Medicine and Health Sciences Commons^™

Translating Pharmacogenetics To Clinical Practice: Do Cytochrome P450 2d6 Ultrarapid Metabolizers Need Higher Atomoxetine Doses?, Jose De Leon

Psychiatry Faculty Publications

No abstract provided.

Onset Time And Durability Of Huntingtin Suppression In Rhesus Putamen After Direct Infusion Of Antihuntingtin Sirna, Richard Grondin, Pei Ge, Qingmin Chen, Jessica E. Sutherland, Zhiming Zhang, Don M. Gash, David K. Stiles, Gregory R. Stewart, Dinah W. Y. Sah, William F. Kaemmerer

Neuroscience Faculty Publications

One possible treatment for Huntington's disease involves direct infusion of a small, interfering RNA (siRNA) designed to reduce huntingtin expression into brain tissue from a chronically implanted programmable pump. Here, we studied the suppression of huntingtin mRNA achievable with short infusion times, and investigated how long suppression may persist after infusion ceases. Rhesus monkeys received 3 days of infusion of Magnevist into the putamen to confirm catheter patency and fluid distribution. After a 1-week washout period, monkeys received radiolabeled siRNA targeting huntingtin. After 1 or 3 days of siRNA delivery, monkeys were either terminated, or their pumps were shut off …

Inotropes Are Linked To Increased Mortality In Heart Failure, M. Chadi Alraies, Bill Tran, Sirtaz Adatya

The VAD Journal

No abstract provided.

Exogenous 17-Β Estradiol Administration Blunts Progression Of Established Angiotensin Ii-Induced Abdominal Aortic Aneurysms In Female Ovariectomized Mice, Sean E. Thatcher, Xuan Zhang, Shannon Woody, Yu Wang, Yasir Alsiraj, Richard Charnigo, Alan Daugherty, Lisa A. Cassis

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: Abdominal aortic aneurysms (AAAs) occur predominately in males. However, AAAs in females have rapid growth rates and rupture at smaller sizes. Mechanisms contributing to AAA progression in females are undefined. We defined effects of ovariectomy, with and without 17-β estradiol (E2), on progression of established angiotensin II (AngII)-induced AAAs in female mice.

METHODS: We used neonatal testosterone exposures at 1 day of age to promote susceptibility to AngII-induced AAAs in adult female Ldlr^-/- mice. Females were infused with AngII for 28 days to induce AAAs, and then stratified into groups that were sham, ovariectomized (Ovx, vehicle), or Ovx …

Flucytosine Pharmacokinetics In A Critically Ill Patient Receiving Continuous Renal Replacement Therapy, Megan E. Kunka, Elizabeth A. Cady, Heejung C. Woo, Melissa L. Thompson Bastin

Pharmacy Practice and Science Faculty Publications

Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH) for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD) recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine …

Inotropes Are Not Linked To Increased Mortality In Heart Failure, Maya Guglin

The VAD Journal

How to use inotropes is one of the most controversial topics in the management of heart failure. While most clinicians use these drugs, and recognize the state of inotrope dependency, current guidelines recommend them onlu as a bridge or palliation. Thus, inotropes are considered either neutral or detrimental in terms of outcomes. Meanwhile, properly designed randomized clinical trials testing the outcomes on inotropes, have never been performed and it is unlikely that they will ever be attempted. These trials would require randomizing patients with advanced heart failure, low output syndrome, and impaired end-organ perfusion into groups that received or not …

Public Health Metrics: Key Considerations And Criteria For Food Safety Modernization, Glen P. Mays

Health Management and Policy Presentations

Robust measures of public health impact are needed to guide implementation of the U.S. Food Safety Modernization Act. This session describes strategies used in the field of public health services research to specify and select measures based on considerations of relevance, tractability, attribution, precision, and feasibility.

Comparison Of The Equine Reference Sequence With Its Sanger Source Data And New Illumina Reads, Jovan Rebolledo-Mendez, Matthew S. Hestand, Stephen J. Coleman, Zheng Zeng, Ludovic Orlando, James N. Macleod, Ted Kalbfleisch

Maxwell H. Gluck Equine Research Center Faculty Publications

The reference assembly for the domestic horse, EquCab2, published in 2009, was built using approximately 30 million Sanger reads from a Thoroughbred mare named Twilight. Contiguity in the assembly was facilitated using nearly 315 thousand BAC end sequences from Twilight's half brother Bravo. Since then, it has served as the foundation for many genome-wide analyses that include not only the modern horse, but ancient horses and other equid species as well. As data mapped to this reference has accumulated, consistent variation between mapped datasets and the reference, in terms of regions with no read coverage, single nucleotide variants, and small …

Annotation Of The Protein Coding Regions Of The Equine Genome, Matthew S. Hestand, Theodore S. Kalbfleisch, Stephen J. Coleman, Zheng Zeng, Jinze Liu, Ludovic Orlando, James N. Macleod

Veterinary Science Faculty Publications

Current gene annotation of the horse genome is largely derived from in silico predictions and cross-species alignments. Only a small number of genes are annotated based on equine EST and mRNA sequences. To expand the number of equine genes annotated from equine experimental evidence, we sequenced mRNA from a pool of forty-three different tissues. From these, we derived the structures of 68,594 transcripts. In addition, we identified 301,829 positions with SNPs or small indels within these transcripts relative to EquCab2. Interestingly, 780 variants extend the open reading frame of the transcript and appear to be small errors in the equine …

Iron Toxicity In The Retina Requires Alu Rna And The Nlrp3 Inflammasome, Bradley D. Gelfand, Charles B. Wright, Younghee Kim, Tetsuhiro Yasuma, Reo Yasuma, Shengjian Li, Benjamin J. Fowler, Ana Bastos-Carvalho, Nagaraj Kerur, Annette Uittenbogaard, Youn Seon Han, Dingyuan Lou, Mark E. Kleinman, W. Hayes Mcdonald, Gabriel Núñez, Philippe Georgel, Joshua L. Dunaief, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Publications

Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting …

D-Tagatose-Based Compositions And Methods For Preventing And Treating Atherosclerosis, Metabolic Syndrome, And Symptoms Thereof, Robert A. Lodder, Lisa A. Cassis

Pharmacology and Nutritional Sciences Faculty Patents

Pharmaceutical compositions including D-tagatose along with a stilbene or stilbenoid component, or a salt or derivative thereof. Methods of prophylaxis and therapy by administering to a mammal a pharmaceutically effective amount of D-tagatose, optionally in combination with a stilbene or stilbenoid component, or a salt or derivative thereof to prevent or treat atherosclerosis, the metabolic syndrome, obesity, or diabetes.

St-Segment Elevation Myocardial Infarction In Patient With Left Ventricular Assist Device, Navin Rajagopalan, Ryan E. Wilson

The VAD Journal

Acute myocardial infarction is a rare event in a patient with a left ventricular assist device (LVAD). We present a case of ST-segment elevation myocardial infarction in a LVAD patient.

Rna Nanoparticle As A Vector For Targeted Sirna Delivery Into Glioblastoma Mouse Model, Tae Jin Lee, Farzin Haque, Dan Shu, Ji Young Yoo, Hui Li, Robert A. Yokel, Craig Horbinski, Tae Hyong Kim, Sung-Hak Kim, Chang-Hyuk Kwon, Ichiro Nakano, Balveen Kaur, Peixuan Guo, Carlo M. Croce

Pharmaceutical Sciences Faculty Publications

Systemic siRNA administration to target and treat glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP) based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA for gene silencing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly …

Procollagen C-Endopeptidase Enhancer Protein 2 (Pcpe2) Reduces Atherosclerosis In Mice By Enhancing Scavenger Receptor Class B1 (Sr-Bi)-Mediated High-Density Lipoprotein (Hdl)-Cholesteryl Ester Uptake, Ricquita D. Pollard, Christopher N. Blesso, Manal Zabalawi, Brian Fulp, Mark Gerelus, Xuewei Zhu, Erica W. Lyons, Nebil Nuradin, Omar L. Francone, Xiang-An Li, Daisy Sahoo, Michael J. Thomas, Mary G. Sorci-Thomas

Pediatrics Faculty Publications

Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr^-/-, PCPE2^-/- mice, which had elevated HDL levels compared with LDLr^-/- mice with similar …

Telemetric Blood Pressure Assessment In Angiotensin Ii-Infused Apoe-/- Mice: 28 Day Natural History And Comparison To Tail-Cuff Measurements, Christopher M. Haggerty, Andrea C. Mattingly, Ming C. Gong, Wen Su, Alan Daugherty, Brandon K. Fornwalt

Saha Cardiovascular Research Center Faculty Publications

Abdominal aortic aneurysm (AAA) is a disease of the aortic wall, which can progress to catastrophic rupture. Assessment of mechanical characteristics of AAA, such as aortic distensibility, may provide important insights to help identify at-risk patients and understand disease progression. While the majority of studies on this topic have focused on retrospective patient data, recent studies have used mouse models of AAA to prospectively evaluate the evolution of aortic mechanics. Quantification of aortic distensibility requires accurate measurement of arterial blood pressure, particularly pulse pressure, which is challenging to perform accurately in murine models. We hypothesized that volume/pressure tail-cuff measurements of …

Space Environmental Factor Impacts Upon Murine Colon Microbiota And Mucosal Homeostasis, Lauren E. Ritchie, Stella S. Taddeo, Brad R. Weeks, Florence Lima, Susan A. Bloomfield, M. Andrea Azcarate-Peril, Sara R. Zwart, Scott M. Smith, Nancy D. Turner

Internal Medicine Faculty Publications

Astronaut intestinal health may be impacted by microgravity, radiation, and diet. The aim of this study was to characterize how high and low linear energy transfer (LET) radiation, microgravity, and elevated dietary iron affect colon microbiota (determined by 16S rDNA pyrosequencing) and colon function. Three independent experiments were conducted to achieve these goals: 1) fractionated low LET γ radiation (¹³⁷Cs, 3 Gy, RAD), high Fe diet (IRON) (650 mg/kg diet), and a combination of low LET γ radiation and high Fe diet (IRON+RAD) in male Sprague-Dawley rats; 2) high LET ³⁸Si particle exposure (0.050 Gy), 1/6 G …

Neuron-Based Heredity And Human Evolution, Don M. Gash, Andrew S. Deane

Neuroscience Faculty Publications

It is widely recognized that human evolution has been driven by two systems of heredity: one DNA-based and the other based on the transmission of behaviorally acquired information via nervous system functions. The genetic system is ancient, going back to the appearance of life on Earth. It is responsible for the evolutionary processes described by Darwin. By comparison, the nervous system is relatively newly minted and in its highest form, responsible for ideation and mind-to-mind transmission of information. Here the informational capabilities and functions of the two systems are compared. While employing quite different mechanisms for encoding, storing and transmission …

Effects Of Sucroferric Oxyhydroxide Compared To Lanthanum Carbonate And Sevelamer Carbonate On Phosphate Homeostasis And Vascular Calcifications In A Rat Model Of Chronic Kidney Failure, Olivier Phan, Marc Maillard, Hartmut H. Malluche, Jean-Christophe Stehle, Felix Funk, Michel Burnier

Internal Medicine Faculty Publications

Elevated serum phosphorus, calcium, and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease in chronic renal disease. This study evaluated the effects of sucroferric oxyhydroxide (PA21), a new iron-based phosphate binder, versus lanthanum carbonate (La) and sevelamer carbonate (Se), on serum FGF23, phosphorus, calcium, and intact parathyroid hormone (iPTH) concentrations, and the development of vascular calcification in adenine-induced chronic renal failure (CRF) rats. After induction of CRF, renal function was significantly impaired in all groups: uremic rats developed severe hyperphosphatemia, and serum iPTH increased significantly. All uremic rats (except controls) then received phosphate binders for 4 weeks. …

Using Network Analysis To Understand Public Health Delivery Systems & Community Health Initiatives, Glen P. Mays

Health Management and Policy Presentations

The increasingly connected world of health care delivery relies on an expanding frontier of multi-stakeholder structures and processes, from interdisciplinary patient-centered care teams, to virtual accountable care organizations (ACOs), to complex community-level interventions. This session highlights recent advances in applying social network analysis (SNA) methods to study the implementation and impact of these types of innovations. This methods workshop examines the benefits and limits of novel SNA applications based on the expanding availability of large, linkable electronic clinical and administrative data sources with dependent data structures. This paper profiles examples of using SNA principles and methods to study the implementation …

Learning From Network Analysis: Care Transitions, Market Competition, & Community Interventions, Glen P. Mays

Health Management and Policy Presentations

The increasingly connected world of health care delivery relies on an expanding frontier of multi-stakeholder structures and processes, from interdisciplinary patient-centered care teams, to virtual accountable care organizations (ACOs), to complex community-level interventions. This methods workshop highlights recent advances in applying social network analysis (SNA) methods to study the implementation and impact of these types of innovations. This session will examine the benefits and limits of novel SNA applications based on the expanding availability of large, linkable electronic clinical and administrative data sources with dependent data structures.

Learning From Delivery System Behavior, Dynamics & Interactions To Advance A Culture Of Health, Glen P. Mays

Health Management and Policy Presentations

A new "Systems for Action" national research program flows directly from the Robert Wood Johnson Foundation's Culture of Health action framework. This program will build evidence on how best to align the delivery and financing systems for medical care, public health, and community services & supports so as to promote wellbeing and resiliency, realize efficiencies in resource use, and reduce inequities in health.

Changes In Public Health System Capital And Long-Run Health And Economic Outcomes: 1998 To 2014, Glen P. Mays, Cezar B. Mamaril

Health Management and Policy Presentations

Research Objective: The Affordable Care Act created new resources and incentives for hospitals, insurers, public health agencies, and others to contribute to disease prevention and health promotion activities, potentially changing the structure of public health delivery systems and expanding the implementation of strategies that improve population health. This study uses data from the 1998-2014 National Longitudinal Survey of Public Health Systems to examine: (1) the extent and nature of change in inter-organizational contributions to public health activities, which we use as indicators of public health “system capital”; and (2) the effects of these changes on preventable mortality and resource use. …

High-Risk Travel Distance And Number Of Primary Care Visits In A North Carolina Medicaid Population, Justin Allred, Christopher Duffrin, Jason Brinkley, John Jones

Frontiers in Public Health Services and Systems Research

Background: With nearly 20% of the U.S. population in rural areas, a lack of access to primary care may cause rural residents to forego recommended preventive care procedures, and suffer higher morbidity rates than their urban counterparts.

Methods: Medicaid billing data from 2009 to 2011 were analyzed to calculate the distance and duration that a Medicaid patient population had to travel when seeking primary care in the 29 rural counties of eastern North Carolina. Primary care codes were analyzed to detect any differences in access patterns for various complexity levels of physician visits. Data were also used to evaluate health …

Apoε2 And Education In Cognitively Normal Older Subjects With High Levels Of Ad Pathology At Autopsy: Findings From The Nun Study, Diego Iacono, Peter Zandi, Myron Gross, William R. Markesbery, Olga Pletnikova, Gay Rudow, Juan C. Troncoso

Sanders-Brown Center on Aging Faculty Publications

Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE …

Akt Inhibition Overcomes Rapamycin Resistance By Enhancing The Repressive Function Of Pras40 On Mtorc1/4e-Bp1 Axis, Wenting Mi, Qing Ye, Side Liu, Qing-Bai She

Markey Cancer Center Faculty Publications

The mTORC1 inhibitors, rapamycin and its analogs, are known to show only modest antitumor activity in clinic, but the underlying mechanisms remain largely elusive. Here, we found that activated AKT signaling is associated with rapamycin resistance in breast and colon cancers by sustained phosphorylation of the translational repressor 4E-BP1. Treatment of tumor cells with rapamycin or the AKT inhibitor MK2206 showed a limited activity in inhibiting 4E-BP1 phosphorylation, cap-dependent translation, cell growth and motility. However, treatment with both drugs resulted in profound effects in vitro and in vivo. Mechanistic investigation demonstrated that the combination treatment was required to effectively …

The National Health Security Preparedness Index: National Advisory Committee Meeting, Glen P. Mays, Michael Childress, Anna Goodman Hoover, Chris Bollinger

Health Management and Policy Presentations

This meeting of the National Advisory Committee for the National Health Security Preparedness Index program discussed strategies for improving the theoretical framework, measures, and analytic methodologies used in assessing and comparing preparedness levels across U.S. states and the nation as a whole.

Calcium Channel Blockers, Progression To Dementia, And Effects On Amyloid Beta Peptide Production, Mark A. Lovell, Erin Abner, Richard Kryscio, Liou Xu, Shuling X. Fister, Bert C. Lynn

Sanders-Brown Center on Aging Faculty Publications

Previous epidemiologic studies suggest that antihypertensive drugs may be protective against cognitive decline. To determine if subjects enrolled in the University of Kentucky longitudinal aging study who used antihypertensive drugs showed diminished progression to dementia, we used a 3-parameter logistic regression model to compare the rate of progression to dementia for subjects who used any of the five common categories of antihypertensive drugs to those with similar demographic characteristics but who did not use antihypertensives. Regression modeling showed that subjects who used calcium channel blockers (CCBs) but not the other classes of antihypertensives showed a significant decrease in the rate …

Arsenic Inhibits Dna Mismatch Repair By Promoting Egfr Expression And Pcna Phosphorylation, Dan Tong, Janice Ortega, Christine Kim, Jian Huang, Liya Gu, Guo-Min Li

Toxicology and Cancer Biology Faculty Publications

Both genotoxic and non-genotoxic chemicals can act as carcinogens. However, while genotoxic compounds lead directly to mutations that promote unregulated cell growth, the mechanism by which non-genotoxic carcinogens lead to cellular transformation is poorly understood. Using a model non-genotoxic carcinogen, arsenic, we show here that exposure to arsenic inhibits mismatch repair (MMR) in human cells, possibly through its ability to stimulate epidermal growth factor receptor (EGFR)-dependent tyrosine phosphorylation of proliferating cellular nuclear antigen (PCNA). HeLa cells exposed to exogenous arsenic demonstrate a dose- and time-dependent increase in the levels of EGFR and tyrosine 211-phosphorylated PCNA. Cell extracts derived from arsenic-treated …

Cost Estimation In Public Health Services & Systems Research, Glen P. Mays

Health Management and Policy Presentations

Considerable uncertainty persists about the resources required to implement public health programs and policies, and about the factors that drive variation in resource needs and utilization across community and institutional settings. This paper reviews several alternative approaches to cost estimation that we have used in the field of public health services & systems research (PHSSR). This review was prepared for an expert panel meeting convened as part of a study commissioned by the U.S. Assistant Secretary for Planning and Evaluation (ASPE) to estimate the costs associated with public health emergency preparedness capabilities.

Use Of Parthenolide Derivatives As Antileukemic And Cytotoxic Agents, Peter A. Crooks, Craig T. Jordan, Xiaochen Wei

Pharmaceutical Sciences Faculty Patents

To read this abstract, please download this patent.