Orientadores: Maria Valeriana Leme de Moura-Ribeiro, Vanda Maria Gimenes Gonçalves / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T01:04:01Z (GMT). No. of bitstreams: 1 Goto_MauraMikieFukujima_D.pdf: 2655677 bytes, checksum: a6211b2d1e84c6f7b12224b3506f1e05 (MD5) Previous issue date: 2009 / Resumo: A desnutrição intra-uterina tem sido associada à morbidade neurológica em longo prazo, sendo o lactente nascido pequeno para a idade gestacional um modelo de estudo para essa situação. O presente estudo teve por objetivo avaliar e comparar os indicadores do neurodesenvolvimento segundo as Escalas Bayley do Desenvolvimento Infantil, no primeiro ano de vida, entre lactentes nascidos a termo pequenos para a idade gestacional e lactentes nascidos com peso adequado. Foram selecionados 125 neonatos no Centro de Atenção Integral à Saúde da Mulher da UNICAMP, obedecendo aos critérios de inclusão: neonatos cujos pais ou responsáveis legais que assinaram o Termo de Consentimento Informado; que não necessitaram de cuidados especiais; com idade gestacional entre 37 e 41 semanas; com avaliação no 1º, 2º, 3º e 6º, 9º e 12º meses. Foram excluídos neonatos com infecção congênita, malformações diagnosticadas no período neonatal e aqueles resultantes de gestação múltipla. A casuística, composta por 95 lactentes que compareceram para pelo menos uma avaliação programada no 1º ano de vida, foi dividida em dois grupos de acordo com a adequação peso/idade gestacional: grupo PIG, constituído por 33 lactentes com peso ao nascimento abaixo do percentil 10 e grupo AIG por 62 lactentes com peso entre o percentil 10 e 90 da curva de crescimento fetal de Battaglia e Lubchenco (1967). Foram utilizadas as Escalas Bayley de Desenvolvimento Infantil II (1993), aplicadas no 1º, 2º, 3º, 6º, 9º e 12º meses de vida, no Laboratório de Estudos do Desenvolvimento Infantil I. Para a análise de resultados, a casuística do grupo PIG foi reagrupada de acordo com a proporcionalidade corporal ao nascimento em: PIG com crescimento intra-uterino simétrico (PIG-S) e PIG com crescimento intra-uterino assimétrico (PIG-A). Os grupos não apresentaram diferenças na performance nas escalas mental e motora quando classificados em inadequados (Index Score < 85) (IS) e adequados (IS = 85). O grupo PIG apresentou pontuações menores de IS na escala mental nas avaliações do primeiro semestre, sendo que esses resultados foram influenciados pelo grupo PIG-S. No entanto, não houve diferenças estatisticamente significativas em nenhum dos meses analisados. Na escala motora, o grupo PIG apresentou médias menores no 2º e no 12º meses (p = 0,008 e 0,046 Teste Mann-Whitney, respectivamente); e o grupo PIG-S no 2º mês (p = 0,016 Teste Kruskal Wallis). Considerando-se a Escala de Classificação do Comportamento (ECC), observou-se risco de associação à performance inadequada 5,19 vezes maior no grupo PIG (IC95%: 1,03-29,12) no 2º mês de vida. Quando classificados pela proporcionalidade corporal ao nascimento, observou-se risco de associação à performance inadequada 8,39 vezes maior no grupo PIG-S (IC95%: 1,53-57,40) no 2º mês e risco 22,0 vezes maior no grupo PIG-A no 3º mês na ECC. Considerando o perímetro craniano ao nascimento, o lactente nascido com microcefalia apresentou maior proporção com performance inadequada no 1º mês de vida (p = 0,011 Teste Exato de Fisher). Não foram observadas associações na análise univariada considerando-se a associação entre as variáveis biológicas e as relacionadas às condições sócio-demográficas com as performances mental e motora nos meses analisados. No estudo evolutivo comparando-se os resultados obtidos no primeiro semestre e no 9º mês com os resultados do 12º mês observou-se que, em grande proporção, os lactentes que apresentaram performance inadequada nas primeiras três avaliações apresentaram recuperação no 12º mês; os lactentes com performance inadequada no 6º e no 9º mês mantiveram-se inadequados no 12º mês / Abstract: Intrauterine malnutrition has been associated to long-term neurological morbidity and the small for gestational age infant is considered as a model for study this propose. The objective of this study was to evaluate the neurodevelopmental indicators according to Bayley Scales of Infant Development of full-term small-for-gestational age (SGA) infants compared with those born appropriate for gestational age (AGA), in the first year of life. The research design was a prospective study of two cohorts, one of full-term SGA group and other of control AGA group; with cross-sectional data analysis. A hundred and twenty five full-term neonates were selected at Neonatology Service in the Center of Integral Attention to the Woman's Health (CAISM) of the University of Campinas (UNICAMP), São Paulo, Brazil. Ethical permission was obtained from the Research Ethics Committee of the Medical Faculty of UNICAMP and the parents also gave the fully informed consent. They were selected on the following criteria: subjects living in the metropolitan area of Campinas; neonates considered in good health for going home within 2 days after birth; gestational age categorized as full-term (37-41 weeks) by Capurro postnatal method; expected birth weight for determined gestational age by Battaglia and Lubchenco method; birth weight less than the 10th percentile for the SGA group and between the 10th and the 90th percentile for the AGA group. Genetic syndromes, multiple congenital malformations and verified congenital infections (syphilis, toxoplasmosis, rubella, citomegalovirus, herpes) were excluded. The SGA group infants were classified according to body proportionality as symmetric SGA (S-SGA) and asymmetric SGA (A-SGA) for data analysis. All children were scheduled for developmental evaluation by the Bayley Scales of Infant Development II (Bayley, 1993) and two professionals who were unaware of the classification of the neonate's group performed the assessments of the infants, in the presence of their mothers, at 1, 2, 3, 6, 9 and 12 months of age. The infant's score for each item was registered in the Mental and Motor Scale Record Form. A total of 95 infants were performed. No differences were observed in Mental and Motor Scales performance, when classified as adequate (IS = 85) or inadequate (IS < 85). In the Mental Scale, means comparison between the groups showed no statistical differences. Considering the Motor Scale the SGA group showed lower IS means in the 2nd and in the 12th months (p = 0,008 and 0,046, respectively, Mann-Whitney test) and the S-SGA group in the 2hd month of age (p = 0,016 Kruskal Wallis test). Considering the Behavior Rating Scale, the inadequate performance were associated in the 2nd month of life, 5,19 times in higher proportion to SGA group (IC95%: 1,03-29,12) and 8,89 times to S-SGA group (IC95%: 1,53-57,40). In the 3rd month of age, was 22,0 times in higher proportion to A-SGA infants. Considering the occipitofrontal circumference at birth, the microcephalic born infants demonstrated association with inadequate performance in higher proportion in the 1st month of life (p = 0,011 Exact Fisher test) in the Mental Scale. Analyzing the relationship between biologic and socio-demographic variables using the univariate analysis, there was no association with theses variables and mental and motor performances in any month of the first year of life / Doutorado / Neurologia / Doutor em Ciências Médicas

The nervous system is the most complex system in an organism. Functioning of the nervous system requires proper formation of neural cells, as well as accurate connectivity and signaling among them. While the major events that occur during these processes are known, the finer details are yet to be understood. Hence, an attempt was made to look for novel genes that could be involved in them. The focus of the present study is on CG9650, a gene that was uncovered in a misexpression screen, as a possible player in neuronal development in Drosophila melanogaster. The first chapter of the thesis reviews existing knowledge about neuronal development and function. The first section of this chapter explains in brief the formation and specification of neural stem cells, and their differentiation to neurons and glia. Sections 2 and 3 describe neuronal connectivity and signaling with respect to axon growth, synapse formation, function and plasticity. A comparison of invertebrate and vertebrate neuronal development is provided in section 4 of this chapter. This part also explains the use of Drosophila as a model for neuronal development and function. Chapter 2 describes the expression pattern of CG9650, which was characterized to gain insights into the possible role it plays during Drosophila neurogenesis.CG9650 is expressed in multiple cell types in the nervous system at the embryonic stage. Some of the cell sub-types have been identified from their morphology and position. Expression was restricted to neurons in the larval stage (except in the optic lobe, where it was expressed in precursors also), and continued in the pupal stage. No expression was seen in adults (except in the optic lobe). CG9650 has a putative DNA binding region, which bears homology to the mouse proteins CTIP1 and CTIP2, implying that CG9650 is possibly a transcription factor. In order to understand the function of CG9650, the protein was knocked down panneuronally. The resultant animals showed locomotor defects at both larval and adult stages, which have been described in chapter 3. Knock down larvae showed reduced displacement and speed of movement. The number of peristaltic cycles was also reduced in these animals but the cycle period was normal. In adults, movement was uncoordinated and righting reflex was lost, resulting in inability to walk, climb or fly. These results imply a defect in neuronal signaling. Sensory perception was unaffected in these animals. Stage specific knockdown of CG9650 indicated that the requirement for this protein is primarily during the larval stage. All CG9650-expressing neurons in the ventral nerve cord were glutamatergic, implying that its role in controlling locomotor activity is likely through glutamatergic circuits. Following up on these observations, signaling at the neuromuscular junction was assessed in CG9650 knock down animals. Chapter 4 discusses the signaling defects seen on CG9650 knock down, and the possible role of this protein. Electrophysiological recordings from Dorsal Longitudinal Muscles showed reduced and irregular neuronal firing in the knock down animals. These animals also had reduced bouton and active zone numbers. Moreover, overexpression of BRP, an active zone protein, rescued the locomotor defects caused by knock down of CG9650. Chapter 5 reports the effect of over expression of CG9650. Pan-neural over expression of CG9650 resulted in embryos with severe axon scaffolding defects, as well as aberrant neuronal and glial pattern. However, the incorrectly positioned glial cells in these embryos did not express CG9650, indicating that their aberrant positioning was probably due to incorrect signaling from the neurons. In conclusion, this study reports the requirement for CG9650, a hitherto unknown protein, in locomotor activity and signaling, thus ascribing for it a role in neuronal development and function of Drosophila melanogaster.