Digital Commons Network^™

Rapid No• Measures In Rat Nucleus Accumbens And Frontal Cortex Following Nasal Administration Of Nitroglycerin, Victoria A. Scott

Theses and Dissertations--Medical Sciences

Nitric Oxide (NO) is a powerful endogenous free radical that has numerous biological functions including vasodilation and serves as a post synaptic second messenger in the central nervous system (CNS). Numerous studies implicate NO• involvement in CNS disorders such as schizophrenia and drug abuse. These studies address the direct in vivo determination of an FDA-approved NO• donor (nitroglycerin) on extracellular levels of NO• in the frontal cortex and core of the nucleus accumbens in a lightly anesthetized rat. State-of-the-art in vivo amperometric recording techniques coupled with a novel 4-channel low noise pre-amplifier system and new generation microelectrode arrays (MEAs) will …

The Stimulation Of Dendritic Cells By Cationic Lipids, John Peyton Bush

Theses and Dissertations--Medical Sciences

The discovery that cationic lipids can independently stimulate the immune system has generated interest in their potential as vaccine adjuvants. Here, we show that the cationic lipid R-DOTAP can independently stimulate type 1 interferon production in dendritic cells in both primary culture and immortalized cell culture. Levels of type 1 interferon production are cell line-dependent and limited in vitro by lipid-induced cell death. We show that cationic lipids can independently activate TLR-7 and TLR-9, suggesting a mechanism for type 1 interferon induction. This TLR-stimulatory activity is not restricted to R-DOTAP and can be extended to other similar cationic lipids in …

Integrin Α5Β1 As A Novel Target With The Small Peptide, Atn-161, In The Treatment Of Ischemic Stroke, Danielle Nichele Edwards

Theses and Dissertations--Neuroscience

Stroke is the 5^th leading cause of death and the leading cause of disability in the United States, but there are only two available therapies, tissue plasminogen activator and endovascular thrombectomy. As both therapies focus on removal of the clot, the subsequent pathologic processes, i.e. inflammation, cerebrovascular breakdown, ATP depletion, etc. are left untreated, contributing to worsened patient outcome. Many clinical trials have unsuccessfully attempted to address these mechanisms. The blood-brain barrier (BBB), a system of non-fenestrated endothelial cells, extracellular matrix, and astrocytic endfeet, is significantly impacted after ischemic stroke in its role of preventing the free movement of …

The Role Of Cd8 T Cell Immunodominance And Regulatory T Cells In Neonatal Immunity To Influenza Virus, Luke Heil

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality as well as delayed clearance of the virus. Efforts to improve influenza infection outcomes in neonates typically center on prevention, although current vaccines fall short of complete protection and can only be administered in humans after 6 months of life. We propose that as the neonatal immune system responds differently than the adult immune system, interventions that are efficacious or tolerable in adults cannot be guaranteed to perform the same in neonates. T cell vaccines that target conserved influenza virus epitopes have been proposed …

Neuroprotective Strategies Following Experimental Traumatic Brain Injury: Lipid Peroxidation-Derived Aldehyde Scavenging And Inhibition Of Mitochondrial Permeability Transition, Jacqueline Renee Kulbe

Theses and Dissertations--Neuroscience

Traumatic brain injury (TBI) represents a significant health crisis. To date there are no FDA-approved pharmacotherapies available to prevent the neurologic deficits caused by TBI. Following TBI, dysfunctional mitochondria generate reactive oxygen and nitrogen species, initiating lipid peroxidation (LP) and the formation of LP-derived neurotoxic aldehydes, which bind mitochondrial proteins, exacerbating dysfunction and opening of the mitochondrial permeability pore (mPTP), resulting in extrusion of mitochondrial sequestered calcium into the cytosol, and initiating a downstream cascade of calpain activation, spectrin degradation, neurodegeneration and neurologic impairment.

As central mediators of the TBI secondary injury cascade, mitochondria and LP-derived neurotoxic aldehydes make promising …

Tgf-Β, Wnt, And Fgf Signaling Pathways During Axolotl Tail Regeneration And Forelimb Bud Development, Qingchao Qiu

Theses and Dissertations--Neuroscience

Tgf-β, Wnt, and Fgf signaling pathways are required for many developmental processes. Here, I investigated the requirement of these signaling pathways during tail regeneration and limb development in the Mexican axolotl (Ambystoma mexicanum).

Using small chemical inhibitors during tail regeneration, I found that the Tgf-β signaling pathway was required from 0-24 and 48-72 hours post tail amputation (hpa), the Wnt signaling pathway was required from 0-120 hpa, and the Fgf signaling pathway was required from 0-12hpa. Tgf-β1 was upregulated after amputation and thus may mediate Tgf-β signaling pathway during tail regeneration. Both Smad-mediated and non-Smad mediated Tgf-β signaling …

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …

Essays On Price Discrimination And Demand Learning, Benjamin E. Wallace

Theses and Dissertations--Economics

This dissertation consists of three essays examining how and why firms set prices in markets. In particular, this dissertation shows how firms may utilize nonlinear pricing to price discriminate, how firms may experiment with the prices they set to learn about the demand function in the market they serve in later periods and the effects of these pricing strategies on consumer welfare.

In Essay 1, I show how firms in the milk market use nonlinear price schedules -- quantity discounts -- to price discriminate and increase profits. I find that firms have a greater ability to price discriminate on their …

Depressive Symptoms Among Farm Women Aged 50 And Older, Cheryl Dean Witt

Theses and Dissertations--Nursing

Alarming rates of suicide among production farmers have prompted researchers to investigate factors associated with depressive symptoms among this population. Aspects of farm life and farming can contribute to higher levels of depressive symptoms. Higher levels of depression can also increase an individual’s risk of injury and development of chronic disease, impacting overall quality of life. Despite the approximate 3.5 million farm women in the U.S., current research has focused on the male farmer.

Men and women have different responses to stressors, and women in general have a higher prevalence of depressive symptoms. Farm women can be further subjected to …

Neurochemical Factors Associated With The Initial Pathophysiological Reaction To Large Vessel Occlusion Stroke, Sarah R. Martha

Theses and Dissertations--Nursing

Ischemic stroke is the leading cause of disability world-wide and affects over 800,000 people per year in the United States. The majority of these strokes are ischemic due to a blockage of blood flow to the brain. Damage to the brain occurs at the onset of stroke, neuronal cell death is irreversible and therefore, quick treatment to remove blockage is critical factor in the recovery from stroke. Mechanical thrombectomy as a treatment for ischemic stroke provides an ideal opportunity to collect blood distal and proximal to the cerebral thrombus to examine neurochemical changes occurring during stroke.

The purpose of this …

Gay Men And Satisfaction With Health Care Interactions, Michael Huggins

Theses and Dissertations--Nursing

The purpose of this research was to determine relationships among depression, anxiety, self-rated physical and mental health, self-advocacy, internalized homophobia, and quality of patient-provider communication to satisfaction with health care interactions. These were measured while controlling for select demographic variables: age; ethnicity; urban or rural domicile; relationship status; household income; highest educational attainment; health insurance; disclosure to health care provider as a gay man; reason for last healthcare visit; and, general health self-rating. The specific aims of this study were to: 1) identify general characteristics of gay men in this sample; 2) examine how levels of satisfaction with health care …

Developing A Workflow To Evaluate Medications For Repurposing Using Health Claims Data: Application To Substance Use Disorders, Emily Ruth Hankosky

Theses and Dissertations--Pharmacy

Healthcare big data are a growing source of real-world data with which to identify and validate medications with repurposing potential. Previously, we developed a claims-based workflow to evaluate medications with potential to treat stimulant use disorders. In order to test the workflow, the framework was applied in the context of opioid use disorders (OUDs), for which there are medications with known efficacy. Using the Truven Marketscan Commercial Claims Database, a nested case-control analysis was conducted to determine the association between OUD medications (buprenorphine, naltrexone) and remission. Cases were defined as enrollees with a remission diagnosis and matched (1:4) to controls …

The Development Of Novel Proteasome Inhibitors For The Treatment Of Multiple Myeloma And Alzheimer’S Disease, Min Jae Lee

Theses and Dissertations--Pharmacy

Over a decade, proteasome inhibitors (PIs), bortezomib, carfilzomib (Cfz) and ixazomib, have contributed to a significant improvement in the overall survival for multiple myeloma (MM) patients. However, the response rate of PI was fairly low, leaving a huge gap in MM patient care. Given this, mechanistic understanding of PI resistance is crucial towards developing new therapeutic strategies for refractory/relapsed MM patients.

In this dissertation work, we found H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). It indicated H727 cells may serve as a …

Carbapenem-Resistant Enterobacteriaceae: Epidemiology, Genetics, In Vitro Activity, And Pharmacodynamic Modeling, Brandon Kulengowski

Theses and Dissertations--Pharmacy

Background: Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) such as Escherichia coli and Klebsiella pneumoniae are among the most urgent threats of the infectious disease realm. The incidence of these infections has been increasing over the years and due to very limited treatment options, mortality is estimated at about 50%. By 2050, mortality from antimicrobial resistant infections is expected to surpass cancer at 10 million deaths annually.

Methods: We evaluated 18 contemporary antimicrobials against 122 carbapenem-resistant Enterobacteriaceae using a variety of antimicrobial susceptibility testing methods according to Clinical Laboratory Standards Institute guidelines. Time-kill studies were performed on clinical isolates with variable …

Pharmacokinetic And Pharmacodynamic Evaluation Of Cocaine Hydrolases For The Treatment Of Cocaine Overdose And Cocaine Addiction Using Rodent Models, Xirong Zheng

Theses and Dissertations--Pharmacy

Overdose and addiction are two medical complications of cocaine abuse. To date, there is no FDA approved pharmacotherapy specific for cocaine abuse. Cocaine hydrolases (CocHs) have been extensively investigated for its potential in anti-cocaine therapy. Previous studies have demonstrated that CocHs efficiently hydrolyze cocaine to generate biologically inactive metabolites both in vivo and in vitro. However, it has not been studied whether there is gender difference in the therapy using CocHs. In addition, the effectiveness of CocHs is unknown for treating cocaine toxicity when alcohol is co-administered.

The main purpose of this dissertation is to characterize and evaluate efficient …

Discovery Of Novel Pharmacotherapeutics For Substance Use Disorders, Na-Ra Lee

Theses and Dissertations--Pharmacy

Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding …

Development Of Mithramycin Analogues With Improved Efficacy And Reduced Toxicity For Treatment Of Ets-Dependent Tumors In Ewing Sarcoma And Prostate Cancer, Joseph Michael Eckenrode

Theses and Dissertations--Pharmacy

Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor …

Computational Modeling Guided Discovery Of Novel Inhibitors Of Mpges-1 And Butyrylcholinesterase As Drug Candidates, Shuo Zhou

Theses and Dissertations--Pharmacy

Ever since the advent of computer-aided drug design (CADD), in silico simulation methods have greatly accelerated the drug discovery process and lead to the discovery of numerous drug candidates. With the exponential growth of computational power, we nowadays simulate biologic systems at a scale unimaginable a decade ago and thus provides perspectives for drug design. In this dissertation research, combining in silico simulation methods like molecular docking and molecular dynamics (MD) simulation with organic synthesis, in vitro/in vivo experiments and clinical data mining, we developed new drug discovery strategies. These strategies were applied in our drug discovery projects and led …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Investigation Of Factors Influencing Protein Stability In Lyophilized Formulations Using Solid-State Nmr Spectroscopy, Ashley Lay-Fortenbery

Theses and Dissertations--Pharmacy

Many proteins are unstable in solution and must be formulated in the solid state. This has led to an increase in the use of lyophilized dosage forms. Lyophilization is a complicated processing method consisting of three major steps: freezing, primary drying, and secondary drying. This can lead to several formulation stability challenges including changes in ionization within the matrix, phase separation of the protein drug from added stabilizers, sufficient mobility within the system for movement of reactive species and protein side chains, and crystallization of excipients upon storage. Solid-State Nuclear Magnetic Resonance Spectroscopy (SSNMR) is used to characterize many important …

Suicide Attitudes And Terror Management Theory, Athena Kheibari

Theses and Dissertations--Social Work

Virtually every mental health problem carries stigma, but suicide appears to run so counter to our accumulative, achievement-oriented society, that it poses even greater threat of stigma. While suicide is inherently troubling in that it opposes the fundamental human instinct for self-preservation, the tendency to stigmatize and reject individuals affected by suicide appears to be counterproductive and excessive. Hence, the purpose of this three-manuscript dissertation is to gain a more nuanced understanding of suicide attitudes from an exploratory and terror management theory perspective. More specifically, this dissertation attempts to answer three general questions: (1) how do suicide attitudes differ from …

Quantification Of Myocardial Mechanics In Left Ventricles Under Inotropic Stimulation And In Healthy Right Ventricles Using 3d Dense Cmr, Zhan-Qiu Liu

Theses and Dissertations--Mechanical and Aerospace Engineering

Statistical data from clinical studies indicate that the death rate caused by heart disease has decreased due to an increased use of evidence-based medical therapies. This includes the use of magnetic resonance imaging (MRI), which is one of the most common non-invasive approaches in evidence-based health care research. In the current work, I present 3D Lagrangian strains and torsion in the left ventricle of healthy and isoproterenol-stimulated rats, which were investigated using Displacement ENcoding with Stimulated Echoes (DENSE) cardiac magnetic resonance (CMR) imaging. With the implementation of the 12-segment model, a detailed profile of regional cardiac mechanics was reconstructed for …

Quantification Of Papillary Muscle Motion And Mitral Regurgitation After Myocardial Infarction, Connor R. Ferguson

Theses and Dissertations--Mechanical and Aerospace Engineering

Change in papillary muscle motion as a result of left ventricular (LV) remodeling after posterolateral myocardial infarction is thought to contribute to ischemic mitral regurgitation. A finite element (FE) model of the LV was created from magnetic resonance images acquired immediately before myocardial infarction and 8 weeks later in a cohort of 12 sheep. Severity of mitral regurgitation was rated by two-dimensional echocardiography and regurgitant volume was estimated using MRI. Of the cohort, 6 animals (DC) received hydrogel injection therapy shown to limit ventricular remodeling after myocardial infarction while the control group (MI) received a similar pattern of saline injections. …

A Computational Study Of Patch Implantation And Mitral Valve Mechanics, Dara Singh

Theses and Dissertations--Mechanical and Aerospace Engineering

Myocardial infarction (i.e., a heart attack) is the most common heart disease in the United States. Mitral valve regurgitation, or the backflow of blood into the atrium from the left ventricle, is one of the complications associated with myocardial infarction. In this dissertation, a validated model of a sheep heart that has suffered myocardial infarction has been employed to study mitral valve regurgitation. The model was rebuilt with the knowledge of geometrical changes captured with MRI technique and is assigned with anisotropic, inhomogeneous, nearly incompressible and highly non-linear material properties. Patch augmentation was performed on its anterior leaflet, using a …

Pyocyanin, A Virulence Factor Produced By Sepsis-Causing Pseudomonas Aeruginosa, Promotes Adipose Wasting And Cachexia, Nika Larian

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis is a leading cause of death among critically ill patients that results in metabolic alterations including hypercatabolism, lipoatrophy, and muscle wasting, contributing to the development of cachexia. Septic cachexia is associated with loss of body weight, fat mass, and lean mass and dysregulated immune function. There are currently no efficacious treatment strategies for septic cachexia, and nutritional interventions have limited success in preventing hypercatabolic wasting. Pyocyanin is a virulence factor produced by sepsis-causing Pseudomonas aeruginosa that has been shown to activate the aryl hydrocarbon receptor (AhR), increase inflammation, and produce reactive oxygen species. Thus, pyocyanin represents a novel mechanistic …

The Role Of Endoplasmic Reticulum Stress In Ethanol-Induced Neurodegeneration, Yongchao Wang

Theses and Dissertations--Pharmacology and Nutritional Sciences

Heavy ethanol use causes neurodegeneration manifested by neuronal loss and dysfunction. It is becoming imperative to delineate the underlying mechanism to promote the treatment of ethanol-induced neurodegeneration. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases. This study aims to investigate the role of ER stress in ethanol-induced neurodegeneration. In experimental design, adult mice were exposed to binge ethanol drinking by daily gavage for 1, 5, or 10 days and the response of ER stress was examined. We found the induction of ER stress appeared at 5 days and remained at 10 days. Moreover, …

Azithromycin Therapy Reduces Cardiac Inflammation And Mitigates Adverse Cardiac Remodeling After Myocardial Infarction, Ahmed Hamish Neamah Al-Darraji

Theses and Dissertations--Pharmacology and Nutritional Sciences

Introduction: Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Induced by cardiomyocyte death, MI initiates a prolonged and uncontrolled inflammatory response which impairs the healing process. Immune cells, such as macrophages, play a central role in organizing the early post-MI inflammatory response and the subsequent repair phase. Two activation states of macrophages have been identified with distinct and complementary functions (inflammatory vs. reparatory). This bimodal pattern of macrophage activation is an attractive therapeutic target to favorably resolve post-MI inflammation and enhance recovery. It has been demonstrated that azithromycin (AZM), a commonly used antibiotic with immunomodulatory effects, …

Pathological Tau As A Cause, And Consequence, Of Cellular Dysfunction, Shelby Meier

Theses and Dissertations--Physiology

Tauopathies are a group of neurodegenerative diseases characterized by the abnormal deposition of the protein tau, a microtubule stabilizing protein. Under normal physiological conditions tau is a highly soluble protein that is not prone to aggregation. In disease states alterations to tau lead to enhanced fibril formation and aggregation, eventually forming neurofibrillary tangles (NFTs). The exact cause for NFT deposition is unknown, but increased post-translational modifications and mutations to the tau gene can increase tangle formation.

Tauopathic brains are stuck in a detrimental cycle, with cellular dysfunction contributing to the development of tau pathology and the development of tau pathology …

Development And Evaluation Of Nonradioactive Methods For Monitoring T Lymphocyte Response To Equine Arteritis Virus (Eav) In Horses, Annet Kyomuhangi

Theses and Dissertations--Veterinary Science

Target cell lysis is the hallmark of immune effector responses of cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and monocytes. The most commonly used assay to measure target cell lysis is the 51Cr release assay and is considered the ‘gold standard’. However, this assay has many disadvantages that limit its use by most laboratories. Thus, several alternative assays have been developed. Some of these alternative assays are more sensitive, easy to perform and do not use radioactive elements.

In this study, four of these assays were evaluated for their ability to detect antigen- specific CTL responses in equine blood. …

Effects Of Pituitary Pars Intermedia Dysfunction And Prascend® Treatment On Endocrine And Immune Function In Senior Horses, Ashton B. Miller

Theses and Dissertations--Veterinary Science

Pituitary pars intermedia dysfunction (PPID) is one of the most common endocrine diseases affecting senior horses. PPID causes abnormally high concentrations of adrenocorticotropic hormone (ACTH) in the plasma and a very distinct, long, shaggy haircoat (hypertrichosis). At present, the recommended treatment for PPID is daily oral administration of pergolide mesylate. Due to the increased ACTH levels associated with PPID, it is commonly thought that these horses are immunosuppressed and at increased risk of opportunistic infections, although current research in this area is sparse. Additionally, it is not well-understood how treatment with Prascend^® (pergolide tablets) affects endocrine measures other than …