Medicine and Health Sciences Commons^™

Functional Neuroplasticity In The Nucleus Tractus Solitarius And Increased Risk Of Sudden Death In Mice With Acquired Temporal Lobe Epilepsy, Isabel D. Derera, Brian P. Delisle, Bret N. Smith

Physiology Faculty Publications

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with refractory acquired epilepsy. Cardiorespiratory failure is the most likely cause in most cases, and central autonomic dysfunction has been implicated as a contributing factor to SUDEP. Neurons of the nucleus tractus solitarius (NTS) in the brainstem vagal complex receive and integrate vagally mediated information regarding cardiorespiratory and other autonomic functions, and GABAergic inhibitory NTS neurons play an essential role in modulating autonomic output. We assessed the activity of GABAergic NTS neurons as a function of epilepsy development in the pilocarpine-induced status epilepticus (SE) model of …

Direct Effects Of The Home, School, And Consumer Food Environments On The Association Between Food Purchasing Patterns And Dietary Intake Among Rural Adolescents In Kentucky And North Carolina, 2017, Alison Gustafson, Stephanie Jilcott Pitts, Jordan Mcdonald, Hannah Ford, Paige Connelly, Rachel Gillespie, Emily Liu, Heather M. Bush, Candace Brancato, Toyin Babatande, Janet Mullins

Dietetics and Human Nutrition Faculty Publications

Background: Obesity rates are higher among rural versus urban adolescents. To examine possible mechanisms for the rural-urban adolescent obesity disparity, we examined the direct and indirect effects of food purchasing patterns, and the home, school, and consumer food environments on dietary intake among rural adolescents. Methods: A baseline survey was conducted among adolescents in eight rural high schools (four in Eastern Kentucky, and four in Eastern North Carolina). Participants answered questions about food purchasing patterns, dietary intake, home food availability, and demographics. The school and consumer food environments were assessed using validated measures from the School Meals Cost Study (United …

Differential Roles For Inner Membrane Complex Proteins Across Toxoplasma Gondii And Sarcocystis Neurona Development, Rashmi Dubey, Brooke Harrison, Sriveny Dangoudoubiyam, Giulia Bandini, Katherine Cheng, Aziz Kosber, Carolina Agop-Nersesian, Daniel K. Howe, John Samuelson, David J. P. Ferguson, Marc-Jan Gubbels

Maxwell H. Gluck Equine Research Center Faculty Publications

The inner membrane complex (IMC) of apicomplexan parasites contains a network of intermediate filament-like proteins. The 14 alveolin domain-containing IMC proteins in Toxoplasma gondii fall into different groups defined by their distinct spatiotemporal dynamics during the internal budding process of tachyzoites. Here, we analyzed representatives of different IMC protein groups across all stages of the Toxoplasma life cycle and during Sarcocystis neurona asexual development. We found that across asexually dividing Toxoplasma stages, IMC7 is present exclusively in the mother’s cytoskeleton, whereas IMC1 and IMC3 are both present in mother and daughter cytoskeletons (IMC3 is strongly enriched in daughter buds). In …

Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Pharmacology and Nutritional Sciences Faculty Publications

Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr^−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated …

Structure-Based Drug Discovery: Computational Virtual Screening, Robert C. Monsen, Lynn Deleeuw, Jon Maguire, William L. Dean, Robert D. Gray, Jonathan B. Chaires, John O. Trent

Commonwealth Computational Summit

No abstract provided.

Parallelization Of A Three-Dimensional Full Multigrid Algorithm To Simulate Tumor Growth, Dylan Goodin, Chin F. Ng, Hermann B. Frieboes

Commonwealth Computational Summit

We present the performance gains of an openMP implementation of a fully adaptive nonlinear full multigrid (FMG) algorithm to simulate three-dimensional multispecies desmoplastic tumor growth on computer systems of varying processing capabilities. The FMG algorithm is applied to solve a recently published thermodynamic mixture model that uses a diffuse interface approach with fourth-order reaction-advection-diffusion PDEs (Cahn-Hilliard-type equations) that are coupled, nonlinear, and numerically stiff. The model includes multiple cell species and extracellular matrix (ECM), with adhesive and elastic energy contributions in chemical potential terms, as well as including blood and lymphatic vessels represented as continuous vasculatures. Advection-reaction-diffusion PDEs are employed …

How Low Can You Go? Feature Selection For Drug Discovery, Derek Jones, Sally R. Ellingson, W. A. De Jong

Commonwealth Computational Summit

The cost of bringing a drug to market depends on how quickly a candidate drug can be “discovered” and evaluated to ensure safety and effectiveness. In this work we develop a method for predicting whether a given drug and protein compound will “bind.” Our aim is to select a set of features to predict drug-protein interactions.

This study focuses on kinases. Kinase inhibitors are the largest class of new cancer therapies. Selective inhibition is difficult due to high sequence similarity, leading to off-target interactions and side-effects. Pictured here human c-SRC.

Mri Of Suspected Appendicitis During Pregnancy: Interradiologist Agreement, Indeterminate Interpretation And The Meaning Of Non-Visualization Of The Appendix, Richard Tsai, Constantine Raptis, Kathryn J. Fowler, Joseph W. Owen, Vincent M. Mellnick

Radiology Faculty Publications

Objective: To determine the degree of interradiologist agreement between the MRI features of appendicitis during pregnancy, the outcomes associated with an indeterminate interpretation and the negative predictive value of non-visualization of the appendix.

Methods: Our study was approved by the institutional review board at the Washington University in St. Louis, Missouri (WUStL) and was HIPAA (Health Insurance Portability and Accountability Act of 1996)-compliant. The informed consent requirement was waived. Cases of suspected appendicitis during pregnancy evaluated using MRI were retrospectively identified using search queries. Scans were re-reviewed by two radiologists (7 and 9 years experience, respectively) to evaluate the interradiologist …

Compositions And Methods Of Modulating 15-Pgdh Activity, Sanford Markowitz, James K. V. Willson, Bruce A. Posner, Joseph Ready, Yongyou Zhang, Hsin-Hsiung Tai, Monika Antczak, Stanton Gerson, Kibeom Bae, Sung Yeun Yang, Amar Desai

Pharmaceutical Sciences Faculty Patents

Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors and 15-PGDH activators described herein.

A Latent Propriospinal Network Can Restore Diaphragm Function After High Cervical Spinal Cord Injury, Jared M. Cregg, Kevin A. Chu, Lydia E. Hager, Rachel S. J. Maggard, Daimen R. Stoltz, Michaela Edmond, Warren J. Alilain, Polyxeni Philippidou, Lynn T. Landmesser, Jerry Silver

Spinal Cord and Brain Injury Research Center Faculty Publications

Spinal cord injury (SCI) above cervical level 4 disrupts descending axons from the medulla that innervate phrenic motor neurons, causing permanent paralysis of the diaphragm. Using an ex vivo preparation in neonatal mice, we have identified an excitatory spinal network that can direct phrenic motor bursting in the absence of medullary input. After complete cervical SCI, blockade of fast inhibitory synaptic transmission caused spontaneous, bilaterally coordinated phrenic bursting. Here, spinal cord glutamatergic neurons were both sufficient and necessary for the induction of phrenic bursts. Direct stimulation of phrenic motor neurons was insufficient to evoke burst activity. Transection and pharmacological manipulations …

Nanoparticle Delivery Of Mir-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells Via Targeting C22orf28 Directly, Xiaoti Lin, Weiyu Chen, Fengqin Wei, Binhua P. Zhou, Mien-Chie Hung, Xiaoming Xie

Molecular and Cellular Biochemistry Faculty Publications

Rationale: Cancer stem cells (CSCs) have been implicated as the seeds of therapeutic resistance and metastasis, due to their unique abilities of self-renew, wide differentiation potentials and resistance to most conventional therapies. It is a proactive strategy for cancer therapy to eradicate CSCs. Methods: Tumor tissue-derived breast CSCs (BCSC), including XM322 and XM607, were isolated by fluorescence-activated cell sorting (FACS); while cell line-derived BCSC, including MDA-MB-231.SC and MCF-7.SC, were purified by magnetic-activated cell sorting (MACS). Analyses of microRNA and mRNA expression array profiles were performed in multiple breast cell lines. The mentioned nanoparticles were constructed following the standard molecular cloning …

Leadership For Public Health 3.0: A Preliminary Assessment Of Competencies For Local Health Department Leaders, Emmanuel D. Jadhav, James W. Holsinger Jr., Billie W. Anderson, Nicholas Homant

Health Management and Policy Faculty Publications

Background: The foundational public health services model V1.0, developed in response to the Institute of Medicine report For the Public’s Health: Investing in a Healthier Future identified important capabilities for leading local health departments (LHDs). The recommended capabilities include the organizational competencies of leadership and governance, which are described as consensus building among internal and external stakeholders. Leadership through consensus building is the main characteristic of Democratic Leadership. This style of leadership works best within the context of a competent team. Not much is known about the competency structure of LHD leadership teams. The objectives of this study characterize …

Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good …

Glycolytic Reprogramming Through Pck2 Regulates Tumor Initiation Of Prostate Cancer Cells, Jiangsha Zhao, Jieran Li, Teresa W.M. Fan, Steven X. Hou

Toxicology and Cancer Biology Faculty Publications

Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein …

No Difference In Myosin Kinetics And Spatial Distribution Of The Lever Arm In The Left And Right Ventricles Of Human Hearts, Divya Duggal, S. Requena, Janhavi Nagwekar, Sangram Raut, Ryan Rich, Hriday Das, Vipul Patel, Ignacy Gryczynski, Rafal Fudala, Zygmunt Gryczynski, Cheavar Blair, Kenneth S. Campbell, Julian Borejdo

Physiology Faculty Publications

The systemic circulation offers larger resistance to the blood flow than the pulmonary system. Consequently, the left ventricle (LV) must pump blood with more force than the right ventricle (RV). The question arises whether the stronger pumping action of the LV is due to a more efficient action of left ventricular myosin, or whether it is due to the morphological differences between ventricles. Such a question cannot be answered by studying the entire ventricles or myocytes because any observed differences would be wiped out by averaging the information obtained from trillions of myosin molecules present in a ventricle or myocyte. …

Marketing Strategies To Encourage Rural Residents Of High-Obesity Counties To Buy Fruits And Vegetables In Grocery Stores, Emily Liu, Tammy Stephenson, Jessica Houlihan, Alison Gustafson

Dietetics and Human Nutrition Faculty Publications

Introduction

Obesity rates in Appalachia are among the highest in the United States, and knowledge of upstream approaches to decrease prevalence among this vulnerable population is limited. The primary aim of this study was to examine the association between healthy, diet-based, social marketing interventions in grocery stores and frequency of fruit and vegetable intake.

Methods

A social marketing campaign was conducted among 17 grocery stores (N = 240 participant surveys) over 4 months in 5 rural Kentucky counties. Interventions included providing food samples, recipe cards, and promotional discounts on fruits and vegetables and moving high-calorie foods to side aisles.

Results …

Ambulance Services For Medicare Beneficiaries: State Differences In Usage, 2012-2014, Suzanne Troske, Alison Davis

Rural & Underserved Health Research Center Publications

Ambulance services are at risk of scaling back or dissolving in some places. We analyzed Medicare beneficiaries’ use of ambulance services across the U.S. Improved understanding of how beneficiaries, most of whom are elderly, use these services provides vital information for policymakers who set rules and regulations about access to the services.

The Molecular Mechanism Of N-Acetylglucosamine Side-Chain Attachment To The Lancefield Group A Carbohydrate In Streptococcus Pyogenes, Jeffrey Rush, Rebecca J. Edgar, Pan Deng, Jing Chen, Haining Zhu, Nina M. Van Sorge, Andrew J. Morris, Konstantin V. Korotkov, Natalia Korotkova

Molecular and Cellular Biochemistry Faculty Publications

In many Lactobacillales species (i.e. lactic acid bacteria), peptidoglycan is decorated by polyrhamnose polysaccharides that are critical for cell envelope integrity and cell shape and also represent key antigenic determinants. Despite the biological importance of these polysaccharides, their biosynthetic pathways have received limited attention. The important human pathogen, Streptococcus pyogenes, synthesizes a key antigenic surface polymer, the Lancefield group A carbohydrate (GAC). GAC is covalently attached to peptidoglycan and consists of a polyrhamnose polymer, with N-acetylglucosamine (GlcNAc) side chains, which is an essential virulence determinant. The molecular details of the mechanism of polyrhamnose modification with GlcNAc are …

Heroin Use Onset Among Nonmedical Prescription Opioid Users In The Club Scene, Hilary L. Surratt, Steven P. Kurtz, Mance Buttram, Maria A. Levi-Minzi, Maria E. Pagano, Theodore J. Cicero

Center for Health Services Research Faculty Publications

Background—Nonmedical prescription opioid use (NMPOU) is well documented among participants in the club scene, yet prior studies have not examined transition to heroin use. We prospectively examined heroin initiation among a sample of young adults with drug involvement associated with participation in the club scene, to understand factors that influence transition from NMPOU to heroin and to identify opportunities for intervention.

Methods—Data were drawn from a randomized trial that enrolled 750 Miami-based club and prescription drug users through respondent driven sampling, and tested the efficacy of assessment interventions in reducing risk. Participants reported current substance use at baseline, …

Hne-Modified Proteins In Down Syndrome: Involvement In Development Of Alzheimer Disease Neuropathology, Eugenio Barone, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi

Sanders-Brown Center on Aging Faculty Publications

Down syndrome (DS), trisomy of chromosome 21, is the most common genetic form of intellectual disability. The neuropathology of DS involves multiple molecular mechanisms, similar to AD, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylating in neurofibrillary tangles. Interestingly, many genes encoded by chromosome 21, in addition to being primarily linked to amyloid-beta peptide (Aβ) pathology, are responsible for increased oxidative stress (OS) conditions that also result as a consequence of reduced antioxidant system efficiency. However, redox homeostasis is disturbed by overproduction of Aβ, which accumulates into plaques across the lifespan in DS as well as …

Clinically Silent Alzheimer's And Vascular Pathologies Influence Brain Networks Supporting Executive Function In Healthy Older Adults, Brian T. Gold, Christopher A. Brown, Jonathan G. Hakun, Leslie M. Shaw, John Q. Trojanowski, Charles D. Smith

Neuroscience Faculty Publications

Aging is associated with declines in executive function. We examined how executive functional brain systems are influenced by clinically silent Alzheimer’s disease (AD) pathology and cerebral white matter hyperintensities (WMHs). Twenty-nine younger adults and thirty-four cognitively normal older adults completed a working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Older adults further underwent lumbar cerebrospinal fluid (CSF) draw for assessment of AD pathology and FLAIR imaging for assessment of WMHs. Accurate working memory performance in both age groups was associated with high fronto-visual functional connectivity (fC). However, in older adults, higher expression of fronto-visual fC was linked …

Secondhand Smoke Exposure And Preclinical Markers Of Cardiovascular Risk In Toddlers, Judith A Groner, Hong Huang, Mandar S. Joshi, Nicholas Eastman, Lisa Nicholson, John Anthony Bauer

Pediatrics Faculty Publications

Objective: Links between secondhand smoke (SHS) exposure and cardiovascular disease in adults are well established but seldom reported during childhood. Although rates of smoking have decreased, young children from low-income backgrounds remain likely to be exposed to SHS. The purpose of this study was to investigate relationships between SHS exposure in young children and several preclinical markers of cardiovascular risk that have been established as relevant to adult populations.

Methods: 139 children, 2–5 years of age, were enrolled in a cross-sectional study. SHS exposure was objectively determined by hair nicotine level; a comprehensive panel of clinical markers (AM blood pressure, …

Associative Learning Contributes To The Increased Water Intake Observed After Daily Injections Of Angiotensin Ii, Maggie Postolache, Jessica Santollo, Derek Daniels

Biology Faculty Publications

Daily injections of angiotensin II (AngII) cause a progressive increase of water intake that resembles a classically ascribed non-associative sensitization. Consistent with the presumption that the observed increase in intake was sensitization, we hypothesized that it resulted from a pharmacological interaction between AngII and its receptor. To test this hypothesis, and remove the influence of drinking itself, we implemented a delay in water access after injection of AngII (icv) on four consecutive ‘induction days,’ and then measured intake on the next day (‘test day’) when rats were allowed to drink immediately after AngII. The delay in water access effectively reduced …

Design And Validation Of Patient-Centered Communication Tools (Pact) To Measure Students' Communication Skills, Gloria R. Grice, Nicole M. Gattas, Theresa Prosser, Mychal Voorhees, Clark D. Kebodeaux, Amy Tiemeier, Tricia M. Berry, Alexandria Garavaglia Wilson, Janelle Mann, Paul Juang

Pharmacy Practice and Science Faculty Publications

Objective. To develop a comprehensive instrument specific to student pharmacist-patient communication skills, and to determine face, content, construct, concurrent, and predictive validity and reliability of the instrument.

Methods. A multi-step approach was used to create and validate an instrument, including the use of external experts for face and content validity, students for construct validity, comparisons to other rubrics for concurrent validity, comparisons to other coursework for predictive validity, and extensive reliability and inter-rater reliability testing with trained faculty assessors.

Results. Patient-centered Communication Tools (PaCT) achieved face and content validity and performed well with multiple correlation tests with significant findings for …

Statin Use And Venous Thromboembolism In Cancer: A Large, Active Comparator, Propensity Score Matched Cohort Study, Sherif M. El-Refai, Esther P. Black, Val R. Adams, Jeffery C. Talbert, Joshua D. Brown

Pharmaceutical Sciences Faculty Publications

Background—Statins have been shown to have a protective effect for venous thromboembolism (VTE) in the general population. This study sought to assess the association between statins and the risk for cancer-associated deep vein thrombosis (DVT) and pulmonary embolism (PE).

Methods—Patients with newly diagnosed cancer were followed for up to one year in a healthcare claims database (2010–2013). Three treatment groups included statin users, non-statin cholesterol lowering medication users, and an untreated group with pre-existing indications for statin therapy (hyperlipidemia, diabetes, or heart disease). Propensity score matched groups were compared using competing risks survival models for DVT and PE …

Blockade Of Α2-Adrenergic Receptors In Prelimbic Cortex: Impact On Cocaine Self-Administration In Adult Spontaneously Hypertensive Rats Following Adolescent Atomoxetine Treatment, Britahny M. Baskin, Bríd Á. Nic Dhonnchadha, Linda P. Dwoskin, Kathleen M. Kantak

Pharmaceutical Sciences Faculty Publications

Rationale

Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self-administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR.

Objectives

We determined if enhanced noradrenergic transmission at α2-adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR.

Methods

Following treatment from postnatal days 28–55 with atomoxetine (0.3 mg/kg) or vehicle, adult male SHR and control rats from Wistar-Kyoto (WKY) and …

Report Of The Ishlt Working Group On Primary Lung Graft Dysfunction Part Iii: Mechanisms: A 2016 Consensus Group Statement Of The International Society For Heart And Lung Transplantation, Andrew E. Gelman, Andrew J. Fisher, Howard J. Huang, Maher A. Baz, Ciara M. Shaver, Thomas M. Egan, Micheal S. Mulligan

Surgery Faculty Publications

No abstract provided.

Interactions Of Primary Insult Biomechanics And Secondary Cascades In Spinal Cord Injury: Implications For Therapy, Michael B. Orr, John C. Gensel

Spinal Cord and Brain Injury Research Center Faculty Publications

No abstract provided.

Acute Treatment With Doxorubicin Affects Glutamate Neurotransmission In The Mouse Frontal Cortex And Hippocampus, Theresa Currier Thomas, Joshua A. Beitchman, Francois Pomerleau, Teresa Noel, Paiboon Jungsuwadee, D. Allan Butterfield, Daret K. St. Clair, Mary Vore, Greg A. Gerhardt

Spinal Cord and Brain Injury Research Center Faculty Publications

Doxorubicin (DOX) is a potent chemotherapeutic agent known to cause acute and long-term cognitive impairments in cancer patients. Cognitive function is presumed to be primarily mediated by neuronal circuitry in the frontal cortex (FC) and hippocampus, where glutamate is the primary excitatory neurotransmitter. Mice treated with DOX (25 mg/kg i.p.) were subjected to in vivo recordings under urethane anesthesia at 24h post-DOX injection or 5 consecutive days of cognitive testing (Morris Water Maze; MWM). Using novel glutamate-selective microelectrode arrays, amperometric recordings measured parameters of extracellular glutamate clearance and potassium-evoked release of glutamate within the medial FC and dentate gyrus (DG) …

Targeting Mitochondrial Dysfunction In Cns Injury Using Methylene Blue; Still A Magic Bullet?, Hemendra J. Vekaria, Lora Talley Watts, Ai-Ling Lin, Patrick G. Sullivan

Spinal Cord and Brain Injury Research Center Faculty Publications

Complex, multi-factorial secondary injury cascades are initiated following traumatic brain injury, which makes this a difficult disease to treat. The secondary injury cascades following the primary mechanical tissue damage, are likely where effective therapeutic interventions may be targeted. One promising therapeutic target following brain injury are mitochondria. Mitochondria are complex organelles found within the cell, which act as powerhouses within all cells by supplying ATP. These organelles are also necessary for calcium cycling, redox signaling and play a major role in the initiation of cell death pathways. When mitochondria become dysfunctional, there is a tendency for the cell to loose …