Les causes génétiques des syndromes avec déficiences intellectuelles sont encore peu élucidées. Les données actuelles disponibles sont très récentes et encore incomplètes. Le syndrome de Mowat-Wilson appartient à ce cadre nosologique. Il associe une déficience intellectuelle profonde et un syndrome polymalformatif comprenant une maladie de Hirschsprung, des anomalies du corps calleux, des anomalies cardiaques et urogénitales. Les causes moléculaires sont, dans la très grande majorité des cas, des mutations tronquantes de ZEB2 (ou SIP1 ou ZFHX1B). Ces anomalies surviennent de novo à l'état hétérozygote. Récemment, nous avons identifié dans notre laboratoire, trois nouvelles mutation faux-sens de ZEB2 chez trois patients ayant un phénotype modéré de la maladie. Nous montrons que ces anomalies moléculaires induisent une perte de fonction de la protéine. Les techniques de sauvetage du phénotype par injection d'ARN ZEB2 sauvage et muté montrent que, chez les embryons morphants sip1b, les protéines mutées participent partiellement au développement des dérivés neuraux et des crêtes neurales.Parallèlement à cette étude, par séquençage de l'exome, nous avons identifié chez un patient atteint de déficience intellectuelle syndromique, une mutation de CSDE1. Ce gène code une protéine à 5 domaines cold-shock, liant l'ARN et régulant la traduction dépendante de l'IRES. C'est la première fois que CSDE1 est impliqué en pathologie. Nous montrons que la mutation entraine une haploinsuffisance et dérégule la traduction de ZEB2. / [Translated by Reverso web site - The genetic causes of the syndromes with intellectual deficiencies are again little clarified. The available current data are very recent and still incomplete. The syndrome of Mowat-Wilson belongs to this nosologique frame(executive). He(it) associates a deep intellectual deficiency and a polymalformatif syndrome understanding(including) a disease of Hirschsprung, anomalies of the corpus callusum, the cardiac anomalies and urogénitales. The molecular causes are, in her(it) very great majority of the cases, tronquantes transfers(transformations) of ZEB2 (or SIP1 or ZFHX1B). These anomalies arise of novo in the heterozygous state. Recently, we identified in our laboratory, three news(short stories) transfer(transformation) misinterpretation of ZEB2 at three patients having a moderate phenotype of the disease. We show that these molecular anomalies lead(infer) a loss of function(office) of the protein. The techniques of rescue of the phenotype by injection of wild and moved ARN ZEB2 show that, to morphants embryos sip1b, moved proteins participate partially in the development of by-products neuraux and neurales crests. In a parallel to(at the same time as) this study, by sequencing of the exome, we identified at a patient's reached(affected) by intellectual syndromique deficiency, a transfer(transformation) of CSDE1. This gene codes a protein in 5 domains cold-shock, linking(binding) ARN and regulating the dependent translation of IRES. It is the first time when CSDE1 is involved in pathology. We show that the transfer(transformation) entraine a haploinsuffisance and deregulate the translation of ZEB2.]

Le terme de neurodéveloppement dans son acception la plus large renvoie à l'ensemble des processus permettant le développement du système nerveux depuis les étapes les plus précoces de sa formation in utero jusqu'aux étapes plus tardives de maturation à l'adolescence aboutissant au système nerveux adulte. Les travaux de ces quarante dernières années ont conduit à proposer un modèle neurodéveloppemental des troubles psychiatriques, notamment schizophréniques, sur la base d'arguments génétiques, épidémiologiques et d'imagerie. Ce modèle propose que l'apparition de la maladie soit liée à une/des anomalie(s) dans les processus de formation (neurodéveloppement précoce) et de maturation (neurodéveloppement tardif) du système nerveux, sous l'effet combiné de facteurs génétiques et environnementaux. Dans ce contexte, ce travail de thèse vise à préciser les effets des anomalies neurodéveloppementales sur les troubles psychiatriques, notamment schizophréniques à travers l'étude de différents marqueurs. La première étude a pour objectif d'étudier les corrélations entre deux marqueurs du développement cérébral précoce : un marqueur clinique (les signes neurologiques mineurs) et un marqueur en imagerie (la sulcation du cortex cérébral) dans une population de sujets atteints de schizophrénie. Une corrélation entre ces deux marqueurs est mise en évidence : l'index de sulcation est d'autant plus faible que les sujets présentent des signes neurologiques mineurs significatifs. Notre conclusion est que l'étude combinée de différents marqueurs peut permettre d'isoler des sous-groupes de patients ayant eu des atteintes neurodéveloppementales précoces plus marquées. La deuxième étude a pour objectif de caractériser l'effet de différents marqueurs d'anomalies neurodéveloppementales précoces sur le fonctionnement cognitif de sujets atteints de schizophrénie. L'effet sur le contrôle exécutif (mesuré par la tâche du Trail Making Test) de marqueurs cliniques (signes neurologiques mineurs, latéralisation manuelle) et en imagerie (sulcation du cortex cingulaire antérieur et élargissement des ventricules ventraux) est mesuré en recherchant les effets principaux et les interactions entre chaque marqueur. Nous trouvons des interactions entre différents marqueurs, avec principalement un effet de sommation non-linéaire. Notre interprétation est que les différents marqueurs reflètent des atteintes distinctes, bien que toutes précoces, du développement cérébral avec un effet final commun sur les fonctions exécutives. La troisième étude a pour objectif de préciser la spécificité de la sulcation comme marqueur d'anomalies neurodéveloppementales précoces à travers son étude dans une population de sujets adultes présentant un trouble du spectre autistique (TSA), pathologie débutant dès la petite enfance, en lien évident avec des atteintes neurodéveloppementales précoces. Des anomalies de sulcation du cortex cingulaire antérieur, similaires à celles observées chez les patients atteints de troubles schizophréniques, sont détectées chez les patients présentant un TSA. Ces résultats sont en faveur d'anomalies neurodéveloppementales précoces partagées entre différentes pathologies psychiatriques : les modifications de la sulcation corticale sont spécifiques non pas d'un trouble donné mais de la précocité des atteintes. En conclusion, nous proposons que l'étude des anomalies neurodéveloppementales soit intégrée dans une approche dimensionnelle en psychiatrie. / The term neurodevelopment in its broadest sense refers to all of the processes encompassing development of the nervous system from the earliest stages of formation in utero to later stages of maturation during adolescence to produce the fully functional adult nervous system. Work over the last thirty years has led to a neurodevelopmental model of human psychiatric disorders, including schizophrenia, based on genetic, epidemiological and imaging evidence. This model asserts that disease is fundamentally linked to or develops from abnormality(s) in the formation processes (early neurodevelopment) and maturation (late neurodevelopment) of the nervous system due to a combination of genetic and environmental factors. In this context this thesis aims to clarify the effects of neurodevelopmental abnormalities on psychiatric disorders, including schizophrenia, through the study of different markers. The first study aims to investigate correlations between markers of early brain development: a clinical marker (neurological soft signs) and an imaging marker (sulcation of the cerebral cortex) in a population of subjects with schizophrenia. A correlation between these two markers is presented: the sulcation index was found to be lower in subjects that had significant neurological soft signs. We concluded that the combined study of different markers may help to isolate subgroups of patients with greater early neurodevelopmental damage. The second study aims to characterize effects of different markers of early neurodevelopmental abnormalities on cognitive functioning in patients with schizophrenia. Effects on executive control (as measured by the Trail Making Test) were correlated with clinical markers (neurological soft signs, handedness) and imaging (sulcation of the anterior cingulate cortex and enlargment of the ventricles). We found interactions between different markers with a mainly non-linear summation effect. Our interpretation is that different markers reflect separate insults, though all early, on brain development with a common final effect on executive function. The third study aims to clarify the specificity of sulcation as a marker of early neurodevelopmental abnormalities by studying a population of adult subjects with autism spectrum disorder (ASD), a patholody beginning in early childhood and linked with evidence of early neurodevelopmental damage. Sulcation abnormalities of the anterior cingulate cortex, similar to those observed in patients with schizophrenia are detected in patients with ASD. These results suggest early neurodevelopmental abnormalities are shared by different psychiatric disorders and that changes in cortical sulcation are not specific to a given disorder but the early damage. In conclusion, we suggest that the study of neurodevelopmental abnormalities should be integrated into a dimensional approach in psychiatry.

Introdução: Recém-nascidos prematuros são considerados vulneráveis às complicações da prematuridade, incluindo o insulto neurológico e os déficits a longo prazo no crescimento e no desenvolvimento. Objetivo: Investigar o desenvolvimento psicomotor e o crescimento de crianças prematuras, nascidas com muito baixo peso, aos 8 e 18 meses de idade corrigida, comparando com seus pares nascidos de termo; e verificar a relação do crescimento com os resultados do desenvolvimento. Método: Estudo de coorte prospectivo, incluindo 83 recém-nascidos com peso de nascimento≤1500g e idade gestacional≤32 semanas, e um grupo controle de 52 crianças nascidas de termo saudáveis. A Alberta Infant Motor Scale (AIMS) e a Escala Brunet-Lèzini (EBL) foram utilizadas para avaliar o desenvolvimento aos 8 e 18 meses de idade (corrigida para a prematuridade - ICo). Medidas antropométricas foram coletadas para avaliar o crescimento nas duas faixas etárias. Resultados: Aos 8 meses de ICo, os prematuros pontuaram significativamente inferior no escore bruto da AIMS (p=0,001). Aos 18 meses, pontuaram significativamente inferior na subescala em pé da AIMS (p=0,040) e apresentaram pobre desenvolvimento psicomotor na EBL (p=0,006). O estado nutricional apresentou diferenças significativas entre os grupos, nas duas faixas etárias (p<0,001). Ocorreu correlação positiva do estado nutricional dos prematuros com a AIMS (r=0,395; p<0,001) e com a EBL (r=0,346; p<0,01) aos 8 meses de ICo; e do perímetro cefálico com a AIMS (r=0,282; p<0,05) aos 18 meses de ICo. Conclusões: Crianças prematuras, nascidas com muito baixo peso, aos 8 e 18 meses de ICo, apresentaram diferenças significativas no desenvolvimento e no padrão de crescimento, quando comparadas aos seus pares de termo. Os resultados demonstram o impacto do crescimento junto ao desenvolvimento, reforçando a importância do acompanhamento multidisciplinar dessa população de risco. / Introduction: Preterm infants are considered vulnerable to the prematurity complications, including the neurological insult and the deficits in the long term growth and development. Objective: To investigate the psychomotor development and growth of preterm infants born with very low weight, at 8 and 18 months corrected age, compared with their peers born at term; and to verify the growth relation with the development results. Methods: A prospective cohort study including 83 infants with birth weight≤1500g and gestational age≤32 weeks, and a control group of 52 healthy term born children. Alberta Infant Motor Scale (AIMS) and Brunet-Lèzini scale (EBL) were used to evaluate the development at 8 and 18 months of age (corrected for prematurity-CA). Anthropometric measurements were collected to evaluate the growth in both age groups. Results: At 8 months of CA, premature infants scored significantly lower in gross score of the AIMS (p=0.001). At 18 months, they scored significantly lower on the standing up subscale from AIMS (p=0.040) and exhibited poor psychomotor development in the EBL (p=0.006). The nutritional status showed significant differences between the groups, in both age groups (p<0.001). There was a positive correlation of nutritional status of preterm infants with the AIMS (r=0.395; p<0.001) and with the EBL (r=0.346; p<0.01) at 8 months of CA; and the head circumference at birth with the AIMS (r=0.282; p<0.05) at 18 months of CA. Conclusions: Preterm infants born with very low birth weight, at 8 and 18 months of CA, showed significant differences in the development and growth pattern, when compared with their peers born at full term. The results demonstrate the impact of growth on the development, reinforcing the importance of monitoring this at risk population.

La navigation des axones sur de longues distances est jalonnée de zones de choix, entraînant des changements de direction pour suivre des trajectoires hautement stéréotypées. Dans ce modèle de guidage séquentiel, chaque étape est vue comme essentielle à la suivante. De façon intrigante, quelques exemples suggèrent que le suivi strict de la trajectoire puisse être dispensable pour que les axones atteignent leur destination finale. Nous nous sommes intéressés à cette capacité trajectoire indépendante des axones à localiser leur cible. Pour ce faire, nous avons utilisé deux populations neuronales de la moelle épinière ayant des cibles diamétralement opposées dans l'organisme : les interneurones dorsaux, qui projettent dans le système nerveux central, et les motoneurones ventraux, qui ciblent les muscles en périphérie. Après avoir été déplacés chirurgicalement dans des embryons de poulet, ces deux populations de neurones envoient des axones vers leurs territoires cibles qu'ils atteignent par des trajectoires inédites. Ces observations suggèrent l'existence d'un système de guidage global délivrant aux axones des informations spatiales à large échelle. Outre les signaux moléculaires de guidage bien connus, les signaux bioélectriques sont également des candidats intéressants pour remplir cette fonction. Des champs électriques (CE) ont été détectés dans les embryons en développement et sont connus pour être des vecteurs d'information spatiale. Nous avons testé sur des neurones en culture si des CE comparables à ceux mesurés pendant le développement embryonnaire pourraient guider l'élongation des axones moteurs et d'interneurones dorsaux de poulet. Nous avons trouvé que les deux types d'axones s'orientent en direction de la cathode (-) dans un CE. Cependant, ils présentent des sensibilités significativement différentes aux CE, qui pourraient contribuer à des choix de trajectoires différents in vivo. Ensuite, nous avons observé un effet inhibiteur de la Concanavaline A (ConA) sur la réponse des axones aux champs, indiquant un rôle des récepteurs membranaires connus pour lier la ConA. Nous avons donc réalisé un screen pharmacologique sur des pompes et des canaux ioniques qui se lient à la ConA, conduisant à l'identification des pompes Na+/K+ ATPases comme des candidats prometteurs. Des expériences préliminaires d'invalidation des sous-unités de ces pompes suggèrent qu'elles contribuent à la réponse aux CE et à la navigation axonale in vitro et in vivo. Finalement, nos résultats apportent une vision nouvelle des mécanismes assurant la fidélité et la résilience du guidage axonal, et révèlent la contribution méconnue des signaux bioélectriques et des pompes Na+/K+ ATPases au développement neuronal / Long distance navigation of axons is marked by choice points, instructing highly stereotyped directional changes of axon trajectories. In this stepwise model, each step is thought to be essential for the next one, but intriguingly, examples suggest that pathway experience can be dispensable for axons to reach their final destination. We investigated pathway-independent ability of axons to locate their target, using two populations of spinal cord neurons having drastically different target location in the organism: the dorsal interneurons, which target the central nervous system and ventral motoneurons, which target muscles. After grafting these neurons at ectopic positions in the chicken embryo, both neuron-types were observed to form axons which, remarkably, oriented towards and reached appropriate targets. This suggests that, in the embryo, an overall guidance information might exist that enables the axons to locate positions over large scales. Beside well-studied chemical cues, bioelectric signals are attractive candidates for this function. Electric Fields (EF) were detected in the embryo and reported to encode spatial information. Thus, using in vitro set-ups, we investigated whether EFs in the range of the ones measured in the embryo could influence the navigation of chick motor and dorsal interneuron axons. We found that both axon subsets orient parallel to EFs. Yet, they significantly exhibited different sensitivities, which could contribute to elicit different trajectory choices in vivo. Next, we found that Concanavalin A (ConA) could block axon response to EF, supporting a role of cell surface receptors known to bind to ConA. Thus, we performed a pharmacological screening on ion channels and pumps that bind ConA and identified Na+/K+ ATPases as promising candidates. Preliminary knock-down experiments targeting Na+/K+ ATPases subunits suggest their contribution to CE response and axon navigation in vitro and in vivo. Collectively, our findings should provide novel insights into the mechanisms ensuring axon guidance fidelity and resilience and reveal unknown contributions of bioelectric signals and Na+/K+ ATPases during neuronal development

Objetivo: Avaliar, em uma coorte de bebês prematuros de muito baixo peso de nascimento, a influência da idade gestacional e da nutrição perinatal no desenvolvimento aos 24 meses de idade corrigida. Método: Foram estudadas 125 crianças pré-termo de muito baixo peso de nascimento nascidas ou internadas em uma unidade de terapia intensiva neonatal nas primeiras 48 horas de vida. Os bebês foram classificados como pequenos para a idade gestacional no nascimento (PIG) e na alta (PIG/PIG); adequados para a idade gestacional no nascimento (AIG) e pequenos para idade gestacional na alta (AIG/PIG); e adequados para a idade gestacional no nascimento (AIG) e na alta (AIG/AIG). A Bayley Scales of Infant and Toddler Development III (BSID-III) foi utilizada para a avaliação do neurodesenvolvimento aos 24 meses de idade corrigida. Resultados: 15 recém-nascidos nasceram ≤ 27 semanas, 73 entre 28-31 semanas e 37 > 31 semanas, as menores pontuações na BSID-III ocorreram no grupo mais imaturo. Por outro lado, 56 foram classificados como PIG/PIG, 55 como AIG/PIG, e 14 como AIG/AIG, não havendo diferença na BSID-III entre estes grupos, embora o grupo PIG/PIG tenha apresentado idade gestacional significativamente maior. Conclusão: Os recém-nascidos que foram PIG/PIG tinham idade gestacional maior do que os outros, e tiveram avaliação do neurodesenvolvimento semelhante, sugerindo que a nutrição perinatal desempenha um papel importante no desenvolvimento aos 2 anos de idade corrigida. / Aim: To assess the influence of gestational age and perinatal nutrition on development at 24 months corrected age in a cohort of very low birth weight preterm infants. Method: 125 very low birth weight preterm infants admitted to a neonatal intensive care unit within the first 48 hours of life were studied. The infants were classified as born small for gestational age (SGA) and still SGA at discharge (SGA/SGA); born adequate for gestational age (AGA) and SGA at discharge (AGA/SGA); and born AGA and still AGA age at discharge (AGA/AGA). The Bayley Scales of Infant and Toddler Development III (BSID-III) were used for assessment of neurodevelopment at 24 months corrected age. Results: 15 neonates were born at ≤27 weeks, 73 at 28–31 weeks, and 37 at >31 weeks with lowest BSID-III scores in the more immature group. 56 were classified as SGA/SGA, 55 as AGA/SGA, and 14 as AGA/AGA with no difference in BSID-III among the groups even though SGA/SGA group had significantly higher gestational age. Conclusion: Neonates who were SGA/SGA had higher gestational age than the others, and they had similar neurodevelopment assessment suggesting that perinatal nutrition plays an important role in development at 2 years corrected age.

Introdução: Recém-nascidos prematuros são considerados vulneráveis às complicações da prematuridade, incluindo o insulto neurológico e os déficits a longo prazo no crescimento e no desenvolvimento. Objetivo: Investigar o desenvolvimento psicomotor e o crescimento de crianças prematuras, nascidas com muito baixo peso, aos 8 e 18 meses de idade corrigida, comparando com seus pares nascidos de termo; e verificar a relação do crescimento com os resultados do desenvolvimento. Método: Estudo de coorte prospectivo, incluindo 83 recém-nascidos com peso de nascimento≤1500g e idade gestacional≤32 semanas, e um grupo controle de 52 crianças nascidas de termo saudáveis. A Alberta Infant Motor Scale (AIMS) e a Escala Brunet-Lèzini (EBL) foram utilizadas para avaliar o desenvolvimento aos 8 e 18 meses de idade (corrigida para a prematuridade - ICo). Medidas antropométricas foram coletadas para avaliar o crescimento nas duas faixas etárias. Resultados: Aos 8 meses de ICo, os prematuros pontuaram significativamente inferior no escore bruto da AIMS (p=0,001). Aos 18 meses, pontuaram significativamente inferior na subescala em pé da AIMS (p=0,040) e apresentaram pobre desenvolvimento psicomotor na EBL (p=0,006). O estado nutricional apresentou diferenças significativas entre os grupos, nas duas faixas etárias (p<0,001). Ocorreu correlação positiva do estado nutricional dos prematuros com a AIMS (r=0,395; p<0,001) e com a EBL (r=0,346; p<0,01) aos 8 meses de ICo; e do perímetro cefálico com a AIMS (r=0,282; p<0,05) aos 18 meses de ICo. Conclusões: Crianças prematuras, nascidas com muito baixo peso, aos 8 e 18 meses de ICo, apresentaram diferenças significativas no desenvolvimento e no padrão de crescimento, quando comparadas aos seus pares de termo. Os resultados demonstram o impacto do crescimento junto ao desenvolvimento, reforçando a importância do acompanhamento multidisciplinar dessa população de risco. / Introduction: Preterm infants are considered vulnerable to the prematurity complications, including the neurological insult and the deficits in the long term growth and development. Objective: To investigate the psychomotor development and growth of preterm infants born with very low weight, at 8 and 18 months corrected age, compared with their peers born at term; and to verify the growth relation with the development results. Methods: A prospective cohort study including 83 infants with birth weight≤1500g and gestational age≤32 weeks, and a control group of 52 healthy term born children. Alberta Infant Motor Scale (AIMS) and Brunet-Lèzini scale (EBL) were used to evaluate the development at 8 and 18 months of age (corrected for prematurity-CA). Anthropometric measurements were collected to evaluate the growth in both age groups. Results: At 8 months of CA, premature infants scored significantly lower in gross score of the AIMS (p=0.001). At 18 months, they scored significantly lower on the standing up subscale from AIMS (p=0.040) and exhibited poor psychomotor development in the EBL (p=0.006). The nutritional status showed significant differences between the groups, in both age groups (p<0.001). There was a positive correlation of nutritional status of preterm infants with the AIMS (r=0.395; p<0.001) and with the EBL (r=0.346; p<0.01) at 8 months of CA; and the head circumference at birth with the AIMS (r=0.282; p<0.05) at 18 months of CA. Conclusions: Preterm infants born with very low birth weight, at 8 and 18 months of CA, showed significant differences in the development and growth pattern, when compared with their peers born at full term. The results demonstrate the impact of growth on the development, reinforcing the importance of monitoring this at risk population.

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-09-06T13:39:22Z No. of bitstreams: 1 arquivototal.pdf: 1210497 bytes, checksum: 5ff208589c9b231bd6d78cd27745e0d7 (MD5) / Made available in DSpace on 2017-09-06T13:39:22Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1210497 bytes, checksum: 5ff208589c9b231bd6d78cd27745e0d7 (MD5) Previous issue date: 2016-03-18 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The essential fatty acids are important lipids for formation of the central nervous system. During pregnancy and lactation the intake need is increased to further development of this system. The conjugated linoleic acid (CLA) is a fatty acid consisting of isomers of linoleic acid. The CLA is naturally produced by ruminant animals and is found in food products such as milk fat and meat of these animals. The CLA has been widely investigated because of its many beneficial health effects, however the effects of CLA on isolated CNS changes at this stage of life have not yet been investigated. This study aims to investigate the impact of maternal diet with different concentrations of CLA during pregnancy and lactation on the neonatal reflex maturation and cognitive function in rats. To this end, three groups were formed: the control group (GC) received a standard diet without added CLA; The GCLA1 group received the experimental diet containing 1% CLA and GCLA3 containing 3% CLA. After birth, the reflex responses were surveyed between 1 and 21 postnatal day, as well as the measurement of head size and body weight. At 42 days old, the animals participated in the habituation to the open field test, the second exposure occured after 7 days. For the evaluation of declarative memory, it was performed for object recognition test 3 days after the habituation test using the open field. After the test the animals were anesthetized and euthanized by cardiac puncture. The analyzes were compared by one way ANOVA test followed by the Holm Sidak test, considering significant difference for p <0.05. We used the Sigma start program for data analysis. The GCLA 1 and GCA3 showed acceleration in reflex maturation of puppies for most of the evaluated parameters. Body weight was higher compared to the control group (p <0.05). To assess the extent of the head, it can be seen that the GCLA1 and GCLA3 presented in laterolateral size measurements when compared to controls. In the anteroposterior extent GCLA1 and GCA3 shown to be lower when compared to the control group on day 1, with an increase in the perimeter evaluated in GCLA3 to compare it GCLA1 on the 7th and 21th day (p <0.05). On habituation in the open field test just wandered GCLA3 least the second open field indicating exposure to facilitating memory (p <0.05). In the long term object recognition test, a significant difference when comparing the time of exploration of familiar object to the time of operation of the new object occured in the GC, GCLA1 and GCLA3. Moreover, with respect to the explored ratio of the objects in GCLA1 there was a significant increase compared to GC and GCLA3 compared with GCLA1 (p <0.05). Maternal treatment with CLA anticipates reflex maturation, increases body weight, head size and improves responses in memory tests in the offspring of rats. / Os ácidos graxos essenciais são lipídios muito importantes para a formação do sistema nervoso central (SNC). Durante a gestação e lactação sua necessidade encontra-se aumentada para melhor desenvolvimento deste sistema. O Ácido Linoleico Conjugado (CLA) é um ácido graxo formado por isômeros de ácido linoleico. Este ácido graxo vem sendo investigado devido aos seus prováveis efeitos benéficos à saúde, porém os efeitos da mistura de CLA sobre alterações do SNC durante a fase de gestação e lactação ainda não foram investigados. Assim, este estudo tem como objetivo investigar o impacto de dieta materna com diferentes concentrações de CLA durante a gestação e lactação sobre a maturação reflexa neonatal e função cognitiva em ratos. Para tanto, foram formados 3 grupos: O Grupo Controle (GC) recebeu a dieta padrão sem adição de CLA; O Grupo GCLA1, a dieta experimental contendo 1% de CLA e o GCLA3, contendo 3% de CLA. Após o nascimento, as respostas reflexas foram avaliadas entre o 1º e 21º dia pós-natal, como também a aferição do tamanho da cabeça e o peso corporal. Aos 42 dias de vida, os animais participaram do teste de habituação ao campo aberto, sendo a segunda exposição após 7 dias. Para a avaliação da memória declarativa, foi realizado o teste de reconhecimento de objetos 7 dias após o teste de habituação, usando o campo aberto. Após os testes os animais foram anestesiados e eutanasiados por punção cardíaca. Os dados foram analisados pelo teste One Way ANOVA seguidas pelo teste de Tukey para os dados paramétricos e o teste Kruskal Wallis para os dados não paramétricos, considerando-se diferença significativa para p < 0,05. Utilizou-se o programa Sigma Start para a análise dos dados. Os GCLA 1 e GCA3 mostraram aceleração na maturação reflexa de filhotes para a maioria dos parâmetros avaliados. O peso corporal foi mais elevado em comparação com o grupo de controlo (p <0,05). Ao avaliar a medida da cabeça, podese observar que o GCLA1 e o GCLA3 apresentaram maior tamanho nas medidas laterolateral quando comparado ao controle. Já na medida anteroposterior o GCLA1 e GCLA3 mostraram-se menor quando comparado ao GC no 1º dia, havendo um aumento no perímetro avaliado no GCLA3 ao compara-lo GCLA1 no 7º e 21º dia (p<0,05). No teste de habituação no campo aberto apenas o GCLA3 deambulou menos na segunda exposição ao campo aberto indicando facilitação da memória (p<0,05). No teste de reconhecimento de objetos a longo prazo, houve diferença estatística significativa quando comparado o tempo de exploração do objeto familiar ao tempo de exploração do objeto novo nos GC, GCLA1 e GCLA3. Além disso, com relação à taxa de exploração dos objetos, no GCLA1 essa diferença foi observada quando comparado ao GC, e o GCLA3 ao GCLA1 (p<0,05). O tratamento materno com CLA antecipa maturação reflexa, aumenta o peso corporal, tamanho da cabeça e melhora respostas em testes de memória na prole de ratas.

Introdução: Recém-nascidos prematuros são considerados vulneráveis às complicações da prematuridade, incluindo o insulto neurológico e os déficits a longo prazo no crescimento e no desenvolvimento. Objetivo: Investigar o desenvolvimento psicomotor e o crescimento de crianças prematuras, nascidas com muito baixo peso, aos 8 e 18 meses de idade corrigida, comparando com seus pares nascidos de termo; e verificar a relação do crescimento com os resultados do desenvolvimento. Método: Estudo de coorte prospectivo, incluindo 83 recém-nascidos com peso de nascimento≤1500g e idade gestacional≤32 semanas, e um grupo controle de 52 crianças nascidas de termo saudáveis. A Alberta Infant Motor Scale (AIMS) e a Escala Brunet-Lèzini (EBL) foram utilizadas para avaliar o desenvolvimento aos 8 e 18 meses de idade (corrigida para a prematuridade - ICo). Medidas antropométricas foram coletadas para avaliar o crescimento nas duas faixas etárias. Resultados: Aos 8 meses de ICo, os prematuros pontuaram significativamente inferior no escore bruto da AIMS (p=0,001). Aos 18 meses, pontuaram significativamente inferior na subescala em pé da AIMS (p=0,040) e apresentaram pobre desenvolvimento psicomotor na EBL (p=0,006). O estado nutricional apresentou diferenças significativas entre os grupos, nas duas faixas etárias (p<0,001). Ocorreu correlação positiva do estado nutricional dos prematuros com a AIMS (r=0,395; p<0,001) e com a EBL (r=0,346; p<0,01) aos 8 meses de ICo; e do perímetro cefálico com a AIMS (r=0,282; p<0,05) aos 18 meses de ICo. Conclusões: Crianças prematuras, nascidas com muito baixo peso, aos 8 e 18 meses de ICo, apresentaram diferenças significativas no desenvolvimento e no padrão de crescimento, quando comparadas aos seus pares de termo. Os resultados demonstram o impacto do crescimento junto ao desenvolvimento, reforçando a importância do acompanhamento multidisciplinar dessa população de risco. / Introduction: Preterm infants are considered vulnerable to the prematurity complications, including the neurological insult and the deficits in the long term growth and development. Objective: To investigate the psychomotor development and growth of preterm infants born with very low weight, at 8 and 18 months corrected age, compared with their peers born at term; and to verify the growth relation with the development results. Methods: A prospective cohort study including 83 infants with birth weight≤1500g and gestational age≤32 weeks, and a control group of 52 healthy term born children. Alberta Infant Motor Scale (AIMS) and Brunet-Lèzini scale (EBL) were used to evaluate the development at 8 and 18 months of age (corrected for prematurity-CA). Anthropometric measurements were collected to evaluate the growth in both age groups. Results: At 8 months of CA, premature infants scored significantly lower in gross score of the AIMS (p=0.001). At 18 months, they scored significantly lower on the standing up subscale from AIMS (p=0.040) and exhibited poor psychomotor development in the EBL (p=0.006). The nutritional status showed significant differences between the groups, in both age groups (p<0.001). There was a positive correlation of nutritional status of preterm infants with the AIMS (r=0.395; p<0.001) and with the EBL (r=0.346; p<0.01) at 8 months of CA; and the head circumference at birth with the AIMS (r=0.282; p<0.05) at 18 months of CA. Conclusions: Preterm infants born with very low birth weight, at 8 and 18 months of CA, showed significant differences in the development and growth pattern, when compared with their peers born at full term. The results demonstrate the impact of growth on the development, reinforcing the importance of monitoring this at risk population.

Objetivo: Avaliar, em uma coorte de bebês prematuros de muito baixo peso de nascimento, a influência da idade gestacional e da nutrição perinatal no desenvolvimento aos 24 meses de idade corrigida. Método: Foram estudadas 125 crianças pré-termo de muito baixo peso de nascimento nascidas ou internadas em uma unidade de terapia intensiva neonatal nas primeiras 48 horas de vida. Os bebês foram classificados como pequenos para a idade gestacional no nascimento (PIG) e na alta (PIG/PIG); adequados para a idade gestacional no nascimento (AIG) e pequenos para idade gestacional na alta (AIG/PIG); e adequados para a idade gestacional no nascimento (AIG) e na alta (AIG/AIG). A Bayley Scales of Infant and Toddler Development III (BSID-III) foi utilizada para a avaliação do neurodesenvolvimento aos 24 meses de idade corrigida. Resultados: 15 recém-nascidos nasceram ≤ 27 semanas, 73 entre 28-31 semanas e 37 > 31 semanas, as menores pontuações na BSID-III ocorreram no grupo mais imaturo. Por outro lado, 56 foram classificados como PIG/PIG, 55 como AIG/PIG, e 14 como AIG/AIG, não havendo diferença na BSID-III entre estes grupos, embora o grupo PIG/PIG tenha apresentado idade gestacional significativamente maior. Conclusão: Os recém-nascidos que foram PIG/PIG tinham idade gestacional maior do que os outros, e tiveram avaliação do neurodesenvolvimento semelhante, sugerindo que a nutrição perinatal desempenha um papel importante no desenvolvimento aos 2 anos de idade corrigida. / Aim: To assess the influence of gestational age and perinatal nutrition on development at 24 months corrected age in a cohort of very low birth weight preterm infants. Method: 125 very low birth weight preterm infants admitted to a neonatal intensive care unit within the first 48 hours of life were studied. The infants were classified as born small for gestational age (SGA) and still SGA at discharge (SGA/SGA); born adequate for gestational age (AGA) and SGA at discharge (AGA/SGA); and born AGA and still AGA age at discharge (AGA/AGA). The Bayley Scales of Infant and Toddler Development III (BSID-III) were used for assessment of neurodevelopment at 24 months corrected age. Results: 15 neonates were born at ≤27 weeks, 73 at 28–31 weeks, and 37 at >31 weeks with lowest BSID-III scores in the more immature group. 56 were classified as SGA/SGA, 55 as AGA/SGA, and 14 as AGA/AGA with no difference in BSID-III among the groups even though SGA/SGA group had significantly higher gestational age. Conclusion: Neonates who were SGA/SGA had higher gestational age than the others, and they had similar neurodevelopment assessment suggesting that perinatal nutrition plays an important role in development at 2 years corrected age.

Objetivo: Avaliar, em uma coorte de bebês prematuros de muito baixo peso de nascimento, a influência da idade gestacional e da nutrição perinatal no desenvolvimento aos 24 meses de idade corrigida. Método: Foram estudadas 125 crianças pré-termo de muito baixo peso de nascimento nascidas ou internadas em uma unidade de terapia intensiva neonatal nas primeiras 48 horas de vida. Os bebês foram classificados como pequenos para a idade gestacional no nascimento (PIG) e na alta (PIG/PIG); adequados para a idade gestacional no nascimento (AIG) e pequenos para idade gestacional na alta (AIG/PIG); e adequados para a idade gestacional no nascimento (AIG) e na alta (AIG/AIG). A Bayley Scales of Infant and Toddler Development III (BSID-III) foi utilizada para a avaliação do neurodesenvolvimento aos 24 meses de idade corrigida. Resultados: 15 recém-nascidos nasceram ≤ 27 semanas, 73 entre 28-31 semanas e 37 > 31 semanas, as menores pontuações na BSID-III ocorreram no grupo mais imaturo. Por outro lado, 56 foram classificados como PIG/PIG, 55 como AIG/PIG, e 14 como AIG/AIG, não havendo diferença na BSID-III entre estes grupos, embora o grupo PIG/PIG tenha apresentado idade gestacional significativamente maior. Conclusão: Os recém-nascidos que foram PIG/PIG tinham idade gestacional maior do que os outros, e tiveram avaliação do neurodesenvolvimento semelhante, sugerindo que a nutrição perinatal desempenha um papel importante no desenvolvimento aos 2 anos de idade corrigida. / Aim: To assess the influence of gestational age and perinatal nutrition on development at 24 months corrected age in a cohort of very low birth weight preterm infants. Method: 125 very low birth weight preterm infants admitted to a neonatal intensive care unit within the first 48 hours of life were studied. The infants were classified as born small for gestational age (SGA) and still SGA at discharge (SGA/SGA); born adequate for gestational age (AGA) and SGA at discharge (AGA/SGA); and born AGA and still AGA age at discharge (AGA/AGA). The Bayley Scales of Infant and Toddler Development III (BSID-III) were used for assessment of neurodevelopment at 24 months corrected age. Results: 15 neonates were born at ≤27 weeks, 73 at 28–31 weeks, and 37 at >31 weeks with lowest BSID-III scores in the more immature group. 56 were classified as SGA/SGA, 55 as AGA/SGA, and 14 as AGA/AGA with no difference in BSID-III among the groups even though SGA/SGA group had significantly higher gestational age. Conclusion: Neonates who were SGA/SGA had higher gestational age than the others, and they had similar neurodevelopment assessment suggesting that perinatal nutrition plays an important role in development at 2 years corrected age.