Medicine and Health Sciences Commons^™

Regulation Of Pancreatic Β-Cell Function By The Renin-Angiotensin System In Type 2 Diabetes, Robin C. Shoemaker

Theses and Dissertations--Pharmacology and Nutritional Sciences

Diet-induced obesity promotes type 2 diabetes (T2D). Drugs that inhibit the renin-angiotensin system (RAS) have been demonstrated in clinical trials to decrease the onset of T2D. Previously, we demonstrated that mice made obese from chronic consumption of a high-fat (HF) diet have marked elevations in systemic concentrations of angiotensin II (AngII). Pancreatic islets have been reported to possess components of the renin-angiotensin system (RAS), including angiotensin type 1a receptors (AT1aR), the primary receptor for AngII, and angiotensin converting-enzyme 2 (ACE2), which negatively regulates the RAS by catabolizing AngII to angiotensin-(1-7) (Ang-(1-7)). These two opposing proteins have been implicated in the …

Roles Of Abcg5 Abcg8 Cholesterol Transporter In Lipid Homeostasis, Yuhuan Wang

Theses and Dissertations--Pharmacy

The ABCG5 ABCG8 (G5G8) sterol transporter promotes cholesterol secretion into bile and opposes dietary sterol absorption in the small intestine. An emerging body of literature suggests that G5G8 links sterol flux to various risk factors for metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD). Therapeutic approaches that accelerate G5G8 activity may augment reverse cholesterol transport (RCT) and provide beneficial effects in the prevention and treatment of cardiovascular and liver disease.

Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant in part due to the reduced levels of hepatic G5G8 and biliary cholesterol. …

Medication Misadventures: The Case Of Benzodiazepines, Sarah E. Wixson

Theses and Dissertations--Pharmacy

For patients afflicted with symptoms of anxiety and insomnia, benzodiazepines are generally a safe and effective short-term pharmacological treatment option. Although considered safer than other sedative-hypnotic medications, substantial concern exists regarding the addictive nature and abuse potential of benzodiazepines along with potentially inappropriate prescribing and utilization in clinically vulnerable populations. These medication misadventures can have a significant impact on public health. Examples of medication misadventures as they pertain to benzodiazepines include the prescribing and use in clinically vulnerable populations for whom they are contraindicated or their efficacy has not been evaluated, the development of tolerance or addiction, abuse of the …

Kinetics And Mechanisms Of Crystal Growth Inhibition Of Indomethacin By Model Precipitation Inhibitors, Dhaval D. Patel

Theses and Dissertations--Pharmacy

Supersaturating Drug Delivery Systems (SDDS) could enhance oral bioavailability of poorly water soluble drugs (PWSD). Precipitation inhibitors (PIs) in SDDS could maintain supersaturation by inhibiting nucleation, crystal growth, or both. The mechanisms by which these effects are realized are generally unknown. The goal of this dissertation was to explore the mechanisms underpinning the effects of model PIs including hydroxypropyl β-cyclodextrins (HP-β-CD), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP) on the crystal growth of indomethacin, a model PWSD. At high degrees of supersaturation (S), the crystal growth kinetics of indomethacin was bulk diffusion-controlled, which was attributed to a high energy form deposited …

Design, Synthesis, And Pharmacological Evaluation Of Three Series Of Lobelane Analogs As Inhibitors Of The Vesicular Monoamine Transporter (Vmat2), John P. Culver

Theses and Dissertations--Pharmacy

Methamphetamine (METH) abuse is a serious problem in the United States and worldwide. The reward experienced by METH users is due to the increase in extracellular dopamine (DA) concentrations caused by an interaction between METH and the DA transporter (DAT) as well as the Vesicular Monoamine Transporter-2 (VMAT2). The reward felt by users of METH leads to further use of the drug and subsequent abuse. The current project examined the ability of three novel series of lobelane analogs to interact with a binding site on the Vesicular Monoamine Transporter-2 (VMAT2) in an attempt to inhibit the effects of METH. Lobelane …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

A Molecular-Level View Of The Physical Stability Of Amorphous Solid Dispersions, Xiaoda Yuan

Theses and Dissertations--Pharmacy

Many pharmaceutical compounds being developed in recent years are poorly soluble in water. This has led to insufficient oral bioavailability of many compounds in vitro. The amorphous formulation is one of the promising techniques to increase the oral bioavailability of these poorly water-soluble compounds. However, an amorphous drug substance is inherently unstable because it is a high energy form. In order to increase the physical stability, the amorphous drug is often formulated with a suitable polymer to form an amorphous solid dispersion. Previous research has suggested that the formation of an intimately mixed drug-polymer mixture contributes to the stabilization …

Molecular And Functional Investigation Of Cancer-Type And Liver-Type Variants Of Organic Anion Transporting Polypeptide 1b3, Nilay Thakkar

Theses and Dissertations--Pharmacy

OATP1B3 belongs to the OATP (organic anion transporting polypeptides) superfamily, responsible for mediating the transport of various endogenous and xenobiotic substrates. OATP1B3 was initially reported to be expressed exclusively in the hepatocytes where it mediates the uptake of numerous endogenous substrates (e.g. bile acids, steroid hormone conjugates) and several clinically relevant drugs including anticancer drugs. Later, a number of studies reported that OATP1B3 is also frequently expressed in multiple types of cancers and may be associated with differing clinical outcomes. However, a detailed investigation on the expression, localization and functions of OATP1B3 expressed in cancer has been lacking. In this …

Antibiotics Targeting Tuberculosis: Biosynthesis Of A-102395 And Discovery Of Novel Actinomycins, Wenlong Cai

Theses and Dissertations--Pharmacy

The increase in antibiotic resistance of many bacterial strains including multidrug-resistant tuberculosis (MDR-TB) due to over- and misuse of antibiotics is a serious medical and economical problem. Therefore discovery and development of new antibiotics are urgently needed. Two projects were undertaken to address the need for new anti-tuberculosis antibiotics.

1. Discovery of new chemical entities. A-102395, a new nucleoside inhibitor of bacterial MraY (translocase I, EC 2.7.8.13) that is essential for bacterial survival, was isolated from the culture broth of Amycolatopsis sp. SANK 60206 in 2007. Although A-102395 is a potent inhibitor of translocase I with IC50 of 11 nM, …

Elucidating The Mechanism Of Lipl: A Non-Heme Fe(Ii), Α -Ketoglutarate: Uridine-5’-Monophosphate Dioxygenase, Anwesha Goswami

Theses and Dissertations--Pharmacy

Several nucleoside natural product antibiotics from Streptomyces sp. and actinomycetes have recently been shown to target bacterial peptidoglycan cell wall biosynthesis by inhibiting the bacterial translocase I (MraY). The biosynthetic gene clusters for A-90289, liposidomycins and caprazamycins revealed a protein with sequence similarity to proteins annotated as α-KG:taurine dioxygenases (TauD). This enzyme (LipL) is a mononuclear, non-heme, Fe(II) dependent α-keto glutarate (α-KG) :uridine monophosphate (UMP) dioxygenase responsible for the net dephosphorylation and two electron oxidation of UMP to uridine-5’-aldehyde. The postulated reaction coordinates involving the activation of the C-5’ center in UMP and the corresponding formation of uridine-5’-aldehyde are modeled …

Evidence-Based Hospitals, David R. Bardach

Theses and Dissertations--Epidemiology and Biostatistics

In 2011 the University of Kentucky opened the first two inpatient floors of its new hospital. With an estimated cost of over $872 million, the new facility represents a major investment in the future of healthcare in Kentucky. This facility is outfitted with many features that were not present in the old hospital, with the expectation that they would improve the quality and efficiency of patient care. After one year of occupancy, hospital administration questioned the effectiveness of some features. Through focus groups of key stakeholders, surveys of frontline staff, and direct observational data, this dissertation evaluates the effectiveness of …

Developments In Nonparametric Regression Methods With Application To Raman Spectroscopy Analysis, Jing Guo

Theses and Dissertations--Epidemiology and Biostatistics

Raman spectroscopy has been successfully employed in the classification of breast pathologies involving basis spectra for chemical constituents of breast tissue and resulted in high sensitivity (94%) and specificity (96%) (Haka et al, 2005). Motivated by recent developments in nonparametric regression, in this work, we adapt stacking, boosting, and dynamic ensemble learning into a nonparametric regression framework with application to Raman spectroscopy analysis for breast cancer diagnosis. In Chapter 2, we apply compound estimation (Charnigo and Srinivasan, 2011) in Raman spectra analysis to classify normal, benign, and malignant breast tissue. We explore both the spectra profiles and their derivatives to …

Nonlinear Hierarchical Models For Longitudinal Experimental Infection Studies, Michael David Singleton

Theses and Dissertations--Epidemiology and Biostatistics

Experimental infection (EI) studies, involving the intentional inoculation of animal or human subjects with an infectious agent under controlled conditions, have a long history in infectious disease research. Longitudinal infection response data often arise in EI studies designed to demonstrate vaccine efficacy, explore disease etiology, pathogenesis and transmission, or understand the host immune response to infection. Viral loads, antibody titers, symptom scores and body temperature are a few of the outcome variables commonly studied. Longitudinal EI data are inherently nonlinear, often with single-peaked response trajectories with a common pre- and post-infection baseline. Such data are frequently analyzed with statistical methods …

The Non-Steroidal Anti-Inflammatory Drugs-Myocardial Infarction Association: An Investigation Of Kentucky Medicaid Prescription Claims, Leonard A. Gordon

Theses and Dissertations--Epidemiology and Biostatistics

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications globally. There are generally two types: selective (COX-2) and traditional NSAIDs (COX-1). They are primarily used for the treatment of pain. They gained attention after a study about their basic mechanisms highlighted their toxicity.

Several studies have reported an association between NSAIDs and risk of myocardial infarction (MI). However, the direction of the relationship is not conclusive. Further studies are needed to ascertain the direction of this relationship and evaluate the present situation with available drugs. Due to the seriousness of cardiovascular diseases as one of the leading cause …

Clinical And Pathologic Significance Of Integrin Α6Β4 Expression In Human Malignancies, Rachel L. Stewart

Theses and Dissertations--Clinical and Translational Science

Integrins are cellular adhesion molecules that bind cells to the extracellular matrix. The integrin α6β4, a receptor for laminins, is predominantly expressed on epithelial cells where it is present at the basal surface adjacent to the basement membrane. This integrin plays a critical role in maintaining normal cellular functions, yet has also been implicated in promoting invasion and metastasis in human malignancies. While overexpression of the integrin α6β4 has been detected in select human cancers, the clinical significance of integrin α6β4 expression in a number of malignancies has not been determined. The purpose of this study was to examine integrin …

Emotional Enhancement And Repetition Effects During Working Memory In Persons With Mild Cognitive Impairment, Lucas S. Broster

Theses and Dissertations--Clinical and Translational Science

This dissertation introduces a framework for understanding differences in how emotional enhancement effects might influence memory in aging adults and then summarizes the findings of three studies of how repetition effects and emotional enhancement effects influence working memory in older adults without cognitive impairment (NC), older adults with amnestic mild cognitive impairment (MCI), and older adults with mild Alzheimer’s disease (AD). In these experiments, individuals with AD showed cognitive impairment in terms of accuracy and reaction time, but individuals with MCI showed milder behavioral impairment that was confined to manipulations of working memory. Individuals with AD showed relative sparing of …

The Metabolomic Effects Of Metformin On Colon Cancer, Jennifer W. Harris

Theses and Dissertations--Clinical and Translational Science

Metformin is an oral biguanide that is prescribed to over 120 million people worldwide for the treatment of conditions including type II diabetes mellitus, polycystic ovarian syndrome, and gestational diabetes. This hypoglycemic agent is rapidly emerging as a potential cost-effective anti-oncogenic agent. Over the past decade multiple epidemiologic studies have consistently associated metformin with decreased cancer incidence and cancer-related mortality. More recently numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to the proposal of numerous clinical trials to better understand this drug and its mechanism of action.

Previously experts believed metformin primarily targeted AMP-activated protein kinase …

Parent/Caregiver Knowledge And Satisfaction Of Information And Referrals Related To Speech-Language Pathology Services For Children With Down Syndrome, Erin K. Salmons

Theses and Dissertations--Communication Sciences and Disorders

Down syndrome, also known as Trisomy 21, is the most commonly occurring chromosomal abnormality present at birth. The Centers for Disease Control and Prevention estimates that there are approximately 6,000 diagnoses of Down syndrome per year in the United States, further indicating that 1/700 infants are born with Down syndrome. A diagnosis of Down syndrome can be made either prenatally or postnatally. Early intervention services will be warranted to address underlying deficits associated with the syndrome, (i.e., speech-language/feeding/swallowing). Communicative disorders are among the most prominent concomitant deficits associated with Down syndrome. Therefore, it is critical that parents/caregivers of children with …

Dialect And Word Learning: Are Phonological Properties Maintained When Dialectal Influence Changes Word Meaning?, Heather C. Iwinski

Theses and Dissertations--Communication Sciences and Disorders

Word learning requires the accurate encoding and decoding of a word’s phonological and semantic properties. Errors in establishing an accurate phonemic-semantic connection can hinder accurate word comprehension and use. Geographical location, culture, and ethnicity can affect the phonology used by a speaker referred to as dialect. African American Vernacular English (AAVE) is one of the most commonly used dialects in the United States. In addition to grammatical changes AAVE is characterized by phonemic changes. The current study sought to determine the effects of AAVE use on the receptive and expressive learning of nonsense words that differ in meaning as noted …

The Role Of Apob-Containing Lipoproteins In Abdominal Aortic Aneurysm, Jing Liu

Theses and Dissertations--Pharmacology and Nutritional Sciences

Abdominal aortic aneurysm (AAA) is a devastating disease that exhibits permanent lumen expansion typically in the infrarenal aorta. AAA is prevalent among aged population, especially in males. Despite the incidence in women is lower, studies indicate the tortuosity is more severe and aortic rupture risk is higher in women. In most patients, AAA remains asymptomatic until it ruptures leading to sudden and fatal hemorrhage.

To date, there is no proven medical therapy that can prevent the expansion or rupture. Human observational studies implicate the presence of AAA is associated with both high plasma low-density lipoprotein-cholesterol (HDL-C) and low plasma high-density …

Tumor-Derived Proteins And Mitochondrial Dysfunction In Lung Cancer-Induced Cachexia, Julie B. Mclean

Theses and Dissertations--Physiology

Lung tumors secrete multiple factors that contribute to cachexia, a severe wasting syndrome that includes loss of muscle mass, weakness, and fatigue. 80% of advanced lung cancer patients experience cachexia, which cannot be reversed by nutritional interventions, diminishes response to and tolerance of cancer treatments, and increases morbidity and mortality. Despite a multitude of clinical trials, there are currently no approved treatments. This deficiency suggests that not all of the factors that contribute to cachexia have been identified.

Cancer is frequently accompanied by an increase in cyclooxygenase-2 (COX-2), a hallmark of inflammation. Clinical trials for COX-2 inhibitors have resulted in …

The Skeletal Muscle Molecular Clock Regulates The Timing Of Substrate Metabolism And The Circadian Expression Of Titin-Cap, Brian A. Hodge

Theses and Dissertations--Physiology

Skeletal muscle is a major contributor to whole-body metabolism as it serves as a depot for both glucose and amino acids, and is a highly metabolically active tissue. An intrinsic molecular clock mechanism exists within skeletal muscle that regulates the timing of physiological processes. A key function of the clock is to regulate the timing of metabolic processes to anticipate time of day changes in environmental conditions. The purpose of this study was to identify metabolic genes that are expressed in a circadian manner and determine if these genes are regulated downstream of the intrinsic molecular clock by assaying gene …

Global-Scale Analysis Of The Dynamic Transcriptional Adaptations Within Skeletal Muscle During Hypertrophic Growth, Tyler Kirby

Theses and Dissertations--Physiology

Skeletal muscle possesses remarkable plasticity in responses to altered mechanical load. An established murine model used to increase mechanical load on a muscle is the surgical removal of the gastrocnemius and soleus muscles, thereby placing a functional overload on the plantaris muscle. As a consequence, there is hypertrophic growth of the plantaris muscle. We used this model to study the molecular mechanisms regulating skeletal muscle hypertrophy.

Aged skeletal muscle demonstrates blunted hypertrophic growth in response to functional overload. We hypothesized that an alteration in gene expression would contribute to the blunted hypertrophic response observed with aging. However, the difference in …

Psychological Well-Being Among Breast Cancer Survivors: Factors That Influence Transition From Primary Treatment To Early Survivorship, Celestine G. Gochett

Theses and Dissertations--Nursing

Eudaimonic psychological well-being (PWB) refers to a lifelong process of purposeful engagement in goal-driven tasks or activities resulting in positive psychological functioning. These activities reflect autonomy, purpose in life, self-acceptance, personal growth, positive relations with others, and environmental mastery. While more women are surviving breast cancer, they face a multitude of late and long term physiopsychosocial challenges that result from being diagnosed and treated. Protective health effects associated with the experience of PWB can potentially mitigate ill-being and benefit overall health of breast cancer survivors (BCS). Adequate preparation by healthcare teams to transition them from primary treatment to early survivorship …

The Impact Of Prenatal Depressive Symptoms, Intimate Partner Relationship, And Immune Status On Postpartum Depression, Julia J. Hall

Theses and Dissertations--Nursing

The prevalence of depression during pregnancy in the U. S. is approximately 13%. Poor quality of the intimate partner relationship is significantly correlated with depression during pregnancy. The adverse effects of antenatal depression have been widely documented. The relationship between the intimate partner relationship and depression during pregnancy has not been well delineated in the literature. Little data exist regarding the impact of prenatal immune status on risk for postpartum depression. Due to limited evidence, there is a critical need to examine the relationship among trimester specific cytokines, quality of the intimate partner relationship, and antenatal depressive symptoms on risk …

Explore The Relationship Among Lung Cancer Stigma, Social Support, And Psychosocial Distress, Lisa Maggio

Theses and Dissertations--Nursing

There is longstanding causal relationship between cigarette smoking and lung cancer. Smoke-free policies and anti-smoking campaigns have been linked to the decline in smoking acceptance and contribute to the unintended consequence of stigmatizing smokers. Lung cancer is viewed as a self-inflicted disease and patients’ feel judged in a manner different from other cancers affecting social interactions between family, friends, and healthcare professionals. Lung cancer stigma contributes to depression, anxiety, poor self-esteem, guilt, shame, blame, threatens a person’s social identity, and limits social support that deeply affects patients and their support persons.

This dissertation contains a review of the literature related …

Reversible Downregulation Of Hypothalamic-Pituitary-Gonadal Axis In The Stallion With A Third-Generation Gnrh Antagonist, Gabriel Monteiro Davolli

Theses and Dissertations--Veterinary Science

The objectives of this thesis were: (1) to evaluate the downregulation of the stallion hypothalamic-pituitary-gonadal (HPG) axis by a GnRH antagonist (acyline) based upon endocrine, seminal, testicular and behavioral effects, and (2) to assess recovery after treatment. Stallions were treated for 50 days (n=4; 330µg/kg acyline q 5d) and controls (n=4) received vehicle alone. Stallions were assessed pre-treatment and for 72 days after last treatment. Treatment induced declines (p<0.05) in FSH, LH, testosterone (to castrate levels) and estrone sulfate. Gonadotropins and testosterone returned to control values within nine days and estrone sulfate by 14 days after treatment discontinuation. Acyline-treated stallions failed to respond with FSH, LH and testosterone increase after exogenous GnRH stimulation (25µg gonadorelin, IV) compared to pre-treatment and control stimulation. Total sperm numbers and motility were reduced in acyline-treated stallions, as well as total seminal plasma protein and testicular volume (p<0.05). Time to ejaculation was increased in acyline group (p<0.5). Testicular, sexual behavior and most seminal parameters regained normal levels within 72 days after treatment ceased. Sperm output of acyline-treated stallions was regained within seven months after ending treatment. Acyline reversibly suppressed the stallion HPG axis, thus has potential for treating the androgen-dependent Equine-Arteritis-Virus carrier state and as behavior modulator.

Glucocorticoid-Induced Chondrocyte Cytotoxicity At Doses Recommended For Intra-Articular Therapy In Horses, Wenying Zhu

Theses and Dissertations--Veterinary Science

Intra-articular glucocorticoid injections are commonly used to treat synovitis and osteoarthritis in horses. These agents are highly effective at relieving pain, swelling, and other symptoms of joint inflammation. The drugs also have therapeutic benefits by down regulating the expression of cytokines and protease enzymes that participate in the degradation of articular cartilage. However, detrimental effects on chondrocyte function and cell viability that is independent of osteoarthritis pathogenesis have been described and linked to glucocorticoid use. These side effects are both drug- and dose-dependent. This study tested the hypothesis that manufacture recommended dosage levels of methylprednisolone, betamethasone, and triamcinolone that are …

Uterine Artery Rupture, An Angiopathy Of The Reproductive System Of The Mare: Occurrence And Potential Effects, Ana G. Toro Mayorga

Theses and Dissertations--Veterinary Science

The intent of this research was to identify if the degenerative changes within arteries in the endometrium (endometrial angiopathies) correlate with degenerative changes in the uterine arteries and can be used as a predictor of increased risk for uterine artery rupture (UAR). With this objective specimens from 20 mares that died from uterine artery rupture and 21 control mares that died from unrelated causes were obtained from cases submitted to the University of Kentucky Veterinary Diagnostic Laboratory (UKVDL) over a two-year period. Postmortem specimens of each mare were collected from the left and right uterine arteries at the origin, bifurcation, …

Adhd Children And Mental Health Service Use: Maternal Determinants, Katarina Krizova

Theses and Dissertations--Family Sciences

The current study investigated maternal determinants of mental health service use, namely, individual child therapy, among preadolescent children diagnosed with ADHD. The Behavioral Model of Health Care Utilization (Andersen, 2008) was used as a theoretical framework for the study. Data from the last three rounds of ECLS-K dataset were employed to test a longitudinal model using Bayesian analysis. Socio-demographic variables and maternal mental health were tested as exogenous variables and mother-child relationship variables, discipline variables, and perceived maternal concern about child’s overall behavior and child’s emotional symptoms were tested as intervening variables. Results showed that only maternal mental health remained …