Medicine and Health Sciences Commons^™

Comparing American Retail Pharmacies To Italian And Greek Retail Pharmacies, Shea C. Dolan

Undergraduate Theses, Professional Papers, and Capstone Artifacts

No abstract provided.

Assessing The Accuracy And Deficits Of Popular Drug-Interaction Software Programs In Detecting Interactions Between Cannabis And Pharmaceutical Drugs, Nathan C. Ramsbacher

Undergraduate Theses, Professional Papers, and Capstone Artifacts

- Purpose – The management of drug interactions in healthcare is a large concern for pharmacists and other healthcare professionals, especially for patients requiring large amounts of medications. Healthcare professionals and patients alike utilize drug-interaction software programs (DISPs) frequently to manage medications and make clinical decisions. There is a large discrepancy between DISPs in terms of detecting clinically significant drug interactions. Notably, cannabis does not flag as an interaction as reliably as pharmaceutical drugs on many DISPs. With rising cannabis use in the United States, patients deserve to make decisions on how to safely use cannabis with their prescription drugs …

Equitable Pharmacogenetic Testing Implementation For Rural And Underserved Populations, Shayna Killam

Graduate Student Theses, Dissertations, & Professional Papers

Pharmacogenetic testing has potential to transform healthcare, yet implementation strategies have been limited to major academic medical centers serving metropolitan communities and large health systems. In contrast, rural, community-based health systems are slow to implement these advances, threatening to exacerbate existing healthcare disparities for rural populations. A majority of Montanans live in rural areas, with unique challenges in providing access to pharmacogenetics.

We have established partnerships with three clinical sites who serve rural, underserved populations including American Indian, pediatric, and low socioeconomic status patients. We conducted a needs assessment for pharmacogenetic testing implementation by interviewing 48 key stakeholders. Interview questions …

Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive And Electrophysiological Impairments In Tg2576 App Transgenic Mice, Madhumathi Gnanaprakash, Agnieszka Staniszewski, Hong Zhang, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ).

Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo. …

Supplemental Ascorbate Diminishes Dna Damage Yet Depletes Glutathione And Increases Acute Liver Failure In A Mouse Model Of Hepatic Antioxidant System Disruption, Colin G. Miller, Jean A. Kundert, Justin R. Prigge, Julie A. Amato, Allison E. Perez, Lucia Coppo, Gabrielle N. Rizzo, Michael P. Kavanaugh, David J. Orlicky, Colin T. Shearn, Edward E. Schmidt

Biomedical and Pharmaceutical Sciences Faculty Publications

Cellular oxidants are primarily managed by the thioredoxin reductase-1 (TrxR1)- and glutathione reductase (Gsr)-driven antioxidant systems. In mice having hepatocyte-specific codisruption of TrxR1 and Gsr (TrxR1/Gsr-null livers), methionine catabolism sustains hepatic levels of reduced glutathione (GSH). Although most mice with TrxR1/Gsr-null livers exhibit long-term survival, ~25% die from spontaneous liver failure between 4- and 7-weeks of age. Here we tested whether liver failure was ameliorated by ascorbate supplementation. Following ascorbate, dehydroascorbate, or mock treatment, we assessed survival, liver histology, or hepatic redox markers including GSH and GSSG, redox enzyme activities, and oxidative damage markers. Unexpectedly, rather than providing protection, ascorbate …

Investigations On Novel Cyp26a1/B1 Inhibitor, Dx308: Using Atra Response As A Theraputic Target For Traumatic Brain Injury And Parkinson’S Disease, Jacob Morgan Leatherwood

Graduate Student Theses, Dissertations, & Professional Papers

Neurodegenerative diseases (NDs) take a wide spectrum of pathologies and have a tendency to present themselves later in life. Neurodegenerative diseases affect 6 million Americans annually with ~1 million currently living with Parkinson’s disease (PD). One of the greatest contributors to the pathogenesis of neurodegenerative diseases is the occurrence of a traumatic brain injury (TBI) during life.

All-trans-retinoic acid (atRA) is the active metabolite of Vitamin A. The retinoic acid pathway is known to be activated following TBI and is reduced in PD patients. Previous studies found a decrease in inflammation and behavioral deficits following administration of Vitamin …

Prion Protein Lowering Is A Disease-Modifying Therapy Across Prion Disease Stages, Strains And Endpoints, Eric Vallabh Minikel, Hien T. Zhao, Jason Le, Jill O'Moore, Rose Pitstick, Samantha Graffam, George A. Carlson, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.

Reduced Expression Of The Pp2a Methylesterase, Pme-1, Or The Pp2a Methyltransferase, Lcmt-1, Alters Sensitivity To Beta-Amyloid-Induced Cognitive And Electrophysiological Impairments In Mice, Agnieszka Staniszewski, Hong Zhang, Kesava Asam, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls

Biomedical and Pharmaceutical Sciences Faculty Publications

Beta-amyloid (Ab) is thought to play a critical role in Alzheimer’s disease (AD), and application of soluble oligomeric forms of Ab produces AD-like impairments in cognition and synaptic plasticity in experimental systems. We found previously that transgenic overexpression of the PP2A methylesterase, PME-1, or the PP2A methyltransferase, LCMT-1, altered the sensitivity of mice to Ab-induced impairments, suggesting that PME-1 inhibition may be an effective approach for preventing or treating these impairments. To explore this possibility, we examined the behavioral and electrophysiological effects of acutely applied synthetic Ab oligomers in male and female mice heterozygous for either a PME-1 KO or …

Modeling Of Excitatory Amino Acid Transporters And Clearance Of Synaptic Cleft On Millisecond Time Scale, Denis M. Shchepakin, Leonid Kalachev, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Excitatory Amino Acid Transporters (EAATs) operate over wide time scales in the brain. They maintain low ambient concentrations of the primary excitatory amino acid neurotransmitter glutamate, but they also seem to play a significant role in clearing glutamate from the synaptic cleft in the millisecond time-scale process of chemical communication that occurs between neurons. The detailed kinetic mechanisms underlying glutamate uptake and clearance remain incompletely understood. In this work we used a combination of methods to model EAAT kinetics and gain insight into the impact of transport on glutamate dynamics in a general sense. We derive reliable estimates of the …

Xflow: An Algorithm For Extracting Ion Chromatograms, Mathew M. Gutierrez, Rob Smith

Graduate Student Theses, Dissertations, & Professional Papers

Abstract: Mass spectrometry is a fundamental tool for modern proteomics. The increasing availability of mass spectrometry data paired with the increasing sensitivity and fidelity of the instruments necessitates new and more potent analytical methods. To that end, we have created and present XFlow, a feature detection algorithm for extracting ion chromatograms from MS1 LC-MS data. XFlow is a parameter-free procedurally agnostic feature detection algorithm that utilizes the latent properties of ion chromatograms to resolve them from the surrounding noise present in MS1 data. XFlow is designed to function on either profile or centroided data across different resolutions and instruments. This …

Epigenetic Biomarkers For Alzheimer’S Disease Using A Transgenic Porcine Model, Yoon Hee Cho

University Grant Program Reports

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for approximately 60~70% of dementia cases. AD afflicts more than 35.6 million individuals worldwide and is expected to increase to 65.7 million by 2030 and 115.4 million by 2050 ¹; AD is a serious public health problem that is causing increased health care costs worldwide. Typically, AD is a relentlessly progressive disorder that initially manifests as severe loss of memory, particularly episodic memory.² The disorder is not curable at present, and the mechanisms driving development of AD are not fully understood. Therefore, there is an urgent need …

A Multifactorial Cytochrome P450 2d6 Genotype-Phenotype Prediction Model To Improve Precision Of Clinical Pharmacogenomic Tests, Rachel Dalton

Graduate Student Theses, Dissertations, & Professional Papers

BACKGROUND: CYP2D6 is difficult to accurately genotype due to a large number of single nucleotide variants (SNVs), indels, and structural variation such as deletions, duplications, and CYP2D6/CYP2D7 hybrid genes. CYP2D6 targeted genotyping panels are of limited utility; clinically relevant variants that are not genotyped will be missed. Sequencing solves this problem but requires additional tools to address structural variation. The goal of our study was to determine the predictive power of Stargazer, a novel allele-calling program, which combines SNV/indel calls with structural variation identification.

METHODS: In a panel of 309 human livers, CYP2D6 diplotypes and activity scores were initially assigned …

Epigenetic Biomarkers For Mwcnt Exposure And Lung Disease, Yoon Hee Cho

University Grant Program Reports

Multi-walled carbon nanotubes (MWCNT) are engineered nano-materials being developed and used in a wide variety of medical, engineering, and personal products with many potential benefits [1]. However, MWCNT have been shown to cause significant pathological changes in animal models, particularly in the airways, raising the concern that adverse human health effects will emerge with increasing use and exposure to these materials [2-4]. Potential bioactivity of MWCNT, including in vitro and in vivo toxicity and increased inflammation and pathology, has been attributed to their unique physical and chemical characteristics such as length, diameter, contaminants and rigidity [5]. However, MWNCT toxicity and/or …

Survey Of Prescription Medication Disposal Practices In Older Patients, Kimberly A. Madson

University Grant Program Reports

The purpose of the proposed study was to survey participants on current medication disposal practices, and to gather preliminary data on the types of medications found in the home environment.

Secondary Data Analysis Of Informal Caregiving In A Medicare Population, Jean T. Carter

University Grant Program Reports

The purpose of the study is to describe the status of informal caregiving within a subset of the Medicare population that is receiving some of its health care in the home and patient outcomes associated with informal caregiving. Rural settings and medication issues will be a particular focus.

D-Serine Is A Substrate For Neutral Amino Acid Transporters Asct1/Slc1a4 And Asct2/Slc1a5, And Is Transported By Both Subtypes In Rat Hippocampal Astrocyte Cultures, Alan C. Foster, Jill Farnsworth, Genevieve Lind, Yong-Xin Lin, Jia-Ying Yang, Van Dang, Mahmud Penjwini, Veena Viswanath, Ursula Staubli, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

N-methyl-D-aspartate (NMDA) receptors play critical roles in synaptic transmission and plasticity. Activation of NMDA receptors by synaptically released L-glutamate also requires occupancy of co-agonist binding sites in the tetrameric receptor by either glycine or D-serine. Although D-serine appears to be the predominant co-agonist at synaptic NMDA receptors, the transport mechanisms involved in D-serine homeostasis in brain are poorly understood. In this work we show that the SLC1 amino acid transporter family members SLC1A4 (ASCT1) and SLC1A5 (ASCT2) mediate homo- and hetero-exchange of D-serine with physiologically relevant kinetic parameters. In addition, the selectivity profile of D-serine uptake in cultured rat hippocampal …

Modeling Of Ambient Glutamate Concentration Measurement In The Mammalian Nervous System, Denis M. Shchepakin, Michael Kavanaugh, Leonid Kalachev

Biomedical and Pharmaceutical Sciences Faculty Publications

A neuron is an electrically excitable cell that processes and transmits information through electrical and chemical signals. Neurons connect and pass signals to other cells through the structure called synapse. We focus on synapses through which the signals are transferred by signaling molecules called neurotransmitters. One of the predominant excitatory neurotransmitters in the central nervous system of the mammals, including humans, is glutamate. It is directly or indirectly involved in most brain functions. However, the excessive stimulation of the glutamate receptors is toxic to neurons, therefore it is important to rapidly clear the glutamate from the extra-cellular space and keep …

Temporal And Spatial Changes In The Pattern Of Iba1 And Cd68 Staining In The Rat Brain Following Severe Traumatic Brain Injury, Debbie Smith, Diane Brooks, Eric Wohlgehagen, Thomas Rau, David Poulsen

Biomedical and Pharmaceutical Sciences Faculty Publications

We have previously demonstrated that acute treatment with low dose methamphetamine is neuroprotectivein a rat model of severe traumatic brain injury (TBI). Using gene expression analysis, we further showed that methamphetamine treatment significantly reduced the expression of proinflammatory genes after severe TBI. Therefore, to further investigate the potential effects of methamphetamine treatment on the neuroinflammatory response, we examined immunofluorescent staining of Iba1 and CD68, two marker of neuroinflammation, in the rat lateral fluid percussion injury model of severe TBI. In this study, we observed temporal and spatial alterations in the pattern of Iba1 and CD68 labeling within two weeks after …

Establishment Of Immortalized Innate Lymphoid Cell Lines From The Mouse Lung, Celine A. Beamer

University Grant Program Reports

The purpose of this proposal was to create immortalized innate lymphoid cell (ILC) lines from normal and transgenic mice

Dendritic Distributions Of LH Channels In Experimentally-Derived Multi-Compartment Models Of Oriens-Lacunosum/Moleculare (O-Lm) Hippocampal Interneurons, Vladislav Sekulic, Tse-Chiang Chen, J. Josh Lawrence, Frances K. Skinner

Biomedical and Pharmaceutical Sciences Faculty Publications

The O-LM cell type mediates feedback inhibition onto hippocampal pyramidal cells and gates information flow in the CA1. Its functions depend on the presence of voltage-gated channels (VGCs), which affect its integrative properties and response to synaptic input. Given the challenges associated with determining densities and distributions of VGCs on interneuron dendrites, we take advantage of computational modeling to consider different possibilities. In this work, we focus on hyperpolarization-activated channels (h-channels) in O-LM cells. While h-channels are known to be present in O-LM cells, it is unknown whether they are present on their dendrites. In previous work, we used ensemble …

Using Multi-Compartment Ensemble Modeling As An Investigative Tool Of Spatially Distributed Biophysical Balances: Application To Hippocampal Oriens-Lacunosum/Moleculare (O-Lm) Cellns, Vladislav Sekulic, J. Josh Lawrence, Frances K. Skinner

Biomedical and Pharmaceutical Sciences Faculty Publications

Multi-compartmental models of neurons provide insight into the complex, integrative properties of dendrites. Because it is not feasible to experimentally determine the exact density and kinetics of each channel type in every neuronal compartment, an essential goal in developing models is to help characterize these properties. To address biological variability inherent in a given neuronal type, there has been a shift away from using hand-tuned models towards using ensembles or populations of models. In collectively capturing a neuron’s output, ensemble modeling approaches uncover important conductance balances that control neuronal dynamics. However, conductances are never entirely known for a given neuron …

Synthesis, Characterization, And Bioactivity Of Carboxylic Acid-Functionalized Titanium Dioxide Nanobelts, Raymond F. Hamilton, Nianqiang Wu, Chengcheng Xiang, Ming Li, Feng Yang, Michael Wolfarth, Dale W. Porter, Andrij Holian

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Surface modification strategies to reduce engineered nanomaterial (ENM) bioactivity have been used successfully in carbon nanotubes. This study examined the toxicity and inflammatory potential for two surface modifications (humic acid and carboxylation) on titanium nanobelts (TNB).

Methods: The in vitro exposure models include C57BL/6 alveolar macrophages (AM) and transformed human THP-1 cells exposed to TNB for 24 hrs in culture. Cell death and NLRP3 inflammasome activation (IL-1β release) were monitored. Short term (4 and 24 hr) in vivo studies in C57BL/6, BALB/c and IL-1R null mice evaluated inflammation and cytokine release, and cytokine release from ex vivo cultured AM. …

Assessment Of Resident And Faculty Preferences For Clinical Pharmacy Services Within A Developing Family Medicine Residency Program, Kerry Haney

University Grant Program Reports

No abstract provided.

Radiation-Induced Genomic Instability And Line-1 Hypomethylation In Radiographers, Yoon Hee Cho

University Grant Program Reports

Genomic instability is an important factor in cancer induced by ionizing radiation. Global DNA hypomethylation has been recently proposed as a potential biomarker for cancer risk through genomic instability. However the association between low-dose ionizing radiation exposure and DNA methylation changes is unclear. This study aimed to understand the epigenetic mechanisms associated with low-level radiation exposure and radiation-induced genomic instability (RIGI) among industrial radiographers.

Household Reporting Of Childhood Respiratory Health And Air Pollution In Rural Alaska Native Communities, Desirae N. Ware, Johnnye Lewis, Scarlett Hopkins, Bert Boyer, Luke Montrose, Curis W. Noonan, Erin O. Semmens, Tony J. Ward

Biomedical and Pharmaceutical Sciences Faculty Publications

Background. Air pollution is an important contributor to respiratory disease in children.

Objective. To examine associations between household reporting of childhood respiratory conditions and household characteristics related to air pollution in Alaska Native communities.

Design. In-home surveys were administered in 2 rural regions of Alaska. The 12-month prevalence of respiratory conditions was summarized by region and age. Odds ratios (ORs) were calculated to describe associations between respiratory health and household and air quality characteristics.

Results. Household-reported respiratory health data were collected for 561 children in 328 households. In 1 region, 33.6% of children aged/or bronchitis. Children with these conditions …

The Effect Of Size On Ag Nanosphere Toxicity In Macrophage Cell Models And Lung Epithelial Cell Lines Is Dependent On Particle Dissolution, Raymond F. Hamilton, Sarah Buckingham, Andrij Holian

Biomedical and Pharmaceutical Sciences Faculty Publications

Silver (Ag) nanomaterials are increasingly used in a variety of commercial applications. This study examined the effect of size (20 and 110 nm) and surface stabilization (citrate and PVP coatings) on toxicity, particle uptake and NLRP3 inflammasome activation in a variety of macrophage and epithelial cell lines. The results indicated that smaller Ag (20 nm), regardless of coating, were more toxic in both cell types and most active in the THP-1 macrophages. TEM imaging demonstrated that 20 nm Ag nanospheres dissolved more rapidly than 110 nm Ag nanospheres in acidic phagolysosomes consistent with Ag ion mediated toxicity. In addition, there …

Glutamate Transporter Control Of Ambient Glutamate Levels, Weinan Sun, Denis M. Shchepakin, Leonid Kalachev, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Accurate knowledge of the ambient extracellular glutamate concentration in brain is required for understanding its potential impacts on tonic and phasic receptor signaling. Estimates of ambient glutamate based on microdialysis measurements are generally in the range of ∼2–10 μM, approximately 100-fold higher than estimates based on electrophysiological measurements of tonic NMDA receptor activity (∼25–90 nM). The latter estimates are closer to the low nanomolar estimated thermodynamic limit of glutamate transporters. The reasons for this discrepancy are not known, but it has been suggested that microdialysis measurements could overestimate ambient extracellular glutamate because of reduced glutamate transporter activity in a …

Hilar Mossy Cells Provide The First Glutamatergic Synapses To Adult-Born Dentate Granule Cells, Jessica H. Chancey, David J. Poulsen, Jacques I. Wadiche, Linda Overstreet-Wadiche

Biomedical and Pharmaceutical Sciences Faculty Publications

Adult-generated granule cells (GCs) in the dentate gyrus must establish synapses with preexisting neurons to participate in network activity. To determine the source of early glutamatergic synapses on newborn GCs in adult mice, we examined synaptic currents at the developmental stage when NMDA receptor-mediated silent synapses are first established. We show that hilar mossy cells provide initial glutamatergic synapses as well as disynaptic GABAergic input to adult-generated dentate GCs.

Phenoxybenzamine Is Neuroprotective In A Rat Model Of Severe Traumatic Brain Injury, Thomas Rau, Aakriti Kothiwal, Annela Rova, Joseph F. Rhoderick, David J. Poulsen

Biomedical and Pharmaceutical Sciences Faculty Publications

Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced neuronal death in rat hippocampal slice cultures following exposure to oxygen glucose deprivation (OGD). Using this system, we found that phenoxybenzamine reduced neuronal death over a broad dose range (0.1 μM–1 mM) and provided efficacy when delivered up to 16 h post-OGD. We further tested phenoxybenzamine in the rat lateral fluid percussion model of TBI. When administered …

Analgesic Effect Of A Mixed T-Type Channel Inhibitor/Cb2 Receptor Agonist, Vinicius M. Gadotti, Haitao You, Ravil R. Petrov, N. Daniel Berger, Philippe Diaz, Gerald W. Zamponi

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. Results: NMP-181 action on CB1 and CB2 receptors was characterized in radioligand binding and in vitro GTP gamma[S-35] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak Ca(V)3.2 currents with IC50 values …