Medical Specialties Commons^™

Dystrophic Microglia Are Associated With Neurodegenerative Disease And Not Healthy Aging In The Human Brain, Ryan K. Shahidehpour, Rebecca E. Higdon, Nicole G. Crawford, Janna H. Neltner, Eseosa T. Ighodaro, Ela Patel, Douglas Price, Peter T. Nelson, Adam D. Bachstetter

Spinal Cord and Brain Injury Research Center Faculty Publications

Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were performed for total microglia, 2 microglia morphologies (hypertrophic and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could …

Mitochondria Exert Age-Divergent Effects On Recovery From Spinal Cord Injury, Andrew N. Stewart, Katelyn E. Mcfarlane, Hemendra J. Vekaria, William M. Bailey, Stacey A. Slone, Lauren A. Tranthem, Bei Zhang, Samir P. Patel, Patrick G. Sullivan, John C. Gensel

Physiology Faculty Publications

The extent that age-dependent mitochondrial dysfunction drives neurodegeneration is not well understood. This study tested the hypothesis that mitochondria contribute to spinal cord injury (SCI)-induced neurodegeneration in an age-dependent manner by using 2,4-dinitrophenol (DNP) to uncouple electron transport, thereby increasing cellular respiration and reducing reactive oxygen species (ROS) production. We directly compared the effects of graded DNP doses in 4- and 14-month-old (MO) SCI-mice and found DNP to have increased efficacy in mitochondria isolated from 14-MO animals. In vivo, all DNP doses significantly exacerbated 4-MO SCI neurodegeneration coincident with worsened recovery. In contrast, low DNP doses (1.0-mg/kg/day) improved tissue …

Mutyh As An Emerging Predictive Biomarker In Ovarian Cancer, Megan L. Hutchcraft, Holly H. Gallion, Jill M. Kolesar

Obstetrics and Gynecology Faculty Publications

Approximately 18% of ovarian cancers have an underlying genetic predisposition and many of the genetic alterations have become intervention and therapy targets. Although mutations in MutY homolog (MUTYH) are best known for MUTYH associated polyposis and colorectal cancer, it plays a role in the development of ovarian cancer. In this review, we discuss the function of the MUTYH gene, mutation epidemiology, and its mechanism for carcinogenesis. We additionally examine its emerging role in the development of ovarian cancer and how it may be used as a predictive and targetable biomarker. MUTYH mutations may confer the risk of ovarian …

Excess Extracellular K+ Causes Inner Hair Cell Ribbon Synapse Degeneration, Hong-Bo Zhao, Yan Zhu, Li-Man Liu

Otolaryngology--Head & Neck Surgery Faculty Publications

Inner hair cell (IHC) ribbon synapses are the first synapse in the auditory system and can be degenerated by noise and aging, thereby leading to hidden hearing loss (HHL) and other hearing disorders. However, the mechanism underlying this cochlear synaptopathy remains unclear. Here, we report that elevation of extracellular K⁺, which is a consequence of noise exposure, could cause IHC ribbon synapse degeneration and swelling. Like intensity dependence in noise-induced cochlear synaptopathy, the K⁺-induced degeneration was dose-dependent, and could be attenuated by BK channel blockers. However, application of glutamate receptor (GluR) agonists caused ribbon swelling but …

Management Of The Sensitized Cardiac Transplantation Recipient, Michael Mazzei, Suresh Keshavamurthy, Olga Timofeeva, Yoshiya Toyoda

Surgery Faculty Publications

Preoperative sensitization of the cardiac transplant recipient, defined as the presence of anti-Human Leukocyte Antigen (HLA) antibodies before transplant, represents a significant management challenge for physicians. Sensitization prolongs the pre-transplant wait time and is associated with postoperative transplant complications and death. It is critical that sensitized heart transplant candidates be identified and optimized before surgery. In this review, we describe the risk for sensitization, discuss the means through which sensitization may be diagnosed, and highlight some of the new therapeutic options for managing the sensitized cardiac transplant patients.

Commentary: Use Of Bactrac Proteomic Database-Uromodulin Protein Expression During Ischemic Stroke, Gabriella-Salome K. Armstrong, Jacqueline A. Frank, Christopher J. Mclouth, Ann M. Stowe, Jill M. Roberts, Amanda L. Trout, Justin F. Fraser, Keith R. Pennypacker

Neurology Faculty Publications

Introduction: Uromodulin (UMOD) is a glycoprotein expressed by the epithelial cells of the thick ascending limb of Henle's loop in the kidney. Research has shown that increased uromodulin expression may be associated with lower risk of cardiovascular disease in adults. Utilizing the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) (clinicaltrials.gov NCT03153683), a continuously enrolling tissue bank, we aimed to examine the associations between serum uromodulin, age, and high BMI (BMI> 25) and its relationship to stroke in patients.

Methods: Arterial blood distal and proximal to the thrombus was collected during a thrombectomy procedure using the BACTRAC protocol and sent …

Relationship Between Preoperative Frailty And Postoperative Outcomes After Lvad Implantation, Katherine L. Wilhelm

DNP Projects

Abstract

Background: Frailty is common in many patients with advanced heart failure, including those who undergo left ventricular assist device (LVAD) implantation. Frailty has been associated with worse outcomes after other cardiac surgeries; however, little is known about the effect of frailty on postoperative outcomes after LVAD implant.

Purpose: The purpose of this project was to evaluate whether preoperative frailty [as determined by either short physical performance battery (SPPB) score ≤ 7/12 or 6-minute walk test (6-MWT) <200 >meters] is associated with poorer postoperative outcomes after LVAD implantation than non-frailty in adults with advanced heart failure.

Setting and Sample: This project …

Complications In Cardiac Surgery, Christine Williamitis

Theses and Dissertations--Nursing

Quality of care and outcomes from cardiac surgery have always been of primary importance to providers and the entire health care team when caring for cardiac surgical patients. Providers in cardiac surgery have had a long history of tracking procedural morbidity and mortality rates in programs nationally and internationally. Morbidity and mortality rates vary widely among hospitals. In most studies in which procedural outcomes from cardiac surgery are evaluated, the focus has been on operative morbidity and mortality and the probability of death after a cardiac surgical procedure. Less attention has been paid to predictors of perioperative complications, and sample …

Development And Clinical Validation Of Knowledge-Based Planning Models For Stereotactic Body Radiotherapy Of Early-Stage Non-Small-Cell Lung Cancer Patients, Justin David Visak

Theses and Dissertations--Radiation Medicine

Lung stereotactic body radiotherapy (SBRT) is a viable alternative to surgical intervention for the treatment of early-stage non-small-cell lung cancer (NSCLC) patients. This therapy achieves strong local control rates by delivering ultra-high, conformal radioablative doses in typically one to five fractions. Historically, lung SBRT plans are manually generated using 3D conformal radiation therapy, dynamic conformal arcs (DCA), intensity-modulated radiation therapy, and more recently via volumetric modulated arc therapy (VMAT) on a C-arm linear accelerator (linac). Manually planned VMAT is an advanced technique to deliver high-quality lung SBRT due to its dosimetric capabilities and utilization of flattening-filter free beams to improve …

New Evidence For P-Gp-Mediated Export Of Amyloid-Β Peptides In Molecular, Blood-Brain Barrier And Neuronal Models, Amanda B. Chai, Anika M. S. Hartz, Xuexin Gao, Alryel Yang, Richard Callaghan, Ingrid C. Gelissen

Sanders-Brown Center on Aging Faculty Publications

Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ₄₀ and Aβ₄₂ peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the …

Characterizing The Physiology And Genetics Of Contact Dependent Growth Inhibiton Systems In Burkholderia Species, Alice Elizabeth Oates

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Contact-dependent growth inhibition (CDI) systems mediate interbacterial competition. The genes encoding these systems are widespread among Gram-negative bacteria, including Burkholderia pathogens. CDI systems of Burkholderia species are composed of two-partner secretion pathway proteins and function to deliver the toxic C-terminus of a polymorphic surface-exposed exoprotein BcpA (Burkholderia CDI protein A) to the cytoplasm of neighboring recipient bacteria upon cell-cell contact. Specific outer and inner membrane proteins facilitate BcpA translocation both out of the donor bacterium and into the recipient cell cytoplasm. Most Burkholderia species-specific CDI translocation factors in recipient cells are unknown. BcpA intoxication functions as a mechanism by …

Precision Drug Delivery For Vancomycin Efficacy And Safety In Critically Ill Patients, Alexander Flannery

Theses and Dissertations--Clinical and Translational Science

Vancomycin is the most commonly prescribed antibiotic for hospitalized patients. Despite this fact and decades of clinical use, clinicians remain challenged to meet dosing targets of this narrow therapeutic index drug as well as minimize the risks of therapy, primarily nephrotoxicity. These concerns are magnified in critically ill patients given their severity. Accordingly, in a series of five clinical studies, we sought to identify optimal methods of vancomycin administration in critically ill patients to maximize efficacy and minimize nephrotoxicity via three techniques: use of continuous versus intermittent infusion, use of first-dose pharmacokinetic calculations to guide dosing, and use of loading …

Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids To Predict Carboplatin Resistance, Justin W. Gorski

Theses and Dissertations--Clinical and Translational Science

The development of patient-derived tumor organoids (TOs) from epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine.

Here, we utilize TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high grade serous epithelial ovarian cancer tumor organoids from tissue obtained during debulking surgery (2 neoadjuvant carboplatin exposed, 4 chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1 and 0.1µM). Cell viability curves and resultant EC50 values were determined …

Metabolic And Electrophysiological Effects Of Fibroblast Growth Factor 19 In The Dorsal Vagal Complex, Jordan Wean

Theses and Dissertations--Physiology

The dorsal vagal complex (DVC) is an important homeostatic regulatory center located in the hindbrain that alters vagal parasympathetic activity in response to central, viscerosensory, and humoral cues. Within the DVC, second-order sensory neurons in the nucleus tractus solitarius (NTS) integrate ascending vagal sensory input with descending regulatory inputs from higher brain areas and respond to circulating hormones and glucose. In turn, the NTS projects to the dorsal motor nucleus of the vagus (DMV) which is comprised of cholinergic motor neurons and regulates gastric motility, hepatic glucose production, and pancreatic hormone release functions, among others.

Fibroblast growth factor 19 (FGF19) …

Development Of A Robust Linac-Based Radiosurgery Program For Multiple Brain Metastases & Estimation The Radiobiological Response Of Indirect Cell Kill, Allison Palmiero

Theses and Dissertations--Radiation Medicine

Accurate and precise delivery of Stereotactic Radiosurgery (SRS) using Gamma Knife (GK) unit by Leksell is a gold standard for multiple intracranial lesions. SRS provides less brain toxicity compared to whole brain radiotherapy techniques historically used. However, these treatments are limited in availability and are accompanied by long treatment times with painful, intolerable headframe fixation. With advancements in linear accelerator (Linac) based SRS, multiple brain lesions can be treated separately with individual isocenters or, more recently, altogether with a single isocenter multi-target (SIMT) volumetric modulated arc therapy (VMAT) technique. SIMT methods reduce the challenges of treating patients with GK by …

Applying Mixed-Effects Modeling To Behavioral Economic Demand: An Introduction, Brent A. Kaplan, Christopher T. Franck, Kevin Mckee, Shawn P. Gilroy, Mikhail N. Koffarnus

Family and Community Medicine Faculty Publications

Behavioral economic demand methodology is increasingly being used in various fields such as substance use and consumer behavior analysis. Traditional analytical techniques to fitting demand data have proven useful yet some of these approaches require preprocessing of data, ignore dependence in the data, and present statistical limitations. We term these approaches “fit to group” and “two stage” with the former interested in group or population level estimates and the latter interested in individual subject estimates. As an extension to these regression techniques, mixed-effect (or multilevel) modeling can serve as an improvement over these traditional methods. Notable benefits include providing simultaneous …

Laparoscopic Partial Splenectomy For A Splenic Hamartoma, Vashisht Madabhushi, Timothy Horrell, John M. Draus

Surgery Faculty Publications

Objective

We discuss current knowledge and management of splenic hamartoma, an uncommon form of benign tumor.

Summary background data

A splenic hamartoma is a rare form of benign splenic mass, often found incidentally while working up other complaints, and is typically treated by surgical resection of the mass. In this case, we discuss the management of an incidentally found splenic hamartoma that was treated with laparoscopic partial splenectomy.

Methods

The patient presented in the Emergency Department complaining of periumbilical pain after having been struck in the abdomen with a soccer ball the previous day. Following a physical exam and blood …

Dual-Functional Phosphorene Nanocomposite Membranes For The Treatment Of Perfluorinated Water: An Investigation Of Perfluorooctanoic Acid Removal Via Filtration Combined With Ultraviolet Irradiation Or Oxygenation, Joyner Eke, Lillian Banks, M. Abdul Mottaleb, Andrew J. Morris, Olga V. Tsyusko, Isabel C. Escobar

Internal Medicine Faculty Publications

Nanomaterials with tunable properties show promise because of their size-dependent electronic structure and controllable physical properties. The purpose of this research was to develop and validate environmentally safe nanomaterial-based approach for treatment of drinking water including removal and degradation of per- and polyfluorinated chemicals (PFAS). PFAS are surfactant chemicals with broad uses that are now recognized as contaminants with a significant risk to human health. They are commonly used in household and industrial products. They are extremely persistent in the environment because they possess both hydrophobic fluorine-saturated carbon chains and hydrophilic functional groups, along with being oleophobic. Traditional drinking water …

Impact Of Smoking And Hpv Status On Cervical Cancer Survival In Women Living In Kentucky, 2004-2005 And 2014-2015, Brittany M. Mckinley

Theses and Dissertations--Public Health (M.P.H. & Dr.P.H.)

BACKGROUND/ OBJECTIVE: Cervical cancer is the fourth most commonly occurring malignancy in women worldwide, with an estimated 530,000 new cases and 270,000 new deaths each year (Small et al, 2017). While the incidence of cervical cancer has decreased by approximately 1.9% per year between 2007 and 2011, the death rate has remained stable (Bernard et al, 2014). Studies have shown that nearly all cervical cancer cases are associated with the Human Papilloma Virus (HPV). Many studies support the association of smoking with increased risk of invasive cervical cancer in women with high-risk HPV (Castle et al, 2002; Fang et al, …

Methenamine Prophylaxis For Recurrent Urinary Tract Infections In A Tertiary Referral Center, Cameron A. Wade

Theses and Dissertations--Public Health (M.P.H. & Dr.P.H.)

Purpose: Methenamine hippurate (MH) is a urinary antiseptic, indicated for prophylaxis of recurrent urinary tract infections (UTIs) but with only few and limited studies regarding its efficacy. To help address this knowledge gap we reviewed our experience with MH for UTI prophylaxis, focusing on women with recurrent uncomplicated UTIs.

Materials and Methods: The University of Kentucky electronic health record was queried to identify adults who were prescribed MH from the Urology clinic between January 2013 and January 2019. Charts were reviewed to assess patient-reported UTI frequency, demographics and relevant health factors. Treatment success was defined as 0-1 UTI in 6 …

Therapeutic Targeting Of Leukemia Stem Cells To Prevent T-Cell Acute Lymphoblastic Leukemia Relapse, Meghan G. Haney

Theses and Dissertations--Molecular and Cellular Biochemistry

The survival rate of T-cell Acute Lymphoblastic Leukemia (T-ALL) relapse is a dismal 10% of affected adults and 30% of children, largely due to the relapsed disease being more aggressive and treatment resistant than the initial disease. Relapse is thought to occur because conventional chemotherapies are unable to reliably eliminate a unique cell type known as leukemia stem (or propagating) cells (LSCs). LSCs are the only cells within the leukemia with the ability to self-renew and remake or replenish the ALL from a single cell. Currently, the pathways governing self-renewal in LSCs are largely unknown, precluding our ability to successfully …

Promotion Of Most Forms Through Education About Importance Of Advance Care Planning In Seriously Ill Patients, Nidhi More

DNP Projects

Abstract

Purpose: To establish the importance of early Advance Care Planning (ACP) and improve the utilization of Medical Orders for Scope of Treatment (MOST) forms in seriously ill patients by educating providers and nurses to identify patients who meet specified criteria. The goals of this intervention are reduction of readmissions and better quality of life for this patient population.

Methods: A quasi-experimental design was used for evaluation of an Educational intervention to promote MOST forms, Advance Directives (AD) and Palliative Care (PC) consults. A retrospective and prospective chart review was conducted to determine the number of patients who met criteria …

Identification Of Infant Feeding Practices In Eastern Kentucky And Southern West Virginia That Correlate With High Weight-For-Length, Havilah R. Adkins

DNP Projects

Background: Approximately 20% of children in the United States are obese. West Virginia and Kentucky rank in the top 10 for obesity rates in children as young as 2-4 years old. Obesity increases the risk for numerous short-term health problems and impacts long-term health, development, quality of life, and life expectancy. Research indicates that obesogenic behaviors can be addressed prior to the development of obesity or significant health problems to prevent, rather than treat. Interventions targeting caregivers of infants younger than 2-years can promote early development of healthy feeding habits that persist through the developmental stages of nutrition. Before a …

Evaluating The Use Of Telehealth To Manage Hypertension In Primary Care, Alexandra M. Wiesner

DNP Projects

Background: Hypertension remains one of the most common chronic conditions in the United States leading to several health complications and immense financial burdens, yet it remains grossly undertreated despite the availability of evidence-based treatment options. The 2017 guidelines from the American College of Cardiology and American Heart Association recommended the use of home blood pressure monitoring with a telehealth component as an adjunct to regular hypertension treatment; however, implementing this into practice can be difficult depending on the setting, available resources, and the knowledge and skills of the providers. Aims: The purpose of this investigation is to evaluate patient adherence …

Effectiveness Of Point-Of-Care Ultrasound Education For Advanced Practice Providers, Nicole Brumfield

DNP Projects

Abstract

Background: Provider shortages and demands for inpatient providers have led to an increase in the utilization of Advanced Practice Providers (APPs). The increased use and specialization of APPs has brought attention to education and skills that have been instituted for other provider types but remains missing from the APP curricula. One such example is point-of-care ultrasound (POCUS) education. This technology and skill set have been shown to enhance clinical skills, confidence levels, and provide useful information for the provider to enhance clinical decision making for the patient.

Purpose: The purpose of this project was to evaluate the effectiveness of …

Bone In The Breast: A Case Report Of A Metaplastic Breast Cancer With Osseous Differentiation, Kyle Luo, Xiaoqin Wang

Radiology Faculty Publications

Metaplastic breast carcinoma is an uncommon malignant tumor with various pathologic subtypes. Diagnosis is often challenging due to the wide spectrum of clinical and imaging presentations. Here, we present the case of a very rare subtype of metaplastic breast carcinoma-a mixed-type metaplastic breast cancer with osseous differentiation in a 55-year-old female patient. The clinical presentation, imaging-pathology diagnosis, and treatment options are reviewed. Knowing this rarely reported but aggressive breast cancer is very important for clinicians to establish a timely diagnosis for effective management.

Dach1 Mutation Frequency In Endometrial Cancer Is Associated With High Tumor Mutation Burden, Mckayla J. Riggs, Nan Lin, Chi Wang, Dava W. Piecoro, Rachel W. Miller, Oliver A. Hampton, Mahadev Rao, Frederick R. Ueland, Jill M. Kolesar

Obstetrics and Gynecology Faculty Publications

OBJECTIVE: DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population.

METHODS: We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), …

Loss-Of-Function Genomic Variants Highlight Potential Therapeutic Targets For Cardiovascular Disease, Jonas B. Nielsen, Oren Rom, Ida Surakka, Sarah E. Graham, Wei Zhou, Tanmoy Roychowdhury, Lars G. Fritsche, Sarah A. Gagliano Taliun, Carlo Sidore, Yuhao Liu, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, William Overton, Ying Zhao, Jin Chen, He Zhang, Whitney E. Hornsby, Akua Acheampong, Austen Grooms, Amanda Schaefer, Gregory J. M. Zajac, Luis Villacorta, Jifeng Zhang, Ben Brumpton, Mari Løset, Vivek Rai, Pia R. Lundegaard, Morten S. Olesen, Kent D. Taylor, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of …

Epigenetic Regulation Of Wnt Signaling By Carboxamide-Substituted Benzhydryl Amines That Function As Histone Demethylase Inhibitors, Wen Zhang, Vitaliy M. Sviripa, Yanqi Xie, Tianxin Yu, Meghan G. Haney, Jessica S. Blackburn, Charles A. Adeniran, Chang-Guo Zhan, David S. Watt, Chunming Liu

Molecular and Cellular Biochemistry Faculty Publications

Aberrant activation of Wnt signaling triggered by mutations in either Adenomatous Polyposis Coli (APC) or CTNNB1 (β-catenin) is a hallmark of colorectal cancers (CRC). As part of a program to develop epigenetic regulators for cancer therapy, we developed carboxamide-substituted benzhydryl amines (CBAs) bearing either aryl or heteroaryl groups that selectively targeted histone lysine demethylases (KDMs) and functioned as inhibitors of the Wnt pathway. A biotinylated variant of N-((5-chloro-8-hydroxyquinolin-7-yl) (4-(diethylamino)phenyl)-methyl)butyramide (CBA-1) identified KDM3A as a binding partner. KDM3A is a Jumonji (JmjC) domain-containing demethylase that is significantly upregulated in CRC. KDM3A regulates the demethylation of histone H3's lysine …

Compositions And Methods For Treating Retinal Degradation, Jayakrishna Ambati, Benjamin Fowler

Ophthalmology and Visual Science Faculty Patents

The present disclosure relates to compositions and methods for treating retinal damage and/or retinal degradation. More specifically, this disclosure relates to methods for treating degradation of the retinal pigment epithelium by administering compositions comprising a nucleoside and/or a nucleoside or nucleotide reverse transcriptase inhibitor.