Associations between psychophysiological, immune, endocrine, and serotonergic biomarkers of stress and gastrointestinal symptoms in autism spectrum disorder

Dissertation supervisor: Dr. David Q. Beversdorf.Includes vita.Autism spectrum disorder (ASD) is often accompanied by gastrointestinal (GI) disturbances, which also may impact behavior. Alterations in autonomic, endocrine, and immune system functioning are also frequently observed in ASD, however, the relationship between these findings in ASD is not known. To study this relationship, an initial pilot study was conducted in our lab which revealed increased autonomic nervous system (ANS) functioning in response to brief stress-invoking peripheral stimuli and GI disorders in ASD. Preliminary data suggested an enhanced stress response in individuals with ASD and co-occurring GI disorders. In a subsequent multi-site study, we examined the relationship between GI symptomatology, examining upper and lower GI tract symptomatology separately, ANS functioning, and salivary cortisol at baseline and in response to stress in a sample of 120 children with ASD. The stress-associated proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-[alpha]) and whole blood serotonin concentrations were also assessed. While the number of participants with significant upper GI tract problems was small in this sample, 42.5% of participants met criteria for functional constipation, a disorder of the lower GI tract. Heart rate variability, a measure of parasympathetic modulation of cardiac activity, was found to be positively associated with lower GI tract symptomatology at baseline. This relationship was particularly strong for participants with co-occurring diagnoses of anxiety disorder and for those with a history of regressive ASD or loss of previously acquired skills. A greater amount of lower GI tract symptoms was significantly associated with post-stress cortisol concentration, and this relationship was greatest for individuals with regressive ASD. However, symptoms of the lower GI tract were not associated with the stress-responsive cytokines IL-6 and TNF-[alpha]. Finally, in a sample of 82 of the 120 children mentioned above, a significant positive correlation was found between lower GI tract symptoms and whole-blood serotonin. These findings suggest that systems involved in the response to mild stimuli are different in individuals with ASD and co-occurring GI issues, especially for constipation; although it is not possible to assess causality in this data set. Future work should examine the impact of treatment of GI problems on autonomic function and anxiety, as well as the impact of anxiety treatment on GI problems. Thus, clinicians should be aware that GI problems, anxiety, autonomic, endocrine, and immune dysfunction may cluster in children with ASD and should be addressed in a multidisciplinary treatment plan.Includes bibliographical references (pages 75-90)

The Specific Globular Cluster Frequencies of Dwarf Elliptical Galaxies from the Hubble Space Telescope

The specific globular cluster frequencies (S_N) for 24 dwarf elliptical (dE) galaxies in the Virgo and Fornax Clusters and the Leo Group imaged with the Hubble Space Telescope are presented. Combining all available data, we find that for nucleated dEs --- which are spatially distributed like giant ellipticals in galaxy clusters --- S_N(dE,N)=6.5 +- 1.2 and S_N increases with M_V, while for non-nucleated dEs --- which are distributed like late-type galaxies --- S_N(dE,noN)=3.1 +- 0.5 and there is little or no trend with M_V. The S_N values for dE galaxies are thus on average significantly higher than those for late-type galaxies, which have S_N < 1. This suggests that dE galaxies are more akin to giant Es than to late-type galaxies. If there are dormant or stripped irregulars hiding among the dE population, they are likely to be among the non-nucleated dEs. Furthermore, the similarities in the properties of the globular clusters and in the spatial distributions of dE,Ns and giant Es suggest that neither galaxy mass or galaxy metallicity is responsible for high values of S_N. Instead, most metal-poor GCs may have formed in dwarf-sized fragments that merged into larger galaxies.Comment: 12 pages (uses aaspp4.sty), 2 figures, 1 table, to appear in the Astrophysical Journa

Impact of obesity on IL-12 family gene expression in insulin responsive tissues

Mounting evidence has established a role for chronic inflammation in the development of obesity-induced insulin resistance, as genetic ablation of pro-inflammatory cytokines and chemokines elevated in obesity improves insulin signaling in vitro and in vivo. Recent evidence further highlights interleukin (IL)-12 family cytokines as prospective inflammatory mediators linking obesity to insulin resistance. In this study, we present empirical evidence demonstrating that IL-12 family related genes are expressed and regulated in insulin-responsive tissues under conditions of obesity. First, we report that respective mRNAs for each of the known members of this cytokine family are expressed within detectable ranges in WAT, skeletal muscle, liver and heart. Second, we show that these cytokines and their cognate receptors are divergently regulated with genetic obesity in a tissue-specific manner. Third, we demonstrate that select IL-12 family cytokines are regulated in WAT in a manner that is dependent on the developmental stage of obesity as well as the inflammatory progression associated with obesity. Fourth, we report that respective mRNAs for IL-12 cytokines and receptors are also expressed and divergently regulated in cultured adipocytes under conditions of inflammatory stress. To our knowledge, this report is the first study to systemically evaluated mRNA expression of all IL-12 family cytokines and receptors in any tissue under conditions of obesity highlighting select family members as potential mediators linking excess nutrient intake to metabolic diseases such as insulin resistance, diabetes and heart disease. © 2012 Elsevier B.V

Mitogen-Dependent Regulation of DUSP1 Governs ERK and p38 Signaling During Early 3T3-L1 Adipocyte Differentiation

© 2015 Wiley Periodicals, Inc. Knowledge concerning mechanisms that control proliferation and differentiation of preadipocytes is essential to our understanding of adipocyte hyperplasia and the development of obesity. Evidence has shown that temporal regulation of mitogen-activated protein kinase (MAPK) phosphorylation and dephosphorylation is critical for coupling extracellular stimuli to cellular growth and differentiation. Using differentiating 3T3-L1 preadipocytes as a model of adipocyte hyperplasia, we examined a role for dual-specificity phosphatase 1 (DUSP1) on the timely modulation of MAPK signaling during states of growth arrest, proliferation, and differentiation. Using real-time reverse transcription PCR (qRT-PCR), we report that DUSP1 is induced during early preadipocyte proliferation concomitant with ERK and p38 dephosphorylation. As deactivation of ERK and p38 is essential for the progression of adipocyte differentiation, we further showed that de novo mRNA synthesis was required for ERK and p38 dephosphorylation, suggesting a role for inducible phosphatases in regulating MAPK signaling. Pharmacological and genetic inhibition of DUSP1 markedly increased ERK and p38 phosphorylation during early adipocyte differentiation. Based on these findings, we postulated that loss of DUSP1 would block adipocyte hyperplasia. However, genetic loss of DUSP1 was not sufficient to prevent preadipocyte proliferation or differentiation, suggesting a role for other phosphatases in the regulation of adipogenesis. In support of this, qRT-PCR identified several MAPK-specific DUSPs induced during early (DUSP2, -4, -5, & -6), mid (DUSP4 & -16) and late (DUSP9) stages of adipocyte differentiation. Collectively, these data suggest an important role for DUSPs in regulating MAPK dephosphorylation, with an emphasis on DUSP1, during early adipogenesis

The Relationship Among Gastrointestinal Symptoms, Problem Behaviors, and Internalizing Symptoms in Children and Adolescents With Autism Spectrum Disorder

Background: Many individuals with autism spectrum disorder (ASD) have co-occurring gastrointestinal (GI) symptoms, but the etiology is poorly understood. These GI symptoms often coincide with problem behaviors and internalizing symptoms, which reduces the quality of life for these individuals.Methods: This study examined the relationships among GI problems, problem behaviors, and internalizing symptoms in a sample of 340 children and adolescents with ASD who are patients at the University of Missouri Thompson Center for Autism &amp; Neurodevelopmental Disorders.Results: The majority of patients experienced constipation (65%), about half experienced stomachaches or stomach pain (47.9%), and others experienced nausea (23.2%) or diarrhea (29.7%). Young children with aggressive problem behaviors were 11.2% more likely to have co-occurring nausea; whereas, older children showed more complex relationships between internalizing symptoms and GI symptoms. Older children with greater anxiety symptoms were 11% more likely to experience constipation, but 9% less likely to experience stomachaches. Older children with greater withdrawn behavior were 10.9% more likely to experience stomachaches, but 8.7% less likely to experience constipation. Older children with greater somatic complaints were 11.4% more likely to experience nausea and 11.5% more likely to experience stomachaches.Conclusions: Results suggest that the presentation of externalizing problem behavior and internalizing symptoms associated with GI problems differs between young children and older children with ASD. Therefore, behavior may have different relationships with GI symptoms at different ages, which may have implications for the treatment of and clinical approach to GI disturbances in ASD

The Internet of Things: the future or the end of mechatronics.

The advent and increasing implementation of user configured and user oriented systems structured around the use of cloud configured information and the Internet of Things is presenting a new range and class of challenges to the underlying concepts of integration and transfer of functionality around which mechatronics is structured. It is suggested that the ways in which system designers and educators in particular respond to and manage these changes and challenges is going to have a significant impact on the way in which both the Internet of Things and mechatronics develop over time. The paper places the relationship between the Internet of Things and mechatronics into perspective and considers the issues and challenges facing systems designers and implementers in relation to managing the dynamics of the changes required