Autism spectrum disorder (ASD) is a lifelong disability that has seen a rise in prevalence from 1 in 150 children to 1 in 59 between 2000 and 2014. Patients show behavioral abnormalities in the areas of social interaction, communication, and restrictive and repetitive behaviors. As of now, the exact cause of ASD is unknown and literature points to multiple causes. The work contained within this dissertation explored the reduction of oxidative stress in brain tissue induced by xanthine oxidase (XO). Febuxostat is a new FDA approved XO-inhibitor that has been shown to be more selective and potent than allopurinol in patients with gout. The first study developed a computational model to calculate an effective diffusion constant (Deff) of lipophilic compounds, such as febuxostat, that can cross endothelial cells of the blood-brain barrier (BBB) by the transcellular pathway. In the second study, male juvenile autistic (BTBR) mice were treated with febuxostat for seven days followed by behavioral testing and quantification of oxidative stress in brain tissue compared to controls. Results of the first study showed that the lipophilic tracer chosen, as a substitute for febuxostat, could be modeled under the assumption of passive diffusion while experimental controls did not fit this model. The second study revealed no significant differences between BTBR mice that received febuxostat or the drug vehicle in both behavioral testing and quantification of oxidative stress in brain tissue. In the final study, of the four models proposed, one model was selected as the most plausible that considered transport into the CNS. As there is currently no literature surrounding tissue and organ ADME for febuxostat the final proposed model would need to be updated as new information becomes available. / PhD / Autism spectrum disorder (ASD) is a lifelong disability that has seen a rise in prevalence from 1 in 150 children to 1 in 59 between 2000 and 2014. Patients show behavioral abnormalities in the areas of (1) social interaction, how an individual acts and reacts to others around them, (2) communication, the use of and understanding of language and facial expressions, and (3) restrictive and repetitive behaviors where individuals may have focused interests on specific topics/subjects and stick to set routines. As of now, the exact cause of ASD is unknown and literature points to multiple causes. The work contained within this dissertation explored the reduction of oxidative stress in brain tissue induced by the enzyme xanthine oxidase (XO). Oxidative stress is noted as the imbalance between free radicals (pro-oxidant) and antioxidant defenses where the pro-oxidant levels are greater than the antioxidant defenses leading to cell and tissue damage. Febuxostat is a new FDA approved XO-inhibitor that has been shown to target and inhibit XO better than allopurinol (an older XO-inhibitor) in patients with gout. The first study developed a computational model to calculate an effective diffusion constant (Def f ) that explained the free movement of a compound (substance) across cells, also known as trancellular movement. The transcellular pathway is the direct movement of compounds into a cell that requires no additional cellular energy or specialized transport routes to get the compounds into the cell. In the second study, male juvenile autistic (BTBR) mice were treated with febuxostat for seven days followed by behavioral testing to study social interaction and restrictive and repetitive behaviors in autistic mice compared to non- autistic mice. Next, oxidative stress levels were measured in the brain tissue of autistic mice and compared to non-autistic mice. The third study developed four hypothesis-based human pharmacokinetic (PK) multi-compartment models of drug absorption, distribution, metabolism, and excretion (ADME). Pharmacokinetics is the study of what the body does to a drug once it is given, i.e how it gets into the bloodstream, where it goes in the body, how it is broken down, and how it is removed from the body . Compartments in PK models can be used to represent parts of the body such as blood, tissues, and organs. Results of the first study showed that the compound chosen as a substitute for febuxostat could be modeled under the assumption of passive diffusion, free movement across cells without use of energy or specialized routes, while the other compounds did not fit this model. The second study revealed no significant differences between autistic (BTBR) mice, those that received febuxostat treatment, and non-autistic mice for behavioral testing and oxidative stress levels in brain tissue. In the final study, of the four models proposed, one model was selected as the most plausible that considered drug movement into the brain and spinal cord regions. As there is currently no literature surrounding tissue and organ ADME for febuxostat the final proposed model would need to be updated as new information becomes available.

Thesis (M.A.)--York University, 2006. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 67-75). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR29592

Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in Microbiology and Molecular Genetics." Includes bibliographical references (p. 74-83).

Thesis (Ph. D.)--University of California, San Diego, 2008. / Title from first page of PDF file (viewed February 14, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.

Thesis (Ph.D.)--University of Western Australia, 2006.

Thesis(M.S.)--Auburn University, 2006. / Abstract. Vita. Includes bibliographic references (p.88-97).

Thesis (Ed. D.)--West Virginia University, 2000. / Title from document title page. Document formatted into pages; contains v, 145 p. : ill. Includes abstract. Includes bibliographical references (p. 91-98).

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Existing literature about autistic workers concentrates on the troubles autistics have in the workplace; these problems are linked back to documented deficits in autistic people, thereby constructing a picture of autistic workers as people who need to be helped. There have been no academic studies asking autistic adults to give their general impressions on their work environments. The paucity of narratives from working autistic authorities has effectively made them into a hidden, or invisible population. We do not know if they agree with the views presented about them. We do not know what jobs they are in or in what levels of authority they are working. The only way to understand working autistic adults and their worth and presence in the workforce, is to ask them. This exploratory, qualitative study asked 38 autistic adults (currently working or who have a past work history) 55 questions about their work environments. Most participants provided elaborative answers about their work experiences. Participant experiences often contradicted current literature about autistic adults or mentioned little known phenomenon. Confirmation of existing themes in autism literature was sometimes arguable. The narrative accounts gathered in this study give new opportunities for research into autistic adults and their places in society. / Master of Science

This study examined the moderating role of motivational tendencies for social approach and avoidance behavior, as measured by anterior EEG asymmetry, on symptom expression. In particular, this study aimed to replicate and extend previous findings that measures of anterior EEG asymmetry provide an important marker of subgroups of HFA children that significantly differ from each other, and controls, on measures of social communication impairment. EEG data were collected across two occasions on 51 HFA and 44 non-HFA children. EEG asymmetry was computed for homologous electrode pairs (e.g., lnF4-lnF3). More positive scores were indicative of relative left frontal asymmetry. Data on social and behavioral functioning were collected via parent- and self-report. Results of this short-term longitudinal study revealed moderate test-retest reliability for midfrontal asymmetry, r (65) = .39, p < .01. Results supported previous research demonstrating the differential relation of EEG asymmetry to symptom impairment among HFA children, such that parents of LFA-HFA children reported lower levels of impairment than RFA-HFA children on the SCQ Total Score, F (3, 47) = 3.58, p = .065, and Social Interaction Domain, F (3, 47) = 4.59, p < .05. Results also indicated that parents of LFA-HFA children reported higher levels of general communicative competence on the CCC-2, GCC, F (3, 47) = 6.83, p = .01, but greater impairment in pragmatic communication when compared to RFA-HFA children, SIDC, F (3, 47) = 4.41, p < .05. Additional analyses indicated that RFA was associated with early and more confident recognition of atypical (and stereotypically autistic) development based on retrospective parent-report (ADI-R #86), while LFA was associated with early, but less unambiguously autistic impairment, X2 (51) = 3.75, p = .05. This study demonstrates that anterior EEG asymmetry subgroups are reliable and useful markers of phenotypic variability that are meaningfully related to the experience and expression of symptoms of core autism impairment.