Medicine and Health Sciences Commons^™

Biochemical Characterization Of Human Mismatch Recognition Proteins Mutsα And Mutsβ, Lei Tian

University of Kentucky Doctoral Dissertations

The integrity of an organism's genome depends on the fidelity of DNA replication and the efficiency of DNA repair. The DNA mismatch repair (MMR) system, which is highly conserved from prokaryotes to eukaryotes, plays an important role in maintaining genome stability by correcting base-base mismatches and insertion/deletion (ID) mispairs generated during DNA replication and other DNA transactions. Mismatch recognition is a critical step in MMR. Two mismatch recognition proteins, MutSα (MSH2-MSH6 heterodimer) and MutSβ (MSH2-MSH3 heterodimer), have been identified in eukaryotic cells. MutSα and MutSβ have partially overlapping functions, with MutSα recognizing primarily base-base mismatches and 1-2 nt ID mispairs …

Dissecting The Biosyntheses Of Gilvocarcins And Ravidomycins, Madan Kumar Kharel

University of Kentucky Doctoral Dissertations

Gilvocarcin V (GV) and ravidomycin (RMV) exhibit excellent antitumor activities in the presence of near-UV light at low concentration maintaining a low in vivo cytotoxicity. Although, the exact molecular mechanism for in vivo actions of these antibiotics has yet to be determined, a [2+2] cycloaddition reaction of the vinyl side chain with DNA thymidine residues in addition to the inhibition of topoisomerase II and DNAhistone H3 cross-linking are reported for the GV’s mechanism of action. Such activities have made these molecules interesting candidates for the biosynthetic investigation to generate analogues with improved activity/solubility. Previous biosynthetic studies have suggested that the …

The Effect Of Acupressure On Constipation, Quality Of Life, And Depressive Symptoms In Cancer Patients With Constipation, Eun Jin Lee

University of Kentucky Doctoral Dissertations

Constipation is the most common gastrointestinal complaint in the United States, resulting in about 2 million annual visits to the doctor.

The purposes of this dissertation were to: 1) describe four theories of traditional Korean medicine; 2) review mechanisms of acupuncture and moxibustion and develop a conceptual model; 3) review findings from randomized controlled trials that tested the effects of acupressure used for the management of symptoms such nausea, pain, and dyspnea; 4) examine the reliability and validity of the Patient Health Questionnaire-9 (PHQ-9) in heart failure patients with constipation compared to those with gastrointestinal disease; 5) describe how Korean …

Injury-Induced Hand Dominance Transfer, Kathleen E. Yancosek

University of Kentucky Doctoral Dissertations

Hand dominance is the preferential use of one hand over the other for motor tasks. 90% of people are right-hand dominant, and the majority of injuries (acute and cumulative trauma) occur to the dominant limb, creating a double-impact injury whereby a person is left in a functional state of single-handedness and must rely on the less-dexterous, non-dominant hand. When loss of dominant hand function is permanent, a forced shift of dominance is termed injury-induced hand dominance transfer (I-IHDT).

Military service members injured in combat operation may face I-IHDT following mutilating injuries (crush, avulsion, burn and blast wounds) that result in …

The Role Of The L-Type Calcium Channel And Its Carboxyl-Terminus, Miranda Jean Byse

University of Kentucky Doctoral Dissertations

In the heart, the primary role of the L-type calcium channel (LTCC) Ca_V1.2 is to conduct calcium into cardiomyocytes and initiate contraction. However, part of the Ca_V1.2 channel itself, the cleaved carboxyl-terminus (CCt) can also localize to the nucleus and regulate gene transcription. Therefore, the goal of this dissertation project was to determine the role and regulation of CCt in the embryonic and adult heart. The global hypothesis of my dissertation project is that CCt localizes to the nucleus in embryonic and adult cardiomyocytes via a calcium-mediated mechanism and regulates transcription. A model of pharmacological LTCC …

Tobacco-Free Prison Policies And Health Outcomes Among Inmates, Alison R. Connell

University of Kentucky Doctoral Dissertations

This study was the first to examine the effect of tobacco policies in prisons on the health of inmates. Kentucky has two types of tobacco policies in its 16 state prisons: indoor smoke-free policies, where smoking is allowed outdoors and tobacco-free policies, in which no tobacco of any kind is allowed on the grounds of the prison. The smoking rate of inmates is three times higher than that of current smokers in the non-incarcerated population which results in high rates of tobacco-related health conditions such as heart disease and lung cancer.

A literature review discussed the evolution of tobacco policies …

Essays On Human Capital, Health Capital, And The Labor Market, Charles Hokayem

University of Kentucky Doctoral Dissertations

This dissertation consists of three essays concerning the effects of human capital and health capital on the labor market. Chapter 1 presents a structural model that incorporates a health capital stock to the traditional learning-by-doing model. The model allows health to affect future wages by interrupting current labor supply and on-the-job human capital accumulation. Using data on sick time from the Panel Study Income of Dynamics the model is estimated using a nonlinear Generalized Method of Moments estimator. The results show human capital production exhibits diminishing returns. Health capital production increases with the current stock of health capital, or better …

A Markov Transition Model To Dementia With Death As A Competing Event, Liou Xu

University of Kentucky Doctoral Dissertations

The research on multi-state Markov transition model is motivated by the nature of the longitudinal data from the Nun Study (Snowdon, 1997), and similar information on the BRAiNS cohort (Salazar, 2004). Our goal is to develop a flexible methodology for handling the categorical longitudinal responses and competing risks time-to-event that characterizes the features of the data for research on dementia. To do so, we treat the survival from death as a continuous variable rather than defining death as a competing absorbing state to dementia. We assume that within each subject the survival component and the Markov process are linked by …

Neural Mechanisms Of Sympathetic Activation During Hyperinsulinemia And Obesity-Induced Hypertension, Megan Elyse Bardgett

University of Kentucky Doctoral Dissertations

Obesity afflicts more than 30% of the U.S. population and is a major risk factor for the development of hypertension, type II diabetes, and cardiovascular disease. Studies in humans and animals indicate that obesity is associated with increased sympathetic outflow to the vasculature and kidneys. One mechanism postulated to underlie the increase in sympathetic nerve activity (SNA) in obesity is hyperinsulinemia. Little is known regarding the central circuitry underlying elevated SNA and arterial blood pressure (ABP) during hyperinsulinemia and obesity or if sympathoexcitatory circuits are still responsive to insulin in obesity.

Hyperinsulinemic-euglycemic clamps elevate SNA to the hind limb vasculature …

Explorations In Homeoviscous Adaptation And Mass Spectral Analysis Of Membrane Lipids, Michael Douglas Timmons

University of Kentucky Doctoral Dissertations

The focus of this dissertation is centered on the mass spectral analysis of lipids and changes occurring in keeping with the concept of homeoviscous adaptation [1]. Homeoviscous adaptation is the process of modification of membrane lipids in response to environmental stimuli [1]. Dissertation investigations applied this concept to prokaryotic and eukaryotic organisms, and expanded the perception of environmental factors from exogenous organic solvents to intracellular environment.

The field of lipidomics deals with the analysis of phospholipid and fatty acid components of membranes the changes that occur due to environmental stimuli and their biological significance [2-6]. The high sensitivity of mass …

Nm23-H1 Blocks Cell Motility Independently Of Its Known Enzymatic Activities In A Cohort Of Human Melanoma Cells, Joseph Robert Mccorkle

University of Kentucky Doctoral Dissertations

The metastasis suppressor gene NM23-H1 has been shown to possess three enzymatic activities including nucleoside diphosphate kinase, histidine-dependent protein kinase and 3’-5’ exonuclease activity. While these properties have been demonstrated in vitro using recombinant proteins, the contribution of these activities to suppression of metastatic dissemination is unknown. Site-directed mutagenesis studies were used to identify amino acid residues which are required for proper function of each enzymatic activity associated with H1, providing a platform for studying the importance of each function on an individual basis. To assess the relevance of these activities to melanoma progression, a panel of mutants harboring selective …

Studies Of The Effects Of Dopamine Neuron Stimulating Peptides In Rodent Models Of Normal And Dysfunctional Dopaminergic Systems, Joshua Lee Fuqua

University of Kentucky Doctoral Dissertations

A theoretical post-translational processing model of the proprotein form of glial cell line-derived neurotrophic factor (GDNF) likely produces three biologically active peptides. The three prospective peptides formed are 5, 11, and 17 amino acid peptides, entitled dopamine neuron stimulating peptide -5 (DNSP-5), -11 (DNSP-11), and -17 (DNSP-17), respectively. The DNSPs were hypothesized to increase dopaminergic neuron function because of their relationship to GDNF: a molecule with established neurotrophic actions on dopaminergic neurons. The DNSPs have the potential to provide a therapeutic molecule similar to GDNF, but with increased ease of delivery and improved bioavailability.

Neurochemical effects of DNSPs were examined …

Development Of Novel Ahr Antagonists, Hyosung Lee

University of Kentucky Doctoral Dissertations

Aryl hydrocarbon receptor (AHR) is a sensor protein, activated by aromatic chemical species for transcriptionally regulating xenobiotic metabolizing enzymes. AHR is also known to be involved in a variety of pathogenesis such as cancer, diabetes mellitus, cirrhosis, asthma, etc. The AHR signaling induced by xenobiotics has been intensively studied whereas its physiological role in the absence of xenobiotics is poorly understood. Despite a number of ligands of AHR have been reported thus far, further applications are still hampered by the lack of specificity and/or the partially agonistic activity. Thus, a pure AHR antagonist is needed for deciphering the AHR cryptic …

Cognitive Therapy For The Treatment Of Depressive Symptoms In Patients With Heart Failure, Rebecca L. Dekker

University of Kentucky Doctoral Dissertations

Depressive symptoms are common in patients with heart failure (HF) and adversely affect mortality, morbidity, and health-related quality of life. Cognitive therapy (CT) has been proposed as a non-pharmacological treatment for depressive symptoms in patients with HF. However, there is currently little evidence to support use of CT in patients with HF.

The purpose of this dissertation was to develop and test a brief, nurse-delivered CT intervention for the treatment of depressive symptoms in patients with HF. Prior to testing the intervention, preliminary work was conducted resulting in four manuscripts: 1) a review of the evidence for CT in treating …

Inhibition Of Cholesterol Synthesis By Policosanol, Subhashis Banerjee

University of Kentucky Doctoral Dissertations

Cholesterol is an essential component of the cell, but excessive blood levels are a major risk factor for the development of atherosclerotic plaques that can lead to heart disease and stroke, the foremost cause of premature death in Western societies. Policosanol, a mixture of very long chain alcohols derived from sugarcane, has gained considerable attention among the public as safe and effective means to reduce blood cholesterol levels, a belief based on some early clinical studies. My research investigates one possible mechanism by which policosanol might decrease blood cholesterol levels: the inhibition of cholesterol synthesis in the liver. Previous studies …

Executive Deficits In Amyotrophic Lateral Sclerosis: Examining The Consequences Of Self-Regulatory Impairment On Quality Of Life, Abbey R. Roach

University of Kentucky Doctoral Dissertations

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that attacks the motor system and contributes to a range of cognitive and behavioral impairments (e.g., behavioral and emotional disinhibition, planning and problem solving difficulties, impulsivity, attention, and personality change). This executive dysfunction may contribute to selfregulatory impairment across several domains, including cognitive skills, thought processes, emotion regulation, interpersonal skills, and physiology, that may be crucial to the quality of life (QOL), or well being, of patients and their caregivers. Given the relentless course and prognosis of ALS, palliative treatments for ALS should target the full range of self-regulatory deficits. Thirty-seven …

The Radiosensitization Effect Of Parthenolide In Prostate Cancer: Implications For Selective Cancer Killing By Modulation Of Intracellular Redox State, Yulan Sun

University of Kentucky Doctoral Dissertations

Parthenolide (PN), a major active component of the traditional herbal medicine feverfew, has been shown to have anti-inflammatory and anti-tumor properties. More remarkably, the cytotoxicity of PN seems selective to tumor cells but not their normal cell counterparts. In the present study, we investigate whether and how PN selectively enhances tumor sensitivity to radiation therapy by using prostate cancer cells LNCaP, DU145 and PC3, as well as normal prostate epithelial cells PrEC.

Our study demonstrates that inhibition of NF-κB pathway and suppression of its downstream target MnSOD are common mechanisms for the radiosensitization effect of PN in prostate cancer cells. …

The Role Of Abcg2 In Drug Active Transport In Milk, Lipeng Wang

University of Kentucky Doctoral Dissertations

Drug active transport into milk is a major concern for breastfeeding mothers and healthcare providers. Studies from the literature indicated that breast cancer resistance protein (ABCG2) plays an important role in drug transfer into milk. There has been limited study on stereoselective interactions with ABCG2. A mechanistic analysis of flux across cell monolayer model is a critical first step toward extrapolating in vitro results for predicting in vivo disposition (including distribution into milk), drug disposition or drug-drug interactions.

The objectives of this thesis were (1) to establish a “Chemical knockout model” in rat for studying drug accumulation into milk, (2) …

Health System Processes, Clinician Attitudes, And Referrals To Tobacco Treatment Programs, Karma Bryan Cassidy

University of Kentucky Doctoral Dissertations

Assisting smokers to quit and stay quit is the most important intervention clinicians can undertake to improve the length and quality of life of patients who use tobacco. The chronic, relapsing nature of tobacco dependence complicates tobacco treatment. Tobacco treatment counseling programs provide on-going support to help patients avoid relapse. Assistance with a referral increases the likelihood that patients will participate in counseling, but few clinicians regularly assist with referrals to tobacco treatment programs. This dissertation examined health system processes and clinician attitudes that influence the likelihood that clinicians will refer their patients for tobacco treatment counseling.

Three papers examined …

Screen Door Medicine: The Informal Medical Consultation, Debra Faith Nickell

University of Kentucky Doctoral Dissertations

This study explores the phenomenon of the informal medical consultation, a communication event in which an individual asks for medical information, advice, or care from an off-duty health professional with whom the individual has no formal patient-provider relationship. Using surveys and interviews, the study describes these consultations from the perspective of the health care professional and the informal patient. The study explores foundational theories that offer explanations for the phenomenon. The theories considered include social support, decision-making, social exchange, perceived partner responsiveness to needs, and uncertainty management.

This study suggests health care providers perceive informal medical consultations to be more …

Health Promotion And Health Education: Nursing Students’ Perspectives, Kathleen Ann Halcomb

University of Kentucky Doctoral Dissertations

The purpose of this study was to determine student nurses’ perceptions of (1) the role of the nurse in health promotion, and (2) how the concept of health promotion is presented in nursing curricula. Research questions for this study included the following: 1) Can nursing students explain the difference between health education and health promotion? 2) What have nursing students been exposed to within their curriculum regarding health promotion? 3) What health promoting behaviors are nursing faculty role modeling as perceived by nursing students? 4) What is the role of the nurse in implementing health promotion as perceived by nursing …

Auditory Training At Home For Adult Hearing Aid Users, Anne D. Olson

University of Kentucky Doctoral Dissertations

Research has shown that re-learning to understand speech in noise can be a difficult task for adults with hearing aids (HA). If HA users want to improve their speech understanding ability, specific training may be needed. Auditory training is one type of intervention that may enhance listening abilities for adult HA users.

The purpose of this study was to examine the behavioral effects of an auditory training program called Listening and Communication Enhancement (LACE™) in the Digital Video Display (DVD) format in new and experienced HA users. No research to date has been conducted on the efficacy of this training …

Lactone-Carboxylate Interconversion As A Determinant Of The Clearance And Oral Bioavailabilty Of The Lipophilic Camptothecin Analog Ar-67, Eyob Debebe Adane

University of Kentucky Doctoral Dissertations

The third generation camptothecin analog, AR-67, is undergoing early phase clinical trials as a chemotherapeutic agent. Like all camptothecins it undergoes pH dependent reversible hydrolysis between the lipophilic lactone and the hydrophilic carboxylate. The physicochemical differences between the lactone and carboxylate could potentially give rise to differences in transport across and/or entry into cells. In vitro studies indicated reduced intracellular accumulation and/or apical to basolateral transport of AR-67 lactone in P-gp and/or BCRP overexpressing MDCKII cells and increased cellular uptake of carboxylate in OATP1B1 and OATP1B3 overexpressing HeLa-pIRESneo cells. Pharmacokinetic studies were conducted in rats to study the disposition and …

Cardiac Rhythm During Mechanical Ventilation And Weaning From Ventilation, Muna Hassan Hammash

University of Kentucky Doctoral Dissertations

The transition from mechanical ventilation (MV) to spontaneous ventilation during weaning is associated with hemodynamic alterations and autonomic nervous system (ANS) alterations (reflected by heart rate variability [HRV]). Although cardiac dysrhythmias are an important manifestation of hemodynamic alterations, development of dysrhythmias during MV and weaning and subsequent impact on length of MV has received little attention.

The purposes of this dissertation were to 1) evaluate the relationship of heart rate variability (HRV) during weaning to the development of cardiac dysrhythmias and 2) determine the relationship of cardiac dysrhythmias to length of MV.

A convenience sample of 35 patients (66.7% men; …

What Nurses Say: Communication Behaviors Associated With The Competent Nursing Handoff, Anne Claiborne Ray Streeter

University of Kentucky Doctoral Dissertations

Communication competence and medical communication competence served as the theoretical framework for this research that seeks to identify specific communication behaviors associated with what nurses say constitute a communicatively competent patient handoff at the nursing change of shift. Data collected from 286 nurses responding to an online modified Medical Communication Competence Scale posted at www.allnurses.com supported the hypotheses that information exchange (information giving, seeking and verifying) and socioemotional communication behaviors are rated more highly in the best patient handoffs than in the worst ones. Research questions found that the incoming nursing role rated behaviors associated with information verifying and socioemotional …

Structural Instability Of Human Ribosomal Rna Gene Clusters, Dawn Michelle Stults

University of Kentucky Doctoral Dissertations

The human ribosomal RNA genes are critically important for cell metabolism and viability. They code for the catalytic RNAs which, encased in a housing of more than 80 ribosomal proteins, link together amino acids by peptide bonds to generate all cellular proteins. Because the RNAs are not repeatedly translated, as is the case with messenger RNAs, multiple copies are required. The genes which code for the human ribosomal RNAs (rRNAs) are arranged as clusters of tandemly repeated sequences. Three of four catalytic RNAs are spliced from a single transcript. The genes are located on the short arms of the five …

Social Categories And Health Care Outcomes: African American Women And Hiv Survival In The Urban South, Alyson J. O'Daniel

University of Kentucky Doctoral Dissertations

This ethnographic research examines the daily life and institutional conditions under which low-income Black women in urban North Carolina perceived and attended to HIV health-related needs. I focus specifically on the interplay among women’s living conditions, programmatic service needs, and their strategies for navigating the local system of care to explore and refine the categorical label “low income.” I found that there were significant differences among study participants in terms of their monthly incomes and financial resources, housing quality and status, and personal experiences with incarceration and substance abuse. The economic differences among women translated into social differences within the …

Local Synaptic Network Interactions In The Dentate Gyrus Of A Cortical Contusion Model Of Posttraumatic Epilepsy, Robert F. Hunt Iii

University of Kentucky Doctoral Dissertations

Posttraumatic epilepsy is a common consequence of brain trauma. However, little is known about how long-term changes in local excitatory and inhibitory synaptic networks contribute to epilepsy after closed-head brain injury. This study adapted a widely used model of experimental brain injury as a mouse model of posttraumatic epilepsy. Behavioral seizure activity and alterations in synaptic circuitry in the dentate gyrus were examined in mice after experimental cortical contusion brain injury. Spontaneous behavioral seizures were observed in 20% of mice after moderate injury and 36-40% of mice weeks after severe injury. In the dentate gyrus, most mice displayed regionally localized …

Function Of Androgen Receptor In Prostate Cancer Epithelial Mesenchymal Transition And Microtubule Targeting, Menglei Zhu

University of Kentucky Doctoral Dissertations

Prostate cancer is the most frequently diagnosed non-skin cancer and the third leading cause of cancer mortality among men in the US. Androgens are functionally required for the normal growth of the prostate gland and play a critical role in prostate tumor development and progression. Epithelial-mesenchymal-transition (EMT) is an important process during normal development, and cancer cell metastasis.

This study examined the ability of androgens to influence EMT of prostate cancer epithelial cells and evaluate the effect of taxol chemotherapy on androgen signaling in prostate cancer cells in prostate cancer. The EMT pattern was evaluated on the basis of expression …

Characterization And Optimization Of Microelectrode Arrays For Glutamate Measurements In The Rat Hippocampus, Pooja Mahendra Talauliker

University of Kentucky Doctoral Dissertations

An overarching goal of the Gerhardt laboratory is the development of an implantable neural device that allows for long-term glutamate recordings in the hippocampus. Proper L-glutamate regulation is essential for hippocampal function, while glutamate dysregulation is implicated in many neurodegenerative diseases. Direct evidence for subregional glutamate regulation is lacking in previous in vivo studies because of limitations in the spatio-temporal resolution of conventional experimental techniques. We used novel enzyme-coated microelectrode arrays (MEAs) for rapid measurements (2Hz) of extracellular glutamate in urethane-anesthetized rats. Potassium-evoked glutamate release was highest in the cornu ammonis 1 (CA1) subregion and lowest in the cornu ammonis …