Medicine and Health Sciences Commons^™

High-Activity Mutants Of Human Butyrylcholinesterase For Cocaine Abuse Treatment, Liu Xue

Theses and Dissertations--Pharmacy

Cocaine is a widely abused drug without an FDA-approved medication. It has been recognized as an ideal anti-cocaine medication to accelerate cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e. butyrylcholinesterase (BChE)-catalyzed hydrolysis. However, the native BChE has a low catalytic activity against cocaine. We recently designed and discovered a set of BChE mutants with a high catalytic activity specifically for cocaine. An ideal, therapeutically valuable mutant of human BChE should have not only a significantly improved catalytic activity against cocaine, but also certain selectivity for cocaine over neurotransmitter acetylcholine (ACh) such …

Computational Modeling, Design, And Characterization Of Cocaine-Metabolizing Enzymes For Anti-Cocaine Medication, Lei Fang

Theses and Dissertations--Pharmacy

Cocaine is a widely abused and addictive drug, resulting in serious medical and social problems in modern society. Currently, there is no FDA-approved medication specific for cocaine abuse treatment. The disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. However, despite decades of efforts, traditional pharmacodynamic approach has failed to yield a truly useful small-molecule drug due to the difficulties inherent in blocking a blocker like cocaine without affecting the normal functions of the transporters or receptors. An alternative approach, i.e. pharmacokinetic approach, is to interfere with the delivery of …

Multistate Markov Chains And Their Application To The Biologically Resilient Adults In Neurological Studies Cohort, Erin L. Abner

Theses and Dissertations--Epidemiology and Biostatistics

Dementia is increasingly recognized as a major and growing threat to public health worldwide, and there is a critical need for prevention and treatment strategies. However, it is necessary that appropriate methodologies are used in the identification of risk factors. The purpose of this dissertation research was to develop further the body of literature featuring Markov chains as an analytic tool for data derived from longitudinal studies of aging and dementia.

Data drawn from 649 participants in the University of Kentucky’s Alzheimer’s Disease Center’s (UK ADC) Biologically Resilient Adults in Neurological Studies (BRAiNS) cohort, which was established in 1989 and …

Alterations In Visual Processing And Its Impact On Upright Postural Stability In Athletes Following Sport-Related Concussion, Andrea E. Cripps

Theses and Dissertations--Rehabilitation Sciences

Athletes are at risk of sustaining a concussion in all sports and at all competitive levels which may lead to balance impairments. Balance results from the integration of visual, vestibular, and somatosensory information. The underlying pathophysiology for balance impairments is not well understood and visuo-motor processing impairments and how these impairments contribute to balance in concussed athletes has not been reported. Objectives: (1) to investigate the influence of visual perturbation on upright postural stability and balance in athletes who have recently suffered a sports-related concussion, (2) to establish the test-retest reliability of a simple visuo-motor processing task. Design: A longitudinal, …

Scapular Muscle Assessment In Patients With Lateral Epicondylalgia, Joseph M. Day

Theses and Dissertations--Rehabilitation Sciences

The role rehabilitation plays in the management of patients with lateral epicondylalgia (LE) remains elusive secondary to high recurrence rates. Addressing scapular muscle deficits may be important in the rehabilitation of patients with LE. However, it is unknown if scapular muscle impairments exist in a working population of patients with LE. The purpose of this dissertation was to assess scapular muscle strength and endurance in a working population of patients with LE.

Clinical scapular muscle assessment tools are limited in their ability to isolate specific muscles. Rehabilitative ultrasound imaging (RUSI) is a potentially useful tool but few studies have investigated …

Nmda Receptors In The Dorsal Vagal Complex Of Normal And Diabetic Mice, Eva C. Bach

Theses and Dissertations--Physiology

The dorsal vagal complex (DVC), containing the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus nerve (DMV), plays a pivotal role in autonomic regulation. Afferent fibers from peripheral organs and higher brain centers synapse in the NTS, which integrates these synaptic connections as well as information from systemically circulating hormones and metabolites. The integrated information is relayed to the dorsal motor nucleus of the vagus nerve (DMV), which in turn, projects motor fibers to elicit parasympathetic control of digestive and other viscera. Physiological functions mediated by the DVC are disrupted in diabetic patients and …

Defining The Role Of Reactive Oxygen Species, Nitric Oxide, And Sphingolipid Signaling In Tumor Necrosis Factor - Induced Skeletal Muscle Weakness, Shawn Stasko

Theses and Dissertations--Physiology

In many chronic inflammatory diseases, patients suffer from skeletal muscle weakness, exacerbating their symptoms. Serum levels of tumor necrosis factor-alpha (TNF) and sphingomyelinase are increased, suggesting their possible role in the progression of this weakness. This dissertation focuses on the role that reactive oxygen species (ROS) and nitric oxide (NO) play in mediating TNF-induced skeletal muscle weakness and to what extent sphingolipid signaling mediates cellular response to TNF.

The first aim of this work was to identify which endogenous oxidant species stimulated by TNF contributes to skeletal muscle weakness. In C57BL/6 mice (n=38), intraperitoneal injection of TNF elicited a 25% …

Influence Of Coping Styles On Emotional State, Illness Perception, And Information Sources Of Men With Prostate Cancer, Gwendolyn M. Hooper

Theses and Dissertations--Nursing

Prostate cancer (PCa) has been the leading cause of cancer death in men since1930. While studies pertaining to PCa have primarily focused on the disease and the subsequent side effects of treatment, psychological distress in this group has yet to be adequately addressed. The purpose of this dissertation was to: 1) conceptualize health related quality of life (HRQL) and health seeking behavior of men by describing lifestyle, cultural and health risks associated with being male, 2) evaluate the psychometric properties of the SF-12 Health Survey (SF-12) combined with the urinary and sexual portions of the UCLA PCa Index (UCLA-PCI), 3) …

Barriers To Effective Pain Management In Preterm And Critically Ill Neonates, Sharon W. Lake

Theses and Dissertations--Nursing

The purpose of this dissertation is to explore potential barriers nurses experience in providing effective pain management for preterm and critically ill infants in neonatal intensive care units (NICUs). The specific aims of the study conducted are to examine (a) NICU caregivers’ knowledge about pain, (b) scales used to evaluate pain in infants, (c) NICU nurses’ documented pain practices, and (d) bias in treating pain of certain types of infants.

This dissertation is comprised of three manuscripts. The first manuscript is an integrated review of the literature describing caregiver knowledge, barriers, and bias in the management of pain in neonates. …

Adherence To Physical Activity Among Individuals With Or Without Cardiovascular Disease, Zyad T. Saleh

Theses and Dissertations--Nursing

Cardiovascular disease (CVD) is a major public health problem and a primary cause of morbidity and mortality in the United States. Regular physical activity is recommended for prevention and management of CVD. Despite the cardiovascular health benefits of physical activity most adults are physically inactive. Therefore, the aim of this dissertation was to examine the factors associated with adherence to physical activity among individuals with or without CVD.

The first paper is a report of a study conducted to examine which baseline demographic (age, gender, marital status, socioeconomic status, and place of residency), psychosocial (social support, depression, anxiety, and fatalism), …

The Factors That Influence Duration Of Exclusive Breastfeeding: A Mixed Methods Design, Roxanne K. Bowman

Theses and Dissertations--Nursing

Breastfeeding is the gold standard of infant feeding and its benefits extend beyond the mother and child. Multiple organizations recommend exclusive breastfeeding for the first six months of an infant’s life. Exclusive breastfeeding rates nationally and in the state of Kentucky fall below the Healthy People 2020 goals. A mother’s intention to breastfeed has been shown to impact actual breastfeeding behavior. The current state of the measurement of intention was explored through a literature review. A majority of the measures were single item scales. The reliability and validity of the scales should be further tested in diverse populations.

The purposes …

Diet-Induced Obesity: Dopaminergic And Behavioral Mechanisms As Outcomes And Predictors, Vidya Narayanaswami

Theses and Dissertations--Pharmacy

Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to …

A Grounded Theory Model Of Mother Role Development While In The Neonatal Intensive Care Unit, Kathy B. Isaacs

Theses and Dissertations--Nursing

When a woman discovers that she is pregnant, she begins a process of internal work to develop her mother role. This process has been outlined in the literature for the delivery of a healthy full-term baby, however little is known about the process for mothers of medically fragile babies. A threatened pregnancy and subsequent delivery of a medically fragile baby involves a different process of internal work by the mother to prepare for her role. Mothers with a baby in the Neonatal Intensive Care Unit (NICU) experience stress, uncertainty, and anxiety potentially causing a permanent impact on the successful development …

High Dose Simvastatin As A Potential Anticancer Therapy In Leukemia Patients, Tamer Ahmed

Theses and Dissertations--Pharmacy

Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that is used for the treatment of hyperlipidemia. Simvastatin has recently been studied for its potential use in cancer therapy. In-vitro studies have shown that simvastatin displays anticancer activity, but at concentrations unlikely to be achieved in patients being receiving typical antihyperlipidemic treatment doses. Thus, several clinical trials were conducted to study the tolerability of high dose statins in cancer patients. The maximum tolerated dose of simvastatin was determined to be 15 mg/kg/day, 25-fold higher than a typical dose. However, it is not known if simvastatin plasma concentrations can reach those …

Towards Elucidation Of A Viral Dna Packaging Motor, Chad T. Schwartz

Theses and Dissertations--Pharmacy

Previously, gp16, the ATPase protein of phi29 DNA packaging motor, was an enigma due to its tendency to form multiple oligomeric states. Recently we employed new methodologies to decipher both its stoichiometry and also the mechanism in which the protein functions to hydrolyze ATP and provide the driving force for DNA packaging. The oligomeric states were determined by biochemical and biophysical approaches. Contrary to many reported intriguing models of viral DNA packaging, it was found that phi29 DNA packaging motor permits the translocation of DNA unidirectionally and driven cooperatively by three rings of defined shape. The mechanism for the generation …

Synthesis And Stability Studies Of Prodrugs And Codrugs Of Naltrexone And 6-Β-Naltrexol, Joshua A. Eldridge

Theses and Dissertations--Pharmacy

The present study was divided between two different drug delivery goals, each involving naltrexone (NTX) or its active metabolite, 6-β-naltrexol (NTXOL). First, amino acid esters of NTX and NTXOL were prepared in order to test their candidacy for microneedle-enhanced transdermal delivery. Second, a 3-O-(-)-cytisine-naltrexone (CYT-NTX) codrug was prepared for screening as a potential oral delivery form of NTX and (-)-cytisine (CYT). The amino acid prodrugs were intended for the treatment of alcohol abuse, while the codrug was designed as a single agent for the treatment of alcoholism and tobacco-dependency co-morbidities. One hypothesis of this work was that prodrugs …

Preclinical And Clinical Development Of The Lipophilic Camptothecin Analogue Ar-67, Eleftheria Tsakalozou

Theses and Dissertations--Pharmacy

AR-67 is a lipophilic third generation camptothecin analogue, currently under early stage clinical trials. It acts by targeting Topoisomerase 1 (Top1), a nuclear enzyme essential for DNA replication and transcription and is present in two forms, the pharmacologically active lipophilic lactone and the charged carboxylate. In oncology patients participating in a phase I clinical trial, AR-67 lactone was the predominant species in plasma. Similarly to other camptothecins, the identified dose-limiting toxicities for AR-67 were neutropenia, thrombocytopenia and fatigue. In addition, in vitro metabolism studies indicated AR-67 lactone as a substrate for CYP3A4/5 as well as the UGT1A7 and UGT1A8 enzymes …

Amalgamation Of Nucleosides And Amino Acids In Antibiotic Biosynthesis, Sandra H. Barnard

Theses and Dissertations--Pharmacy

The rapid increase in antibiotic resistance demands the identification of novel antibiotics with novel targets. One potential antibacterial target is the biosynthesis of peptidoglycan cell wall, which is both ubiquitous and necessary for bacterial survival. Both the caprazamycin-related compounds A-90289 and muraminomicin, as well as the capuramycin-related compounds A-503083 and A-102395 are potent inhibitors of the translocase I enzyme, one of the key enzymes required for cell wall biosynthesis. The caprazamycin-related compounds contain a core nonproteinogen b-hydroxy-a-amino acid referred to as 5’-C-glycyluridine (GlyU). Residing within the biosynthetic gene clusters of the aforementioned compounds is a shared open reading …

The Pharmacokinetics Of Metal-Based Engineered Nanomaterials, Focusing On The Blood-Brain Barrier, Mo Dan

Theses and Dissertations--Pharmacy

Metal-based engineered nanomaterials (ENMs) have potential to revolutionize diagnosis, drug delivery and manufactured products, leading to greater human ENM exposure. It is crucial to understand ENM pharmacokinetics and their association with biological barriers such as the blood-brain barrier (BBB). Physicochemical parameters such as size and surface modification of ENMs play an important role in ENM fate, including their brain association. Multifunctional ENMs showed advantages across the highly regulated BBB. There are limited reports on ENM distribution among the blood in the brain vasculature, the BBB, and brain parenchyma.

In this study, ceria ENM was used to study the effect of …

Formulation Optimization For Pore Lifetime Enhancement And Sustained Drug Delivery Across Microneedle Treated Skin, Priyanka Ghosh

Theses and Dissertations--Pharmacy

Microneedle (MN) enhanced drug delivery is a safe, effective and efficient enhancement method for delivery of drug molecules across the skin. The “poke (press) and patch” approach employs solid stainless steel MN to permeablize the skin prior to application of a regular drug patch over the treated area. It has been previously shown that MN can be used to deliver naltrexone (NTX) at a rate that provides plasma concentrations in the lower end of the therapeutic range in humans. The drug delivery potential of this technique is, however, limited by the re-sealing of the micropores in a 48-72h timeframe. The …

Biosynthetic Pathway Of The Aminoribosyl Component Of Lipopeptidyl Nucleoside Antibiotics, Xiuling Chi

Theses and Dissertations--Pharmacy

Several lipopeptidyl nucleoside antibiotics that inhibit bacterial translocase I (MraY) involved in peptidoglycan cell wall biosynthesis contain an aminoribosyl moiety, an unusual sugar appendage in natural products. A-90289 and muraminomicin are the two representative antibiotics that belong to this family. Bioinformatic analysis of the biosynthetic A-90289 gene clusters revealed that five enzymes are likely involved in the assembly and attachment of the aminoribosyl unit. These enzymes of A-90289 are functionally assigned by in vitro characterization. The results reveal a unique ribosylation pathway that highlighted by uridine-5′-monophosphate as the source of the sugar, a phosphorylase strategy to generate a sugar-1-phosphate, and …

Microglia Activation In A Rodent Model Of An Alcohol Use Disorder: The Importance Of Phenotype, Initiation, And Duration Of Activation, Simon A. Marshall

Theses and Dissertations--Pharmacy

Chronic ethanol exposure results in neuroadaptations that drive the progression of an alcohol use disorder (AUD). One such driving force is alcohol-induced neurodegeneration. Neuroinflammation has been proposed as a mechanism underlying this damage. Although neuroinflammation is a physiological response to damage, overactivation of its pathways can lead to neurodegeneration. A hallmark indicator of neuroinflammation is microglial activation, but microglial activation is a heterogeneous continuum of phenotypes that can promote or inhibit neuroinflammation. Furthermore acute microglial activation is necessary to restore homeostasis, but prolonged activation can exacerbate damage. The diversity of microglia makes both the level and timecourse of activation vital …

Polymer Micelles For Tunable Drug Release And Enhanced Antitumor Efficacy, Andrei G. Ponta

Theses and Dissertations--Pharmacy

Cancer remains a leading cause of death in the United States. The most common treatment options include chemotherapy, but poor solubility, adverse side effects and differential drug sensitivity hamper clinical applications. Current chemotherapy generally aims to deliver drugs at the limit of toxicity, assuming that higher dosage increases efficacy, with little attention paid to potential benefits of tunable release. Growing evidence suggests that releasing drugs at a constant rate will be as effective as a single bolus dose. To test this hypothesis, it is critical to develop drug delivery systems that fine-tune drug release and elucidate the impact of tunable …

Methylphenidate And Atomoxetine Treatment During Adolescence In The Spontaneously Hypertensive Rat: Mechanisms Underlying High Cocaine Abuse Liability In Attention Deficit/Hyperactivity Disorder, Sucharita S. Somkuwar

Theses and Dissertations--Pharmacy

Effects of pharmacotherapies for Attention Deficit/Hyperactivity Disorder (ADHD) on cocaine abuse liability in ADHD are not understood. Spontaneously Hypertensive Rats (SHR), an ADHD model, exhibited greater cocaine self-administration than control Wistar-Kyoto and Wistar rats. Methylphenidate, but not atomoxetine during adolescence enhanced cocaine self-administration in adult SHRs compared to controls. The mesocortical dopaminergic system, including medial prefrontal (mPFC) and orbitofrontal (OFC) cortices, is important for ADHD and cocaine addiction. Dopamine and norepinephrine transporter (DAT and NET) are molecular targets for methylphenidate, atomoxetine and cocaine action.

In the current studies, SHR, Wistar-Kyoto and Wistar were administered methylphenidate (1.5 mg/kg/day, p.o.), atomoxetine (0.3 …

Post Use Analysis Of Firefighter Turnout Gear- Phase Iii, Meredith Laine Cinnamon

Theses and Dissertations--Retailing and Tourism Management

The purpose of this research was to perform a post-use evaluation of retired firefighter turnout gear. Garments were categorized as 10-12 years old, 13-17 years old and 18-21 years old. Inspection and test procedures required by National Fire Protection Association (NFPA) 1851 and NFPA 1971 were followed to determine if the current recommended 10 year wear life (retirement age) is appropriate. Testing included a visual inspection (closure system functionality, light evaluation, leakage evaluation and flashlight test) and performance properties (Thermal Protective Performance (TPP), flammability, breaking strength, tear strength, seam strength and water penetration) completed on 108 garments. Ten-year retirement, care, …

Equine Protozoal Myeloencephalitis: Investigation Of Genetic Susceptibility And Assessment Of An Equine Infection Method, Breanna M. Gaubatz

Theses and Dissertations--Veterinary Science

Equine protozoal myeloencephalitis (EPM) is a progressive neurological disease of horses caused by Sarcocystis neurona. Two projects were conducted to identify factors involved in the development of EPM. The first study explored a possible genetic susceptibility to EPM by attempting a genome-wide association study (GWAS) on formalin-fixed, paraffin-embedded (FFPE) tissue from 24 definitively-positive EPM horses. DNA extracted from tissues older than 14 months was inadequate for SNP analysis on the Illumina Equine SNP50 BeadChip probably due to degradation and formalin cross-linking. Results were inconclusive as analysis was not possible with the small sample set. The second study evaluated an …

Determination Of Farm-Specific Lawsonia Intracellularis Seroprevalence In Central Kentucky Thoroughbreds And The Identification Of Factors Contributing To Equine Proliferative Enteropathy, Allen E. Page

Theses and Dissertations--Veterinary Science

Lawsonia intracellularis and the disease it causes in horses, equine proliferative enteropathy (EPE), is an emerging pathogen of increasing importance to the horse industry from both an economic and welfare standpoint. Long recognized as an economically important disease of swine, the hallmark of EPE is a protein-losing enteropathy, where affected horses suffer weight loss and some ultimately succumb to the disease despite aggressive treatment. There are currently no known EPE preventative measures and the epidemiology of the disease remains poorly defined. While EPE is a sporadic disease affecting less than 25% of exposed horses, some farms experience clinical cases year …

Chondrodysplasia-Like Dwarfism In The Miniature Horse, John E. Eberth

Theses and Dissertations--Veterinary Science

Dwarfism is considered one of the most recognized congenital defects of animals and humans and can be hereditary or sporadic in cause and expression. There are two general morphologic categories within this vastly diverse disease. These categories are disproportionate and proportionate dwarfism and within each of these there are numerous phenotypes which have been extensively described in humans, and to a lesser extent in dogs, cattle, mice, chickens, and other domestic species. Ponies and Miniature horses largely differ from full size horses only by their stature. Ponies are often defined as those whose height is not greater than 14.2 hands; …

Celiac Disease: A Gluten Free Diet And Diet Quality, Taylor M. Stauble

Theses and Dissertations--Nutrition and Food Systems

The media has highlighted a proposed link between a gluten free diet (GFD) and weight loss. However, research related to weight gain and a GFD for persons with celiac disease (CD) has shown the opposite effect. A GFD is the only known treatment for persons with CD. If a patient with CD consumes a diet high in GF processed foods, weight management may be difficult to achieve.

Participants with self-reported CD completed a modified GF food frequency questionnaire (FFQ) to assess typical dietary consumption of whole grains, sweets, fruits, vegetables and regular soda. Additionally, body mass index (BMI) and exercise …

Overall Diet Quality Of Collegiate Athletes, Amanda N. Ireland

Theses and Dissertations--Nutrition and Food Systems

Athletes appear healthy according to weight for height and body fat standards. Though athletes appear to be healthy, little is known about their diets. Research states there is a connection between athletic performance and nutrition. The objective of this study was to determine the diet quality of 138 collegiate athletes. Data were collected in a laboratory. Demographics were collected via survey. Anthropometrics were assessed using a free standing stadiometer and the BodPod® for body fat assessment. Block 2005 Food Frequency Questionnaire© was used to assess diets. The Healthy Eating Index (HEI) 2005 was used to calculate diet quality scores. The …