Medicine and Health Sciences Commons^™

Role Of Mel-18 In Regulating Protein Sumoylation And Identification Of A New Polymorphism In Bmi-1, Jie Zhang

University of Kentucky Doctoral Dissertations

Small ubiquitin-like modifier (SUMO) regulates numerous biological functions. In a previous study we found that sumoylation of HSF2 is involved in regulating HSF2 bookmarking function, but the mechanism that mediates this regulation was unknown. The results in my work support the intriguing hypothesis that polycomb protein, Mel-18, actually functions as an anti-SUMO E3 protein, interacting both with HSF2 and the SUMO E2 Ubc9, but acting to inhibit Ubc9 activity and thereby decrease sumoylation of the HSF2.

This study also suggested that Mel-18 negatively regulates the sumoylation of other cellular proteins, and we extend its targets to RanGAP1 protein. The results …

Proximal Sciatic Nerve Intraneural Ganglion Cyst, Karin R. Swartz, Dianne Wilson, Michael Boland, Dominic B. Fee

Neurosurgery Faculty Publications

Intraneural ganglion cysts are nonneoplastic, mucinous cysts within the epineurium of peripheral nerves which usually involve the peroneal nerve at the knee. A 37-year-old female presented with progressive left buttock and posterior thigh pain. Magnetic resonance imaging revealed a sciatic nerve mass at the sacral notch which was subsequently revealed to be an intraneural ganglion cyst. An intraneural ganglion cyst confined to the proximal sciatic nerve has only been reported once prior to 2009.

A Participant Model: Predictive Medical And Behavioral Factors Of Prostate Cancer Screening Attendees At Markey, Shana L. Steinbach

MPA/MPP/MPFM Capstone Projects

Problem Statement

The Prostate Cancer Screening Program at the Markey Cancer Center co-sponsors prostate cancer screenings with the Prostate Cancer Education Council. All participation, including African-American attendance, has decreased 38% from years 2006 to 2008 and program managers are seeking insight to improve program participation by acquiring knowledge of behavioral and medical characteristics that may influence screening attendance. Because of the higher incidence of prostate cancer in African-American men (ACS, 2008), a specific program goal is also to increase screening attendance for this minority population.

Research Strategy

Questions that assess participant behavior, personal, and family medical history are analyzed to …

Insights Into Expression, Cellular Localization, And Regulation Of Supernatant Protein Factor, A Putative Regulator Of Cholesterol Biosynthesis, Elzbieta Ilona Stolarczyk

University of Kentucky Doctoral Dissertations

SPF (Supernatant Protein Factor) is a cytosolic protein that stimulates at least two enzymes in the cholesterol biosynthetic pathway: squalene monooxygenase and HMGCoA reductase. The mechanism of action has not been established but may be related to lipid transfer between intracellular membranes.

There are three human genes for SPF: SEC14L2 (SPF1), SEC14L3 (SPF2) and SEC14L4 (SPF3). The present study differentiates these closely related genes by evaluating their tissue-specific and relative expression levels. SPF1 mRNA was found to be most abundant in liver, mammary gland and stomach. SPF2 showed negligible expression in all tissues tested; SPF3 expression pattern was similar to …

Image Of God: Effect On Coping, Psycho-Spiritual Well-Being And Fear Of Recurrence In Early Breast Cancer Survivors, Judith Anne Schreiber

University of Kentucky Doctoral Dissertations

The purpose of this dissertation was to examine whether a breast cancer survivor’s view of God influences her religious coping strategies, depression, anxiety, stress, fear of recurrence, and psychological well-being. These variables were selected based on literature that demonstrates relationships among them for breast cancer survivors. The specific aims of this dissertation were to: 1) identify religious coping strategies common to each of the four views of God; 2) examine the relationship of psychological well-being (Ryff) and religious coping strategies; and 3) examine differences in depression, anxiety, stress, fear of recurrence, and psychological well-being among women holding various views of …

Human Ribosomal Rna Gene Clusters Are Recombinational Hotspots In Cancer, Dawn Michelle Stults

University of Kentucky Master's Theses

The gene that produces the precursor RNA transcript to the three largest ribosomal RNA molecules (rDNA) is present in multiple copies and organized into gene clusters. They represent 0.5% of the diploid human genome but are critical for cellular viability. The individual genes possess very high levels of sequence identity and are present in high local concentration, making them ideal substrates for genomic rearrangement driven by dysregulated homologous recombination. Our laboratory has developed a sensitive physical assay capable of detecting recombination-mediated genomic restructuring in the rDNA by monitoring changes in lengths of the individual clusters. In order to determine whether …

Thyroid Lymphoma As A Cause Of Dysphagia And Dyspnea In A Patient Without Palpable Nodules Or Goiter, Jarrod D. Frizzell, Brandon J. Perkins, R. Scott Morehead

Internal Medicine Faculty Publications

Tumors originating in the neck are well-known causes of progressive dysphagia and dyspnea (including stridor), and thyroid lymphoma is an uncommon example. Physical examination provides an important first step in the evaluation of such complaints, as tumors large enough to produce such symptoms are typically considered to be palpable, if not able to be seen grossly. In this case presentation, the authors describe a nonsubsternal thyroid lymphoma measuring 3 x 4 cm at its largest diameter, producing dysphagia and leading to respiratory emergency, that was entirely nonpalpable to physical exam even after confirmation of its presence by computed tomography.

Use Of Topical Nsaids In Acute Musculoskeletal Sports Injury: A Brief Review, Amit M. Deokar, Shawn J. Smith, Hatim A. Omar

Pediatrics Faculty Publications

The objective of this chapter is to summarize the current standards of pain management in minor sports-related musculoskeletal injuries. This chapter also addresses the topical form of non-steroidal anti-inflammatory drug as an effective pain management option in an outpatient setting. Design: Quantitive systematic review of randomized controlled trials. Methods: The data was obtained through literature review of articles published in the last 10 years. In addition, FDA information on non-steroidal anti-inflammatory medications was also reviewed. The patient population studied in the articles included children and adults. Conclusion: Current standards of managing pain resulting from sports injuries involve a number of …

Concepts Of Contraception For Adolescents With Obesity: Pathways Of Judicial Moderation, Donald E. Greydanus, Hatim A. Omar, Artemis Tsitsika

Pediatrics Faculty Publications

All sexually active youth, whether obese or normal weight, should be offered counseling regarding contraception and appropriate contraceptive methods. However, obese youth who are sexually active may be less likely than their normal weight peers to use contraceptives correctly. Methods of contraception for obese adolescents are reviewed in this discussion. Combined oral contraceptives (COCs) and the contraceptive patch have higher failure rates in obese versus normal weight females, though failure rates are lower than noted with barrier contraceptives. The risk for venous thrombosis is higher in obese youth on COCs. Progestin-only pills and the levonorgestrel intrauterine system appear to be …

Ethics And Holistic Healthcare Practice, Michael De Vibe, Erica Bell, Joav Merrick, Hatim A. Omar, Søren Ventegodt

Pediatrics Faculty Publications

The paper aims to contribute to integrated discussion of ethics in holistic healthcare. Methods: Noting key aspects of the literature on ethics in holistic healthcare, the authors then focus on describing the working ethical statement for holistic healthcare practitioners produced for the International Society of Holistic Health (ISHH). Ethical principles, aims of holistic practice, and ethical guidelines are presented. The relationship of ethics to quality of care is outlined. Conclusions: The authors conclude that many of the ethical principles and guidelines, as well as expectations of quality and safety, that apply to mainstream healthcare, also apply to holistic practitioners. However, …

Obesity And Hyperandrogenism, Amit M. Deokar, Shawn J. Smith, Amanda J. Goodwin, Hatim A. Omar

Pediatrics Faculty Publications

This chapter has a two-fold objective. One, it addresses the association of hyperandrogenism and obesity and the complex metabolic derangements that are part of the problem. Clinical management of these co-morbidities is challenging and complex. Second, this article will aid health care providers with the key features to an early diagnosis and intervention to decrease the morbidities in the short as well as long term. Method: Systematic review of articles and information on the topic of interest that were published in the last 15 years. Conclusion: Obesity and hyperandrogenism are integral parts of Metabolic Syndrome/Polycystic Ovarian Syndrome (PCOS)/Hyperandrogenism, Insulin resistance, …

Obesity And Lack Of Physical Activity, Hatim A. Omar, Efrat Merrick-Kenig, Joav Merrick

Pediatrics Faculty Publications

Lack of physical activity and overweight status continues to be a significant health problem in the United States. To assess the actual prevalence of these problems, we reviewed data from the School-based Health Promotion Centers in one middle school, and one high school in central Kentucky. A total of 232 6th graders and 607 9th graders were included. A total of 92% of 6th graders and 45% of 9th graders reported complete lack of regular exercise. 37% of 9th graders and 59% of 6th graders had inappropriate nutrition, 47% of 9th graders and 33% of 6th graders had Body Mass …

Psychological And Social Development, Kimberly K. Mcclanahan, Marlene B. Huff, Hatim A. Omar

Pediatrics Faculty Publications

The global epidemic of childhood and adolescent overweight has become a major public health concern. Not only are these youth more likely to become obese as adults, and thus more prone to obesity-related diseases than their non overweight peers, they are also likely to suffer emotional and social effects associated with overweight. Overweight in youth has been linked to depression, low self-esteem, eating disorders, negative body image, and stigma. It appears to be bi-directional in nature, with overweight sometimes predicting certain psychological effects and psychosocial issues sometimes predicting overweight. Effective assessment and treatment of psychological and mental health issues in …

Studies On Drug Solubilization Mechanism In Simple Micelle Systems, Shaoxin Feng

University of Kentucky Doctoral Dissertations

Poor aqueous solubilities of drug candidates limit the biopharmaceutical usefulness in either oral or parenteral dosage forms. Lipid assemblies, such as micelles, may provide a means of enhancing solubility. Despite their usefulness, little is known about the means by which micelles accomplish this result. The goal of the current dissertation is to provide the molecular level understanding of the mechanism by which simple micelle systems solubilize drugs. Specifically, the location, orientation and amount of the drug molecules in micelle systems are the focuses of the work.

Three series of model drugs, steroids, benzodiazepines and parabens, in three surfactant systems with …

Experimental And Molecular Dynamics Simulation Studies Of Partitioning And Transport Across Lipid Bilayer Membranes, Ravindra Wadhumal Tejwani

University of Kentucky Doctoral Dissertations

Most drugs undergo passive transport during absorption and distribution in the body. It is desirable to predict passive permeation of future drug candidates in order to increase the productivity of the drug discovery process. Unlike drug-receptor interactions, there is no receptor map for passive permeability because the process of transport across the lipid bilayer involves multiple mechanisms. This work intends to increase the understanding of permeation of drug-like molecules through lipid bilayers.

Drug molecules in solution typically form various species due to ionization, complexation, etc. Therefore, species specific properties must be obtained to bridge the experiment and simulations. Due to …

Roles Of Emx2 In Odorant Receptor Gene Expression And Olfactory Sensory Neuron Axon Growth, Jeremy Colin Mcintyre

University of Kentucky Doctoral Dissertations

The sense of smell relies upon the detection of odorants by neurons located in the nasal cavity. These neurons, referred to as olfactory sensory neurons (OSNs), line the olfactory epithelium and extend axons that make synaptic connections with mitral/tufted cells in the olfactory bulb. The mechanisms by which these synaptic connections form remain largely unknown. The development of these synaptic connections relies on the axons of immature OSNs innervating the olfactory bulb. The primary goal of this dissertation was to identify components of the mechanisms used by immature OSN axons to innervate the olfactory bulb. To accomplish this goal, a …

Role Of Oxidative Stress And T Cell Homing In The Development Of Murine Syngeneic Graft-Versus-Host Disease, Jacqueline Perez-Rodriguez

University of Kentucky Doctoral Dissertations

Syngeneic graft-versus-host disease (SGVHD) is induced by reconstituting lethally irradiated mice with syngeneic BM cells followed by a 21 day treatment with the immunosuppressive agent cyclosporine A (CsA). Clinical symptoms of the disease appear 2-3 weeks following cessation of CsA therapy and disease-associated inflammation occurs primarily in the colon and liver.

The development of SGVHD is a complex process resulting from the cooperative interaction of multiple effector cell populations including NK cells, T cells and macrophages. T_H1 cytokines (IL-12, TNF-α, IFN- γ), produced by these effector cells, serve as inflammatory mediators contributing to the pathogenesis of SGVHD. The …

Pathogenesis Of Influenza A Virus: Inhibition Of Monocyte Differetiation Into Dendritic Cell, Saikat Boliar

University of Kentucky Doctoral Dissertations

Dendritic cells (DC) are a heterogeneous population of hematopoietic cells that play a versatile role in orchestrating immune responses against an array of invading pathogens, including influenza virus. These cells reside in lymphoid organs as well as in non-lymphoid tissues such as mucosal surfaces of respiratory and gastro-intestinal system. Recent investigations have suggested that in the steady state, dendritic cells are derived mainly from bone marrow precursor cells without a monocytic intermediate whereas during inflammation or infection, monocytes readily differentiate to generate monocyte derived dendritic cells (MoDC). The ability of virus infected monocytes to differentiate into MoDC was investigated and …

The Implementation Of The Kentucky Transitions: A Money Follows The Person Demonstration Grant Program, Amie Goodin

MPA/MPP/MPFM Capstone Projects

Kentucky Transitions is a Kentucky Medicaid program that is funded primarily by a grant from the Centers for Medicare and Medicaid Services. The purpose of this program is to transition individuals residing in long-term care facilities back into the community, where they will continue to receive health, social, and other benefits but do so in an approved residential setting. Individuals living in the community may experience higher quality of life and the increased ability to choose how and when they receive services, while Medicaid reaps the projected financial benefit of providing less-expensive community alternatives for care.

Though Kentucky Transitions operates …

Medication Therapy Management: Is It Worth Medicare’S Time?, Jennifer White

MPA/MPP/MPFM Capstone Projects

Problem:

Medication Therapy Management (MTM) is a service that a pharmacist can provide to any of their patients, but mostly to those who are either high risk patients for adverse events or those who are new to chronic medication therapy. As Medicare Part D has begun to cover MTM services, more and more pharmacists and other clinicians are becoming providers of MTM.

The intent of MTM is to decrease adverse events and healthcare costs to both the patient and the third party payer. In realizing the benefits of MTM, it is important to assess these outcomes to see if clinical, …

Physician Recruitment At Highlands Regional Medical Center: What Works?, Sarabeth Blankenship

MPA/MPP/MPFM Capstone Projects

There is a physician shortage in eastern Kentucky because older physicians are retiring, and younger physicians are choosing to practice in more urban, affluent areas. Eastern Kentucky is plagued with persistent poverty and lacks cultural amenities. These facts put together myths regarding rural practice create a shortage.

My research consisted of interviewing twenty physicians currently practicing at Highlands Regional Medical Center in Prestonsburg, Kentucky. I created a survey instrument that asked questions of physicians regarding demographics characteristics, medical school attended, and what motivated them to practice at Highlands. I chose Highlands because I was able to get interviews scheduled with …

Employability After Substance Abuse Treatment In Kentucky: An Analysis Of The Kentucky Treatment Outcome Study, Steven Scrivner

MPA/MPP/MPFM Capstone Projects

Public funding of substance abuse treatment (SAT) in Kentucky dates back to the 1950s when legislators sought to curb the problem of alcoholism through legislative acts. The definition of substance abuse expanded through the years to include other substances such as cocaine, marijuana and opiates.

Employment after SAT is a critically important outcome for policymakers to consider when allocating funds because it assists in social re-integration, helps to prevent relapse and promotes economic self-sufficiency. Because of this, employment is an important factor to consider when assessing the impact SAT has on its clients (participants).

The Kentucky Alcohol and Other Drug …

Substrate And Regulation Of Mitochondrial Μ-Calpain, Aashish Joshi

University of Kentucky Doctoral Dissertations

μ -Calpain is localized to the mitochondrial intermembrane space. Apoptosisinducing factor (AIF), which executes caspase-independent cell death, is also localized to the mitochondrial intermembrane space. Following processing at the N-terminus, AIF becomes truncated (tAIF) and is released from mitochondria. The protease responsible for AIF processing has not been established. The same submitochondrial localization of mitochondrial μ-calpain and AIF gives support to the hypothesis that mitochondrial μ-calpain may be responsible for processing AIF. Atractyloside-induced tAIF release in rat liver mitochondria was inhibited by cysteine protease inhibitor MDL28170, but not by calpain inhibitors PD150606 or calpastatin. Moreover, μ-calpain immunoreactivity was difficult to …

Role Of Cyclophilin D In Secondary Spinal Cord And Brain Injury, Jordan Mills Clark

University of Kentucky Doctoral Dissertations

In the hours and days following acute CNS injury, a secondary wave of events is initiated that exacerbate spinal tissue damage and neuronal cell death. A potential mechanism driving these secondary events is opening of the mitochondrial permeability transition pore (mPTP) and subsequent release of several cell death proteins. Previous studies have shown that inhibition of cyclophilin D(CypD), the key regulating component in mPTP opening, was protective against insults that induce necrotic cell death. We therefore hypothesized that CypD-null mice would show improved functional and pathological outcomes following spinal cord injury (SCI) and traumatic brain injury (TBI). Moderate and severe …

Glutamate Regulation In The Hippocampal Trisynaptic Pathway In Aging And Status Epilepticus, Michelle Lee Stephens

University of Kentucky Doctoral Dissertations

A positive correlation exists between increasing age and the incidence of hippocampal-associated dysfunction and disease. Normal L-glutamate neurotransmission is absolutely critical for hippocampal function, while abnormal glutamate neurotransmission has been implicated in many neurodegenerative diseases. Previous studies, overwhelmingly utilizing ex vivo methods, have filled the literature with contradicting reports about hippocampal glutamate regulation during aging. For our studies, enzyme-based ceramic microelectrode arrays (MEA) were used for rapid (2 Hz) measurements of extracellular glutamate in the hippocampal trisynaptic pathway of young (3-6 months), late-middle aged (18 mo.) and aged (24 mo.) urethane-anesthetized Fischer 344 rats. Compared to young animals, glutamate terminals …

Angiotensin Ii Induction Of Regional Effects In Murine Vasculature, Albert Phillip Owens Iii

University of Kentucky Doctoral Dissertations

The renin angiotensin system (RAS) exerts many diverse physiological functions throughout the body, mediated by its effector peptide, angiotensin II (AngII). AngII has been linked with a variety of different functions ranging from the initiation of severe vascular pathologies, such as atherosclerosis and abdominal aortic aneurysm (AAA), to mundane physiological processes of fluid homeostasis, vascular contraction, and regulation of blood pressure. To provide a potential link between these functions, an in-depth analysis of regional effects of AngII on aortic vasculature was performed.

The studies presented in this dissertation tested the overall hypothesis of whether regional changes exist in the vasculature …

Regulation Of Low Density Lipoprotein Receptor Splicing Efficiency, I-Fang Ling

University of Kentucky Doctoral Dissertations

Low density lipoprotein receptor (LDLR) is an apolipoprotein E (apoE) receptor and may play a role in Alzheimer’s disease (AD) development. A single nucleotide polymorphism (SNP), rs688, that has been identified to modulate the splicing efficiency of LDLR exon 12 and is associated with higher cholesterol and AD in some case-control populations. The exon 12 deleted mRNA is predicted to produce a soluble form of LDLR that fails to mediate apoE uptake. To gain additional insights, in this study, I seek to understand the regulation of LDLR splicing efficiency. To identify functional cis-elements within LDLR exon 12, I mutated several …

Age May Be Hazardous To Outcome Following Traumatic Brain Injury: The Mitochondrial Connection, Lesley Knight Gilmer

University of Kentucky Doctoral Dissertations

Older individuals sustaining traumatic brain injury (TBI) experience a much higher incidence of morbidity and mortality. This age-related exacerbated response to neurological insult has been demonstrated experimentally in aged animals, which can serve as a model to combat this devastating clinical problem. The reasons for this worse initial response are unknown but may be related to age-related changes in mitochondrial respiration.

Evidence is shown that mitochondrial dysfunction occurs early following traumatic brain injury (TBI), persists long after the initial insult, and is severitydependent. Synaptic and extrasynaptic mitochondrial fractions display distinct respiration capacities, stressing the importance to analyze these fractions separately. …

The Role Of The Hip Abductor Muscle Complex In The Function Of The Pathological Hip Joint, Maureen Kelly Dwyer

University of Kentucky Doctoral Dissertations

The number of patients electing to undergo total hip arthroplasty (THA) in the United States has been projected to double by the year 2030, with a growing number of these patients below the age of 65 years. This cohort of patients not only desires to return to pain free daily activity, but wishes to participate in recreation and sporting activities. However, many of these patients report pain, impairments, and functional limitations following THA. The number one deficit observed for patients who fail conventional post-operative rehabilitation is persistent weakness of the hip abductor muscles. In order to safely progress these patients …

Lipid-Based Paclitaxel And Doxorubicin Nanoparticles To Overcome P-Gp-Mediated Drug Resistance In Solid Tumors, Xiaowei Dong

University of Kentucky Doctoral Dissertations

Multidrug resistance (MDR) is a major obstacle limiting chemotherapeutic efficacy. The purpose of these studies was to investigate the potential application of injectable paclitaxel (PX) and doxorubicin (Dox)-loaded nanoparticles (NPs) engineered from oil-in-water microemulsion precursors for overcoming P-glycoprotein (P-gp)- mediated drug resistance in solid tumors.

An in-vitro study was performed to test whether the oil (stearyl alcohol and cetyl alcohol) used to make lipid nanoparticles could be metabolized. The results showed that the concentrations of the fatty alcohols within nanoparticles, which were quantitatively determined over time by gas chromatography, decreased to only 10-20% of the initial concentration after 15-24 h …