Kernicterus causes damage to the auditory system and the basal ganglia in humans. Although the Gunn rat model of kernicterus has been extensively used to characterize the auditory features, this model has not been utilized to systematically investigate the movement disorder. In the present study, spontaneously jaundiced (jj) 16 day old Gunn rat pups were treated with sulfadimethoxine to exacerbate bilirubin neurotoxicity and compared to saline treated jjs and non-jaundiced (Nj) littermates. Electromyographic (EMG) activity was recorded from antagonistic hip muscles in dystonic and in normal appearing rats. Raw EMG signals were decomposed using the Discrete Wavelet Transform based multi-resolution analysis, and signal coefficients corresponding to the dominant EMG frequency band were chosen. Gunn rats exposed to sulfadimethoxine developed a stable clinical state characterized by prolonged abnormal axial and appendicular postures. Coherence plots revealed 4-7 Hz co-activation in antagonistic muscles that was significantly more prominent in jj sulfa treated dystonic compared to normal rats. The EMG findings support the presence of dystonia in sulfadimethoxine exposed jj Gunn rats.

Objetivos: A deficiência de glicose-6-fosfato desidrogenase (G6PD) está associada a um maior risco de encefalopatia bilirrubínica e de crise hemolítica aguda grave desencadeada por drogas como a primaquina e a dapsona. Conhecer a prevalência dessa deficiência enzimática em área onde a malária e a hanseníase ainda estão presentes e conhecer a prevalência das principais mutações traz subsídios para planejamento de estratégias com vistas à redução de riscos associados a esta deficiência enzimática. Métodos: Estudo descritivo transversal conduzido em uma região do centro-oeste do Brasil. Exame de triagem para deficiência de G6PD foi realizado em 3573 recémnascidos. Exame confirmatório foi necessário em 188 crianças triadas como possíveis portadores de deficiência. Nas crianças em que foi confirmada a deficiência de G6PD foi feita pesquisa das mutações G202A (G6PD A-) e C563T (G6PD Mediterrâneo) por PCR. Resultados: A deficiência de G6PD foi confirmada em 63 crianças, sendo 60 meninos (95,2%) e três meninas (4,8%). O percentual de exames falso-positivos na fase de triagem foi de 66,5%, estando o percentual de falso-positivos associado à temperatura e tempo de transporte das amostras. Entre as crianças que confirmaram deficiência de G6PD, foi mais frequente a história de anemia em familiares e de icterícia neonatal. Houve associação entre hematócrito baixo e deficiência enzimática, mas não com hemoglobina, contagem de reticulócitos ou neutrófilos. A prevalência da deficiência de G6PD (IC95%) foi de 1,76% (1,37; 2,24) entre os recém-nascidos triados e de 3,34% entre os meninos (2,58; 4,25). A mutação C563T não foi identificada em nenhuma criança, mas a mutação G202A estava presente em 58 crianças - 92,06% (IC95%: 83,29 - 97,03): 56/60 meninos e em 2/3 meninas homozigotas. Foi identificado um menino com Kernicterus portador da mutação G202A em hemizigose. Conclusão: O elevado percentual de falso-positivos na etapa de triagem, o tempo necessário entre coleta e confirmação da presença de deficiência enzimática, associado ao alto custo da triagem universal, não apoiam a inclusão da triagem de deficiência de G6PD no programa de triagem neonatal brasileiro. Na região avaliada, a prevalência observada em meninos indica que a triagem de deficiência de G6PD deva ser realizada antes do uso de drogas como a primaquina e a dapsona somente em meninos. Foi elevada a prevalência da mutação G202A, de classe III, sendo esta mutação associada a uma menor morbidade. A identificação de um menino com Kernicterus com deficiência de G6PD indica que há necessidade de se planejar estratégias para minimizar o risco dessa morbidade associada à deficiência enzimática / Objective: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with an increased risk of bilirubin encephalopathy in neonates and acute hemolytic crisis triggered by drugs such as primaquine and dapsone. In an area where malaria and Hansen\'s disease are still present, knowing the prevalence of this enzyme defect and determining the prevalence of major mutations is important for planning strategies for reducing the risks associated with this enzyme deficiency. Methods: Sectional study was conducted in a Midwestern region of Brazil. Screening for G6PD deficiency was performed in 3,573 neonates. Confirmatory tests were necessary for 188 positively screened children. After confirmation, PCR investigation was utilized to identify the mutations. Results: G6PD deficiency was confirmed in 63 children: 60 boys (95.2%) and 3 girls (4.8%). The percentage of false-positive cases in the screening phase, 66.5% and was associated with the temperature and transportation time of the samples. Family history of anemia and jaundice was more frequent among the children with confirmed G6PD deficiency. An association between a low hematocrit and enzyme deficiency was observed. However, there was no association with hemoglobin reticulocyte or neutrophils counts. The prevalence of G6PD deficiency (CI95%) was 1.76% (1.37; 2.24) among all screened neonates and 3.34% (2.58; 4.25) among male children. The C563T mutation was not identified in any child. The G202A mutation was present in 58 children - 92.06% (CI95%: 83.29 - 97.03), 56/60 boys and 2/3 homozygous girls. One boy with a hemizygous G202A mutation was identified as having Kernicterus. Conclusion: The high percentage of false-positive results when first screening for G6PD deficiency; the long delay time between the test and result; along with the high cost of the this screening test, are all factors that do not support adding this test to the already established Brazilian neonatal screening programs. The prevalence observed among boys does indicate that screening for G6PD deficiency should be performed in this region before the use of drugs such as primaquine and dapsone only in boys. This study found a high prevalence of the G202A mutation, a Class III variant associated with lower morbidity. The identification of a G6PD deficient boy with Kernicterus reinforces the necessity for strategies to abolish the morbidity associated with this enzyme deficiency

Objetivos: A deficiência de glicose-6-fosfato desidrogenase (G6PD) está associada a um maior risco de encefalopatia bilirrubínica e de crise hemolítica aguda grave desencadeada por drogas como a primaquina e a dapsona. Conhecer a prevalência dessa deficiência enzimática em área onde a malária e a hanseníase ainda estão presentes e conhecer a prevalência das principais mutações traz subsídios para planejamento de estratégias com vistas à redução de riscos associados a esta deficiência enzimática. Métodos: Estudo descritivo transversal conduzido em uma região do centro-oeste do Brasil. Exame de triagem para deficiência de G6PD foi realizado em 3573 recémnascidos. Exame confirmatório foi necessário em 188 crianças triadas como possíveis portadores de deficiência. Nas crianças em que foi confirmada a deficiência de G6PD foi feita pesquisa das mutações G202A (G6PD A-) e C563T (G6PD Mediterrâneo) por PCR. Resultados: A deficiência de G6PD foi confirmada em 63 crianças, sendo 60 meninos (95,2%) e três meninas (4,8%). O percentual de exames falso-positivos na fase de triagem foi de 66,5%, estando o percentual de falso-positivos associado à temperatura e tempo de transporte das amostras. Entre as crianças que confirmaram deficiência de G6PD, foi mais frequente a história de anemia em familiares e de icterícia neonatal. Houve associação entre hematócrito baixo e deficiência enzimática, mas não com hemoglobina, contagem de reticulócitos ou neutrófilos. A prevalência da deficiência de G6PD (IC95%) foi de 1,76% (1,37; 2,24) entre os recém-nascidos triados e de 3,34% entre os meninos (2,58; 4,25). A mutação C563T não foi identificada em nenhuma criança, mas a mutação G202A estava presente em 58 crianças - 92,06% (IC95%: 83,29 - 97,03): 56/60 meninos e em 2/3 meninas homozigotas. Foi identificado um menino com Kernicterus portador da mutação G202A em hemizigose. Conclusão: O elevado percentual de falso-positivos na etapa de triagem, o tempo necessário entre coleta e confirmação da presença de deficiência enzimática, associado ao alto custo da triagem universal, não apoiam a inclusão da triagem de deficiência de G6PD no programa de triagem neonatal brasileiro. Na região avaliada, a prevalência observada em meninos indica que a triagem de deficiência de G6PD deva ser realizada antes do uso de drogas como a primaquina e a dapsona somente em meninos. Foi elevada a prevalência da mutação G202A, de classe III, sendo esta mutação associada a uma menor morbidade. A identificação de um menino com Kernicterus com deficiência de G6PD indica que há necessidade de se planejar estratégias para minimizar o risco dessa morbidade associada à deficiência enzimática / Objective: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with an increased risk of bilirubin encephalopathy in neonates and acute hemolytic crisis triggered by drugs such as primaquine and dapsone. In an area where malaria and Hansen\'s disease are still present, knowing the prevalence of this enzyme defect and determining the prevalence of major mutations is important for planning strategies for reducing the risks associated with this enzyme deficiency. Methods: Sectional study was conducted in a Midwestern region of Brazil. Screening for G6PD deficiency was performed in 3,573 neonates. Confirmatory tests were necessary for 188 positively screened children. After confirmation, PCR investigation was utilized to identify the mutations. Results: G6PD deficiency was confirmed in 63 children: 60 boys (95.2%) and 3 girls (4.8%). The percentage of false-positive cases in the screening phase, 66.5% and was associated with the temperature and transportation time of the samples. Family history of anemia and jaundice was more frequent among the children with confirmed G6PD deficiency. An association between a low hematocrit and enzyme deficiency was observed. However, there was no association with hemoglobin reticulocyte or neutrophils counts. The prevalence of G6PD deficiency (CI95%) was 1.76% (1.37; 2.24) among all screened neonates and 3.34% (2.58; 4.25) among male children. The C563T mutation was not identified in any child. The G202A mutation was present in 58 children - 92.06% (CI95%: 83.29 - 97.03), 56/60 boys and 2/3 homozygous girls. One boy with a hemizygous G202A mutation was identified as having Kernicterus. Conclusion: The high percentage of false-positive results when first screening for G6PD deficiency; the long delay time between the test and result; along with the high cost of the this screening test, are all factors that do not support adding this test to the already established Brazilian neonatal screening programs. The prevalence observed among boys does indicate that screening for G6PD deficiency should be performed in this region before the use of drugs such as primaquine and dapsone only in boys. This study found a high prevalence of the G202A mutation, a Class III variant associated with lower morbidity. The identification of a G6PD deficient boy with Kernicterus reinforces the necessity for strategies to abolish the morbidity associated with this enzyme deficiency

In hierdie studie word die etiologiese verband tussen verstadigde neurologiese integrasie en latere leerproblematiek by kinders met klinies betekenisvolle neonatale bilirubienmetings ondersoek. Resente navorsing dui aan dat kinders met klinies betekenisvolle bilirubienmetings tydens die neonatale fase ‘n groter risiko loop om later verstadigde neurologiese integrasie te vertoon, veral weens die kwesbaarheid van die neonatale brein vir toksiene. Hierdie navorsingsresultate suggereer ‘n verband tussen klinies betekenisvolle neonatale bilirubienmetings en latere leerproblematiek, aangesien spesifieke breinareas wat deur neonatale bilirubien aangetas word ook vaardighede medieer wat belangrik is vir prestasie in sekere leerareas, te wete lees, skryf en reken. Neonatale fisiologiese geelsug is nie altyd met die blote oog sigbaar nie, en derhalwe word simptome soos oormatige slaperigheid en ingekorte behoefte aan voeding dikwels deur onervare moeders geïgnoreer, omdat die baba nie opmerklik “geel” is nie. Verder word neonatale fisiologiese geelsug nie altyd as sodanig gediagnoseer nie, weens verskeie faktore soos ontoereikende primêre gesondheidsorgdienste op die afgeleë platteland, tuisgeboortes en vroeë ontslag van moeders en babas uit klinieke en hospitale, veral gesien in die lig daarvan dat neonatale geelsug piekvlak tussen dag drie en dag sewe bereik. Bilirubienmeting is nie standaard prosedure by afgeleë klinieke nie, en waar ‘n rowwe skatting deur die klinieksuster op ‘n klinies betekenisvolle bilirubientelling dui, word moeders dan dikwels aangeraai om natuurlike fototerapie (sonlig) toe te pas. Verdermeer vind opvolgkonsultasies by ‘n klinieksuster dikwels eers plaas nadat die baba ongeveer een maand oud is, en voorligting aan die moeder rakende moontlike kwesbaarhede wat verband hou met klinies betekenisvolle neonatale bilirubienmetings is gebrekkig. Sodanige ouers kan dus heeltemal onbewus wees van die potensiële skade wat aangerig kan word aan die ontwikkelende brein, en intervensie vind gevolglik nie tydig plaas nie. Betekenisvolle duidinge wat uit hierdie navorsingsprojek mag voortvloei, kan derhalwe benut word ten einde spesifieke kwesbaarhede in kinders met klinies betekenisvolle neonatale bilirubienmetings tydig te kan identifiseer; en hoë-risiko leerders se moontlike latere leerproblematiek deur tydige intervensie tydens die voorskoolse jare te ondervang, voordat pobleme in die grondslagfase manifesteer. ‘n Empiriese ondersoek is uitgevoer waarby 37 deelnemers betrek is. Gebaseer op die resultate van die data-analise en interpretasie van die resultate word die hipotese aanvaar. Relevante aanbevelings met betrekking to praktykverbetering en verdere navorsing word gemaak. ENGLISH: With this study the etiological link between delayed neurological integration, high neonatal bilirubin measures and learning difficulties were investigated. Recent research findings suggest that children with high neonatal bilirubin measures are at a greater risk for delayed neurological integration later on, especially because of the susceptibility of the neonatal brain for toxins. The results of this research project suggest an etiological link between neonatal hyperbilirubinemia and learning difficulties at a later stage, since specific brain-areas which are affected by the bilirubin do mediate skills important for performance in certain learning areas, e.g. reading, writing and arithmetic. It is not always possible to notice neonatal physiological jaundice; hence, inexperienced mothers tend to ignore symptoms like sleepiness and lack of appetite, merely because their babies do not appear “yellowish”. Neonatal physiological jaundice is often misdiagnosed due to various factors like inadequate primary health care services in rural areas, home births and early discharge from hospitals - particularly in light of the fact that jaundice peaks between day three and day seven after birth. Measurement of neonatal bilirubin levels is not a standard procedure at rural clinics, and mothers are often advised to make use of natural phototherapy (sunlight) when the baby appears “yellowish”. Follow-up consultation often occurs when the baby is already one month old; hence mothers often receive inadequate information concerning neonatal hyperbilirubinemia. Parents might therefore be totally unaware of the potential vulnerability and harm to the developing brain, and intervention often does not take place. Significant indicators of this research project can be used to identify well in advance specific vulnerabilities in learners with neonatal hyperbilirubinemia, as well as potentially high-risk learners during the pre-school years, before such vulnerabilities escalate during the foundation phase. An empirical study with 37 participants was conducted. Based on the data analyses and interpretation of the results, the hypothesis was accepted. Relevant recommendations concerning best practice and further research were done. / Thesis (PhD)--University of Pretoria, 2008. / Educational Psychology / unrestricted