Dissertations / Theses on the topic 'Child neurology'

Ion channels are macromolecular proteins in cell membranes that control the passage of charged particles including sodium, potassium and calcium ions in and out of cells. Rapid electrical signalling in the nervous system is mediated through the passage of ions through these channels. It is therefore not surprising that genetic mutations in the genes coding for these channels can result in neurological disease. Ion channel disorders or channelopathies have emerged in the last ten to fifteen years as an important new way of understanding neurological disease. Many of these conditions are paroxysmal in nature and include generalised and focal epilepsies, movement disorders and neuromuscular disorders. Some of these conditions follow simple Mendelian inheritance and are rare forms of common disorders such as epilepsy but they provide a useful model for more common neurological diseases with complex inheritance. Some conditions such as Dravet syndrome, a severe infantile onset epilepsy and sodium channelopathy produce devastating consequences for the affected child. In this thesis I will describe the clinical work I have undertaken defining phenotypes of this emerging group of disorders. Detailed phenotyping is the first essential step in characterising new aspects of these genetic disorders. I have collaborated closely with molecular geneticists and cell physiologists in units around the world exchanging ideas in order to better understand the mechanisms of disease and hopefully translate this into better care for patients. The main themes covered in the thesis are episodic ataxias type 1 and 2 (EA1 & 2), benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and Dravet syndrome and other SCN1A related epileptic encephalopathies. In the course of this work I have described novel relationships between EA1 and EA2 and epilepsy, described a novel gene and phenotypes associated with frontal lobe epilepsy, a novel presentation of a potassium channelopathy, a family with a new genetic mechanism for their neonatal convulsions and epilepsy, and children with a novel mechanism for Startle disease (hyperekplexia). I have demonstrated the clinical utility of this translational research by establishing a molecular genetic diagnostic service for sodium channel (SCN1A) related infantile epilepsies. A study of the results from this national UK service shows that genetic diagnosis allows early diagnosis of these epilepsies. This can result in earlier focused treatment, and the hope for better epilepsy control and developmental outcome. I discuss the implications of this work and ongoing and future research projects.

Individuals afflicted with childhood and adolescent mental disorders have an increased risk for poor outcome in adulthood. The progression of psychopathology from childhood to adult life may be influenced by a multitude of interacting variables, both biological and psychosocial. There is limited information on the relationships between child psychopathology and adult personality and personality disorders. The main aim of this thesis was therefore to gain better knowledge concerning adult personality outcome in patients with early onset of mental disorders.

Former child psychiatric patients as compared to controls had a significantly higher prevalence of all DSM-IV personality disorders (38.0 vs. 10.9 percent, p<0.001) and also a considerably higher personality disorder co-morbidity. They also had more psychosocial and environmental problems. This was exaggerated in those diagnosed with a personality disorder. Major depression, disruptive disorders and substance use disorders at a young age were strong predictors for adult personality disorder.

Patients with an early onset major depression had more personality disorders and more deviant personality traits than those with a late onset.

Forensic psychiatric male patients diagnosed with a previous conduct disorder as compared to those without had more cluster B personality disorders, and more repeated violent criminality and mixed abuse. They also exhibited more deviant personality traits and higher psychopathy scores.

The instrument "Child and Adolescent Psychiatric Screening Inventory-Retrospect" had acceptable sensitivity and specificity for assessment of child psychiatric disorders. Subscales demonstrated good internal reliability (Crohnbach´s alpha = 0.76-0.93).

The results suggest that adult personality disturbances are prevalent in individuals affected with mental problems at young ages. A better understanding of the transition of psychopathology from childhood to adulthood and a better identification of those at risk will be of help in attempts to prevent permanent impact on the adult personality.

L’àrea de treball de la present tesi doctoral se situa en el context de les malalties genètiques del metabolisme energètic mitocondrial. Són malalties rares i hereditàries que afecten al conjunt de sistemes que fa servir l’organisme per incorporar i transformar els substrats en energia utilitzable per al correcte funcionament cel·lular. El coenzim Q10 és un component lipídic de totes les membranes cel·lulars que realitza un paper essencial a la cadena respiratòria mitocondrial, però també participa en moltes altres funcions cel·lulars, tan dins dels mitocondris com fora. En l’àmbit pediàtric, la deficiència de coenzim Q10 s’associa a estats de malaltia amb expressions fenotípiques heterogènies, i les causes que la expliquen poden ser primàries o bé secundàries (és a dir, per alteració dels gens implicats en la via de síntesi d’aquesta molècula –deficiència primària–, o per alteració d’altres gens no directament relacionats en la via biosintètica del coenzim Q10 –deficiència secundària). Aquesta deficiència bioquímica implica una disfunció del sistema de la fosforilació oxidativa mitocondrial, i normalment es manifesta de forma multiorgànica, alterant en major o menor grau els diferents òrgans, segons els nivells energètics que requereixen els teixits i d’altres factors no massa coneguts. L’objectiu principal d’aquesta tesi ha estat la millora del diagnòstic de pacients amb deficiències de coenzim Q10, a través de l’estudi sistemàtic d’aquest en diverses espècimens biològics i en associació amb dades clíniques, bioquímiques, histoquímiques, enzimàtiques i moleculars. A través de l’estudi i valoració de grans grups de pacients, s’ha pogut intuir la dinàmica d’aquesta molècula en certs tipus de malalties. Hem pogut descriure tres malalties que s’associen a una deficiència de coenzim Q10 de forma secundària, permetent que pacients afectats puguin beneficiar-se de la suplementació oral amb coenzim Q10, la qual ha demostrat millores clíniques de l’estat de pacients afectats amb patologies mitocondrials. També, hem realitzat avenços metodològics i tècnics, a nivell bioquímic i d’anàlisi de dades, que permetran abordar les classificacions actuals dels pacients amb malalties mitocondrials, en les quals és complicat assolir un diagnòstic molecular definitiu degut a la seva immensa complexitat.
Mitochondrial diseases are genetic rare diseases which affect the energetic cellular system to obtain the required energy for basic survival. Coenzyme Q10 is a lipidic antioxidant located in all eukaryotic cellular membranes that is essential for mitochondrial respiratory chain activity, amongst other important roles not strictly related to mitochondrial function. Coenzyme Q10 deficiency is a biochemical trait defined by low coenzyme Q10 levels in tissues, which can manifest in five main classical phenotypes (from isolated nephropathies to fatal infantile multisystemic disease). The ethiology can be primary (when the genetic defect is in a gene affecting the coenzyme Q10 biosynthetic pathway) or secondary (when the altered gene is not directly related to the coenzyme Q10 biosynthesis), and this partially explains the high heterogeneity observed in these patients. The patophysiology is explained because there is a mitochondrial respiratory chain malfunction that affects the oxidative phosphorylation system and unbalances the antioxidant protection, consequently changing normal cellular behaviour. The main objective of this work has been to improve the diagnosis of patients with coenzyme Q10 deficiency, through the systematic analysis of various biological samples in association with clinical, biochemical, histochemical, enzymatic and molecular data. Through the study and evaluation of big cohorts of patients, we could establish that secondary coenzyme Q10 deficiencies are commoner than primary. Furthermore, we have reported an association of three different diseases with secondary coenzyme Q10 deficient states (GLUT-1 deficiency syndrome, pyrivate dehydrogenase deficiency, mucopolysaccharidosis type III), diseases that could benefit from coenzyme Q10 supplementation, which has demonstrated to produce clinical amelioration in mitochondrial patients. Finally, methodological improvements for coenzyme Q10 deficiency diagnosis were done through two different approaches. One is the analysis of coenzyme Q10 in urinary sediment to assess coenzyme Q10 levels of renal system cells, and the other one is the development of a statistical algorithm which shows the potential of coenzyme Q10 as a mitochondrial activity biomarker.

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Several population-based studies have shown been headache as one of the most common symptoms in childhood. These have provided important consequences in headache diagnosis and treatment, since only about 11% of children with chronic headache seek medical treatment. Objectives: This study aimed at selecting a sample of school-aged children who complained headache in the last year, and to assess the headache prevalence in children and adolescents in São José do Rio Preto city (SJRP), SP. Casuistic and Methodology: A total of 5,232 children and adolescents (aged from 6 to 18 years) from SJRP randomly comprised this sample. They have been attended from the 1st to 8th grade in the year of 2004 in 13 schools: 10 public and 3 private. A questionnaire answered by parents and/or responsibles of children and adolescents was handed out in the schools to collect data. The used variables for descriptive demographic profile of the population were: age, gender, color, grade, and school for descriptive analysis of this population s demographic profile. Results: The majority was women (53.3%), white color (74.7%), and attending from the 1st to 4th grade (60%) and from the 5th to 8th grade (40%) of the elementary school. The returning of questionnaires was 61.7% in the public schools and 60% in the private. Out of the children and adolescents who have answered the questionnaire, 70% reported headache complain in the last year, only 7.2% of them did not. Out of the ones who have complained headache in the last year, 51.5% presented it occasionally during the year; 15.5%% once a month at least, 11.9% monthly and 5.2% daily. A significant difference observed in the study was regarding to the complain between the girls and the boys. More frequent headaches were reported by the girls; daily headache was twice higher than the percentile of the boys (6.6% and 3.6%, respectively). A higher headache frequency with the increase of age was observed in relation to headache and age. Our study has pointed out that headache prevalence was high in this studied population; predominantly the frequency being higher (monthly, weekly and daily) in girls and older age group.
Uma série de estudos populacionais tem mostrado que a cefaléia é um dos sintomas mais comuns na infância. Estes estudos têm importantes implicações no diagnóstico e tratamento das cefaléias, desde que somente 11% das crianças com cefaléia crônica procuram atendimento médico. Objetivos: O objetivo deste estudo foi selecionar uma amostra de escolares que declararam ter sentido dor de cabeça no último ano e estimar a prevalência de cefaléia em crianças e adolescentes da cidade de São José do Rio Preto (SJRP), SP. Casuística e Método: O grupo amostral foi constituído por 5.232 crianças e adolescentes (idades de 6 18 anos) de SJRP, que cursaram da 1ª a 8ª série no ano de 2004 em 13 escolas, sendo 10 públicas e 3 particulares, feita por seleção aleatória. A coleta de dados foi realizada por aplicação de um questionário distribuído nas escolas, respondido pelos pais e/ou responsáveis. As variáveis utilizadas foram: idade, gênero, cor, série e escola para a análise descritiva do perfil demográfico desta população. Resultados: O grupo amostral foi composto na maioria por mulheres (53,3%), cor branca (74,7%), cursando da 1ª a 4ª série (60%) e da 5ª a 8ª série (40%) do ensino fundamental. A taxa de devolução dos questionários foi de 61,7% nas escolas públicas e 60,1% nas particulares. Das crianças e adolescentes que participaram do estudo, 70% declararam ter sentido dor de cabeça no último ano, sendo que somente 7,2% nunca se queixaram de dor. Dos que responderam ter sentido cefaléia no último ano, 51,5% apresentaram cefaléia somente algumas vezes ao longo do ano, 15,5% pelo menos uma vez ao mês, 11,9% semanalmente e 5,2% diariamente. Uma diferença significativa observada em nosso estudo foi relacionada à queixa entre meninas e meninos. Cefaléias mais freqüentes foram relatadas pelas meninas, sendo que a queixa de cefaléia diária entre as meninas foi duas vezes maior que o percentual para os meninos (6,6% contra 3,6%). Observou-se uma relação da cefaléia com a idade, indicando que houve um aumento da freqüência da cefaléia com o aumento da idade. Nosso estudo indicou que a prevalência de cefaléia na população estudada foi alta, com maior predomínio de cefaléias mais freqüentes (mensalmente, semanalmente e diariamente) nas meninas e na faixa etária mais velha.

INTRODUÇÃO: Na população infantil, a presença da privação ou de alterações no padrão do sono interfere em diversos processos orgânicos, além de influenciar no comportamento e humor, no desempenho neuropsicomotor, na cognição e nos relacionamentos sociais e familiares, prejudicando sua qualidade de vida. Entre os métodos diagnósticos utilizados na investigação dos distúrbios do sono para essa população incluise a utilização de questionários. Estes são instrumentos de simples administração que facilitam o diagnóstico e determinam a presença de distúrbios do sono e parassônias em crianças. O Questionário do Sono de Reimão e Lefèvre (QRL) é um instrumento de avaliação subjetiva desenvolvido em território nacional, que validado, contribuirá para pesquisas clínicas e epidemiológicas, facilitando também a prática clínica do profissional que atua nessa área. OBJETIVOS: 1)verificar se as propriedades de validade (consistência interna e reprodutibilidade) do QRL permitem que este assuma o papel de um instrumento específico de avaliação de características e distúrbios do sono para a população infantil; 2)determinar a prevalência dos distúrbios do sono relacionados às crianças de três a cinco anos de idade e aos seus diferentes gêneros; 3)estabelecer as características do padrão de sono para crianças de três a cinco anos e; 4)conhecer os principais hábitos e rituais para dormir que crianças com essa faixa etária manifestam. MÉTODOS: Estudo prospectivo e observacional para a avaliação da consistência interna e reprodutibilidade do QRL. Para a avaliação da consistência interna, 60 crianças entre três e cinco anos de idade foram divididas em três subgrupos após diagnóstico médico: GICrianças com diagnóstico de distúrbio do sono; GII- Crianças sem a presença de qualquer distúrbio do sono; GIII- Crianças com ou sem a presença de distúrbio do sono. Os resultados do QRL foram comparados com o diagnóstico feito pelo médico neurologista especialista na área do sono. Para o estudo da reprodutibilidade, o questionário foi aplicado em 1021 crianças entre três e cinco anos de idade de creches municipais de São Paulo e reaplicado após um período que variou entre 14 e 21 dias. RESULTADOS: Os índices de correlação entre o QRL e o diagnóstico médico foram elevados nos três grupos estudados, com alta consistência interna (0,80 a 0,86) segundo Coeficiente Alfa de Cronbach. As questões do QRL apresentaram alta concordância para a reprodutibilidade (0,798 a 1,000) segundo coeficiente Kappa. O tempo total de sono variou entre 10 e 11 horas para as crianças entre três e cinco anos. A movimentação excessiva durante o sono (48,5%), o ronco (35,8%), sonolência diurna (33,2%) e enurese noturna (21,9%), foram os distúrbios com maior prevalência. A maior parte dos distúrbios do sono ocorreu diariamente, foram mais comuns ao gênero feminino e tenderam a diminuir com a idade. CONCLUSÕES: A consistência interna e a reprodutibilidade do QRL indicaram que esse é um instrumento adequado para avaliar a presença de distúrbios do sono na população infantil. A prevalência dos distúrbios do sono variou de acordo com o gênero, idade e frequência da manifestação
INTRODUCTION: The pediatric population, sleep deprivation and disturbance of sleep pattern influences several organic process, also influences behavior and mood, neuropsychomotor performance, cognition and relationships, and it is detrimental to quality of life. The diagnostic method used in this population also includes the use of questionnaires. Sleep questionnaires are instruments which easily assist to diagnose sleep disorders and parasomnias in children. Infant Sleep Questionnaire Reimão and Lefèvre (RLQ) is an instrument of subjective evaluation, developed in Brazil, and if validated, will be very helpful for clinical and epidemiologic research as well as for clinical practice. OBJECTIVES: Is to check validity (internal consistency and reproducibility) of RLQ and to verify if it could be used as specific instrument of evaluation of sleep disorders in children; To check prevalence of sleep disorders in children between three to five years old of both males and females; To establish characteristics of sleep patterns in children between three to five years old and recognize the habits and rituals used by these children to sleep. METHODS: Prospective and observational study for evaluation of internal consistency and reproducibility of RLQ. For the evaluation of internal consistency, 60 children were studied. Age ranged from 3 to 5 years old of both males and females. After medical diagnosis, they were divided in three subgroups: GI- Children with diagnosed sleep disorder; GII - Children without the presence of any sleep disorder; GIII - Children with or without sleep disorders. The results of RLQ were compared with reports from medical neurologist specialized in sleep disorders. For the reproducibility of RLQ, the questionnaire was applied twice to 1021 children between 3 and 5 years old, in public schools in Sao Paulo, during a period that ranged between 14 and 21 days. RESULTS: The questionnaire showed high reproducibility Kappa 0.798 to 1.0, the internal consistency was high for all three groups (080 to 0.86) second coefficient alpha Cronbach. The total sleep time ranged from 10 and 11 hours for children between 3 and 5 years old. The most frequently sleep disorders reported was restlessness during sleep (48.5), snoring (35.8 %), daytime sleepiness (33.2%) and enuresis (21.9 %). Most sleep disorders occurred daily, were more common in females and decreased with age. CONCLUSIONS: The internal consistency and reproducibility of RLQ suggested that this is an adequate instrument for evaluation of sleep disorders in children. The prevalence of sleep disorders varies with gender, age and frequency of this disorder

Orientadores: Maria Valeriana Leme de Moura-Ribeiro, Vanda Maria Gimenes Gonçalves
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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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

Autism spectrum disorders (ASD) are neurodevelopmental disorders with multiple neurobiological aetiologies, which could be genetic, structural, metabolic or immune-mediated. ASDs are diagnosed with deficits in social communication and restricted and repetitive behaviours, and are associated with sensorial atypicalities. 30% of cases have co-existing epilepsy. A series of in vitro, in vivo and post-mortem investigations were undertaken to examine sensory atypicalities in ASD. In vitro characterisation of hippocampal neuronal cultures using immunofluorescence demonstrated the presence of multiple cell types including neurons, astrocytes and microglia. The distribution of ion channels of the Shaker family and tumour necrosis factor α receptors in astrocytes and neurons were identified but not explored further. Neuroanatomical and neuropathological investigations of primary olfactory cortex, using post-mortem stereology, demonstrated a specific increase in glial cell densities in layer II, which was negatively associated with age in ASD. Increases in glia were also associated with symptom severity and often co-localised with the presence of corpora amylacea in layer I. Qualitative analysis of the olfactory tubercle demonstrated that corpora amylacea did not extend to this neighbouring region of the primary olfactory cortex in ASD. These changes were independent of co-existing epilepsy and not observed in epilepsy without ASD. Preliminary pilot studies of the hippocampus provided a stereological sampling strategy to quantify cell densities in future investigations of this area in ASD. Neurophysiological investigations using collected magnetoencephalography data demonstrated diminished occipital gamma oscillatory synchrony in ASD in a visual time perception task. This did not always predict behavioural outcome but was specific to ASD and could not be explained simply in terms of changes in task performance. Moreover, changes in oscillatory synchrony were associated with symptom severity. These observations in primary sensory domains in post-mortem tissue and in patients suggest possible novel mechanisms in ASD and extend knowledge of the neurobiological bases of these disorders.

Abstract Despite improvements in peri- and neonatal care and an increase in the overall survival of very preterm infants, the incidence of neurologic sequelae has remained high. The pathogenesis of many brain imaging findings, such as white matter damage, WMD, is poorly understood. The factors predisposing to brain damage differ between term and preterm infants. More detailed information is needed of how brain imaging correlates with neurodevelopmental impairment after the neonatal period. The present study investigated the pre- and perinatal factors leading to brain damage and their effects on neurologic and neurodevelopmental outcome in very preterm children. We also analyzed the differences in umbilical cord serum cytokines in term and preterm children with cerebral palsy, CP. Furthermore, the correlations between the findings on diffusion-weighted imaging, DWI, measurements in brainstem auditory evoked potentials, and neurodevelopmental outcome were assessed. We demonstrated that pregnancies complicated by combined histologic chorioamnionitis and placental insufficiency independently predicted abnormal neurologic outcome at 2 years of corrected age. WMD additively predicted poor outcome. Isolated fetal inflammatory response, umbilical cord serum acute phase cytokines (IL-1α, IL-1β, IL-6, IL-8, TNF-α), did not associate with neurologic outcome in either term or preterm children. Instead, a cluster of cytokines different from acute phase cytokines were related to CP, and the protein profile differed between term and preterm children. Disturbed hemodynamics during the pre- and perinatal period affected outcome in very preterm infants. In severe placental insufficiency, fetal cardiac compromise associated with suboptimal neurodevelopmental outcome at 1 year of corrected age. In addition, several clinical factors characterising cardiorespiratory status after birth associated with abnormal neurologic outcome at 2 years of corrected age. We found the apparent diffusion coefficient, ADC, a quantitative measurement of water diffusion, in pons to correlate with the conduction rate of impulses travelling through the auditory tract. We also demonstrated a high value of ADC in corona radiata to associate with poor outcome in gross motor and eye-hand coordination skills at 2 years of corrected age. Both pre- and perinatal factors associate with later outcome in very preterm infants. An isolated fetal inflammatory response does not predict neurologic outcome. Findings on DWI in specific brain regions predict abnormal neurodevelopmental outcome
Tiivistelmä Huolimatta vastasyntyneisyyskauden parantuneista hoitotuloksista ja että yhä useampi hyvin ennenaikaisena syntynyt lapsi jää eloon, heidän neurologisen vammautuneisuuden ilmaantuvuus on edelleen korkea. Monien aivojen kuvantamislöydösten, kuten valkean aineen vaurion, syntymekanismit tunnetaan huonosti. Aivojen vaurioitumiselle altistavat tekijät eroavat täysiaikaisena ja ennenaikaisena syntyneillä lapsilla. Tarvitaan myös aiempaa yksityiskohtaisempaa tietoa aivojen kuvantamislöydösten merkityksestä lasten vastasyntyneisyyskauden jälkeiseen kehitykseen. Tässä tutkimuksessa selvitettiin raskauden- ja syntymänaikaisia tekijöitä, jotka vaikuttavat aivojen vaurioitumiseen hyvin ennenaikaisena syntyneillä lapsilla sekä näiden tekijöiden merkitystä lasten neurologiseen kehitykseen. Tarkastelimme myös napaveren seerumin välittäjäaineiden, sytokiinien, eroavuuksia täysiaikaisena ja ennenaikaisena syntyneillä CP-lapsilla. Lisäksi selvitimme diffuusiomagneettitutkimus- ja aivorunkoherätevastelöydösten sekä neurologisen kehityksen välisiä yhteyksiä. Tämän tutkimuksen mukaan kohdunsisäinen tulehdus ja istukan vajaatoiminta yhtä aikaa esiintyessään ovat poikkeavan neurologisen kehityksen itsenäisiä riskitekijöitä lapsilla 2 vuoden korjatussa iässä tutkittuna. Valkoisen aivoaineen vaurio edelleen lisäsi näiden lasten huonon neurologisen kehityksen ennustetta. Raskauden kestosta riippumatta, sikiön tulehdusvastetta kuvaavat napaveren akuutin vaiheen tulehdusvälittäjäaineet (IL-1α, IL-1β, IL-6, IL-8, TNF- α) eivät vaikuttaneet lapsen neurologiseen kehitykseen. Sen sijaan, CP-lasten napaverestä löytyi erityinen joukko ei-akuutin vaiheen välittäjäaineita. Nämä valkuaisaineet erosivat toisistaan täysiaikaisena ja ennenaikaisena syntyneillä CP-lapsilla. Raskauden- ja syntymänaikaiset verenkierron häiriöt vaikuttivat hyvin ennenaikaisena syntyneiden lasten myöhempään kehitykseen. Vaikeassa istukan vajaatoiminassa sikiön sydämen toiminnan heikkeneminen liittyi lapsen suboptimaaliin neurologiseen kehitykseen 1 vuoden korjatussa iässä tutkittuna. Lisäksi useat syntymänjälkeiset keuhkojen ja verenkierron tilaa kuvaavat kliiniset tekijät liittyivät lapsen poikkeavaan neurologiseen kehitykseen 2 vuoden korjatussa iässä tutkittuna. Tutkimuksemme mukaan, veden diffuusiota määrällisesti kuvaava diffuusiokerroin, ADC, aivosillasta mitattuna, liittyi impulssien johtumisnopeutueen kuuloradastossa. Lisäksi korkea ADC-arvo aivojen sepelviuhkassa liittyi karkean motoriikan ja silmä-käsi-yhteistyötaitojen huonoon kehitykseen 2 vuoden korjatussa iässä tutkittuna. Sekä raskauden- että syntymänaikaiset tekijät vaikuttavat hyvin ennenaikaisena syntyneiden lasten myöhempään kehitykseen. Yksittäinen sikiön tulehdusvaste ei ennakoi lapsen neurologista kehitystä. Tiettyjen aivoalueiden diffuusiokuvantamislöydökset ennustavat lapsen poikkeavaa neurologista kehitystä

Grado de magíster en educación en ciencias de la salud
La evaluación del desempeño clínico, y en particular de la competencia compleja Razonamiento Clínico es un desafío para los equipos docentes a cargo de programas de formación de especialistas. Es necesario contar con herramientas de evaluación válidas, confiables y aceptadas para realizar evaluaciones que den cuenta de esta competencia compleja, tanto en instancias formativas, como sumativas. El Programa de Título de Especialista en Neurología Pediátrica de la Universidad de Chile cuenta con tres centros formadores, ubicados geográficamente en los Campus Norte, Oriente y Centro. Tiene un proceso de evaluación final común para los tres centros formadores, constituido por exámenes orales. Los objetivos de esta investigación fueron comprender desde la percepción de los docentes y egresados del Programa el proceso de evaluación final común a los tres centros formadores, la valoración del Razonamiento Clínico durante el examen final y las eventuales propuestas de mejoras. Se diseñó un estudio cualitativo, con enfoque fenomenológico, y entrevistas semi-estructuradas a los participantes del proceso, usando la triangulación como criterio de rigor principal. Entre enero 2013 y junio 2015 se realizaron 23 exámenes finales, con la participación de 16 docentes. Accedieron a participar de este estudio 11 egresados y 14 docentes. El examen final fue percibido por la mayoría de los participantes como confiable y válido, valorado como importante instancia de aprendizaje y aceptado por los equipos docentes, y en menor medida por los egresados. Sin embargo, al profundizar en las características del examen se observaron importantes problemas de Validez y Confiabilidad, relacionados principalmente con la inexistencia de tabla de especificaciones, y ausencia de pauta de observación de los encuentros clínicos. Además se reconocen que la ansiedad del egresado puede interferir fuertemente con su desempeño, existen dificultades de planificación, diferencias en la ejecución del examen práctico entre los diferentes docentes, ausencia de retroalimentación formal, y poca formación de los evaluadores. La principal barrera reconocida por todos los participantes fue la exigencia del trabajo de investigación para acceder al examen final, pero eliminarlo no se percibe como una solución adecuada. Los docentes reconocieron espontáneamente la necesidad de mejorar el entrenamiento de los evaluadores. Los participantes valoraron el proceso evaluativo previo, y en ese sentido el examen final fue percibido por algunos como una ceremonia o trámite. Respecto del Razonamiento Clínico, la mayoría de los participantes reconocieron la recolección de antecedentes y la realización de un examen neurológico exhaustivo como una etapa fundamental en el proceso. Dentro de las particularidades del Razonamiento Clínico en Neurología Pediátrica destacaron: dimensión desarrollo psicomotor, correlato anátomo-clínico (diagnóstico localizatorio), realización de diagnóstico diferencial amplio y priorización de los problemas por gravedad, frecuencia y posibilidad de tratamiento específico. Los participantes percibieron que esta competencia compleja puede evaluarse en los exámenes prácticos en la medida en que se basen en la observación de encuentros clínicos reales, y en el examen teórico con preguntas adecuadas. Como propuestas de mejoras la mayoría de los participantes coincidieron en sugerir el desarrollo de pautas de observación (rúbricas) del desempeño clínico, desarrollar preguntas pre-establecidas para el examen teórico, mejorar la planificación del examen, y optimizar el desarrollo del trabajo de investigación durante el proceso de formación. En síntesis, el proceso de examen final fue valorado en general positivamente. Sin embargo, se reconocen problemas de Validez y Confiabilidad, que generan la necesidad de incorporar estrategias e instrumentos que lo mejoren, como la observación estandarizada de al menos 10 encuentros clínicos, el desarrollo de preguntas pre-establecidas para el examen teórico, la incorporación de retroalimentación formal y la capacitación de los evaluadores. El proyecto fue aprobado por la Escuela de Postgrado y por el Comité de Ética de Investigación en Seres Humanos de la Facultad de Medicina de la Universidad de Chile (Anexo 1).
The evaluation of clinical competence, and in particular of Clinical Reasoning, is a challenge for the medical teachers. It is necessary to have valid, reliable and accepted tools to perform evaluations that assess for this complex competence, both in formative and summative instances. The Program for Specialization in Pediatric Neurology of the University of Chile has three training centers, located geographically in the North, East and Central Campus. There is a common final evaluation process for the three training centers, consisting in oral exams. The objectives of this research were to understand the final evaluation process from the perception of the teachers and graduates that participate, to understand the evaluation of the Clinical Reasoning during the final examination, and to collect possible proposals for improvements. A qualitative study was designed, with a phenomenological approach, and semi-structured interviews to the participants of the process, using triangulation as a criterion of rigor. Between January 2013 and June 2015, 23 final exams were held, with the participation of 16 teachers. 11 graduates and 14 teachers agreed to participate in this study. The final exam was perceived by most of the participants as reliable and valid, was valued as an important instance of learning and was accepted by the teaching teams, and to a lesser extent by the graduates. However, by looking deeply the characteristics of the examination, important Validity and Reliability problems were observed, mainly related to the lack of a table of specifications and the absence of observation guidelines for clinical encounters. It is also recognized that the anxiety of the graduate can strongly interfere with their performance, there are planning difficulties, differences in the execution of the practical exam between the different teachers, absence of formal feedback, and insufficient training of the evaluators. The main barrier recognized by all the participants (teachers and graduates) was the requirement of performing a scientific research in order to access the final exam. But, eliminating this it is not perceived as an adequate solution. The teachers spontaneously recognized the need to improve the training of the evaluators. The participants valued the previous evaluation processes, and in that sense the final exam was perceived by some as a ceremony. Regarding the Clinical Reasoning, most of the participants recognized the collection of antecedents and the performance of a thorough neurological examination as a fundamental stage in the process. Within the particularities of the Clinical Reasoning in Pediatric Neurology, the following stand out: psychomotor development dimension, anatomical-clinical correlate (localizatory diagnosis), realization of a wide differential diagnosis and prioritization of the problems by severity, frequency and possibility of treatment. The participants perceived that this complex competence can be evaluated in the practical exams insofar as they are based on the observation of real clinical encounters, and in the theoretical examination with adequate questions. As proposals for improvements, most participants agreed to suggest the introduction of rubrics to assess clinical performance, develop pre-established questions for the theoretical examination, improve the planning of the exam, and optimize the development of the research during the training process. In summary, the final examination process was generally valued positively, but Validity and Reliability problems are recognized. Is necessary to incorporate strategies and instruments that improve it, such as the standardized observation of at least 10 clinical encounters, the development of standarized questions for the theoretical exam, the incorporation of formal feedback and improve training of the evaluators.

Background and objectives: Middle- and low-income countries face an increasing burden of mortality and disability due to stroke. The aim of this study was to describe the acute care of ischemic stroke, the impact of increased use of intravenous thrombolysis on disability, and survival in patients hospitalized for stroke in Chile. Methods: We retrospectively analyzed the charts of a sample of patients admitted to public hospitals in the Metropolitan Region of Chile. Subsequently, a discrete-event simulation model was applied to determine the population-based impact of greater use of thrombolysis on disability. Survival and its association with sex, age, geographical area, and health insurance were determined by linking national registries of hospital admissions (2003-2007) with deaths (2003-2010). Results: Of 51,130 patients with an ischemic stroke, survival was 88.9% at 7 days, 81.9% at 30-days, 69.9% at 1 year, and 61.2% at 3 years. When adjustment was performed by age, patients with private health insurance (high income) had a lower probability of dying than their lower-income counterparts with public health insurance (HR private health insurance: 0.53). Patients in the north and south of the country had a high probability of dying than those in the center. Adherence to performance measures in hospitals in the Metropolitan Region was low and varied among centers. A total of 23.6% of patients was diagnosed with post-stroke pneumonia. Thrombolysis was administered to only 1.7%. There is no population impact in disability if the current utilization rate is left unchanged. Administering thrombolysis to all patients who currently receive diagnostic confirmation within the 4.5-hour therapeutic window (11.6%) would avoid 779 cases of disability and increase utilization to 25% would prevent 1,783 at the end of the simulation (2017). Conclusions: Organizational changes in the care of stroke are urgently needed. Measures should be intensified in the groups with the worst results.
Antecedentes y Objetivos: Los países de ingresos medios-bajos enfrentan una creciente carga de mortalidad y discapacidad por enfermedades cerebrovasculares (ACV). El objetivo fue describir el cuidado agudo de los ictus-isquémicos, el impacto en discapacidad del incremento de la utilización de trombolisis y la supervivencia de pacientes hospitalizados por ACV en Chile. Métodos: Se revisaron retrospectivamente las historias médicas en una muestra de pacientes admitidos en hospitales públicos de la principal área metropolitana de Chile (RMS). Se aplicó un modelo de simulación de eventos discretos para determinar el impacto poblacional en discapacidad del incremento de utilización de trombolisis. La supervivencia y la asociación por género, edad, territorio y seguro de salud, se obtuvo vinculando los registros nacionales de egresos hospitalarios (2003-2007) con las defunciones (2003-2010). Resultados: De 51.130 pacientes con ictus-isquémico, la supervivencia al séptimo-día fue 88,9%, a 30-días 81,9%, al año 69,9% y a tres años 61,2%. Ajustando por edad, los pacientes con seguro privado de salud (ingreso altos) tenían una probabilidad menor de morir que sus pares de seguro público de menores ingresos (HR seguro privado: 0,53). Los pacientes de la zona norte y sur tenían una mayor probabilidad de morir, comparado con la zona central de Chile. La adherencia de los hospitales públicos-RMS a las medidas de desempeño fue baja y con variabilidad entre centros. Un 23,6% presentó diagnóstico de neumonía post-infarto. La utilización de trombolisis fue solo 1,7%. De mantenerse esta utilización, no hay impacto poblacional en reducir discapacidad. Aumentar a que todos los pacientes que actualmente son confirmados antes de 4.5 horas (11,6%) sean trombolizados evitaría 779 personas discapacitadas y aumentar al 25% de utilización evitaría 1.783 al final de la simulación (2017). Conclusiones: Es urgente implementar cambios organizacionales en la atención de los ACV, intensificando las medidas en grupos que muestran peores resultados.

Objetivos: Avaliar o desenvolvimento neuropsicomotor de crianças com Sequência de Robin isolada (SRI), submetidas ao tratamento de obstrução das vias aéreas conforme protocolo do Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo (HRAC/USP), com intubação nasofaríngea (INF) ou tratamento postural. Verificar se o desenvolvimento neuropsicomotor do grupo INF difere do grupo postural, e avaliar a eficácia da INF em evitar sequelas de hipóxia. Materiais e Métodos: Estudo prospectivo realizado no HRAC/USP, com crianças com SRI, de 2 a 6 anos, divididas em dois grupos de acordo com o tipo de tratamento realizado: INF (Grupo 1), e postural (Grupo 2). Dados do tempo de uso da INF e sonda nasogástrica (SNG), cirurgia de miringotomia, classificação socioeconômica, grau de escolaridade dos pais, entre outros, foram coletados. Os participantes foram avaliados por meio do Teste de Screnning de desenvolvimento de Denver II (Teste de Denver II) e Exame Neurológico Evolutivo Adaptado (ENEA). Resultados: Total de 62 crianças foram avaliadas, sendo 38 do Grupo 1 e 24 do Grupo 2. Os resultados do Teste de Denver II demonstraram que 73,7% das crianças do Grupo 1 e 79,2% do Grupo 2 apresentaram desenvolvimento normal. Os resultados do ENEA apresentaram-se normais para 89,5% das crianças do Grupo 1 e 87,5% do Grupo 2. Não houve diferença significativa entre os dois grupos no Teste de Denver (p=0,854) e no ENEA (p=0,789). Realizaram a miringotomia 47,3% das crianças do Grupo 1 e 58,3% do Grupo 2. Nos resultados dos dois testes, a área do desenvolvimento mais prejudicada foi a linguagem, o que pode ser reflexo das oscilações de audição e da disfunção velofaríngea. Houve concordância moderada (k=0,563) entre os resultados dos dois testes aplicados no Grupo 1, e concordância substancial (k=0,704) no Grupo 2. O tempo médio de uso da INF foi de 60 ± 28 dias. Na análise socioeconômica do Grupo 1, 42,1% se encaixavam na classificação baixa superior, e 28,9% na média inferior; no Grupo 2, 20,8% se encaixavam na baixa inferior, e 58,3% na baixa superior, sem diferença entre os grupos (p=0,211). Não houve associação significativa entre a classificação socioeconômica e os resultados dos testes de desenvolvimento aplicados. O nível de escolaridade mais encontrado entre os pais dos participantes foram: 3º grau completo (Grupo 1) e 2º grau completo (Grupo 2), sem diferença estatística entre os grupos. Conclusões: A maioria das crianças com SRI tratadas com INF apresentaram desenvolvimento neuropsicomotor normal, semelhante aos casos menos graves do grupo postural. As crianças tratadas com INF não apresentaram sinais clínicos evidentes de sequelas neurológicas da hipóxia.
Objectives: To assess the neurological and psychomotor development of children with Isolated Robin Sequence (IRS), submitted to the treatment of airway obstruction according to the protocol of the Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC/USP), with nasopharyngeal intubation (NPI) or postural treatment. Verify if the neurodevelopment of the NPI group differs from postural group, and evaluate the effectiveness of NPI to prevent sequels of hypoxia. Materials and Methods: Prospective study conducted at HRAC/USP, with children SRI, with 2 to 6 years old, divided into two groups according to the type of treatment performed: NPI (Group 1) and postural (Group 2). Time data of use NPI, nasogastric tube (NGT), myringotomy surgery, socioeconomic status, education level of parents, among others, were collected. Participants were assessed through the development of Screnning Denver II Test (Denver II) and Neurologic Evolutionary Examination Adapted (NEEA). Results: The total of 62 children was evaluated, being 38 in the Group 1 and 24 in the Group 2. The results of the Denver Developmental Screening Test II showed that 73.7% of Group 1 and 79.2% of Group 2 presented with normal development. The results of NEEA had presented normal for 89.5% of children in the Group 1 and 87.5% in the Group 2. There was no significantly difference between the two groups at Denver Test (p=0.854) and in the NEEA Test (p=0.789). The myringotomy was performed by 47.3% of children in the Group 1 and 58.3% of children in the Group 2. The results showed language as the most impaired area, which may reflect fluctuations of hearing and velopharyngeal dysfunction. There was moderate agreement (k=0.563) between the results of the two tests applied in the Group 1, and substantial agreement (k=0.704) in the Group 2. The average time of use of the NPI was 60 ± 28 days. In the socioeconomic analysis of Group 1, 42.1% fit the low ranking higher, and 28.9% in the average lower. In the analyses of Group 2, 20.8% were in the low ranking lower, and 58.3% were in the low ranking the top. There was no different statistic between groups (p=0.211). There was no significant association between socioeconomic status and results of development tests performed. The levels of education most found between the participants parents were: completed graduation (Group 1), and secondary school (Group 2) with no statistical difference between groups. Conclusions: Most of children with IRS treated with NPI showed normal neurological and psychomotor development, similar of minor cases of postural group. The children treated with NPI didn\'t show evident clinical signs of neurological sequels of hypoxia.

Orientador: Sylvia Maria Ciasca
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A restrição de crescimento intra-uterina (RCIU) tem sido associada à maior mortalidade perinatal e maior morbidade no neonatal e lactente. Todavia, persiste considerável controvérsia em relação ao desenvolvimento neuromotor, no que se refere ao desempenho inferior dos nascidos a termo pequenos para a idade gestacional (PIG). O presente estudo teve por objetivo avaliar e comparar o desenvolvimento das habilidades motoras finas de lactentes a termo PIG com a termo adequados para a idade gestacional (AIG) no 6º, 9º e 12º meses. Tratou-se de um estudo seccional e longitudinal. Foram selecionados 125 recémnascidos (RN) no Centro de Atenção Integral à Saúde da Mulher (CAISM) da Universidade Estadual de Campinas (UNICAMP). A casuística foi composta por 95 lactentes que compareceram em pelo menos uma avaliação entre o 6º, 9º e 12º meses. Foram estudadas duas coortes de lactentes 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 incluídos: RN cujos pais ou responsável legal assinaram o Termo de Consentimento Livre e Esclarecido, com idade gestacional entre 37 e 41 semanas, residentes na região metropolitana de Campinas, que permaneceram no alojamento conjunto, resultantes de gestação de feto único. Foram excluídos: RN com síndromes genéticas, malformações e infecções congênitas. Como instrumento de avaliação foram utilizadas as Bayley Scales of Infant Development-II (1993). Na análise dos resultados para o perfil sócio-demográfico da família, foi evidenciado que no grupo PIG houve maior número de mães sem ocupação fora do lar e que tinham o hábito de fumar. No estudo seccional, o index score (IS) motor demonstrou diferença entre os grupos PIG e AIG no 6º e 12º meses de vida. Houve diferença significa entre os grupos na escala cognitiva para duas provas no 6º mês e uma prova no 9º mês. No estudo longitudinal, para o IS cognitivo houve diferença significativa apenas entre os meses avaliados, sendo que o 6º mês foi diferente do 9º e do 12º mês. Para o IS motor, observou-se diferença significativa entre os grupos PIG e AIG e entre os meses, sendo o 6º mês diferente dos demais. Para as provas avaliadas, não houve diferença entre os grupos, porém, entre os meses encontrou-se diferença significativa em 12 provas cognitivas e uma prova motora. Concluí-se que os lactentes nascidos a termo PIG estão sob maior risco para o desenvolvimento neuromotor atípico, em especial para as habilidades motoras finas, no 6º, 9º e 12º meses de vida
Abstract: Intrauterine growth restriction (IUGR) has been associated with higher perinatal mortality and major morbidity in newborns and infants. However, there is still considerable controversy regarding the neuromotor development with reference to the inferior performance of term infants born small for gestational age (SGA). The present study aimed to evaluate and compare the fine motor skill development in term infants born SGA and term infants born appropriate for gestational age (AGA) on the 6th, 9th and 12th months of life. This was a cross-sectional and prospective study. One hundred and twenty-five fullterm newborns were selected at the Neonatology Service in the Center of Integral Attention to Women's Health (CAISM) of the University of Campinas (UNICAMP); however, only 95 infants comprised the sample, who attended at least one assessment among 6, 9 and 12 months. Two cohorts of infants were studied according to the adequacy of gestational age/weight: the SGA group comprised 33 infants with birthweight under the 10th percentile and the AGA group comprised 62 infants with birthweight between the 10th and 90th percentiles of fetal growth curves (Battaglia & Lubchenco, 1967). Inclusion criteria were: newborns whose parents or legal guardian signed a consent form, with gestational ages between 37 and 41 weeks, resident in the Metropolitan Region of Campinas, who stayed in nursery, resulting of single fetus pregnancies. Exclusion criteria were: infants with genetic syndromes, malformations and congenital infections. Bayley Scales of Infant Development- II (1993) were used as evaluation tools. In the analysis of results for the family's sociodemographic profile, it was evidenced a great number of mothers in the SGA group with no occupation outside the home and who had the smoking habit. In the cross-sectional study, the motor index score (IS) showed differences between SGA and AGA groups at 6 and 12 months. There was a significant difference between groups in cognitive scale for two tests during the sixth month and one test during the 9th month. In the longitudinal study, there was a significant difference among the months for the cognitive IS, i.e. the 6th month was different from the 9th and the 12th months. Significant differences were found between SGA and AGA groups and among the months for the motor IS, i.e. the 6th month was different from others. There were no differences between groups for the tests; however, a significant difference was found among the months in 12 cognitive tests and one motor test. We concluded that term infants born SGA are at higher risk for atypical neuromotor development, particularly for fine motor skills at 6th, 9th and 12th months of life
Doutorado
Ciencias Biomedicas
Doutor em Ciências Médicas

Introdução: O aperfeiçoamento da assistência pré-natal e dos cuidados intensivos neonatais contribuiu para a redução da mortalidade dos recémnascidos (RN) com riscos para alterações do desenvolvimento neuromotor. Apesar destes avanços, a difícil previsão e prevenção de danos neurológicos está associada ao aumento de crianças com problemas graves como a Paralisia Cerebral (PC). Das avaliações disponíveis atualmente, a que possui melhor valor preditivo de danos neurológicos em bebês até os cinco meses de idade é a \"Avaliação Qualitativa dos Movimentos Generalizados (MGs)\" de Prechtl. No entanto, apresenta pouca aderência na prática clínica devido à sua subjetividade e necessidade de treinamento prévio para aplicação. Objetivos: Desenvolver e analisar a confiabilidade de uma escala de avaliação baseada nos MGs caracterizados a partir da avaliação qualitativa de Prechtl em recémnascidos e lactentes com riscos para alterações no desenvolvimento neuromotor. Método: Estudo observacional transversal com a participação de 30 RNs e lactentes com idade compreendida entre 31 semanas pós-menstrual e 17 semanas pós-termo avaliados no Hospital Universitário da USP. Os MGs normais e anormais foram avaliados segundo a análise qualitativa dos MGs de Prechtl seguindo as três fases: pré-termo (n=7), writhing movements (n=13) e fidgety movements (n=10). A escala foi construída baseando-se nestas fases e foram elaboradas duas versões, sendo analisadas as confiabilidades inter e intra-examinador por meio do ICC e do índice de Kappa. A consistência interna da versão final foi analisada através do alfa de Cronbach. Resultados: Foram analisadas duas versões da escala com três diferentes sistemas de pontuação: respostas do tipo \"SIM ou NÃO\"; do tipo \"SEMPRE, ALGUMAS VEZES e NUNCA\"; e \"SEMPRE, QUASE SEMPRE, ALGUMAS VEZES, QUASE NUNCA E NUNCA\". Os resultados mais significativos foram obtidos com as respostas binárias (SIM ou NÃO), sendo que nas fases pré-termo e writhing movements a pontuação máxima é de 32 pontos e na fase dos fidgety movements é de 12 pontos. A análise da confiabilidade da versão final da escala evidenciou concordância excelente tanto para a confiabilidade intra-avaliador (ICCs: 0.914 a 0.999; Kappa: 0.6 a 1 e 0.606 a 1, considerando a escala binária), como para confiabilidade inter-avaliadores (ICCs: 0.871 a 0.966 para avaliação 1; Kappa: 0.682 a 0.775 para avaliação 1, considerando novamente a escala binária). Apenas o índice Kappa neste caso apresentou concordância boa. Os valores de alfa de Cronbach se mostraram de bons a excelentes (0.866 a 0.980). Verificou-se também que os bebês com MGs anormais apresentaram pontuação abaixo de valores entre 20 e 25 na fase pré-termo e dos writhing movements, e abaixo de valores entre 8 e 12 na fase dos fidgety movements. Conclusão: Foi possível desenvolver uma escala capaz de quantificar os MGs, com pontuação capaz de diferenciar MGs normais de anormais, com excelente confiabilidade inter e intra-avaliador e alta consistência interna. A escala apresenta grande relevância clínica e, aliada ao treinamento no método qualitativo, torna-se um instrumento promissor para a detecção precoce de riscos para atraso do desenvolvimento neuromotor e seleção dos RNs e lactentes para acompanhamento e intervenção precoce
Introduction: The technological improvement of neonatal care and intensive care contributed to reduction of preterm newborn (PTNB) mortality. Despite these improvements, is still difficult to predict and prevent neural damage and neurobehavioral impairments, which are associated to higher proportion of children with severe neurological problems, such as Cerebral Palsy (CP). Between all the available methods of babies\' assessment and examination, the Prechtl´s Method of Qualitative Assessment of General Movements (GMs) shows the higher predictive value to neurological damage. Nevertheless, this assessment is not widely used because of its subjectivity and the necessity of training of the examiners. Objective: To develop a quantitative scale based on GMs in the newborn and infant, and to verify its reliability. Method: Crosssectional observational study involving 30 newborns and infants aged between 31 weeks postmenstrual age and 17 weeks post term age assessed at university hospital of University of São Paulo. The normal and abnormal GMs were evaluated based on the Prechtl´s Method of Qualitative Assessment of GMs following the three phases: preterm GMs (n=7), writhing movements (n=13) and fidgety movements (n=10). The scale was developed based on these phases and Kappa and ICC statistics were applied in the reliability analysis (inter- and intra-observer agreement). Cronbach alpha was applied in the internal consistency analysis. Results: Two versions of the scale were analyzed with three different scoring systems: \"YES or NO\"; \"ALWAYS, SOMETIMES and NEVER; \"ALWAYS, OFTEN, SOMETIMES, ALMOST NEVER and NEVER\". The most significant results were obtained with \"YES or NO\" answers. The total score obtained in preterm and writhing movements phases was 32 points and in the fidgety movements phase was 12 points. Considering the assessment with the final version of the scale, high to very high inter- (ICCs 0.871-0.966; Kappa 0.682-0.775 for the first evaluation, considering \"YES or NO\" answers) and intra-observer reliability (ICCs: 0.914-0.999; Kappa: 0.6-1, considering \"YES or NO\" answers) was found. High to very high Cronbach alpha values was also found (0.866-0.980). The infants showed abnormal GMs score below values between 20 and 25 in preterm phase and writhing movements, and below values between 8 and 12 at fidgety movements age. Conclusion: It was possible to develop a scale able to quantify GMs, with scores that can differentiate normal from abnormal GMs, with excellent inter- and intra-observer reliability and internal consistency. The scale has great clinical relevance and, combined with training in qualitative method, it is a promising tool for early detection of risks for delayed neuromotor development and screening of newborns and infants for monitoring and early intervention

UVOD: Početak multiple skleroze (MS) u dečijem uzrastu je dijagnostički i terapijski izazov. I ako rani početak MS-a uglavnom ukazuje na dobru kratkoročnu prognozu, neka deca razviju tešku onesposobljenost, fizičku ili kognitivnu, a više od 50% obolelih uđe u sekundarno progresivnu formu bolesti pre 30. godine života. Rana dijagnoza je neophodna za uvođenje imunomodulatorne terapije, kojom se obezbeđuje dobra dugoročna prognoza. CILJ: Analiza parametara koji bi omogućili ranu dijagnozu multiple skleroza sa ranim početkom u odnosu na simptome, sprovedene dijagnostičke procedure i tok bolesti. Sagledavanje inicijalnih kliničkih manifestacija multiple skleroze, prisustva ologoklonaliteta, nalaza MRI endokranijuma i njihovih osobenosti u dečijoj populaciji uz komparaciju sa inicijalnim kliničkim manifestacijama kod pacijenata obolelih od multiple skleroze u odraslom dobu. MATERIJALI METODE: Ova retrospektivno/ prospektivna studija obuhvata pacijente lečene na Klinici za neurologiju KCV u Novom Sadu u periodu od dvanaest godina, od januara 2003. godine do januara 2015. godine sa znacima i simptomima inicijalne demijelinacione bolesti CNS. Od ove kohorte izdvojeno je dve grupe pacijenata; prva grupa pacijenata kod kojih je bolest nastala pre 18. godine života, i druga grupa uzrasta od 20-55 godina. Pacijenti su epidemiološki obrađeni prema godinama početka bolesti, polu, porodičnoj istoriji, simptomima na početku bolesti (inicijalni simptom), toku bolesti- pojavi drugog relapsa i vremena do pojave drugog relapsa, nalazu MRI, nalazu evociranih potencijala i prisustvo oligoklonalnih traka u likvoru. Tokom praćenja beleži se vreme do drugog relapsa i tip relapsa. Tražila se korelacija između kliničkih i dijagnostičkih rezultata sa brzinom pojave drugog relapsa. Za testiranje razlika između grupa korišćen je Pirsonov hi-kvadrat test, a za testiranje jačine povezanosti korišćeno je Kramerovo V. Neparametrijski podaci su obrađivani Men-Vitni U testom. REZULTATI: Od ukupnog broja ispitanika, u grupi pacijenata sa ranim početkom MS-a odnos ženskog i muškog pola je bio 1,3:1, a u grupi pacijenata sa uobičajenim početkom MS-a 2,2:1. Iz dobijenih rezultata vidimo da ima manje nego što je očekivano pacijenata rođenih u mesecima decembru 4,6% i januaru (5,9%), a više nego što je očekivanu u mesecima martu (11,3%) i julu (10,6%), što nije statistički značajno (p=0,726). Prema manifestaciji bolesti kod dece 17,6% ima polisimptomatski početak, a kod odraslih 37,6% ima polisimptomatski početak.Polisimptomatski početak statistički je značajno više zastupljen kod odraslih pacijenata (p=0,020).Poremećaj piramidnog sistema (P=0,010) i senzorne smetnje (P=0,006) su zastupljeniji kao inicijalni stimptom u grupi odraslih.Nisu nađene statistički značajne razlike u zastupljenosti optičkog neuritisa (p=0,366 ili p>0,05) i ataksije /stablarne simptomatologije (p= 0,791) u ove dve grupe. Najčešći inicijalni simptom kod dece, gotovo u istoj razmeri su optički neuritis (35,3%) i ataksija (35,3%). U grupi odraslih pacijenata senzorne smetnje (41,6%) su najčešći inicijalni simptom, odmah za njim sledi piramidna simptomatologija (37,6%). Prema nalazu broja lezija na MRI pregledu, u grupi ispitanika sa ranim početkom MS-a više su zastupljeni oni sa manje od 4 lezije, nego što je to slučaj u grupi odraslih. Odnos broja pacijenata sa 4-10 i preko 10 lezija simetričan je u obe grupe. Korelacija između doba početka MS-a i broja lezija viđenih na MRI je statistički značajna i neznatna (P=0,06). Nije nađena statistička značajnost u prisustvu lezija u korpusu kalozumu između ove dve grupe pacijenata ( P=0,920). Primenom Fišerovog dvostranog egzaktnog testa koji je u ovom slučaju statistički značajan (p=0,034), možemo reći da se grupa sa ranim početkom MS-a i ona sa uobičajenim početkom statistički značajno razlikuju, tumefaktivne lezije su prisutnije kod ispitanika sa ranim početkom MS-a. Pozitivni oligoklonali su zastupljeniji u grupi odraslih pacijenata ( P= 0,018). U našoj grupi ispitanika kada smo pratili vreme pojave drugog pogoršanja, najkraće godinu dana, u grupi dece 11 pacijenata (21,6%) nije imalo pogoršanje , dok je 40 pacijenata imalo pogoršanje (78,4%),. Medijana kod grupe dece za pojavu drugog šuba bolesti je 12 meseci. U grupi odraslih 22 pacijenta ( 21,8%) nije imalo drugi relaps tokom perioda praćenja, dok je njih 79 (78,2%) imalo drugi relaps. Prosečno vreme u grupi odraslih pacijenata do drugog relapsa je 9 meseci. U grupi dece ne postoje značajne razlike u odnosu broja lezija viđenih na inicijalnom MRI pregledu i vremenu pojave drugog relapsa ( p=0,884) Kod odraslih postoji značajna razlika u vremenu relapsa između grupe sa manje od 4 lezije i grupe sa 4-10 lezija (p=0,09).Korelirali smo pacijente sa pozitivnim i negativnim ologoklonalnim trakama u likvoru u obe grupe sa vremenom nastanka prvog pogoršanja, pri toj korelaciji nije dobijena statistički značajna razlika ni u grupi dece ( P= 0,598) ni u grupi odraslih (P=0,133). Kod ispitanika sa ranim početkom češća je pozitivna porodična anamneza, u vidu prisustva MS i drugih imunoloških bolesti( P =0,042). ZAKLJUČAK: Polisimptomatski početak je češći kod odraslih, pozitivne oliogoklonalne trake su ređe pozitivne kod dece, kod dece je najčešći inicijalni simptom optički neuritis a kod odraslih senzitivne i motorne smetnje. Manje od 4 lezije se češće javljaju kod dece na inicijalnom MRI pregledu, što je najverovatnije povezano sa vremenom stvarnog početka bolesti i njenom kliničkom manifestacijom. Kod pacijenta sa ranim početkom MS-a duži je period do drugog pogoršanja. U grupi dece ne postoje statistički značajne razlike u odnosu broja lezija viđenih na inicijalnom MRI pregledu i vremenu pojave drugog relapsa. Kod odraslih postoji značajna razlika u vremenu relapsa između grupe sa manje od 4 lezije i grupe sa 4-10 lezija. Inicijalne manifestacije MS-a u dečijem uzrastu ne razlikuje se u mnogome od MS-a kod odraslih po karakteristikama i toku bolesti.
INTRODUCTION: Тhe onset of multiple sclerosis (MS) in childhood poses diagnostic and therapeutic challenges. Althougth the onset of MS in childhood typically predicts a fevoruable short/term prognosis, some children are severy disabled. Etiher physically or cognitively, and more then 50% are predicted to enter the secondary-progressive phase of the disease by the age of 30 years. Immunomodulatory therapies for MS and their safe application in children can improve long-therm prognosis. AIM: We saught to identifay clinical and diagnostic features in children wich inplicate to early diagnosis of MS in children. We aimd to determine the clinical features, cerebro spinal fluid, magnetic resonance imagin (MRI) features of children and their comparation with adult MS patients. METHODS: In this retrospective/prospective study we present data from 152 patients with clinical isolated syndrom (CIS) for the first time, which are obtained throught Clinic of Neurology , Clinical Centre of Vojvodina, Novi Sad from January 2003 to January 2015g. Patients were divided into two grups - in first group patients 51 with early onset of disease before 18 years, and second group patients with adult onset desease (20-55 year). Patients wer observed for a minimum one year. The common presenting symptoms, gender, MRI finding, oligoclonal band (OCB) and Visual evoked potential findings, corse of disease, family history were compared between the two groups and with thime of second relaps. To test the difference between groups was used Chi-square Pearson product moment test, and to test the strength of connection used is a Kramer V. Population data are processed Men-Whitney U test. RESULTS: Of the total number of respondents, in the Group of patients with early beginning MS the ratio of women and men was 1.3:1, and in the group of adult MS patients 2, 2:1. From the results we can see that fewer than expected has patients born in the months December ( 4.6%) and January (5.9%), and higher than expected in a March (11.3%) and July (10.6%), which is not statistically significant (p = 0,726). According to the manifestation of disease in children 17.6% has a polifocal onset, and in adults 37.6% has a polifocal onset. Polifocal beginning is significantly over represented in adult MS patients (p = 0,020). Motor disorder (P = 0,010) and sensory disabilities (P = 0.006) are more present as the initial manifestation illness in the adult. They not found statistically significant differences in the representation of optic neuritis (p = 0,366 or p > 0.05) and ataxia (p = 0.791) in these two groups. The most common initial symptom in children, almost in the same scale are the optical neuritis (35.3%) and ataxia 6 (35.3%). In a group of adult patients sensory disturbances (41.6%) are the most common initial symptom, right behind him follows a motor disturbens (37.6%). According to the number of lesions on the MRI exam, in a group of subjects with early MS more are they less than four lesions, than is the case in the group adults. The ratio of the number of patients with 4-10 and over 10 symmetrical lesions in both groups. Correlation between the time of the beginning of the MS and the number of lesions seen on MRI is statistically significant and insignificant (P = 0.06). There was no statistical significance in the presence of lesions in the corpus callosum indicates between these two groups of patients (P = 0,920). Application of Fisher the exact test case that is in this case a statistically significant (p = 0.034). We can say that the group with the early start of MS and the one with the usual beginning of significantly different, tumefactiv lesions are present in patients with early onset MS, Positive oligoclonal bands are more present in a group with adult MS patients (P = 0.018). In our group of respondents when we track time appear another relapse, minimum one year, 11 children (21,6%) had no deterioration, while the 40 children had worsening (78,4%). The median at groups of children for the appearance of second relapse is 12 months. In the adult these 22 (21,8%) had another relapse for tracking period, while 79 (78.2%) had another relapse. The average amount of time in the adult patients relapse to another is 9 months. In a group of children there are no statistically significant differences in the relative number of lesions seen on the initial MRI examination and time show up another relapse (p = 0,884). In adults there is a significant difference in relapse time between groups with fewer than four lesions and groups with 4-10 lesions (p = 0.09). Pressures are patients with positive and negative ologoclonal bands in the cerebrospinal fluid in both groups with the time of occurrence of the first downturn, when the correlation is not get statistically significant difference in the children (P = 0.598) or in a group of adults (P = 0,133). In patients with early starting stacks is a negative family history, and often the presence of MS and other immunological diseases (P = 0,042). CONCULSIONS: Polisifocal beginning is more common in adults, positive oliogoklonalne bands are less positive in children, with children being the most common initial symptom is optic neuritis, in adult sensitive and motor disturbances. Tumefactiv lesions are present in patients with early onset MS. Less than four lesions are more common in children on the initial MRI examination, which is probably connected with the time of the real onset of the disease and its clinical manifestation n the group of children there are no statistically significant differences in relation to the number of lesions seen on MRI at the initial examination and the timing of another relapse. For adults there is a significant difference in time of relapse between the groups with less than 4 lesions and groups with 4-10 lesions. Children onset MS does not significantly differ from that it has been typically seen in adults in terms of major clinical manifestations and course of disease.

碩士
樹德科技大學
幼兒保育學系
97
Eizo Mizutani (1981) pointed out that the high density of population has narrowed down the size of children’s playroom and the tall residential buildings have kept children away from the outdoor playroom. As the society continuously making progress, the advancement of the high technology has made the electronic game, computer and internet becoming very popular while all kinds of the audio/video entertaining products are changing with each passing day. These changes have made a significant change to children’s playing style. Due to the low birth rate, parents unconsciously overprotect their children; Liu Xian Xiang (1996) believed that the after-school program, talent class, computer games and cable television have filled children’s after-school schedule which further reduced children’s time and space for activity. As a result, a decrease in children’s physical fitness is seen even their physique remaining unchanged. Accordingly, how to develop children’s physical fitness becomes an important topic for study. Based on the above reasons, this research aims at studying: 1.the impact of the physical fitness activity on children’s brain waves. 2. the impact of the physical fitness activity on children’s attention. 3. the impact of the physical fitness activity on children’s balance ability. The research tool of this study includes a biofeedback instrument (I-330 C-2，J+J Engineering), Test for Attentional Performance (TAP) and Denver Development Screening Test. This study targets on the children of the top class of a kindergarten and divides them into the experimental group (24 children) and control group (20 children). The children of the experimental group get involved in the physical fitness activity. The finding shows that the α-wave power of the experimental group children’s brainwave reaction is significantly greater than the one of the control group children but there is no difference in the θ-wave power of children’s brainwave reaction between both groups. The alertness reaction of the experimental group children is significantly lower than the one of the control group children while the score of the visual search of the experimental group children is significantly lower than the one of the control group. In addition, the gross motor development of the experimental group children has reached to the normal development. Based on the research result, it is found that the physical fitness activity can improve children’s brain waves, attention and the performance of gross motor development. Indeed, it is concluded that the physical fitness activity has a positive meaning of all kinds of children’s development.

碩士
樹德科技大學
兒童與家庭服務系碩士班
106
The purpose of the research is to identify whether if Parent-Child sport games can enhance young children''s neuropsychological and physical fitness. This empirical research is based on twenty families in Pingtung from preschool Class A and B children. They are divided into two groups, an experimental group and a control group, and each group includes ten families. The experimental group participate in a 12-week Parent-Child sport games course, while the control group maintained the same instruction as they normally received. The experimental method consists of two parts. Firstly, we evaluate the neuropsychological performance in young children by using alert attention test and selective attention test through "Test of Attentional Performance for children" software. Second, we select five test items from “Toddler fitness test list” (running at 10 meters, standing long jump, arms support, sitting forward and standing on one leg) were used as assessment methods for physical fitness. The pre-test and post-test data obtained from two groups were descriptive statistics. By using covariate analysis, the effects of Parent-Child sport games intervention on toddler attention performance and fitness test scores were discussed. Supplemented by the qualitative analysis of parents'' feelings and feedback information on the implementation of the program. Compare to the control group, the results show that kindergarten Parent-Child sport games intervention of experimental group can effectively improve the children''s alertness attention and selective attention assessment. Besides, this intervention also can significantly improve the performance of young children''s fitness test. According to the findings of this study, Parent-Child sport games programs will serve as a reference point in future and increase the effectiveness of child care promotion in kindergarten by increasing parent-child interaction.