Thesis (M.S.)--Florida State University, 2005. / Advisor: Dr. Jeanne Flannery, Florida State University, School of Nursing. Title and description from dissertation home page (viewed June 16, 2005). Document formatted into pages; contains x, 117 pages. Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 85-88).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1966. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Alteration of serum tryptophan leads to parallel alterations in brain tryptophan levels. Such changes in brain tryptophan levels has been shown to lead to mood disturbances. The primary enzyme responsible for altering serum tryptophan levels is the liver cytosolic enzyme, tryptophan pyrrolase. Activation of this enzyme is responsible for the enhanced catabolism of circulating tryptophan. The purpose of the present study was firstly to establish whether there is a link between sex steroids and tryptophan pyrrolase activity especially since sex steroids are also known to cause mood disturbances and secondly to determine the effects of sex steroids on brain indolamine metabolism. The results show that all three sex steroids induce the activity of tryptophan pyrrolase implying that they decrease serum tryptophan levels by the activation of tryptophan pyrrolase, thus making less tryptophan available for uptake by the brain. It was also shown that the sex steroids enhance the uptake of ¹⁴C-tryptophan by brain synatopsomes. In addition, the sex steroids influenced the pattern of metabolism of serotonin by organ cultures of rat pineal glands. It is possible that the sex steroids regulate the availability and uptake of indoleamines in the brain.

published_or_final_version / Medicine / Master / Master of Philosophy

Thesis (M.S.)--University of Texas at El Paso, 2007. / Title from title screen. Vita. CD-ROM. Includes bibliographical references. Also available online.

Thesis (M.S.)--Ohio University, June, 2009. / Title from PDF t.p. Includes bibliographical references.

Background: Although glucocorticoids are the most effective treatment for asthma, some patients show a poor response. In such patients with steroid resistant asthma, this has been ascribed to altered glucocorticoid receptor (GR) ligand-binding affinity induced by IL-2 combined with IL-4 or IL-13 alone- all of which can also modulate glucocorticoid function in vitro. Objective: We sought to assess the ligand-binding affinity in a distinct group of oral steroid-dependent asthmatic subjects and examine the mechanisms by which IL-2 and IL-4 (or IL-13) modify the ligand-binding affinity of the GR. Methods: Using dexamethasone-binding assays, we examined PBMCs ex vivo from healthy subjects, subjects with controlled asthma, and oral steroiddependent subjects with severe asthma. In addition, IL-2 and IL-4 were used to alter GR affinity in vitro. We used mediators or inhibitors of signal transduction to investigate the mechanisms of resistance. We also determined cytokine production of PBMC's by means of ELISA. Results: GR ligand-binding affinity was significantly reduced in the nucleus but not in the cytoplasm of oral steroid-dependent asthmatic subjects compared with that seen in steroid-sensitive and healthy subjects (dissociation constant, 41.37 ± 17.83 vs. 25.36 ± 2.63 nmol/L vs. 9.40 ± 4.01 nmol/L, respectively [p<.05 for both in comparison to normals] ). This difference in ligand-binding affinity could be mimicked by IL-2 and IL-4 co-treatment and was blocked by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. PBMC's rendered resistant in vitro demonstrated lower IL-10 and increased GM-CSF production following LPS or PMA & PHA stimulation compared to cells with normal GR affinity. Resistant cells also showed reduced dexamethasone repression of LPSstimulated IL-10 release. These effects were also reversed by SB203580. Inhibition of the ERK MAPK pathway by PD098059 (10 mol/L), phosphoinositol 3 kinase by wortmannin (5 nmol/L) or treatment with IL-10 (10 ng/mL) failed to modulate the effect of IL-2 and IL-4 on receptor affinity. Ro318220 (10 nmol/L), a specific protein kinase C inhibitor and theophylline, similarly, had no effect on affinity. Conclusion: GR ligand binding affinity is tiered; compared to normal subjects; steroid responsive asthmatics have a mild reduction in ligand binding whereas oral steroid dependent asthmatics have greater reductions. When mononuclear cells are rendered resistant in vitro, cytokine production (low IL-10 and high GM-CSF) favours a pro-inflammatory state. Our data do not support the ERK MAPK, phosphoinositol 3 kinase, protein kinase C pathways in steroid resistance. Treatment with IL-10 and theophylline also failed to modulate the effect of IL-2 and IL-4 on receptor affinity. However, P38 MAPK inhibitors may have potential in reversing glucocorticoid insensitivity and re-establishing the beneficial effects of glucocorticoids in patients with severe asthma. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2007.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Department of Psychology. Title from pdf file main screen (viewed on November 6, 2009). Includes bibliographical references.

Traumatic brain injury (TBI) is a major cause of hospitalization and death. To mitigate these human costs, the search for effective drugs to treat TBI continues. Even mild injuries can lead to long-term deficits in memory and cognition. Predicting which patients will have long lasting memory issues following mild TBI is challenging. Our group has previously shown that in vitro models of TBI result in cell death, decreased long-term potentiation (LTP), and glial activation. In this thesis, we used chemical and electrical treatments to modulate the outcome following injury to inform future therapies. In the first aim of this thesis, we evaluated the efficacy of a novel neurosteroid, NTS-105, to reduce post-traumatic pathobiology in an in vitro model of moderate TBI that utilizes an organotypic hippocampal slice culture. Treatment with NTS-105 starting an hour after injury decreased post-traumatic cell death in a dose-dependent manner, with 10 nM NTS-105 being most effective. Post-traumatic administration of 10 nM NTS-105 also prevented deficits in LTP without adversely affecting neuronal activity in naïve cultures. Our results suggest that the pleiotropic pharmacology (affinity for the androgen, mineralocorticoid, and progesterone receptors) of NTS-105 may be a promising strategy for the effective treatment of TBI. In the second aim, we evaluated the mechanisms of NTS-105 in an in vitro model of mild blast TBI, a model in which NTS-105 is known to preserve LTP. Treatment with NTS-105 starting an hour after injury reduced a marker of microglial activation and increased expression of the GluR1 subunit of the AMPAR, which is a postsynaptic protein associated with LTP. NTS-105 is known to inhibit activation of the androgen receptor and the mineralocorticoid receptor, partially activate the progesterone B receptor and not activate the glucocorticoid receptor. NTS-105 treatment did not alter the expression of any of the oxosteroid receptors (progesterone, androgen, mineralocorticoid, and glucocorticoid). In order to demonstrate the benefits of mineralocorticoid antagonism following TBI, we administered eplerenone immediately after injury. Eplerenone treatment preserved LTP, but did increase spike magnitude at high concentrations. In the third aim, organotypic hippocampal slice cultures were biaxially stretched to model a mild TBI and serial electrophysiological recordings were collected. In this in vitro model, stretchable microelectrode arrays were embedded within the culture substrate to both deform the adhered culture and record neural signals, which are indicators of neuronal health and network connectivity. Multiple spontaneous and evoked recordings were obtained while maintaining sterility to study and modulate the electrophysiological response to injury. Bursting activity increased 2 hours after injury but returned to baseline by 24 hours. However, 24 hours after injury, both LTP and long-term depression (LTD) were impaired. In another experiment, LTP was induced multiple times, both 24 hours before and 24 hours after injury, to study how the state of the pre-injury network affected electrophysiological outcome after injury. We provide preliminary evidence that induction of LTP before injury to increase synaptic strength was detrimental to neuronal plasticity (LTP) after injury. This thesis has expanded upon the understanding of TBI injury mechanisms and hormone receptor modulators following TBI. Future studies will continue to examine NTS-105 and study the benefits of androgen receptor antagonism. Future studies will also continue to use the stretchable microelectrode arrays and our induction paradigm to test if induction of LTD, a weakening of synaptic strength, could increase resiliency to injury.