Medicine and Health Sciences Commons^™

Tsc2/Mtorc1 Signaling Controls Paneth And Goblet Cell Differentiation In The Intestinal Epithelium, Y. Zhou, Piotr G. Rychahou, Q. Wang, Heidi L. Weiss, B. Mark Evers

Markey Cancer Center Faculty Publications

The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the intestinal epithelium, with a marked …

High Activity Mutants Of Butyrylcholinesterase For Cocaine Hydrolysis, Chang-Guo Zhan, Fang Zheng, Wenchao Yang, Lin Xue, Shurong Hou

Pharmaceutical Sciences Faculty Patents

Butyrylcholinesterase (BChE) polypeptide variants of the presently-disclosed subject matter have enhanced catalytic efficiency for (−)-cocaine, as compared to wild-type BChE. Pharmaceutical compositions of the presently-disclosed subject matter include a BChE polypeptide variant having an enhanced catalytic efficiency for (−)-cocaine. A method of the presently-disclosed subject matter for treating a cocaine-induced condition includes administering to an individual an effective amount of a BChE polypeptide variant, as disclosed herein, to lower blood cocaine concentration.

Method Of Treating Parkinson's Disease In Humans By Convection-Enhanced Infusion Of Glial Cell-Line Derived Neurotrophic Factor To The Putamen, Stephen S. Gill, Don M. Gash, Greg A. Gerhardt

Neuroscience Faculty Patents

A method of treating Parkinson's disease in humans is disclosed, wherein glial cell-line derive neurotrophic factor (GDNF) is chronically administered directly to one or both putamen of a human in need of treatment thereof via convection-enhanced infusion using at least one implantable pump and at least one catheter. In one aspect of the present invention the GDNF is infused directly into one or both putamen through one or more indwelling intraparenchymal multiport brain catheters connected to one or more implantable pumps wherein the flow rate is pulsed.

Method Of Treating Parkinson's Disease In Humans By Convection-Enhanced Infusion Of Glial Cell-Line Derived Neurotrophic Factor To The Putamen, Stephen S. Gill, Don M. Gash, Greg A. Gerhardt

Neuroscience Faculty Patents

A method of treating Parkinson's disease in humans is disclosed, wherein glial cell-line derive neurotrophic factor (GDNF) is chronically administered directly to one or both putamen of a human in need of treatment thereof via convection-enhanced infusion using at least one implantable pump and at least one catheter. In one aspect of the present invention the GDNF is infused directly into one or both putamen through one or more indwelling intraparenchymal mutitiport brain catheters connected to one or more implantable pumps wherein the flow rate is pulsed.

Orientation Virtual Meeting National Advisory Committee For The National Health Security Preparedness Index, Glen P. Mays, Anna Goodman Hoover, Michael Childress

Health Management and Policy Presentations

Refining the measures and methodologies used within the National Health Security Preparedness Index will allow users to make more meaningful comparisons of preparedness levels across U.S. geographic areas and to assess changes in preparedness over time.

Improving Measures Of Public Health Activity At Local And State Levels: The Multi-Network Practice And Outcome Variation Examination Study (Mprove), Glen P. Mays

Health Management and Policy Presentations

Implementation of high-value public health strategies for chronic disease prevention, communicable disease control, and environmental health protection vary widely across U.S. states and communities. The Multi-Network Practice and Outcome Variation Examination Study (MPROVE) supported by the Robert Wood Johnson Foundation creates the measurement and analytic foundation for investigating the causes and consequences of practice variation in public health.

Chiral Symmetry Breaking And Chiral Polarization: Tests For Finite Temperature And Many Flavors, Andrei Alexandru, Ivan Horváth

Anesthesiology Faculty Publications

It was recently conjectured that, in SU(3) gauge theories with fundamental quarks, valence spontaneous chiral symmetry breaking is equivalent to condensation of local dynamical chirality and appearance of chiral polarization scale Λ_ch. Here we consider more general association involving the low-energy layer of chirally polarized modes which, in addition to its width (Λ_ch), is also characterized by volume density of participating modes (Ω) and the volume density of total chirality (Ω_ch). Few possible forms of the correspondence are discussed, paying particular attention to singular cases where Ω emerges as the most versatile …

Factors Affecting The Pharmacokinetics And Pharmacodynamics Of Pegylated Liposomal Irinotecan (Ihl-305) In Patients With Advanced Solid Tumors, Huali Wu, Jeffrey R. Infante, Vicki L. Keedy, Suzanne F. Jones, Emily Chan, Johanna C. Bendell, Wooin Lee, Whitney P. Kirschbrown, Beth A. Zamboni, Satoshi Ikeda, Hiroshi Kodaira, Mace L. Rothenberg, Howard A. Burris, William C. Zamboni

Pharmaceutical Sciences Faculty Publications

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age …

A Coming Disruption In Pharmacy?, Frank Romanelli, Timothy S. Tracy

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Pregnant, Even When You Did Not Want To Be Pregnant, Hatim A. Omar, Joav Merrick

Pediatrics Faculty Publications

No abstract provided.

Validation Of In Vivo 2d Displacements From Spiral Cine Dense At 3t, Gregory J. Wehner, Jonathan D. Suever, Christopher M. Haggerty, Linyuan Jing, David K. Powell, Sean M. Hamlet, Jonathan D. Grabau, Walter Dimitri Mojsejenko, Xiaodong Zhong, Frederick H. Epstein, Brandon K. Fornwalt

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: Displacement Encoding with Stimulated Echoes (DENSE) encodes displacement into the phase of the magnetic resonance signal. Due to the stimulated echo, the signal is inherently low and fades through the cardiac cycle. To compensate, a spiral acquisition has been used at 1.5T. This spiral sequence has not been validated at 3T, where the increased signal would be valuable, but field inhomogeneities may result in measurement errors. We hypothesized that spiral cine DENSE is valid at 3T and tested this hypothesis by measuring displacement errors at both 1.5T and 3T in vivo.

METHODS: Two-dimensional spiral cine DENSE and tagged …

Ketones Prevent Oxidative Impairment Of Hippocampal Synaptic Integrity Through KAtp Channels, Do Young Kim, Mohammed G. Abdelwahab, Soo Han Lee, Derek O'Neill, Roger J. Thompson, Henry J. Duff, Patrick G. Sullivan, Jong M. Rho

Spinal Cord and Brain Injury Research Center Faculty Publications

Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent studies have shown that ketones may modulate neuronal firing through interactions with ATP-sensitive potassium (K_ATP) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of K_ATP channel activation. Ketones dose-dependently …

Designer Receptors Enhance Memory In A Mouse Model Of Down Syndrome, Ashley M. Fortress, Eric D. Hamlett, Elena M. Vazey, Gary Aston-Jones, Wayne A. Cass, Heather A. Boger, Ann-Charlotte E. Granholm

Neuroscience Faculty Publications

Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. …

Activation Of The Nf-Κb Pathway As A Mechanism Of Alcohol Enhanced Progression And Metastasis Of Human Hepatocellular Carcinoma, Fei Wang, Jin-Lian Yang, Ke-Ke Yu, Mei Xu, You-Zhi Xu, Li Chen, Yan-Min Lu, Hao-Shu Fang, Xin-Yi Wang, Zhong-Qian Hu, Fei-Fei Li, Lixin Kan, Jia Luo, Si-Ying Wang

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human. Alcohol is a known risk factor for HCC. However it is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC.

METHODS AND RESULTS: We first retrospectively investigated 52 HCC patients (24 alcohol-drinkers and 28 non-drinkers), and found a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC. Specifically, in …

Undergraduate Public Health Education: Does It Meet Public Health Workforce Needs?, James W. Holsinger Jr., Andrea L. Lewis, Quan Chen

Preventive Medicine and Environmental Health Faculty Publications

The professional bachelor’s degree [Bachelor of Public Health (BPH) or Bachelor of Science (BS) in Public Health] provides a cadre of trained individuals to fill entry-level positions in American public health agencies. The traditional Bachelors of Arts or Science degrees with majors in public health produce an informed citizenry, but may not provide sufficient public health course content to enable graduates of such programs to effectively enter the public health workforce.

Pact/Rax Regulates The Migration Of Cerebellar Granule Neurons In The Developing Cerebellum, Yue Yong, Ya Meng, Hanqing Ding, Zhiqin Fan, Yifen Tang, Chenghua Zhou, Jia Luo, Zun-Ji Ke

Pharmacology and Nutritional Sciences Faculty Publications

PACT and its murine ortholog RAX were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase PKR. Recent studies indicated that RAX played a role in embryogenesis and neuronal development. In this study, we investigated the expression of RAX during the postnatal development of the mouse cerebellum and its role in the migration of cerebellar granule neurons (CGNs). High expression of RAX was observed in the cerebellum from postnatal day (PD) 4 to PD9, a period when the CGNs migrate from the external granule layer (EGL) to the internal granule layer (IGL). The migration of the EGL …

The Tmao-Generating Enzyme Flavin Monooxygenase 3 Is A Central Regulator Of Cholesterol Balance, Manya Warrier, Diana M. Shih, Amy C. Burrows, Daniel Ferguson, Anthony D. Gromovsky, Amanda L. Brown, Stephanie Marshall, Allison Mcdaniel, Rebecca C. Schugar, Zeneng Wang, Jessica Sacks, Xin Rong, Thomas De Aguiar Vallim, Jeff Chou, Pavlina T. Ivanova, David S. Myers, H. Alex Brown, Richard G. Lee, Rosanne M. Crooke, Mark J. Graham, Xiuli Liu, Paolo Parini, Peter Tontonoz, Aldon J. Lusis, Stanley L. Hazen, Ryan E. Temel, J. Mark Brown

Saha Cardiovascular Research Center Faculty Publications

Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here, we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT) and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic endoplasmic reticulum (ER) stress …

Continuing To Confront Copd International Surveys: Comparison Of Patient And Physician Perceptions About Copd Risk And Management, Ana M. Menezes, Sarah H. Landis, Meilan K. Han, Hana Muellerova, Zaurbek Aisanov, Thys Van Der Molen, Yeon-Mok Oh, Masakazu Ichinose, David M. Mannino, Kourtney J. Davis

Preventive Medicine and Environmental Health Faculty Publications

PURPOSE: Using data from the Continuing to Confront COPD International Physician and Patient Surveys, this paper describes physicians' attitudes and beliefs regarding chronic obstructive pulmonary disease (COPD) prognosis, and compares physician and patient perceptions with respect to COPD.

METHODS: In 12 countries worldwide, 4,343 patients with COPD were identified through systematic screening of population samples, and 1,307 physicians who regularly saw patients with COPD were sampled from in-country professional databases. Both patients and physicians completed surveys about their COPD knowledge, beliefs, and perceptions; physicians answered further questions about diagnostic methods and treatment choices for COPD.

RESULTS: Most physicians (79%) responded …

Heartmate Ii Post-Marketing Clinical Studies To Further Establish And Expand Lvad Therapy, Faouzi Kallel

The VAD Journal

No abstract provided.

Zhx2 Enhances The Cytotoxicity Of Chemotherapeutic Drugs In Liver Tumor Cells By Repressing Mdr1 Via Interfering With Nf-Ya, Hongxin Ma, Xuetian Yue, Lifen Gao, Xiaohong Liang, Wenjiang Yan, Zhenyu Zhang, Haixia Shan, Hualin Zhang, Brett T. Spear, Chunhong Ma

Microbiology, Immunology, and Molecular Genetics Faculty Publications

We previously reported the tumor suppressor function of Zinc-fingers and homeoboxes 2 (ZHX2) in hepatocellular carcinoma (HCC). Other studies indicate the association of increased ZHX2 expression with improved response to high dose chemotherapy in multiple myeloma. Here, we aim to test whether increased ZHX2 levels in HCC cells repress multidrug resistance 1(MDR1) expression resulting in increased sensitivity to chemotherapeutic drugs. We showed evidence that increased ZHX2 levels correlated with reduced MDR1 expression and enhanced the cytotoxicity of CDDP and ADM in different HCC cell lines. Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated …

Pyruvate Carboxylase Is Critical For Non-Small-Cell Lung Cancer Proliferation, Katherine Sellers, Matthew P. Fox, Michael Bousamra Ii, Stephen P. Slone, Richard M. Higashi, Donald M. Miller, Yali Wang, Jun Yan, Mariia O. Yuneva, Rahul Deshpande, Andrew N. Lane, Teresa W-M Fan

Toxicology and Cancer Biology Faculty Publications

Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non-small-cell lung cancer (NSCLC) with uniformly 13C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. …

Aca Implementation In The South: The Political Economy Of Full Participation In Kentucky, Glen P. Mays

Health Management and Policy Presentations

This analysis, conducted as part of the ACA Implementation Research Network, examines economic and political forces shaping Kentucky's early experience with implementation of the Patient Protection and Affordable Care Act.

Protective Efficacy Of Centralized And Polyvalent Envelope Immunogens In An Attenuated Equine Lentivirus Vaccine, Jodi K. Craigo, Corin Ezzelarab, Sheila J. Cook, Chong Liu, David Horohov, Charles J. Issel, Ronald C. Montelaro

Maxwell H. Gluck Equine Research Center Faculty Publications

Lentiviral Envelope (Env) antigenic variation and related immune evasion present major hurdles to effective vaccine development. Centralized Env immunogens that minimize the genetic distance between vaccine proteins and circulating viral isolates are an area of increasing study in HIV vaccinology. To date, the efficacy of centralized immunogens has not been evaluated in the context of an animal model that could provide both immunogenicity and protective efficacy data. We previously reported on a live-attenuated (attenuated) equine infectious anemia (EIAV) virus vaccine, which provides 100% protection from disease after virulent, homologous, virus challenge. Further, protective efficacy demonstrated a significant, inverse, linear relationship …

Management Of Bipolar I Depression: Clinical Utility Of Lurasidone, Lillian Jan Findlay, Peggy El-Mallakh, Rif S. El-Mallakh

Nursing Faculty Publications

Lurasidone is a benzisothiazol derivative second-generation antipsychotic. It has been approved in the United States and Europe for treatment of acute schizophrenia and bipolar depression. In type I bipolar subjects, treatment with lurasidone monotherapy of adjunctive therapy to lithium or valproic acid with doses of 20 to 120 mg once daily with food, results in statistically and clinically significant reduction of depressive symptoms. Patients experience relatively few side effects, which include somnolence, akathisia, nausea, and other gastrointestinal upset. Dopamine related side effects, such as Parkinsonism and elevated prolactin, are rare and mild. Longer term safety data obtained in 6 months …

Current And Emerging Treatment Options For Anca-Associated Vasculitis: Potential Role Of Belimumab And Other Baff/April Targeting Agents, Aleksander Lenert, Petar Lenert

Internal Medicine Faculty Publications

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises several clinical entities with diverse clinical presentations, outcomes, and nonunifying pathogenesis. AAV has a clear potential for relapses, and shows unpredictable response to treatment. Cyclophosphamide-based therapies have remained the hallmark of induction therapy protocols for more than four decades. Recently, B-cell depleting therapy with the anti-CD20 antibody rituximab has proved beneficial in AAV, leading to Food and Drug Administration approval of rituximab in combination with corticosteroids for the treatment of AAV in adults. Rituximab for ANCA-associated vasculitis and other clinical trials provided clear evidence that rituximab was not inferior to cyclophosphamide for remission …

Esophageal Fistula Complicating Thyroid Lobectomy, Nicholas D. Ward, Cortney Y. Lee, James T. Lee, David A. Sloan

Surgery Faculty Publications

Thyroidectomy is associated with low morbidity and mortality. Esophageal perforation following thyroidectomy has been reported only three times previously, with subsequent fistulization occurring in two of these cases. The authors present the first such case report in the English-speaking literature.

Comparison Of Transcutaneous Electrical Nerve Stimulation And Cryotherapy For Increasing Quadriceps Activation In Patients With Knee Pathologies, Conrad M. Gabler, Adam S. Lepley, Timothy L. Uhl, Carl G. Mattacola

Physical Therapy Faculty Publications

Proper neuromuscular activation of the quadriceps muscle is essential for maintaining quadriceps strength and lower extremity function. Quadriceps activation failure is a common characteristic observed in patients with knee pathologies, and it is defined as an inability to voluntarily activate the entire alpha motor neuron pool innervating the quadriceps. One of the more popular techniques used to assess quadriceps activation is the superimposed burst (SIB) technique. The SIB technique is a force-based technique which uses a supramaximal, percutaneous electrical stimulation to activate all of the motor units in the quadriceps during a maximal, voluntary isometric contraction of the quadriceps. Central …

Linking The Home And Neighborhood Food Environments Regarding Dietary Intake Among Rural Adolescents, Matthew James Saulnier

Theses and Dissertations--Nutrition and Food Systems

Home availability of both healthful and unhealthful foods may influence consumption among rural adolescent populations. In conjunction, the availability of food in an individual’s local food environment has the potential to significantly impact what is procured for the home and eaten away from the home. The purpose of this study was to determine how in-store food availability and parental purchases influences home availability and, ultimately, dietary intake among adolescents. This study measured perceived home availability, using the University of Minnesota Project EAT Survey, and dietary intake, using the NHANES Dietary Screener Questionnaire, of (n=28) adolescent participants in two Kentucky counties …

How Do Perceived Gender Roles Influence The Number Of Attempted Medical Interventions Of Infertile Couples?, Erin Aiello

Theses and Dissertations--Family Sciences

Infertility affects 1 in 8 couples and the literature discusses the emotional effects infertility has on an individual. One option for infertility is to attempt medical interventions and the literature in the field does not explain why some people attempt more interventions than others. Using data from the 2002 National Survey of Family Growth (NSFG), Cycle 6, this quantitative study aims to understand the relationship between traditional gender roles and values and the attempted number of medical interventions by individuals within a relationship experiencing infertility. The results from this study indicate that both males and females that are in relationship …

Targeting Methylglyoxal And Ppar Gamma To Alleviate Neuropathic Pain Associated With Type 2 Diabetes, Ryan B. Griggs

Theses and Dissertations--Physiology

Neuropathic pain affects up to 50% of the 29 million diabetic patients in the United States. Neuropathic pain in diabetes manifests as a disease of the peripheral and central nervous systems. The prevalence of type 2 diabetes is far greater than type 1 (90%), yet the overwhelming focus on type 1 models this has left the mechanisms of pain in type 2 diabetes largely unknown. Therefore I aimed to improve the current mechanistic understanding of pain associated with type 2 diabetes using two preclinical rodent models: Zucker Diabetic Fatty rats and db/db mice. In addition, I highlight the translational importance …