Medicine and Health Sciences Commons^™

Inhibition Of Allogeneic Inflammatory Responses By The Ribonucleotide Reductase Inhibitors, Didox And Trimidox, Mohammed S. Inayat, Ismail S. El-Amouri, Mohammad Bani-Ahmad, Howard L. Elford, Vincent S. Gallicchio, Oliver R. Oakley

Health and Clinical Sciences Faculty Publications

BACKGROUND: Graft-versus-host disease is the single most important obstacle facing successful allogeneic stem cell transplantation (SCT). Even with current immunosuppressive therapies, morbidity and mortality rates are high. Current therapies including cyclosporine A (CyA) and related compounds target IL-2 signaling. However, although these compounds offer great benefit, they are also associated with multiple toxicities. Therefore, new compounds with a greater efficacy and reduced toxicity are needed to enable us to overcome this hurdle.

METHODS: The allogeneic mixed lymphocyte reaction (MLR) is a unique ex vivo method to study a drug's action on the initial events resulting in T-cell activation and proliferation, …

Diaphragm Weakness And Mechanical Ventilation – What's The Critical Issue?, Leigh Ann Callahan, Gerald S. Supinski

Internal Medicine Faculty Publications

While animal studies indicate that controlled mechanical ventilation (MV) induces diaphragm weakness and myofiber atrophy, there are no data in humans that confirm MV per se produces diaphragm weakness. Whether or not diaphragm weakness results from MV, sepsis, corticosteroids, hyperglycemia, or a combination of these factors, however, is not the most important issue raised by the recent study from Hermans and colleagues. This study makes an important contribution by providing additional evidence that many critically ill patients have profound diaphragm weakness. If diaphragm weakness of this magnitude is present in most mechanically ventilated patients, a strong argument can be made …

Foreign-Born Semi Driver Dies After Driving Over Embankment, Kentucky Injury Prevention And Research Center

Fatality Case Reports--Motor Vehicle

One summer morning in 2009, at approximately 11:30 AM, a 41 year-old male, long-haul, semi tractor-trailer driver drove off an interstate highway, over a guardrail, and continued into a wooded ravine. His trailer was empty and he was travelling to pick up a load of retail goods. The trailer disengaged from the tractor, the fuel tanks ruptured, the tractor overturned and caught fire. As the tractor overturned, the driver was ejected. A passing motorist called emergency medical (EMS) services; EMS arrived and found the driver dead at the scene.

To prevent future occurrences of similar incidents, the following recommendations have …

Cross-Reactivity Of Antibodies Against Leptospiral Recurrent Uveitis-Associated Proteins A And B (Lrua And Lrub) With Eye Proteins, Ashutosh Verma, Pawan Kumar, Kelly Babb, John F. Timoney, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Infection by Leptospira interrogans has been causally associated with human and equine uveitis. Studies in our laboratories have demonstrated that leptospiral lipoprotein LruA and LruB are expressed in the eyes of uveitic horses, and that antibodies directed against LruA and LruB react with equine lenticular and retinal extracts, respectively. These reactivities were investigated further by performing immunofluorescent assays on lenticular and retinal tissue sections. Incubation of lens tissue sections with LruA-antiserum and retinal sections with LruB-antiserum resulted in positive fluorescence. By employing two-dimensional gel analyses followed by immunoblotting and mass spectrometry, lens proteins cross-reacting with LruA antiserum were identified to …

Pemoline And Tetramisole 'Positives' In English Racehorses Following Levamisole Administration, J. Gutierrez, R. L. Eisenberg, N. J. Koval, E. R. Armstrong, J. Tharappel, C. J. Hughes, Thomas Tobin

Veterinary Science Faculty Publications

Pemoline is a central nervous system stimulant that has been used to treat attention-deficit hyperactivity disorder and narcolepsy in humans; its identification in horses could be considered evidence of attempts to influence performance. Two recent pemoline 'positives' in English racehorses led us to review the chemical relationships between tetramisole, levamisole, aminorex and pemoline. Pemoline is a simple oxidation product of aminorex, which has been shown in the United States and elsewhere to be an equine metabolite of levamisole. Based on the clear structural relationships between aminorex and pemoline, we conclude that levamisole can metabolise to pemoline in horses and that …

The Catalytic Function Of The Rev1 Dcmp Transferase Is Required In A Lesion-Specific Manner For Translesion Synthesis And Base Damage-Induced Mutagenesis, Ying Zhou, Jillian Wang, Yanbin Zhang, Zhigang Wang

Toxicology and Cancer Biology Faculty Publications

The Rev1-Polζ pathway is believed to be the major mechanism of translesion DNA synthesis and base damage-induced mutagenesis in eukaryotes. While it is widely believed that Rev1 plays a non-catalytic function in translesion synthesis, the role of its dCMP transferase activity remains uncertain. To determine the relevance of its catalytic function in translesion synthesis, we separated the Rev1 dCMP transferase activity from its non-catalytic function in yeast. This was achieved by mutating two conserved amino acid residues in the catalytic domain of Rev1, i.e. D467A/E468A, where its catalytic function was abolished but its non-catalytic function remained intact. In this mutant …

Bioactive Peptide-Based Probes, Clair D. Hicks, Peter A. Crooks

Pharmaceutical Sciences Faculty Patents

A method for preparing a site-specific peptide probe, wherein the peptide is specific to a receptor, includes modifying a marker to include a tether molecule and covalently binding the tether molecule to the peptide. The present invention also provides a labeled probe, comprising a peptide specific for a receptor and a marker. The marker is modified to include a tether molecule capable of covalently binding to the peptide. The peptide is typically derived from a bacteriophage or is a synthetic analog or derivative of the peptide. The receptor will typically be found on a surface of a bacterial cell. The …

White Matter Diffusion Alterations In Normal Women At Risk Of Alzheimer's Disease, Charles D. Smith, Himachandra Chebrolu, Anders H. Andersen, David A. Powell, Mark A. Lovell, Shuling Xiong, Brian T. Gold

Neurology Faculty Publications

Increased white matter mean diffusivity and decreased fractional anisotropy (FA) has been observed in subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We sought to determine whether similar alterations of white matter occur in normal individuals at risk of AD. Diffusion tensor images were acquired in 42 cognitively normal right-handed women with both a family history of dementia and at least one apolipoprotein E4 allele. These were compared with images from 23 normal women without either AD risk factor. Group analyses were performed using tract-based spatial statistics. Reduced FA was observed in the fronto-occipital and inferior temporal …

Antibodies And Unnatural Substrates Of Prenylation Enzymes For Use In Detecting And Isolating Prenylated Proteins, H. Peter Spielmann, Douglas A. Andres

Molecular and Cellular Biochemistry Faculty Patents

Unnatural substrates of prenylation enzymens and antibodies that recognize unique moieties of prenylated proteins, which unique moieties are transferred from the unnatural substrates are used for detecting and isolating prenylated proteins, and for screening for inhibitors of prenylation enzymes.

Recent Trends In Exposure To Secondhand Smoke In The United States Population, Chieh-I Chen, Tanya Burton, Christine L. Baker, Vera Mastey, David Mannino

Preventive Medicine and Environmental Health Faculty Publications

BACKGROUND: Previous research using the National Health and Nutrition Examination Surveys (NHANES) data documented a significant downward trend in secondhand smoke (SHS) exposure between 1988 and 2002. The objective of this study was to assess whether the downward trend in exposure continued from 2001 through 2006.

METHODS: We analyzed data from the 2001-2006 NHANES to estimate exposure of nonsmokers to SHS. Geometric means of serum cotinine levels for all nonsmokers were computed.

RESULTS: Overall serum cotinine levels (95% Confidence Intervals) in 2001-2002, 2003-2004, and 2005-2006 were 0.06 ng/mL (0.05-0.07), 0.07 ng/mL (0.06-0.09), and 0.05 ng/mL (0.05-0.06), respectively. Subgroup analysis by …

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

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.

High-Throughput Experimental Studies To Identify Mirna Targets Directly, With Special Focus On The Mammalian Brain, Peter T. Nelson, Marianthi Kiriakidou, Zissimos Mourelatos, Grace S. Tan, Mary H. Jennings, Kevin Xie, Wang-Xia Wang

Pathology and Laboratory Medicine Faculty Publications

We review the pertinent literature on methods used in high-throughput experimental identification of microRNA (miRNA) "targets" with emphasis on neurochemical studies. miRNAs are short regulatory noncoding RNAs that play important roles in the mammalian brain. The functions of miRNAs are related to their binding of RNAs including mRNAs. Since mammalian miRNAs tend to bind to target mRNAs via imperfect complementarity, understanding exactly which target mRNAs are recognized by which specific miRNAs is a challenge. Based on early experimental evidence, a set of "binding rules" for miRNAs has been described. These have focused on the 5' "seed" region of miRNAs binding …

Biomarkers For Aging, Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen, Thomas S. Foster

Pharmacology and Nutritional Sciences Faculty Patents

A statistical and functional correlation strategy to identify changes in cellular pathways specifically linked to impaired cognitive function with aging. Analyses using the strategy identified multiple groups of genes expressed in the hippocampi of mammals, where the genes were expressed at different levels for several ages. The aging changes in expression began before mid-life. Many of the genes were involved in specific neuronal and glial pathways with previously unrecognized relationships to aging and/or cognitive decline. These identified genes and the proteins they encode can be used as novel biomarkers of brain aging and as targets for developing treatment methods against …

High-Activity Mutants Of Butyrylcholinesterase For Cocaine Hydrolysis And Method Of Generating The Same, Chang-Guo Zhan, Hoon Cho, Hsin-Hsiung Tai

Pharmaceutical Sciences Faculty Patents

A novel computational method and generation of mutant butyrylcholinesterase for cocaine hydrolysis is provided. The method includes molecular modeling a possible BChE mutant and conducting molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations thereby providing a screening method of possible BChE mutants by predicting which mutant will lead to a more stable transition state for a rate determining step. Site-directed mutagenesis, protein expression, and protein activity is conducted for mutants determined computationally as being good candidates for possible BChE mutants, i.e., ones predicted to have higher catalytic efficiency as compared with wild-type BChE. In addition, mutants A199S/A328W/Y332G, A199S/F227A/A328W/Y332G, A199S/S287G/A328W/Y332G, …

Workers Killed While Collecting Solid Waste, Kentucky Injury Prevention And Research Center

Kentucky Haz Alerts--Motor Vehicle

To prevent solid waste collection injuries:

• An applicable worker safety program should be established
• Before the solid waste truck is moved, visible hand signal communication between the driver and tipper should be established
• A standard operating procedure (SOP) should be established for stacking dumpsters as a result of a job hazard analysis
• A drug testing program should be incorporated in a worker safety program
• Pre-trip and post-trip vehicle inspections should be performed
• An ANSI ISEA 107-1999 safety vest should be worn at all times when on duty
• Do not ride on the steps if the truck is going faster than …

Matrix Metalloproteinase-9 Is Increased In Obese Subjects And Decreases In Response To Pioglitazone, Resat Unal, Aiwei Yao-Borengasser, Vijayalakshmi Varma, Neda Rasouli, Craig Labbate, Philip A. Kern, Gouri Ranganathan

Clinical and Translational Science Faculty Publications

Context: The study investigated the regulation of matrix metalloproteinases (MMP)-9 in obesity-associated insulin resistance in humans.

Objectives: The objectives of the investigation were to study MMP-9 regulation by insulin resistance and pioglitazone treatment in impaired glucose tolerant subjects using adipose tissue biopsies and study the mechanism of MMP-9 regulation by pioglitazone in adipocyte cultures.

Research Design: 86 nondiabetic, weight-stable subjects between 21 and 66 yr of age were recruited in a university hospital research center setting. All subjects underwent a sc adipose tissue incisional biopsy from the lower abdominal wall and insulin sensitivity testing using a frequently sampled iv glucose …

Ethics, Empathy, And The Education Of Dentists, David A. Nash

Oral Health Science Faculty Publications

Professional education in dentistry exists to educate good dentists-dentists equipped and committed to helping society gain the benefits of oral health. In achieving this intention, dental educators acknowledge that student dentists must acquire the complex knowledge base and the sophisticated perceptual-motor skills of dentistry. The graduation of knowledgeable and skilled clinicians in dentistry is a necessary, but not sufficient, condition for ensuring quality oral health care. The further requirement is the commitment of graduates to applying their abilities with moral integrity: providing appropriate and quality care in their patients' best interest. Ultimately, good dentistry depends on individuals committed to treating …

Vampirism, Vampire Cults And The Teenager Of Today, Megan White, Hatim A. Omar

Pediatrics Faculty Publications

The aim of this paper is to summarize the limited literature on clinical vampirism, vampire cults and the involvement of adolescents in vampire-like behavior. The various definitions of clinical vampirism are outlined and the emergence of vampire cults from Gothic culture is examined. Further, the clinical features of cult behavior, the attraction to cults, the risk factors for cult involvement, and the clinical management of cult members are discussed. Additionally, vampire popular media is briefly introduced and a case study presented.

Semi Team Driver Dies After Being Ejected From Sleeper Berth, Kentucky Injury Prevention And Research Center

Fatality Case Reports--Motor Vehicle

In the fall of 2009, a husband-wife semi driver team traveled south on a four-lane interstate. They were driving a semi-tractor trailer loaded with air freight. It was nighttime; the husband was driving, and the wife was in the sleeper berth. There was an unoccupied car parked on the right shoulder. The husband crossed the fog line on the right, sideswiped the car, traveled through a guardrail, and down an embankment toward a road below the interstate. During the trajectory of the semi-tractor trailer, the unit jackknifed; the trailer detached from the semi then struck the semi, and both the …

Organic Cation Transporter Preferentially Expressed In Hematopoietic Cells And Leukemias And Uses Thereof, Jeffrey A. Moscow, Xin Lu, Craig Jordan

Markey Cancer Center Faculty Patents

A novel organic cation transporter (OCT) gene, OCT 6, and use thereof is described. The OCT6 gene is preferentially expressed in human hematopoietic tissues, including CD34+ cells and leukemia cells. Its narrow tissue distribution, substrate specificity, and close homology to other cell membrane transporters make OCT6 an attractive target for the treatment of myeloid diseases.

Policy Analysis: Is There A Relationship Between Required Physical Education In Lower Grades And Adolescent Obesity Rates? A Kentucky Case Study, David A. Gross

Center of Excellence in Rural Health Presentations

Childhood obesity has emerged as a national epidemic − and one with serious short- and long-term personal health, medical system and economic consequences. The prevalence of obesity more than doubled among U.S. children ages 6 to 11 between 1980 and 2006, while the rate for those from ages 12 to 19 more than tripled. This study analyzes whether required physical education in elementary and/or middle school is associated with lower rates of obesity among U.S. high school students, with an emphasis on those living in Kentucky.

Oas1 Polymorphisms Are Associated With Susceptibility To West Nile Encephalitis In Horses, Jonathan J. Rios, Joann G. W. Fleming, Uneeda K. Bryant, Craig N. Carter, John C. Huber Jr., Maureen T. Long, Thomas E. Spencer, David L. Adelson

Veterinary Diagnostic Laboratory Faculty Publications

West Nile virus, first identified within the United States in 1999, has since spread across the continental states and infected birds, humans and domestic animals, resulting in numerous deaths. Previous studies in mice identified the Oas1b gene, a member of the OAS/RNASEL innate immune system, as a determining factor for resistance to West Nile virus (WNV) infection. A recent case-control association study described mutations of human OAS1 associated with clinical susceptibility to WNV infection. Similar studies in horses, a particularly susceptible species, have been lacking, in part, because of the difficulty in collecting populations sufficiently homogenous in their infection and …

Individual Micrornas (Mirnas) Display Distinct Mrna Targeting "Rules", Wang-Xia Wang, Bernard R. Wilfred, Kevin Xie, Mary H. Jennings, Yanling Hu, Arnold J. Stromberg, Peter T. Nelson

Pathology and Laboratory Medicine Faculty Publications

MicroRNAs (miRNAs) guide Argonaute (AGO)-containing microribonucleoprotein (miRNP) complexes to target mRNAs.It has been assumed that miRNAs behave similarly to each other with regard to mRNA target recognition. The usual assumptions, which are based on prior studies, are that miRNAs target preferentially sequences in the 3'UTR of mRNAs,guided by the 5' "seed" portion of the miRNAs. Here we isolated AGO- and miRNA-containing miRNPs from human H4 tumor cells by co-immunoprecipitation (co-IP) with anti-AGO antibody. Cells were transfected with miR-107, miR-124,miR-128, miR-320, or a negative control miRNA. Co-IPed RNAs were subjected to downstream high-density Affymetrix Human Gene 1.0 ST microarray analyses using …

Compositions And Methods Useful For Treating Circulatory And Hypovolemic Shock, Peter R. Oeltgen, Meera Govindaswami

Pathology and Laboratory Medicine Faculty Patents

Polypeptides, compositions, and methods for treating shock are described. A isolated polypeptide, Deltorphin-E, can be administered without concomitant fluid resuscitation, before, concurrently with, or after the onset of shock or the occurrence of an event that creates a risk of shock. Deltorphin-E can be administered in accordance with the method as part of a preconditioning strategy, which reduces the extent of ischemic injury. Deltorphin-E can be used in preparation for planned ischemia or in a prophylactic manner in anticipation of further ischemic events.

Acetylation Of Wrn Protein Regulates Its Stability By Inhibiting Ubiquitination, Kai Li, Rui Wang, Enerlyn Lozada, Wei Fan, David K. Orren, Jianyuan Luo

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: WRN is a multi-functional protein involving DNA replication, recombination and repair. WRN acetylation has been demonstrated playing an important role in response to DNA damage. We previously found that WRN acetylation can regulate its enzymatic activities and nuclear distribution.

METHODOLOGY/PRINCIPAL FINDING: Here, we investigated the factors involved in WRN acetylation and found that CBP and p300 are the only major acetyltransferases for WRN acetylation. We further identified 6 lysine residues in WRN that are subject to acetylation. Interestingly, WRN acetylation can increase its protein stability. SIRT1-mediated deacetylation of WRN reverses this effect. CBP dramatically increases the half-life of wild …

Whole-Genome Snp Association In The Horse: Identification Of A Deletion In Myosin Va Responsible For Lavender Foal Syndrome, Samantha A. Brooks, Nicole Gabreski, Donald Miller, Abra Brisbin, Helen E. Brown, Cassandra Streeter, Jason Mezey, Deborah Cook, Douglas F. Antczak

Veterinary Science Faculty Publications

Lavender Foal Syndrome (LFS) is a lethal inherited disease of horses with a suspected autosomal recessive mode of inheritance. LFS has been primarily diagnosed in a subgroup of the Arabian breed, the Egyptian Arabian horse. The condition is characterized by multiple neurological abnormalities and a dilute coat color. Candidate genes based on comparative phenotypes in mice and humans include the ras-associated protein RAB27a (RAB27A) and myosin Va (MYO5A). Here we report mapping of the locus responsible for LFS using a small set of 36 horses segregating for LFS. These horses were genotyped using a newly available single nucleotide polymorphism (SNP) …

Methods And Compositions For Optimizing Blood And Tissue Stability Of Camptothecin And Other Albumin-Binding Therapeutic Compounds, Thomas G. Burke, Daniel C. Carter

Pharmaceutical Sciences Faculty Patents

The present invention provides methods and formulations for optimizing the anti-cancer and anti-HIV activities of a camptothecin drug, including camptothecin and its related analogs including 9-aminocamptothecin and 9-nitrocamptothecin. The invention involves methodologies and formulations that limit human serum albumin-mediated reduction of the anti-cancer and anti-HIV effects of the camptothecins, and the methods and formulations provide combination therapies in which binding of the camptothecin agent to human serum albumin can be modulated by the administration of a competing agent that also binds human serum albumin. Reduced camptothecin drug binding to human serum albumin can result in elevated camptothecin free drug levels …

Rituximab In The Treatment Of B-Cell Non-Hodgkin Lymphoma, Focus On Outcomes And Comparative Effectiveness, Firas Badin, John Hayslip

Markey Cancer Center Faculty Publications

Rituximab is an important and well established component in the treatment of many patients with B-cell non-Hodgkin lymphoma. In this paper we review recent clinical trials investigating the addition of rituximab to standard chemotherapy regimens for treatment of patients with diffuse large B cell lymphoma and follicular lymphoma. This report focuses upon treatment efficacy, quality of life, and safety of rituximab or rituximab-containing regimens. More uniquely, we review economic aspects of lymphoma treatments, including the cost of standard chemotherapy regimens with or without rituximab, cost effectiveness of rituximab in both induction and maintenance treatment, and lymphoma's impacts on patient's productivity …

Carolus Linnaeus (Carl Von Linné), 1707-1778: The Swede Who Named Almost Everything, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

No abstract provided.

Omega-3 Fatty Acids: Potential Role In The Management Of Early Alzheimer's Disease, Gregory A. Jicha, William R. Markesbery

Sanders-Brown Center on Aging Faculty Publications

Omega-3 fatty acids are essential for brain growth and development. They play an important role throughout life, as critical modulators of neuronal function and regulation of oxidative stress mechanisms, in brain health and disease. Docosahexanoic acid (DHA), the major omega-3 fatty acid found in neurons, has taken on a central role as a target for therapeutic intervention in Alzheimer's disease (AD). A plethora of in vitro, animal model, and human data, gathered over the past decade, highlight the important role DHA may play in the development of a variety of neurological and psychiatric disorders, including AD. Cross sectional and prospective …