Bases neurobiológicas del autismo y modelos celulares para su estudio experimental / Neurobiological bases of autism and cellular models for its experimental study

Los trastornos del espectro autista (TEA) son una alteración funcional de la corteza cerebral, que presenta anomalías estructurales del neurodesarrollo que afectan fundamentalmente a la función sináptica y el patrón de conexiones dentro y entre columnas corticales. Desde su aspecto etiológico, el TEA tiene una importante carga genética, considerándose un desorden derivado de una combinación de mutaciones "de novo", asociadas a una predisposición derivada de variaciones comunes heredadas. Las principales anomalías genéticas asociadas a TEA implican genes que codifican proteínas de la sinapsis. Así, en pacientes con TEA se han descrito alteraciones del desarrollo inicial de las sinapsis en los circuitos de conexión entre áreas corticales de procesamiento complejo. La complejidad molecular observada en la predisposición a desarrollar un TEA, junto con la diversidad de fenotipos estructurales neuronales, ha hecho que los modelos animales reproduzcan solo parcialmente el TEA. Para avanzar en el estudio experimental se hace pues necesario desarrollar modelos más representativos, como son los modelos celulares derivados de células humanas. En las últimas décadas, el desarrollo de la biología de las células madre nos da medios para acceder a paradigmas experimentales sobre células derivadas de individuos con TEA. Actualmente, los modelos de células plutipotentes inducidas (IPs) derivadas de células humanas permiten profundizar en el estudio de las bases moleculares y celulares del TEA. Sin embargo, presentan problemas inherentes derivados de la manipulación experimental que conlleva la reprogramación de la expresión génica, por lo que otros modelos celulares se están también postulando como válidos.

Autism Spectrum Disorders (ASD) are a functional alteration of the cerebral cortex, which presents structural neurodevelopmental anomalies that affect synaptic function and the pattern of connections within and between cortical columns. From its etiological aspect, ASD has an important genetic load, considering a polygenic disorder, derived from a combination of "de novo" genetic mutations, associated to a predisposition derived from common inherited variations. The main genetic anomalies associated with ASD involve genes that encode proteins of the synapse. Thus, in patients with ASD, alterations in the initial development of the synapses have been described in the connection circuits between complex processing cortical areas. The molecular complexity observed in the predisposition to develop an ASD, together with the diversity of structural phenotypes, has made animal models reproduce only partially the ASD. To advance in the experimental study it is therefore necessary to develop representative models, such as cellular models derived from human cells. In recent decades, the advances in stem cell biology give us a way to apply experimental paradigms in cells derived from individuals with ASD. Currently, induced pluripotent cells (IPs) derived from human adult cells allow deepening the study of molecular and cellular bases of the neuronal development in humans, as well as the anomalies in this development, which give rise to disorders such as ASD. However, they present inherent problems derived from the experimental manipulation that involves the reprogramming of gene expression, therefore other models are also been explored.

El sueño del niño con trastornos del neurodesarrollo / The sleep in children with neurodevelopmental disorders

El sueño adecuado es necesario para el desarrollo sináptico y la maduración cerebral, un sueño de mala calidad tiene efectos perjudiciales en las funciones cognitivas, de atención, memoria y conducta de los niños. La preocupación sobre la alta prevalencia de los problemas del sueño es amplia en todo el mundo; las consecuencias de estos problemas son incluso más importantes en los niños portadores de trastornos del neurodesarrollo; estos niños a menudo tienen dificultades de inicio y mantenimiento del sueño y despertares nocturnos frecuentes que afectan a sus problemas de conducta. El propósito de este escrito es revisar el estado del arte de los problemas del sueño en los niños con trastornos del neurodesarrollo. En este punto, es importante tener en cuenta el ritmo circadiano, un reloj que genéticamente dirige los ritmos celulares de transcripción, traslación y metabolismos. Este reloj se combina con el ambiente diurno y nocturno coordinando estos mecanismos durante los ciclos luz/oscuridad, sueño/vigilia, frío/calor, ingesta/ayuno, tanto diariamente como en las diferentes estaciones. En conclusión, los problemas del sueño son un factor condicionante de la evolución y calidad de vida de los niños con trastornos del neurodesarrollo, que debe ser tenido en cuenta en todos los casos y ocupar un lugar preferente tanto en la etapa diagnóstica como en la terapéutica.

Adequate sleep is of critical need for a typical synaptic development and brain maturation, a poor quality sleep can have detrimental effects on children's' cognitive attention, memory, mood regulation, and behavior functions. Great concern has been voiced out regarding the high prevalence of poor sleep in children worldwide, the effects of poor sleep may be even more pronounced in children with neurodevelopmental disorders; these children often have difficulties with falling and staying asleep and with night awakenings, this has a strong association with daytime behavior problems. The purpose of this article is to provide an overview of the state of the science of sleep in children with a neurodevelopmental disorder. In this context, it is important to take the circadian cycle into account, a genetically encoded clock that drives cellular rhythms of transcription, translation and metabolism. The circadian clock interacts with the diurnal and nocturnal environment that also drives transcription and metabolism during light/dark, sleep/wake, hot/cold and feast/fast daily and seasonal cycles In conclusion, the sleep problems are a conditioning factor in the evolution and quality of life of children with neurodevelopmental disorders that must be taken into account in all cases and occupy a preferential place in both the diagnostic and the therapeutic stages.

Male sex is an independent risk factor for poor neurodevelopmental outcome at 20 months' corrected age, in human milk-fed very preterm infants: a cohort study / O sexo masculino é fator de risco independente para pior desenvolvimento neurológico na idade corrigida de 20 meses, em lactentes muito prematuros e alimentados com leite humano: estudo de coorte

ABSTRACT Objective: To determine associations between sex and neurodevelopmental outcomes in human milk-fed very preterm infants, adjusted to early measured nutrient intakes and other neonatal cofactors. Methods: Consecutive inborn human milk-fed infants, with gestational age <33 weeks, were eligible. In-hospital energy and protein intakes have relied on measured human milk composition. The Bayley Scales of Infant Development II mental and psychomotor developmental indexes were used to assess neurodevelopment at 20 months' corrected age. After univariate analysis, some covariables were used for linear multiple regression. Results: Thirty-two infants were included, with a mean (standard deviation) gestational age of 29.8 (1.8) weeks, and a median birth weight of 1168g (interquartile range 990-1419g). Minimum recommended intakes were achieved in 63.6% and 15.2% of infants for protein and energy, respectively. The mental and psychomotor developmental indexes were within normal limits in 93.8% of infants. The mean mental and psychomotor developmental indexes were significantly lower in males. Only male sex negatively and significantly affected the mental and psychomotor developmental indexes (B=-9.44; 95%CI: -17.64- -1.23; adjusted r2=0.17; p=0.026), adjusted to gestational age and measured energy intake. Conclusion: In human milk-fed very preterm infants, males had a significantly lower mental and psychomotor developmental indexes score at 20 months' corrected age, adjusted for gestational age and measured energy intake.

RESUMO Objetivo: Determinar a associação entre sexo e desfechos relativos ao neurodesenvolvimento em lactentes muito prematuros e alimentados com leite humano, ajustada para a ingestão de nutrientes medida nos primeiros dias de vida e outros cofatores neonatais. Métodos: Consideramos, para este estudo, lactentes alimentados com leite humano, consecutivamente nascidos em um centro especializado, com idade gestacional <33 semanas. A ingestão intra-hospitalar de energia e proteínas baseou-se na composição medida do leite humano. Os índices de desenvolvimento mental e psicomotor das Bayley Scales of Infant Development II foram usados para avaliar o neurodesenvolvimento na idade corrigida de 20 meses. Após a análise univariada, algumas covariáveis foram usadas para a regressão múltipla linear. Resultados: Incluímos 32 lactentes, com idade gestacional média (desvio padrão) de 29,8 (1,8) semanas e mediana de peso ao nascimento de 1168g (intervalo interquartil: 990-1419g). A ingestão mínima recomendada foi atingida em 63,6% e 15,2% dos lactentes, para proteínas e energia, respectivamente. Os índices de desenvolvimento mental e psicomotor ficaram dentro dos limites normais em 93,8% dos lactentes. A pontuação média nos índices de desenvolvimento mental e psicomotor foi significativamente menor no bebês do sexo masculino. Somente o sexo masculino afetou negativa e significativamente os índices de desenvolvimento mental e psicomotor (B=-9,44; IC95%: -17,64- -1,23; r2 ajustado=0,17; p=0,026), ajustados para idade gestacional e ingestão de energia medida. Conclusão: Em lactentes muito prematuros e alimentados com leite humano, o sexo masculino teve pontuação significativamente mais baixa nos índices de desenvolvimento mental e psicomotor na idade corrigida de 20 meses, ajustada para idade gestacional e ingestão de energia medida.