSION: It is important to learn patterns of familiar clustering of isolated and syndromic VUR to offer genetic counselling if possible. For this reason, we should be screening carefully all patients suffering from VUR. It is known that limitations in actual indications of genetic study exist. Prenatal diagnosis may be realized if there is a syndromic VUR with known mutation, invariable expressivity or if clinical manifestations involve risk of death. Epidemiological data and laboratory studies may give us guidance to elicit new cases of nephropathy associated to severe VUR.

Embriología y genética del reflujo vesicoureteral primario y de la displasia renal asociada / Embryology and genetics of primary vesicoureteral reflux and associated renal dysplasia

Objetivo: Realizar una aproximación a la embriología y genética del reflujo vesicoureteral (RVU) y de la nefropatía de reflujo (NR). Reconocer los patrones de asociación familiar del RVU y tratar de ver en qué casos se deberían considerar estudios genéticos a estos pacientes y, en tal caso, qué tipo de estudios. Por último, estudiar qué tipo de asociación presentan estos dos fenómenos (RVU y NR). Métodos: Revisión bibliográfica de artículos relacionados hasta junio de 2007. Resultados: Se reconocen dos tipos de RVU primario según la presentación: aislado y sindrómico; de este último se conocen sus mecanismos de transmisión y sigue patrones de herencia mendeliana. Los estudios epidemiológicos ponen de manifiesto que el RVU aislado también presenta asociación familiar, y es objeto de estudio el patrón de herencia del mismo; la mayoría de los autores sostienen la idea de que se trata de un fenómeno genéticamente heterogéneo en el que interactúan diferentes genes y efectos medioambientales. Son múltiples los genes candidatos implicados. Las características del RVU (expresividad y penetrancia variables, resolución espontánea) hacen difícil seleccionar aquellos pacientes subsidiarios de estudio genético. A pesar del tratamiento del RVU, la incidencia de fallo renal crónico secundario al mismo no ha descendido. Algunos de los genes candidatos en estudio para el RVU se han identificado como reguladores de la embriogénesis de la yema ureteral, paso clave para el desarrollo del riñón y tracto urinario. Análisis en ratones y humanos sugieren que parte del daño renal asociado al RVU es congénito y debido a una malformación congénita; por lo que la asociación entre RVU y fallo renal puede deberse a un defecto genético del desarrollo y no a la mala evolución del paciente con RVU. La investigación en animales es un paso clave para profundizar en los conocimientos en este tema (genes candidatos y asociación de RVU con NR). Conclusiones: Es importante conocer los patrones de asociación familiar del RVU (aislado y sindrómico) para dar consejo genético cuando sea posible. Por ello, en todo paciente con RVU, son necesarias una anamnesis y exploración específicas y dirigidas. La indicación actual de estudio genético tiene limitaciones. Se realizará diagnóstico prenatal si existe RVU sindrómico con mutación conocida, expresividad fija y penetrancia completa o si las manifestaciones conllevan riesgo vital. Los datos epidemiológicos y estudios de laboratorio nos orientan a la posibilidad de nefropatía congénita asociada en casos de RVU grave (AU)

Objectives: The main reasons of this review are: To determine some of the embryological and genetic mechanisms of vesicoureteral reflux (VUR) and associated congenital reflux nephropathy (NR); recognize different patterns of familiar clustering and identify appropriate cases where genetic counselling and investigations might be indicated; and finally, to establish the association of these phenomena (VUR and NR). Methods: Bibliographic search of related articles until June 2007. Results: There are two kinds of primary VUR: isolated VUR and syndromic VUR; the last one has an inherited Mendelian transmission and we know the mechanisms. Epidemiological studies seem to demonstrate that isolated VUR also presents familiar clustering and its inheritance pattern is the main object of interest in some studies; most authors support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. There are lots of candidate implicated genes. The characteristics of VUR (incomplete penetrance, variability of expression, spontaneous resolution…) make difficult to configure a selection of patients subsidiary of genetic study. Despite different treatment options, the incidence of renal chronic failure secondary to VUR has not decreased. Some of the candidate genes identified regulate the position of ureteral budding, a critical step in both kidney and urinary tract development. Analysis of data from humans and mice suggests that some of the renal damage associated with VUR is congenital and is due to a kidney malformation. Therefore, in these cases, the association of VUR and renal failure may be caused by a genetic defect affecting the formation of the kidney and the urinary tract and not by evolution of VUR. Investigation in animals is fundamental to know more about this issue (candidate genes and VUR-NR association). Conclusion: It is important to learn patterns of familiar clustering of isolated and syndromic VUR to offer genetic counselling if possible. For this reason, we should be screening carefully all patients suffering from VUR. It is known that limitations in actual indications of genetic study exist. Prenatal diagnosis may be realized if there is a syndromic VUR with known mutation, invariable expressivity or if clinical manifestations involve risk of death. Epidemiological data and laboratory studies may give us guidance to elicit new cases of nephropathy associated to severe VUR (AU)