Diagnosis of fetal alcohol spectrum disorders (FASD) is challenging and typically requires confirmation of in utero alcohol exposure. Due to the poor reliability of maternal self-reports, biomarkers have emerged to address the problem of obtaining exposure history. A relatively novel method for detecting prenatal alcohol exposure is analysis of meconium for fatty acid ethyl esters (FAEEs), which are non-oxidative ethanol metabolites. Screening newborns using meconium FAEEs may facilitate early diagnosis and intervention in alcohol-affected individuals. The overall objective of this thesis is to further investigate, validate, and assess the clinical utility of meconium FAEE analysis as a screening tool for the identification of neonates at-risk for FASD. This objective was addressed in four separate studies. The first study assessed whether meconium FAEE concentrations can be predictive of ethanol-induced organ injury in fetal sheep, and determined that the levels of these esters could be used to identify fetuses at-risk for organ dysfunction that do not display overt physical signs of ethanol teratogenicity. The second study investigated the effect of delayed meconium collection and contamination with postnatal stool on FAEE analysis, and determined it to be a risk factor for false positive test results. In the third study, maternal willingness to partake in an open meconium screening program was assessed and found to be low enough to diminish the utility of meconium FAEE testing for population-based open screening. Lastly, a systematic review examining the capacity for FAEE synthesis and the enzymology of this non-oxidative metabolic pathway in mammalian organs and tissues revealed that FAEE synthesis is mediated by numerous enzymes and isoenzymes, many of which have other primary physiological functions, and that their contribution to overall FAEE-synthesis may be tissue-specific. Overall, the results of this research provide new information on the benefits, limitations, and utility of meconium FAEE testing as a screening tool for identifying prenatal alcohol exposure − a test that may be of great clinical value in the diagnosis and management of FASD.

Diagnosis of fetal alcohol spectrum disorders (FASD) is challenging and typically requires confirmation of in utero alcohol exposure. Due to the poor reliability of maternal self-reports, biomarkers have emerged to address the problem of obtaining exposure history. A relatively novel method for detecting prenatal alcohol exposure is analysis of meconium for fatty acid ethyl esters (FAEEs), which are non-oxidative ethanol metabolites. Screening newborns using meconium FAEEs may facilitate early diagnosis and intervention in alcohol-affected individuals. The overall objective of this thesis is to further investigate, validate, and assess the clinical utility of meconium FAEE analysis as a screening tool for the identification of neonates at-risk for FASD. This objective was addressed in four separate studies. The first study assessed whether meconium FAEE concentrations can be predictive of ethanol-induced organ injury in fetal sheep, and determined that the levels of these esters could be used to identify fetuses at-risk for organ dysfunction that do not display overt physical signs of ethanol teratogenicity. The second study investigated the effect of delayed meconium collection and contamination with postnatal stool on FAEE analysis, and determined it to be a risk factor for false positive test results. In the third study, maternal willingness to partake in an open meconium screening program was assessed and found to be low enough to diminish the utility of meconium FAEE testing for population-based open screening. Lastly, a systematic review examining the capacity for FAEE synthesis and the enzymology of this non-oxidative metabolic pathway in mammalian organs and tissues revealed that FAEE synthesis is mediated by numerous enzymes and isoenzymes, many of which have other primary physiological functions, and that their contribution to overall FAEE-synthesis may be tissue-specific. Overall, the results of this research provide new information on the benefits, limitations, and utility of meconium FAEE testing as a screening tool for identifying prenatal alcohol exposure − a test that may be of great clinical value in the diagnosis and management of FASD.

Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of cognitive impairment in the United States (Sokol et al., 2003). In young school children in North America and some Western European countries, recent reports have estimated the prevalence of FASD to be as high as 2-5% (May et al., 2009). Currently there are no widely accepted treatment options for FASD, mainly due to the fact that the underlying neurological deficits that occur with prenatal ethanol exposure (PNEE) are still largely unknown. This thesis examines the long-lasting changes that occur in the hippocampus following PNEE using biochemical and electrophysiological techniques. We find that PNEE produces a reduction of the endogenous antioxidant glutathione (GSH), resulting in an increase in oxidative stress that is accompanied by long-lasting reductions in long-term potentiation (LTP) of synaptic efficacy. Interestingly, males exhibited greater deficits in synaptic plasticity than females, despite similar reductions in GSH in both sexes. By depleting GSH in control animals we determined that LTP in the DG of female animals is more resistant to changes in GSH, which may explain the sexual dichotomy observed in these studies of PNEE. Based on these findings, ethanol-exposed animals received postnatal dietary supplementation with either a precursor of GSH, N-Acetylcysteine (NAC) or Omega-3 fatty acids. These supplements helped to counteract the effects of PNEE and improved hippocampal function. The findings in this thesis support the hypothesis that increasing antioxidant capacity can enhance hippocampal function, which in turn may improve learning and memory in FASD, providing a therapeutic avenue for children suffering with these disorders. / Graduate / 0570 Nutrition / 0317 Neuroscience / anna.r.patten@gmail.com

Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of cognitive impairment in the United States (Sokol et al., 2003). In young school children in North America and some Western European countries, recent reports have estimated the prevalence of FASD to be as high as 2-5% (May et al., 2009). Currently there are no widely accepted treatment options for FASD, mainly due to the fact that the underlying neurological deficits that occur with prenatal ethanol exposure (PNEE) are still largely unknown. This thesis examines the long-lasting changes that occur in the hippocampus following PNEE using biochemical and electrophysiological techniques. We find that PNEE produces a reduction of the endogenous antioxidant glutathione (GSH), resulting in an increase in oxidative stress that is accompanied by long-lasting reductions in long-term potentiation (LTP) of synaptic efficacy. Interestingly, males exhibited greater deficits in synaptic plasticity than females, despite similar reductions in GSH in both sexes. By depleting GSH in control animals we determined that LTP in the DG of female animals is more resistant to changes in GSH, which may explain the sexual dichotomy observed in these studies of PNEE. Based on these findings, ethanol-exposed animals received postnatal dietary supplementation with either a precursor of GSH, N-Acetylcysteine (NAC) or Omega-3 fatty acids. These supplements helped to counteract the effects of PNEE and improved hippocampal function. The findings in this thesis support the hypothesis that increasing antioxidant capacity can enhance hippocampal function, which in turn may improve learning and memory in FASD, providing a therapeutic avenue for children suffering with these disorders. / Graduate / 0570 Nutrition / 0317 Neuroscience / anna.r.patten@gmail.com

The thesis devotes to the negative effects of alcohol abuse during pregnancy on early psychical development of the child. It surveys the problematic fields of development of the children who were prenatally exposed to alcohol. The theoretical survey is accompanied by qualitative empirical part, which contains four case studies of children in the age of 6 - 72 weeks whose mothers were drinking alcohol during pregnancy. There are several problematic areas in the development of these children, for example growth deficit, retardation of the psychomotor development (especially in speech, gross motor skills and social behaviour), attachment disorders and eating disorders. These signs correspond to the scientific literature, but there are differences in the extent and frequency in the children Key words: alcohol, fetal alcohol syndrome, fetal alcohol spectrum disorders, early psychomotor development

Introdução: O consumo de bebidas alcoólicas por gestantes acarreta alterações de formação e de desenvolvimento fetal, incluindo alterações estruturais e funcionais do Sistema Nervoso Central. Os comprometimentos sensoriais de crianças expostas ao álcool na gestação, como a audição, são uma das morbidades relatadas nesta população. A ocorrência de alteração da sensitividade auditiva é melhor conhecida, mas o envolvimento do sistema nervosos auditivo central ainda carece de pesquisas. Objetivo: Estudar a função auditiva, periférica e central, em crianças em idade escolar com expostas ao álcool no período pré-natal. Métodos: Foram avaliadas 45 crianças, de ambos os gêneros, com 13 e 14 anos, provenientes do projeto INFANTO-ÁLCOOL, divididas em grupo exposto (GE) e não exposto (GNE) ao álcool na gestão. Foram realizadas audiometria tonal limiar, imitânciometria, emissões otoacústicas transientes (EOA-T), potencial evocado auditivo de tronco encefálico (PEATE) e o potencial evocado auditivo tardio, potencial evocado auditivo de longa latência (PEALL) e relacionado a eventos (PEARE), registrado em Cz e Pz. Foi realizada a análise comparativa entre grupos. Resultados: Apenas uma criança do GE apresentou perda auditiva unilateral do tipo mista, sendo os demais com limiares auditivos dentro da normalidade, com predominância de curva timpanomética do tipo \"A\" e presença de reflexo contralateral. Quanto ao funcionamento coclear e avaliação comportamental do processamento auditivo, não houve diferença entre grupos. Embora os resultados do PEATE tenham sido sugestivos de alteração na sincronia neural em nível de tronco encefálico, a diferença entre grupos não foi apontada. Para o PEALL, o GE apresentou menor amplitude de P2, na derivação Pz; no PEARE maiores amplitudes de P3a foram evidenciadas no GE, em Cz. Na comparação entre os eletrodos ativos foi possível constatar maior identificação da P3 com duplo pico para o eletrodo em Pz. Conclusão: O perfil de exposição fetal ao álcool em qualquer trimestre gestacional, esteve relacionado a alteração na sincronia neural em nível de tronco encefálico, bem como na identificação das componentes P2 e P3a. / Introduction: The consumption of alcohol by pregnant women causes abnormalities on fetal growth and development, including structural and functional changes in the Central Nervous System. The sensory impairments of children exposed to alcohol during pregnancy, such as hearing, are one of the morbidities reported in this population. The occurrence of change in hearing sensitivity is better known, but the auditory central nervous system involvement still needs more research. Objective: To study the hearing function, peripheral and central, in school-age children with exposed to alcohol prenatally. Methods: 45 children were assessed, of both genders, in age of 13 and 14 years, from INFANTO-ÁLCOOL project, allocated in two groups, exposed (EG) and not exposed (NEG) to alcohol during pregnancy. Following tests were performed: - pure tone audiometry, acoustic immittance, transient otoacoustic emissions (TOEA), brainstem auditory responses (ABR), late auditory evoked potentials, longlatency auditory evoked potential (LLAEP) and event-related (ERAP), registered in Cz and Pz, with comparative analysis between groups. Results: Only one child of EG had a unilateral mixed hearing loss, being the others participants found in the normal hearing thresholds, with predominance of timpanometric curve of type \"A\" and presence of contralateral acoustic reflex. Regarding the cochlear function and behavioral auditory processing assessment, there were no differences between groups. Although, the ABR results have been suggestive of change in neural synchrony brainstem level, the difference between groups was not confirmed. For the LLAEP, the EG showed lower amplitude of P2, in Pz deriving electrode; to the EARP P3a component had larger amplitudes in EG, in Cz. The comparison between the active electrode was possible to record a greater identification of the P3 components with double peak for the electrode in Pz. Conclusion: The profile of fetal exposure to alcohol in any trimester dates was related to change in neural synchrony in brainstem level as well as in the identification of P2 and P3a components.

Introdução: O consumo de bebidas alcoólicas por gestantes acarreta alterações de formação e de desenvolvimento fetal, incluindo alterações estruturais e funcionais do Sistema Nervoso Central. Os comprometimentos sensoriais de crianças expostas ao álcool na gestação, como a audição, são uma das morbidades relatadas nesta população. A ocorrência de alteração da sensitividade auditiva é melhor conhecida, mas o envolvimento do sistema nervosos auditivo central ainda carece de pesquisas. Objetivo: Estudar a função auditiva, periférica e central, em crianças em idade escolar com expostas ao álcool no período pré-natal. Métodos: Foram avaliadas 45 crianças, de ambos os gêneros, com 13 e 14 anos, provenientes do projeto INFANTO-ÁLCOOL, divididas em grupo exposto (GE) e não exposto (GNE) ao álcool na gestão. Foram realizadas audiometria tonal limiar, imitânciometria, emissões otoacústicas transientes (EOA-T), potencial evocado auditivo de tronco encefálico (PEATE) e o potencial evocado auditivo tardio, potencial evocado auditivo de longa latência (PEALL) e relacionado a eventos (PEARE), registrado em Cz e Pz. Foi realizada a análise comparativa entre grupos. Resultados: Apenas uma criança do GE apresentou perda auditiva unilateral do tipo mista, sendo os demais com limiares auditivos dentro da normalidade, com predominância de curva timpanomética do tipo \"A\" e presença de reflexo contralateral. Quanto ao funcionamento coclear e avaliação comportamental do processamento auditivo, não houve diferença entre grupos. Embora os resultados do PEATE tenham sido sugestivos de alteração na sincronia neural em nível de tronco encefálico, a diferença entre grupos não foi apontada. Para o PEALL, o GE apresentou menor amplitude de P2, na derivação Pz; no PEARE maiores amplitudes de P3a foram evidenciadas no GE, em Cz. Na comparação entre os eletrodos ativos foi possível constatar maior identificação da P3 com duplo pico para o eletrodo em Pz. Conclusão: O perfil de exposição fetal ao álcool em qualquer trimestre gestacional, esteve relacionado a alteração na sincronia neural em nível de tronco encefálico, bem como na identificação das componentes P2 e P3a. / Introduction: The consumption of alcohol by pregnant women causes abnormalities on fetal growth and development, including structural and functional changes in the Central Nervous System. The sensory impairments of children exposed to alcohol during pregnancy, such as hearing, are one of the morbidities reported in this population. The occurrence of change in hearing sensitivity is better known, but the auditory central nervous system involvement still needs more research. Objective: To study the hearing function, peripheral and central, in school-age children with exposed to alcohol prenatally. Methods: 45 children were assessed, of both genders, in age of 13 and 14 years, from INFANTO-ÁLCOOL project, allocated in two groups, exposed (EG) and not exposed (NEG) to alcohol during pregnancy. Following tests were performed: - pure tone audiometry, acoustic immittance, transient otoacoustic emissions (TOEA), brainstem auditory responses (ABR), late auditory evoked potentials, longlatency auditory evoked potential (LLAEP) and event-related (ERAP), registered in Cz and Pz, with comparative analysis between groups. Results: Only one child of EG had a unilateral mixed hearing loss, being the others participants found in the normal hearing thresholds, with predominance of timpanometric curve of type \"A\" and presence of contralateral acoustic reflex. Regarding the cochlear function and behavioral auditory processing assessment, there were no differences between groups. Although, the ABR results have been suggestive of change in neural synchrony brainstem level, the difference between groups was not confirmed. For the LLAEP, the EG showed lower amplitude of P2, in Pz deriving electrode; to the EARP P3a component had larger amplitudes in EG, in Cz. The comparison between the active electrode was possible to record a greater identification of the P3 components with double peak for the electrode in Pz. Conclusion: The profile of fetal exposure to alcohol in any trimester dates was related to change in neural synchrony in brainstem level as well as in the identification of P2 and P3a components.

Background: Prevalence and characteristics of fetal alcohol syndrome (FAS) and total fetal alcohol spectrum disorders (FASD) were studied in a second sample of three South African rural communities to assess change. Methods: Active case ascertainment focused on children with height, weight and/or head circumference <= 25th centile and randomly-selected children. Final diagnoses were based on dysmorphology, neurobehavioral scores, and maternal risk interviews. Results: Cardinal facial features, head circumference, and total dysmorphology scores differentiated specific FASD diagnostic categories in a somewhat linear fashion but all FASD traits were significantly worse than those of randomly-selected controls. Neurodevelopmental delays were significantly worse for children with FASD than controls. Binge alcohol use was clearly documented as the proximal maternal risk factor for FASD, and significant distal risk factors were: low body mass, education, and income; high gravidity, parity, and age at birth of the index child. FAS rates continue to extremely high in these communities at 89-129 per 1000 children. Total FASD affect 196-276 per 1000 or 20-28% of the children in these communities. Conclusions: Very high rates of FASD persist in these general populations where regular, heavy drinking, often in a binge fashion, co-occurs with low socioeconomic conditions.

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