Medicine and Health Sciences Commons^™

Response Of Dopaminergic System To Cocaine Exposure, Recovery After Cocaine Abstinence, And Impact Of A Long-Acting Cocaine Hydrolase, Jing Deng

Theses and Dissertations--Pharmacy

Cocaine produces its physiological effects by targeting multiple proteins in the central nervous system, particularly by binding with dopamine transporter (DAT) to block the normal dopamine (DA) recycling process. This process along with the pleasure feeling would wear off shortly after the abstinence from the drug. However, chronic cocaine use is associated with neuroadaptations in the dopaminergic system, including increases in the density of DAT on plasma membrane of dopaminergic neurons. Given the critical role of DAT in neurotransmission, various studies have been carried out on animal models to learn its structure, function, and distribution. Long-standing evidence supports that DAT …

Liposomal Technologies To Improve Gene Delivery, David Nardo Padron

Theses and Dissertations--Pharmacy

Lipid based nanoparticles (LBNs) are used in myriad applications in medicine from small molecule drug delivery to mRNA vaccines. A major contributing factor to the development of the field has been the ongoing development of novel compounds that retain the functionality of natural lipids but expand upon them through inclusion of functional moieties that can be applied to specific scientific and biomedical questions. In the body of this dissertation, an extensive overview of LBNs is provided, focusing primarily on their use in immune modulation. The research presented herein begins with the synthesis of a novel class of lipids based on …

The Relative Contribution Of Liver And Intestine In Reverse Cholesterol Transport, Rupinder Kaur

Theses and Dissertations--Pharmacy

Despite decades of advances in research, death due to cardiometabolic disease remains the largest contributor to mortality in the US. While present therapies oppose “forward cholesterol transport,” and atherosclerotic plaque progression, they do not remove cholesterol from established atherosclerotic plaques. Reverse cholesterol transport (RCT) is the active process of mobilizing peripheral cholesterol for excretion through the hepatobiliary (transhepatic cholesterol elimination, THCE) or intestinal (transintestinal cholesterol elimination, TICE) pathways. Currently, there are no clinically approved therapeutics that target RCT. Elucidation of the mechanisms that govern RCT and TICE, and the subsequent identification of novel targets is of importance. The present work …

Development Of Accurate And Efficient Computational Methodologies For Predicting Protein-Ligand And Protein-Protein Binding Free Energies, Alexander Hamilton Williams

Theses and Dissertations--Pharmacy

Computational modeling is an invaluable tool in the drug discovery process either for small ligand or protein therapeutics. The widespread availability of protein X-Ray Crystal and Cryo-Electron Microscopy (Cryo-EM) structures has allowed for more accurate molecular dynamics (MD) simulations that are not reliant on methods such as homology modeling, which may produce structures that require significant computational time to demonstrate their stability. In this thesis we describe several novel methodologies for the computationally efficient modeling of protein/ligand and protein/protein complexes that may be employed within both large-scale virtual screenings and lead compound optimization. These methodologies may also be utilized in …

Development Of Zafirlukast Derivatives Active Against Porphyromonas Gingivalis, Kaitlind C. Howard

Theses and Dissertations--Pharmacy

Periodontal diseases are inflammatory diseases that can lead to damage of the soft tissue and bone supporting the teeth. Gingivitis is the reversible early stage of gum disease, which consist of gums that bleed when brushing or flossing teeth. When left untreated, the preventable but irreversible late stage of periodontal disease, periodontitis, can lead teeth to loosen or even fall out. Oral bacterial species, such as the Gram-negative anaerobic pathogen Porphyromonas gingivalis trigger these inflammatory diseases through oral dysbiosis. P. gingivalis is a keystone pathogen, meaning that the damage caused by P. gingivalis is not proportional to its abundance. Treatment …

Addressing Ascertainment Bias In The Study Of Cardiovascular Disease Burden In Opioid Use Disorders - Application Of Natural Language Processing Of Electronic Health Records, Jade Huang Singleton

Theses and Dissertations--Epidemiology and Biostatistics

In the United States, the prevalence of long-term exposure to opioid drugs, for both medically and nonmedically indicated purposes, has increased considerably since the mid-1990’s. Concerns have emerged about the potential health effects of opioid use. There is also growing interest in other possible connections with opioid use including cardiovascular disease. Electronic health records (EHR) contain information about patient care in the form of structured codes and unstructured notes. Natural language processing (NLP) provides a tool for processing unstructured textual data in EHR clinical notes and extracts useful information for research with structured formats. The purpose of this dissertation was …

Opioid Use Disorder Treatment With Buprenorphine: Analysis Of Treatment Utilization And Associated Outcomes In Kentucky, Feitong Lei

Theses and Dissertations--Epidemiology and Biostatistics

Opioid use disorder (OUD) is chronic opioid use that results in clinically significant suffering, impairment, or even death. The opioid epidemic in the United States has become a public health and economic crisis, affecting patients' well-being and the nation's overall health and welfare. Eastern Kentucky was among the first regions affected by the opioid crisis, and Kentucky has historically ranked among the top five states for age-adjusted drug overdose mortality rate.

There are three medications (buprenorphine, methadone, naltrexone) approved by the U.S. Food and Drug Administration to treat OUD. As a partial opioid agonist, buprenorphine is a safe medication for …

Novel Mechanism Of Endogenous Pancreatic Cancer Cell Expression Of Immune Checkpoint Programmed Cell-Death 1 Protein (Pd-1) Inducing Epithelial-To-Mesenchymal Transition (Emt) Through The Met Pathway And Promoting Cancer Progression In An Immune-Independent Process, Megan M. Harper

Theses and Dissertations--Clinical and Translational Science

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with few treatment options, necessitating an urgent need for novel therapeutics. Immuno-oncologic (IO) therapies have revolutionized anti-cancer regimens in the past decade but typically involve reactivation of adaptive immune responses. In particular, immune checkpoint PD-1 is traditionally expressed only on immune cells while PD-L1 (PD-1 ligand) is overexpressed on cancer cells. When tumor-endogenous PD-L1 binds the PD-1 receptor on T-cells, the immune cells undergo anergy resulting in self-tolerance and cancer cell immune evasion. However, contrary to standard dogma, we previously demonstrated tumor-endogenous PD-1 expression in PDAC. Our data indicated that …

Progressive Endoscopic Approach To Balloon Dilation For Benign Esophageal Strictures, Chad J. Cooper

Theses and Dissertations--Clinical and Translational Science

Benign esophageal strictures are a frequently encountered problem in clinical practice. The management of benign esophageal strictures have slowly evolved over the decades based on “expert opinion.” Despite vast amounts of data about the efficacy and safety of dilation, unfortunately there is no consensus on a systematic and safe approach that is efficient, limits complications and provides long lasting improvement of dysphagia. Our group designed a progressive approach to endoscopic balloon dilation based on tailoring certain technical aspects of the dilation process.

Most studies in the literature concluded that endoscopic dilation is safe and effective in relieving dysphagia caused by …

Art Education In Medical Education: Benefits And Challenges, Sara K. Brown

Theses and Dissertations--Art and Visual Studies

Humanity is synergistic with art and medicine. Likewise, art education can be impactful throughout medical education. Art as a tool to develop the next generation of healthcare differs from the clinical goals of creative art therapies. Over the prior decade, many medical schools now provide curricular offerings in the arts and humanities. Less is known about the application in postgraduate medical settings. The focus of this thesis is to review the pairing of artist-educators with postgraduate medical training programs.

One such program is ArtsCAFE (Arts Connect Around Food and Enrichment), an intercollegiate project fusing experienced arts educators with medical educators …

A Study Of The Analysis Of Hemp-Derived Oil Products: Development Of A Method For The Analysis Of Phytocannabinoids In Medicinal Products, Erin Johnson

Theses and Dissertations--Pharmacology and Nutritional Sciences

Human interactions with cannabis have a history spanning millennia as a source of fiber, food, and medicine. The plant came across Asia, Europe, and Africa with the movements of people and travelers eventually coming to the Americas with European explorers. In colonizing North America, cannabis fiber was key to the production of canvas and ropes for ships. Although fiber was the driver for cannabis production in the United States, medicinal uses were prevalent and propelled the eventual regulations. The Pure Food and Drug Act of 1906 mandated accurate labeling on drugs such as cannabis followed by the Marihuana Tax Act …

Modeling The Effects Of Adverse Childhood Experiences Using A Mouse Model Of Neglect: Mechanisms Of Adiposity Expansion In Females, Jacqueline Leachman

Theses and Dissertations--Pharmacology and Nutritional Sciences

Adverse childhood experiences (ACEs) are an independent risk factor for chronic disease, including obesity and metabolic syndrome. We have previously shown that a mouse model of early life stress, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. In agreement, the analysis of several cohorts of participants exposed to ACEs have shown that women are more susceptible to develop obesity than men. Therefore, the aim of this study was to investigate the link between early life stress and obesity in pre-clinical and clinical settings. Male and female MSEW mice fed 1 week a …

Uncovering The Role Of Apoe4 On Alzheimer’S Disease-Related Neuroinflammation, Courtney Marie Kloske

Theses and Dissertations--Physiology

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by two hallmark pathologies: amyloid-beta plaques (Ab plaques) and hyperphosphorylated, aggregated tau tangles. These pathologies are typically accompanied by the presence of neuroinflammation which is primarily mediated by microglia. Interestingly, several genetic risk factors that increase the risk of AD also have direct impacts on neuroinflammation. Of interest, Apolipoprotein E (ApoE) is the largest genetic risk factor for AD. ApoE has three isoforms- E4 confers an increased risk for AD, E3 is considered the “control” phenotype, and E2 is protective against AD. E4 plays a role in virtually …

Regulation Of Skeletal Muscle Plasticity By The Gut Microbiome, Taylor R. Valentino

Theses and Dissertations--Physiology

Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaptation to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight …

Evaluating The Relationship Between Plasma Biomarkers And Dementia Using Hierarchical Clustering Analysis And Linear Modeling, Zachary Winder

Theses and Dissertations--Physiology

Dementia is a disorder characterized by a significant decline from baseline in one or more cognitive domains that interferes with independence. Prevalence of dementia worldwide is estimated at 50 million people, with that number expected to triple by 2030, coming with a cost of roughly $2 trillion. Clinically, dementia is diagnosed using cognitive evaluations, with varying domains affected and to different degrees depending on the underlying pathology and stage of disease. Alzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) are the two leading causes of dementia, and both have pathologies which can be visualized using MRI. …

Investigating The Uncertainties In Ct Non-Small Cell Lung Cancer Radiomics, Gary Ge

Theses and Dissertations--Radiation Medicine

Radiomics is a technique that extracts quantitative features, termed radiomic features, from medical images using data-characterization algorithms. These radiomic features can be used to identify tissue characteristics and radiologic phenotyping that are not observable by clinicians in a non-invasive, low-cost manner, potentially generating image biomarkers for clinical decision. To date, there are still many uncertainties involved in radiomics which limit its clinical implementation. Herein, we propose to explore the impact of each component in the radiomics pipeline on predicting clinical outcomes. In Chapter II, we conduct a thorough review of CT lung cancer radiomics studies to examine the typical feature …

Nutritional Status In Critical Care Of Covid-19 Patients, Dolph Lewis Davis Iii

Theses and Dissertations--Nutrition and Food Systems

Critical care nutrition is a poorly researched, and such a sudden pandemic event requiring manipulation of nutritional status via propofol-induced sedation for mechanical ventilation is potentially impactful on patient outcomes. This paper seeks to provide context to the impact of critical care protocols on the nutritional status of obese patients suffering from COVID-19.

Family And Consumer Sciences Extension Agents Perception Of A Sustainable Eating Curriculum For Kentuckians, Lindley Barker

Theses and Dissertations--Nutrition and Food Systems

The population is rapidly increasing all over the world. As foods are produced for us to consume, the food system generates negative environmental impacts at each step. The extent of damage generated by food production depends on the amount of land, water, and energy depleted. These environmental impacts can result in reduced quantities of food produced, damages to the land and water used to grow/produce food, pollution of food, and food waste. All of which impact the amount of product produced. Thereby, shifting food-related behaviors of consumers toward sustainable eating may be a way to promote the health of people …

Identifying Bisphosphonate Protein Biomarkers In Equine Sera Using Mass Spectrometry Methods, Malinda Jayne Alison Porter

Theses and Dissertations--Veterinary Science

Bone resorptive diseases affect humans and horses, alike. Examples of these diseases include osteoporosis, Paget’s disease, and osteogenesis imperfecta in humans, and navicular disease in the horse (Mitchell et al., 2019; Suva et al., 2021). Bisphosphonates are used to treat these diseases, and may remain in the bone for several years after administration, demonstrating the need for newer drug testing methods.

The purpose of the discovery phase of this study was to use blood samples of in-training horses which had been given an initial administration of the bisphosphonate tiludronate and identify protein biomarkers that changed in response to this class …

The Effect Of Intra-Articular Corticosteroids On The Systemic Messenger Rna Response In An Equine Experimental Inflammation Model, Emma Elaine Partridge

Theses and Dissertations--Veterinary Science

Intra-articular (IA) corticosteroids are regularly used in equine athletes for the control of joint inflammation. The goal of this study was to utilize an acute synovitis inflammation model to determine the residual effects of IA betamethasone and triamcinolone acetonide on various inflammatory parameters and lameness.

Five mixed-breed, 2-year-old horses were randomly allocated to an IA treatment of the radiocarpal joint with 9 mg of either betamethasone or triamcinolone acetonide. Two weeks following treatment, horses were injected with 1μg of lipopolysaccharide (LPS) diluted in 1 mL of 0.9% sterile saline. Following LPS injection, horses were crossed-over and both sets of injections …

The Effects Of Cannabidiol On Senior Equine Health, Shelley Turner

Theses and Dissertations--Veterinary Science

Cannabis sativa L., has been revealed to produce hundreds of phytocannabinoids, of which cannabidiol (CBD) is one of the most desired. It has been revealed that CBD can potentially treat inflammation and act as an analgesic in humans without psychoactive effects of delta-9-tetrahydrocannabinol (THC). Recently, there has been interest in understanding the potential health benefits of CBD for horses. With an increasing senior horse population (< 15 years old), alternatives to the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as phenylbutazone, firocoxib, and flunixin meglumine, are desired as these common anti-inflammatory treatments have negative side effects. Because senior horses may have chronic low-grade inflammation, termed inflamm-aging, they are a natural model to investigate the efficacy of CBD on inflammatory responses as well as other health parameters. Given this interest, and due to the lack of research conducted on CBD in the horse, the overall objective of this dissertation work was to conduct both basic and applied research investigating the effects of CBD on equine immune function and health. The first objective was to determine the in vitro effects of CBD as an anti-inflammatory. Peripheral blood mononuclear cells (PBMCs) from senior horses were cultured in vitro with increasing concentrations of pure CBD dissolved in dimethyl sulfoxide (DMSO). These cells were …

Attentional Bias, Inhibitory Control, And Food Reinforcement As Mechanisms Promoting Eating Behavior After Exercise, Kylie F. L. Mcfee

Theses and Dissertations--Nutrition and Food Systems

Background: Excess weight and obesity are serious health conditions characterized by modifiable and nonmodifiable risk factors. Exercise is a common method for achieving weight loss; however, results are not always achieved due to post-exercise compensatory behaviors. Increased energy intake (EI) is thought to be the main compensatory behavior hindering weight loss among overweight and obese adults. It is important to determine and understand the mechanisms behind energy compensation following exercise, as this will allow for the discovery of future interventions that may provide individuals with ways to improve exercise as a weight loss treatment.

Objective: To determine if a single …

Associations Of Sexual Satisfaction, Relationship Quality, And Cognitive Functioning Within Intimate Relationships In Older Adulthood, Allison G. Smith

Theses and Dissertations--Family Sciences

The roles of sexual satisfaction, relationship quality, and cognitive functioning within older adults (N = 538) intimate relationships are assessed at two timepoints over an 11-year timeframe. Longitudinal data from 63 older adults are assessed through a path modeling approach to examine how sexual satisfaction and relationship quality change throughout older adulthood. Cross-sectional data for 538 older adults are utilized to examine the association between cognitive health and sexual satisfaction/relationship quality. Qualitative data from 125 older adults are utilized to understand how older adults describe their intimate relationships. Results from path models demonstrate that one’s degree of sexual satisfaction …

Impact Of Difelikefalin On 5d-Itch Domains In Patients With Ckd-Associated Pruritus, Anjay Rastogi, Joel M. Topf, Thilo Schaufler, Isabelle Morin, Frederique Menzaghi, Warren Wen, Kieran Mccafferty

Conference Presentation Abstracts

Background: Chronic kidney disease-associated pruritus (CKD-aP) is common in hemodialysis (HD) patients, impacting quality of life (QoL). In the Phase 3 KALM studies, difelikefalin (DFK), a selective kappa opioid receptor agonist approved in the United States and Europe for the treatment of moderate–severe pruritus in adults undergoing HD, improved itch intensity and QoL. The impact of DFK treatment on the subdomains of the 5D-itch scale (a multidimensional questionnaire validated in patients with chronic pruritus) were explored.

Methods: In this pooled KALM-1 and KALM-2 analysis (n=712), HD patients with moderate–severe CKD-aP were randomized 1:1 to receive intravenous DFK 0.5 µg/kg or …

#Askrenal: Use Of An Automated Twitter Account To Crowdsource Nephrology Queries, Jade M. Teakell, Alicja Rosolowska, Swapnil Hiremath, Matthew A. Sparks, Edgar V. Lerma, Joel M. Topf, Nikhil A. Shah

Conference Presentation Abstracts

Background: Social media platforms are used in contemporary crowdsourcing, and Twitter is apt for reaching a large number of people with a common interest. Users, especially those with a small follower count may find it challenging to reach a large audience. #AskRenal was developed as a Twitter crowdsourcing tool to help users get answers to nephrology questions. We hypothesized that the #AskRenal hashtag could be used by anyone to receive helpful and timely responses to simple or complex nephrology questions posed on the social media platform. Methods: A Twitter account @AskRenal, and an online Twitter bot that automatically retweeted any …

Re: Safety, Tolerability, And Efficacy Of Liris 400 Mg In Women With Interstitial Cystitis/Bladder Pain Syndrome With Or Without Hunner Lesions, R Evans, A Kohan, R Moldwin, D Radecki, T Geib, K M. Peters

Articles

Editorial Comment: The lidocaine-releasing intravesical system (LiRIS) is a passive, nonresorbable intravesical system inserted cystoscopically and designed to provide continuous, controlled release of lidocaine into the bladder over a 2-week period, after which it is removed. There was a positive anticipation that this treatment system might provide symptomatic relief for at least a segment of patients with interstitial cystitis/bladder pain syndrome (IC/BPS), based on the logic of the rationale and from results in 2 small studies, 1 of which was presented at the American Urological Association annual meeting in 2016,1 showing positive results in patients with Hunner lesions (HL). This …

Modulation Of Electrocochleography Responses By Contralateral Broadband Noise In Young Adults, Riley J. Rickman

Graduate Theses/Dissertations

While it is known the auditory efferent system contains two distinct subgroups – the medial olivocochlear nucleus (MOC) and the lateral olivocochlear nucleus (LOC) – not much is known regarding the function of the LOC in humans. This study aims to evaluate the effect of activating the lateral olivocochlear (LOC) neurons via contralateral broad band noise (CBBN) on electrocochleography responses. A ten-minute time-blocked paradigm was utilized to evaluate both the slow and fast effect of the LOC neurons. Recordings were obtained at four points within this ten-minute block both with and without the presence of 50 dB SPL CBBN to …

Intracellular Trafficking And Distribution Of Cd And Inp Quantum Dots In Hela And Ml-1 Thyroid Cancer Cells, Min Zhang

Graduate Theses/Dissertations

The study of the interaction of engineered nanoparticles, including quantum dots (QDs), with cellular constituents and the kinetics of their localization and transport, has provided new insights into their biological consequences in cancers and for the development of effective cancer therapies. The present study aims to elucidate the toxicity and intracellular transport kinetics of CdSe/ZnS and InP/ZnS QDs in late-stage ML-1 thyroid cancer using well-tested HeLa cells as a control. The XTT viability assay showed that ML-1 cells, and non-cancerous mouse fibroblast cells, exhibit no viability defect in response to these QDs, whereas HeLa cell viability decreases. These results suggest …

Effect Of Electrocochleography Stimulus Rate And Intensity On Identification Of Noise Induced Hidden Hearing Loss In Humans, Amanda E. Mccarthy

Graduate Theses/Dissertations

Noise exposure has been known to cause both temporary and permanent shifts in hearing thresholds in humans. Animal and human studies have shown noise exposure to lead to damage to the ribbon synapses of the cochlea. This damage, referred to as noise induced hidden hearing loss (NIHHL), is not detectable with standard hearing assessments, though can be the cause of difficulties understanding speech in the presence of background noise. Recent studies have begun to explore the use of electrocochleography (ECochG) to detect this neural damage in humans. Such studies strive to aid in the development of a clinical tool for …

A Study Of Cobalt (Iii) Oxide Nanoparticle Delivery Of Sirna Molecules Directed Against Signaling Intermediates Of The P2y2 Receptor, Rachel Blair Stroud

Graduate Theses/Dissertations

G protein-coupled receptors are evolutionarily ubiquitous sensors of extracellular signals, propagating intracellular signal cascades through heterotrimeric G proteins. P2Y₂ receptors are GPCRs which are activated by extracellular nucleotides to mediate signaling cascades via Gαq coupling. Many GPCRs are subject to a common mechanism for signal termination involving phosphorylation of the C-terminal tail followed by β-arrestin binding and subsequent endocytic internalization of the complex. This effect has been described for the P2Y₂ R in the 1321N1 astrocytoma cell line, and UTP-induced activation and desensitization profiles have been previously defined. There is need to develop molecular vehicles for safe and …