A prospective cohort study of the prevalence of growth, facial, and central nervous system abnormalities in children with heavy prenatal alcohol exposure.

BACKGROUND: Most children who are exposed to large quantities of alcohol in utero do not develop fetal alcohol syndrome (FAS). Population-based prospective data on the risk of developing components of fetal alcohol spectrum disorders (FASD), however, are limited. METHODS: This was a prospective cohort study of 9,628 women screened during their first prenatal appointment in Chile, which identified 101 who consumed at least 4 drinks/d (exposed) matched with 101 women with no reported alcohol consumption during pregnancy (unexposed). Detailed alcohol consumption data were collected during the pregnancy. Children were evaluated up to 8.5 years of age by clinicians masked to exposure status. RESULTS: One or more functional central nervous system abnormalities were present in 44.0% (22/50) of the exposed children compared to 13.6% (6/44) of the unexposed (p = 0.002). Growth restriction was present in 27.2% (25/92) of the exposed and 12.5% (12/96) of the unexposed (p = 0.02). Abnormal facial features were present in 17.3% (14/81) of the exposed children compared to 1.1% (1/89) of the unexposed children (p = 0.0002) by direct examination. Of the 59 exposed children with data available to detect at least 1 abnormality, 12 (20.3%) had no abnormalities. Binge drinking from conception to recognition of pregnancy (OR = 1.48 per day, 95% CI: 1.15 to 1.91, p = 0.002) and after recognition of pregnancy (OR= 1.41 per day, 95% CI: 1.01 to 1.95, p = 0.04) and total number of drinks consumed per week from conception to recognition of pregnancy (OR = 1.02 per drink, 95% CI: 1.01 to 1.04, p = 0.0009) were significantly associated with abnormal child outcome. CONCLUSIONS: After exposure to heavy alcohol consumption during pregnancy, 80% of children had 1 or more abnormalities associated with alcohol exposure. Patterns of alcohol use that posed the greatest risk of adverse outcomes were binge drinking and high total weekly intake. Functional neurologic impairment occurred most frequently and may be the only sign to alert physicians to prenatal alcohol exposure.

Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis.

Mutations in the methyl-CpG-binding protein 2 (MeCP2) are associated with Rett syndrome and other neurological disorders. MeCP2 represses transcription mainly by recruiting various co-repressor complexes. Recently, MeCP2 phosphorylation at Ser 80, Ser 229 and Ser 421 was shown to occur in the brain and modulate MeCP2 silencing activities. However, the kinases directly responsible for this are largely unknown. Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo. HIPK2 modulates cell proliferation and apoptosis, and the neurological defects of Hipk2-null mice indicate its role in proper brain functions. We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. These data are, to our knowledge, the first that describe a kinase associating with MeCP2, causing its specific phosphorylation in vivo and, furthermore, they reinforce the role of MeCP2 in regulating cell growth.

Identidad personal en niños y adolescentes: estudio cualitativo / Personal identity in children and adolescents: a qualitative study / Identidade pessoal em crianças e adolescentes: estudo qualitative

Resumen (analítico) La construcción de identidad personal es un proceso evolutivo. Escasas investigaciones estudian este proceso en la infancia. El objetivo de esta investigación es describir la construcción de identidad personal de niños y adolescentes entre 6 y 18 años, desde un enfoque constructivista evolutivo. Se realiza un análisis temático de narrativas autobiográficas escritas por 119 niños y adolescentes. Los resultados se organizaron en torno a tres dimensiones de la identidad personal: unidad de identidad, integración de identidad, integración con otros; observándose que desde la infancia hay un reconocimiento personal, luego se integran diferentes eventos vitales significativos y en la adolescencia se complejiza su construcción, incorporando mayor reflexión y aspectos ideológicos. Se discuten implicancias para favorecer un desarrollo adaptativo de la identidad en todas las edades, validando diversidad de opciones.

Abstract (analytical) Construction of personal identity is a developmental process. Few research investigates this process in children. The research objective is to describe the personal identity construction of children and adolescents between 6 and 18 years old, from a developmental constructivist approach. Thematic analysis of autobiographical narratives written by 119 children and adolescents is performed. Results were organized around the three personal identity dimensions: unity of self, integration of self and integration with others. Results show from childhood there is a personal recognition, then different significant life events are integrated, and in adolescense this construction becomes more complex, integrating more reflection and ideological aspects. Implications are discussed to promote an adaptive development of identity through lifespam, validating a diversity of options.

Resumo (analítico) A construção da identidade pessoal é um processo evolutivo. Poucas pesquisas investigam esse processo na infância. O objetivo desta pesquisa é descrever a construção da identidade pessoal de crianças e adolescentes entre 6 e 18 anos, a partir de uma abordagem construtivista evolutiva. É realizada uma análise temática das narrativas autobiográficas escritas por 119 crianças e adolescentes. Os resultados foram organizados em torno de três dimensões da identidade pessoal: unidade de identidade, integração de identidade, integração com os outros; e mostram que desde a infância há um reconhecimento pessoal, logo diversos acontecimentos significativos da vida são integrados, e na adolescência sua construção torna-se mais complexa, incorporando mais reflexão e aspectos ideológicos. As implicações para promover o desenvolvimento adaptativo da identidade em todas as idades são discutidas, validando a diversidade de opções.

Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions.