This dissertation is based on an ethnographic study of Fetal Alcohol Spectrum Disorders (FASD) and the racial, cultural and political considerations that shape the meaning of diagnosis for Alaska Native individuals and families in Anchorage, Alaska. During the period from August 6, 2010 to through August 5, 2011, I worked with foster families and extended natural families living with and supporting individuals diagnosed with FASD. Documenting the experiences of families in their interactions with clinical, state, tribal and non-profit institutions, I sought to understand how a diagnosis of FASD structures opportunities, outcomes and everyday life experiences across several critical life domains, including health, education, employment, kinship and identity. Family narratives and experiences are highlighted to illustrate the ways in which difference is reproduced in everyday public understanding and clinical practice.

Abstract: Background: Fetal Alcohol Syndrome (FAS), located on the severe end of a spectrum of disorders known as Fetal Alcohol Spectrum Disorders (FASDs), is one of the most detrimental, and publicized, teratogenic outcome of alcohol consumption during pregnancy within the United States. During pregnancy, alcohol that is consumed by the mother passes through the placenta and transfers to the baby via the umbilical cord. The same prenatal transference of alcohol that leads to FAS and FASDs might also be contributing to an increased likelihood of hypertension in youth. Additionally, factors such as stress influenced by familial instability, an increased likelihood of developing congenital and conotruncal heart defects, and a reduction in nephron count might be leading to an increased likelihood of hypertension in FAS-affected youth. The purpose of this study is to examine the relationship between prenatal exposure to alcohol, manifested through FAS, and hypertension in children, adolescents, and young adults. Methods: A case-control study design was incorporated to analyze the association between FAS status and hypertensions status; cases (n=165) were collected from a FAS clinical database in Atlanta, Georgia. Controls (n=177) were taken from the National Health and Nutrition Examination Survey (NHANES). Chi-square analyses were used to examine the extent to which FAS status, sex, race/ethnicity, medication use, and obesity status each relate to hypertension status. A logistic regression was performed analyzing the relationship between FAS status (y/n: independent) and hypertension status (y/n: dependent) whilst controlling for sex, race/ethnicity, medication use, and obesity status. Results: The univariate relationships between FAS status and hypertension status (OR=4.491, p<.001) as well as medication use and hypertension status (OR= 2.951, p=.002) proved to be statistically significant (p<.05). Through the regression, FAS status significantly predicted hypertension status (β = 1.646, OR = 5.184, p< .001) after accounting for sex, race/ethnicity, medication use, and obesity status. Those with a race/ethnicity categorized as either Non-Hispanic African American (β =1.259, OR = 3.523, p = .049) or Hispanic (β = 1.192, OR = 3.294, p = .061) were significantly more likely to have hypertensions than those categorized as non-Hispanic Caucasian. Conclusion: The major findings of this study suggest a significant relationship between FAS and hypertension in youth. Race/ethnicity also proved important in predicting hypertensive blood pressure readings independent of FAS diagnosis. The most obvious biological mechanism catalyzing the relationship between FAS and hypertension is prenatal alcohol exposure. Because prenatal alcohol exposure is the primary definitional and diagnostic factor of FAS, associative connectivity may exist independently between prenatal alcohol exposure and blood pressure at various levels of severity along an alcohol exposure dose-response spectrum. Further research is needed to isolate and measure the effect that prenatal alcohol exposure has on blood pressure independently of FAS as well as to assess the extent to which the risk for hypertension in alcohol-affected individuals increases with age and through the life course.

"I'm sure you'll figure out that since I'm telling you this story, I didn't die when it happened… But someone did." Thus begins the story of Matt Eyering and his journey from Staten Island to the small New Mexican town of Socorro. He goes for one reason: to exact revenge on his estranged mother. But all sorts of odd characters live in this forgotten place along the Rio Grande, and none of them intends to let Matt pursue his goals smoothly. From revolutionaries to drug lords, romance to addiction, revenge to life threatening illness, what begins as a quest for vindication explodes into an adventure through a gauntlet of small-town politics, class discrimination, racial tension, organized crime, and self-discovery. It is a touching and serious, yet humorous exploration of the human condition, and of life in a place most of America conveniently ignores.

Alcohol use and abuse has many harmful effects, especially to children exposed prenatally, including fetal alcohol spectrum disorders (FASDs). The disabilities due to fetal alcohol exposure continue throughout life and cause major financial burdens to society. The molecular mechanisms underlying FASDs are not well understood. We have taken a genetic approach to characterize ethanol’s effect on changing a discrete cell fate decision during embryogenesis in the nematode, Caenorhabditis elegans (C. elegans). Our preliminary data suggest that ethanol can affect the development of AWC neurons, a pair of olfactory neurons in C. elegans. We suggest that lipids can protect AWC neurons from ethanol’s effects. Importantly, we show that altering the metabolism of triacylglycerols (TAGs) can rescue this cell fate change in behavioral assays. By identifying molecular causes of fetal alcohol damage in humans we hope to be able to develop a greater understanding of how to prevent these detrimental effects.

Fetal alcohol spectrum disorder is the leading cause of mental retardation in the western world. It is associated with learning and sensory deficits. Some of these deficits are a result of faulty neuronal plasticity. Previously our lab has used ferrets to demonstrate that alcohol exposure during the third trimester of human gestation results in impaired ocular dominance plasticity (ODP). Here we have transferred this model to mice. Mice, treated with 5 mg/kg of ethanol on postnatal days 5, 7 and 9, exhibit a lack of ODP plasticity after 10 days of monocular deprivation (MD) during the critical period of visual cortex plasticity, as seen by optical imaging of intrinsic signals. This deficit in ODP was rescued by treatment with a phosphodiesterase type 1 inhibitor (PDEi1), vinpocetine. This rescue did not occur after treatment with a PDEi4 (rolipram) or a PDEi5 (vardenafil) inhibitor alone. Interestingly when these drugs were given concurrently, ODP was rescued. To further explore the effect of early alcohol exposure on ODP, we used Visually Evoked Potentials to examine the potentiation and depression components of ODP. Ethanol exposed and saline control animals were MD for 5, 7 or 10 days during the critical period of the visual cortex. Here we saw that although saline animals exhibited a normal depression of contralateral eye responses and a potentiation of ipsilateral eye responses, ethanol animals exhibited only a depression of contralateral eye responses. Additional ethanol animals were then MD for 3 days to test for changes in the on-set of contralateral eye depression. Yet, these animals exhibited normal contralateral eye response changes. In conclusion early ethanol exposure disrupts only the potentiation of the ipsilateral eye inputs, while leaving the contralateral eye response depression in tact. This model provides a new approach to studying ODP after early alcohol exposure, opening the door for studies using transgenic animals to further elucidate the mechanisms behind these alcohol induced deficits.

Ethanol exposure during pregnancy is one of the leading causes of preventable birth defects, leading to a range of symptoms collectively known as fetal alcohol spectrum disorder (FASD). More moderate levels of prenatal ethanol exposure (PNE) lead to a range of behavioural deficits including aggression, poor social interaction, poor cognitive performance and increased likelihood of addiction in later life. Current theories suggest that adaptation in the hypothalamic-pituitaryadrenal (HPA) axis and neuroendocrine systems contributes to mood alterations underlying behavioural deficits and vulnerability to addiction. This has led to the suggestion that corticotrophin-releasing factor (CRF) antagonists and glucocorticoid (steroid) inhibitors may be potential therapeutics to address the deficits of PNE and for the treatment of addiction. The zebrafish (Danio rerio) has several advantages over mammalian models, such as low cost of maintenance, short life cycle, easy embryological manipulation and the possibility of large-scale genetic screening. By using this model, our aim is to determine whether developmental ethanol exposure provokes changes in the HPA axis (HPI axis in fish), as it does in mammalian models, therefore opening the possibilities of using zebrafish to elucidate the mechanisms involved, and to test novel therapeutics to alleviate deleterious symptoms. Thus this thesis focuses solely on the effect of developmental ethanol exposure on the functioning of the HPI axis in zebrafish. Stress-reactivity in zebrafish larvae ethanol-treated 1-9 days post 4 fertilisation (dpf) was assessed using thigmotaxis and thigmotaxis following airstress. In both tests, lower stress-related responses were obtained with ethanol treated animals, in that they spent less time at the edges of the apparatus (P<0.01, n=3). They also showed lower total body cortisol (P=0.04, n=14). Larvae also showed the same behaviour pattern two weeks after ethanol exposure, (23dpf) (P=0.04, n=3), again with reduced total cortisol (P=0.03, n=4). HPI-related gene transcription was also assessed in 9dpf ethanol treated zebrafish larvae, by qRT-PCR. Revealing up-regulation of CRH, CRHBP and CRHR2, normalized against β-Actin, Elav1 and Gap43 housekeeping genes. In situ hybridization revealed no spatial changes in CRH, CRH-BP and POMC with animals at the same stage. Behavioural stress-reactivity differences in 6-months old adults that had been exposed developmentally to ethanol were assessed using novel tank diving and thigmotaxis. Both assays indicated a decrease in stress-like behaviour due to early ethanol exposure compared to controls (P<0.05, n=5 both). Finally, cortisol levels were assayed from 9dpf larvae and 6-month-old adults that had been treated with ethanol during early development showed a significant reduction in cortisol output when air-exposed stressed compared to controls (P=0.04, n=5). Conclusion: Early ethanol exposure produced significant changes in cortisol, HPI gene mRNA expression and stress-reactive behaviour in 9dpf animals. Changes in cortisol and behaviour were still detected in 6-months old adults, developmentally treated with ethanol, indicating that early ethanol exposure has permanent effects on the HPI axis. 5 As our data contradicts the findings in mammalian literature where early ethanol exposure increases stress-like behaviour in later life, it is also possible that more permanent effects of PNE in mammals may arise through maternal-offspring interactions, during and post gestation, such as breastfeeding and maternal grooming of the offspring, which are absent in the zebrafish model.

Maternal alcohol consumption during pregnancy is a public health concern due to the possible lifelong physical and cognitive effects in offspring. Prevention of alcohol-exposed pregnancies (AEP) should begin preconceptionally, either by preventing unintended pregnancies or by discouraging alcohol consumption in women who are at-risk for pregnancy. The purpose of this dissertation is to utilize the Theory of Planned Behavior's construct of perceived behavioral control (PBC)--including perceived power and control beliefs--to guide the measurement and understanding of two behaviors related to AEP among non-pregnant women: birth control use and binge drinking. For the first specific aim--to estimate the prevalence of alcohol-exposed pregnancies--a secondary data analysis was conducted using surveillance data from North Dakota and South Dakota women who have had a child with FAS. The FAS prevalence estimates (per 1,000 live births) in both states (ND=0.8/1,000; SD=0.9/1,000) were found to be higher than that calculated from national averages (0.7/1,000) using a comparable surveillance methodology. The goal of Specific Aim 2 was to determine risk for AEP among a random group of women, while Specific Aim 3 determined the control beliefs and perceived power to using birth control and decreasing binge drinking levels, and Specific Aim 4 focused on relating PBC of these two behaviors to behavioral intentions. Data for aims 2-4 were derived from a mailed, cross-sectional survey of 190 non-pregnant women randomly chosen from an electronic health records system in the upper Midwest. Of the 190 women included in the analyses, eight (6.6%) were binge drinking while being at-risk for pregnancy (i.e., being sexually active but not always using an effective form of birth control) (Specific Aim 2). This is lower than national estimates. For Specific Aim 3, there were high direct PBC scores for both birth control and binge drinking, and there was a positive correlation between birth control direct and indirect scores (although a negative correlation between binge drinking direct and indirect scores). Finally, Specific Aim 4 uncovered high intentions to both use birth control and to not binge drink. Also, the direct birth control PBC measure was significantly associated with birth control intention when controlling for other variables, although neither PBC nor intention appeared to be associated with actual birth control behavior. For binge drinking, the intention score and the direct measure of PBC were significantly associated with one another; as well, the direct measure of PBC and intention were both significantly associated with actual binge drinking behavior. Therefore, the relationship between PBC and intention was validated for both behaviors, and the association between PBC, intention, and actual behavior was indicated for binge drinking. Overall, the study both supported and disagreed with previous research, indicating that additional research with this theory and topic matter is necessary.

Fetal alcohol spectrum disorders (FASD) are caused by alcohol exposure during pregnancy and is the leading cause of mental retardation. Alcohol exposure during development results in the loss of neurons in the developing brain. The underlying molecular mechanisms are unclear and there currently is no cure for FASD. Ethanol-induced neuronal death is accompanied by neuroinflammation. Chemokine monocyte chemoattractant protein 1 (MCP-1) and its receptor C-C chemokine receptor type 2 (CCR2) are critical mediators of neuroinflammation and microglial activation. Using a third trimester equivalent mouse model of ethanol exposure, we found that treatment of Bindarit (MCP-1 synthesis inhibitor) and RS504393 (CCR2 antagonist) significantly reduced ethanol-induced microglia activation/neuroinflammation, and neuroapoptosis in the developing brain. Moreover, ethanol plus MCP-1 caused more neuronal death in a neuron/microglia co-culture system than neuronal culture alone, and Bindarit and RS504393 attenuated ethanol-induced neuronal death in the co-culture system. Ethanol activated TLR4 and GSK3β, two key mediators of microglial activation in the brain and cultured microglial cells (SIM-A9). Blocking MCP-1/CCR2 signaling attenuated ethanol-induced activation of TLR4 and GSK3β. Further, we determined whether knocking out of MCP-1/CCR2 ameliorates neonatal alcohol exposure-induced long-lasting behavioral deficits in adolescent and adult mice. C57BL/6 and MCP-1-/-/CCR2-/- mice were exposed to alcohol (5 g/kg) by subcutaneously injection on PD4. A series of behavioral tests including Open Field (PD 35-36 and PD 70-71), Rotor-Rod (PD 38 and PD 73), Balance Beam (PD 40 and PD75) and Morris Water Maze (PD 42 and PD77) were performed in the adolescence and adulthood. We found that MCP-1-/-/CCR2-/- mice were resistant to neonatal alcohol exposure-induced deficits in motor function in the Rotor-Rod and Balance Beam tests; MCP-1 and CCR2 deficiency also protected mice against neonatal ethanol exposure induced long lasting deficits in learning and memory in the Morris Water Maze testing. Collectively, these results suggest that MCP-1/CCR2 signaling plays an important role in ethanol-induced microglial activation/neuroinflammation and neurodegeneration in the developing brain and also plays an important role in developmental alcohol exposure induced long-lasting behavioral deficits in adolescence and adulthood.

The present study examined the scores of 450 Kainaiwa children from Kindergarten to grade 3 on social, behavioral, cognitive and cultural measures. The subjects consisted of children in three different classification groups: Fetal Alcohol Syndrome (FAS), Special Education, and Regular Education. The purpose of the study was to examine group membership to determine whether or not children who were diagnosed as FAS presented unique intellectual, behavioral, social and cultural characteristics from those of their regular and special education peers. These results support the conclusion of previous research that FAS children differ significantly from their special and regular education peers. No statistically significant differences were found on cultural measures. This study provides useful information for future diagnosis and psychoeducational assessment for FAS children in early childhood.

Philosophiae Doctor - PhD / Introduction: Maternal alcohol consumption during pregnancy can result to birth defects, which may be developmental, intellectual and physical. Fetal alcohol spectrum disorder (FASD) is a term used to describe an array of disorders related to alcohol consumption during pregnancy. FASD is a severe public health problem globally, with South Africa having the highest prevalence (29 to 290 per 1000 live births). What makes the FASD problem severe in the country is rife of maternal risk factors and widespread binge drinking during pregnancy. There is no policy specifically addressing FASD despite being pervasive in South Africa. Government programmes to prevent and manage FASD remain limited and fragmental across relevant departments. Herein, we aimed to conduct a multi-method study with a modified Delphi approach to developing a guideline to inform the development of a comprehensive and multi-sectoral policy for the prevention and management of FASD. Method and analysis: We used a modified version of the World Health Organization’s approach to guideline development in three phases. In phase 1, we conducted four different studies to design the initial guideline prototype. The studies include an in-depth interview with policymakers and a focus group with relevant service providers on policy requirements for FASD, a document review of policies on FASD and a scoping review of various interventions employed for the prevention and management of FASD. The second phase involved using the initially developed guideline prototype to engage with the local and international experts on FASD for improvement on the content. In the third phase, we refined the prototype using a modified Delphi approach. Framework method and content analysis were used to analyse the qualitative data while the Statistical Package for Social Science (SPSS) software was used to analyse the quantitative data.