Medicine and Health Sciences Commons^™

Successfully Climbing The "Stairs": Surmounting Failed Translation Of Experimental Ischemic Stroke Treatments, Michael Kahle, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

The Stroke Therapy Academic Industry Roundtable (STAIR) provided initial (in 1999) and updated (in 2009) recommendations with the goal of improving preclinical stroke therapy assessment and to increase the translational potential of experimental stroke treatments. It is important for preclinical stroke researchers to frequently consider and revisit these concepts, especially since promising experimental stroke treatments continue to fail in human clinical trials. Therefore, this paper will focus on considerations for several key aspects of preclinical stroke studies including the selection and execution of the animal stroke model, drug/experimental treatment administration, and outcome measures to improve experimental validity and translation potential. …

Global Profiling Of Alternative Splicing Events And Gene Expression Regulated By Hnrnph/F, Erming Wang, Vahid Aslanzadeh, Filomena Papa, Haiyan Zhu, Pierre De La Grange, Franca Cambi

Neurology Faculty Publications

In this study, we have investigated the global impact of heterogeneous nuclear Ribonuclear Protein (hnRNP) H/F-mediated regulation of splicing events and gene expression in oligodendrocytes. We have performed a genome-wide transcriptomic analysis at the gene and exon levels in Oli-neu cells treated with siRNA that targets hnRNPH/F compared to untreated cells using Affymetrix Exon Array. Gene expression levels and regulated exons were identified with the GenoSplice EASANA algorithm. Bioinformatics analyses were performed to determine the structural properties of G tracts that correlate with the function of hnRNPH/F as enhancers vs. repressors of exon inclusion. Different types of alternatively spliced events …

Elevated Cardiovascular Risk Among Adults With Obstructive And Restrictive Airway Functioning In The United States: A Cross-Sectional Study Of The National Health And Nutrition Examination Survey From 2007 - 2010, Earl S. Ford, Ann G. Wheaton, David M. Mannino, Latitia Presley-Cantrell, Chaoyang Li, Janet B. Croft

David M. Mannino

Background

Reasons for the excess risk for cardiovascular disease among people with chronic obstructive pulmonary disease remain unclear. Our objective was to examine the cardiovascular risk profile for adults with obstructive and restrictive impairments of lung functioning in a representative sample of adults from the United States.

Methods

We used data from adults aged 20–79 years who participated in the National Health and Nutrition Examination Survey from 2007 to 2010 and had a pulmonary function test. The severity of obstructive impairment was defined by adapting the Global Initiative for Chronic Obstructive Lung Disease criteria.

Results

Among 7249 participants, 80.9% had …

Effects Of Exercise On Ampk Signaling And Downstream Components To Pi3k In Rat With Type 2 Diabetes, Shicheng Cao, Bowen Li, Xuejie Yi, Bo Chang, Beibei Zhu, Zhenzhen Lian, Zhaoran Zhang, Gang Zhao, Huili Liu, He Zhang

Barnstable Brown Diabetes Center Faculty Publications

Exercise can increase skeletal muscle sensitivity to insulin, improve insulin resistance and regulate glucose homeostasis in rat models of type 2 diabetes. However, the potential mechanism remains poorly understood. In this study, we established a male Sprague-Dawley rat model of type 2 diabetes, with insulin resistance and β cell dysfunction, which was induced by a high-fat diet and low-dose streptozotocin to replicate the pathogenesis and metabolic characteristics of type 2 diabetes in humans. We also investigated the possible mechanism by which chronic and acute exercise improves metabolism, and the phosphorylation and expression of components of AMP-activated protein kinase (AMPK) and …

Depletion Of Endothelial Or Smooth Muscle Cell-Specific Angiotensin Ii Type 1a Receptors Does Not Influence Aortic Aneurysms Or Atherosclerosis In Ldl Receptor Deficient Mice, Debra L. Rateri, Jessica J. Moorleghen, Victoria Knight, Anju Balakrishnan, Deborah A. Howatt, Lisa A. Cassis, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: Whole body genetic deletion of AT1a receptors in mice uniformly reduces hypercholesterolemia and angiotensin II-(AngII) induced atherosclerosis and abdominal aortic aneurysms (AAAs). However, the role of AT1a receptor stimulation of principal cell types resident in the arterial wall remains undefined. Therefore, the aim of this study was to determine whether deletion of AT1a receptors in either endothelial cells or smooth muscle cells influences the development of atherosclerosis and AAAs.

METHODOLOGY/PRINCIPAL FINDINGS: AT1a receptor floxed mice were developed in an LDL receptor -/- background. To generate endothelial or smooth muscle cell specific deficiency, AT1a receptor floxed mice were bred with …

The P2y(12) Antagonists, 2mesamp And Cangrelor, Inhibit Platelet Activation Through P2y(12)/G(I)-Dependent Mechanism, Binggang Xiang, Guoying Zhang, Hongmei Ren, Manjula Sunkara, Andrew J. Morris, T. Kent Gartner, Susan S. Smyth, Zhenyu Li

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: ADP is an important physiological agonist that induces integrin activation and platelet aggregation through its receptors P2Y(1) (Gα(q)-coupled) and P2Y(12) (Gα(i)-coupled). P2Y(12) plays a critical role in platelet activation and thrombosis. Adenosine-based P2Y(12) antagonists, 2-methylthioadenosine 5'-monophosphate triethylammonium salt hydrate (2MeSAMP) and Cangrelor (AR-C69931MX) have been widely used to demonstrate the role of P2Y(12) in platelet function. Cangrelor is being evaluated in clinical trials of thrombotic diseases. However, a recent study reported that both 2MeSAMP and Cangrelor raise intra-platelet cAMP levels and inhibit platelet aggregation through a P2Y(12)-independent mechanism.

METHODOLOGY/PRINCIPAL FINDINGS: The present work, using P2Y(12) deficient mice, sought to …

Occupational Chronic Obstructive Pulmonary Disease: An Update, Enrique Diaz-Guzman, David M. Mannino, Shambhu Aryal

David M. Mannino

Chronic obstructive pulmonary disease represents a major cause of morbidity and mortality in industrialized and nonindustrialized countries. Although tobacco use remains the main factor associated with development of the disease, occupational risk factors represent an important and preventable cause. The most common occupationally related factors include exposure to organic dusts, metallic fumes, and a variety of other mineral gases and/or vapors. This article summarizes the literature on the subject and provides an update of the most recent advances in the field.

Epidemiology Of Comorbidities In Chronic Obstructive Pulmonary Disease: Clusters, Phenotypes And Outcomes, Shambhu Aryal, Enrique Diaz-Guzman, David M. Mannino

David M. Mannino

COPD is a complex multisystem disease often accompanied by multiple co-morbidities that contribute to symptoms, exacerbations, hospital admissions and mortality. Individual comorbidities can be grouped into clusters of common human pathology: inflammation/immune response (e.g., ischemic heart disease, metabolic syndrome), thrombosis/hemorrhage (e.g., cerebrovascular diseases, pulmonary embolism), fibrosis/cell proliferation (e.g., lung cancer and other malignancies) and apoptosis/necrosis (e.g., osteoporosis, skeletal muscle dysfunction). While the prevalence of the co-morbidities has been described in a number of observational studies, there is considerable variability in results; moreover characterization of cluster of co-morbidities with the most clinical significance in terms of morbidity and mortality is still …

Fak Is A Critical Regulator Of Neuroblastoma Liver Metastasis, Sora Lee, Jingbo Qiao, Pritha Paul, Kathleen L. O'Connor, B. Mark Evers, Dai H. Chung

Surgery Faculty Publications

Neuroblastomas express increased levels of gastrin-releasing peptide receptor (GRP-R). However, the exact molecular mechanisms involved in GRP-R-mediated cell signaling in neuroblastoma growth and metastasis are unknown. Here, we report that focal adhesion kinase (FAK), as a critical downstream target of GRP-R, is an important regulator of neuroblastoma tumorigenicity. We found that FAK expression correlates with GRP-R expression in human neuroblastoma sections and cell lines. GRP-R overexpression in SK-N-SH cells increased FAK, integrin α3 and β1 expressions and cell migration. These cells demonstrated flatter cell morphology with broad lamellae, in which intense FAK expression was localized to the leading edges of …

Rorα, A Potential Tumor Suppressor And Therapeutic Target Of Breast Cancer, Jun Du, Ren Xu

Markey Cancer Center Faculty Publications

The function of the nuclear receptor (NR) in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORα, one member of the retinoid orphan nuclear receptor (ROR) subfamily of orphan receptors, regulates various cellular and pathological activities. RORα is commonly down-regulated and/or hypoactivated in breast cancer compared to normal mammary tissue. Expression of RORα suppresses malignant phenotypes in breast cancer cells, in vitro and in vivo. Activity of RORα can be categorized into the …

Practice Effects In A Longitudinal, Multi-Center Alzheimer's Disease Prevention Clinical Trial, Erin L. Abner, Brandon C. Dennis, Melissa J. Mathews, Marta S. Mendiondo, Allison Caban-Holt, Richard J. Kryscio, Frederick A. Schmitt, John J. Crowley

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Practice effects are a known threat to reliability and validity in clinical trials. Few studies have investigated the potential influence of practice on repeated screening measures in longitudinal clinical trials with a focus on dementia prevention. The current study investigates whether practice effects exist on a screening measure commonly used in aging research, the Memory Impairment Screen (MIS).

METHODS: The PREADViSE trial is a clinical intervention study evaluating the efficacy of vitamin E and selenium for Alzheimer's disease prevention. Participants are screened annually for incident dementia with the MIS. Participants with baseline and three consecutive follow-ups who made less …

Association Of Intimate Partner Violence And Childhood Sexual Abuse With Cancer-Related Well-Being In Women, Ann L. Coker, Diane R. Follingstad, Lisandra S. Garcia, Corrine M. Williams, Timothy N. Crawford, Heather M. Bush

Obstetrics and Gynecology Faculty Publications

BACKGROUND: Limited evidence suggests that intimate partner violence (IPV) may be associated with poorer cancer outcomes. We hypothesized that timing and type of IPV as well as childhood sexual abuse (CSA) may negatively affect depression, perceived stress, and cancer-related well-being.

METHODS: This was a cross-sectional study of women diagnosed with either breast, cervical, or colorectal cancer in the prior 12 months included in the Kentucky Cancer Registry. Consenting women were interviewed by phone (n=553). Multivariate analysis of covariance (MANCOVA) was used to determine the association between IPV (37% lifetime prevalence) and type, timing, and the range of correlated cancer-related well-being …

Regional Variation In Aortic At1b Receptor Mrna Abundance Is Associated With Contractility But Unrelated To Atherosclerosis And Aortic Aneurysms, Aruna Poduri, A. Phillip Owens, Deborah A. Howatt, Jessica J. Moorleghen, Anju Balakrishnan, Lisa A. Cassis, Alan Daugherty

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Angiotensin II (AngII), the main bioactive peptide of the renin angiotensin system, exerts most of its biological actions through stimulation of AngII type 1 (AT1) receptors. This receptor is expressed as 2 structurally similar subtypes in rodents, termed AT1a and AT1b. Although AT1a receptors have been studied comprehensively, roles of AT1b receptors in the aorta have not been defined.

METHODOLOGY/RESULTS: We initially compared the regional distribution of AT1b receptor mRNA with AT1a receptor mRNA in the aorta. mRNA abundance of both subtypes increased from the proximal to the distal aorta, with the greatest abundance in the infra-renal region. Corresponding …

Withanolide Compounds As Inhibitors Of Fibrosis And Identification Of Molecular Targets For Anti-Fibrotic Drug Development, Royce Mohan, Paola Bargagna-Mohan

Ophthalmology and Visual Science Faculty Patents

Provided are methods for screening for drugs effective for treating fibrotic conditions. One screening method comprises exposing a cell to a test compound, monitoring the effect of the test compound on the amount or form of a cell molecule, comparing the amount or form of the cell molecule with the result obtained by treatment of the cell with an anti-fibrotic -effective amount of a withanolide compound, and selecting a drug effective for treating a fibrotic disease based on the ability of the test compound to provide the effect obtained by the withanolide compound on the cell molecule. Also provided is …

Characterization Of Secretory Sphingomyelinase Activity, Lipoprotein Sphingolipid Content And Ldl Aggregation In Ldlr-/- Mice Fed On A High-Fat Diet, Gergana M. Deevska, Manjula Sunkara, Andrew J. Morris, Mariana N. Nikolova‑Karakashian

Physiology Faculty Publications

The propensity of LDLs (low-density lipoproteins) for aggregation and/or oxidation has been linked to their sphingolipid content, specifically the levels of SM (sphingomyelin) and ceramide. To investigate this association in vivo, ldlr (LDL receptor)-null mice (ldlr-/-) were fed on a modified (atherogenic) diet containing saturated fats and cholesterol. The diet led to significantly elevated SM content in all serum lipoproteins. In contrast, ceramide increased only in the LDL particles. MS-based analyses of the lipid acyl chain composition revealed a marked elevation in C16:0 fatty acid in SM and ceramide, consistent with the prevalence of palmitic acid in the modified diet. …

Doxycycline Does Not Influence Established Abdominal Aortic Aneurysms In Angiotensin Ii-Infused Mice, Xiaojie Xie, Hong Lu, Jessica J. Moorleghen, Deborah A. Howatt, Debra L. Rateri, Lisa A. Cassis, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

Background: There is no proven medical approach to attenuating expansion and rupture of abdominal aortic aneurysms (AAAs). One approach that is currently being investigated is the use of doxycycline. Despite being primarily used as an antimicrobial drug, doxycycline has been proposed to function in reducing AAA expansion. Doxycycline is effective in reducing the formation in the most commonly used mouse models of AAAs when administered prior to the initiation of the disease. The purpose of the current study was to determine the effects of doxycycline on established AAAs when it was administered at a dose that produces therapeutic serum …

Perlecan Domain V Induces Vegf Secretion In Brain Endothelial Cells Through Integrin Α5Β1 And Erk-Dependent Signaling Pathways, Douglas N. Clarke, Abraham Al Ahmad, Boyeon Lee, Christi Parham, Lisa Auckland, Andrezj Fertala, Michael Kahle, Courtney S. Shaw, Jill Roberts, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α(5)β(1) integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5)β(1) and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction …

Development Of Chinese Adolescents: Assessment, Issues, And Intervention, Daniel T. L. Shek, Rachel C. F. Sun, Joav Merrick

Pediatrics Faculty Publications

No abstract.

Arthroscopic Ulnar Nerve Identification During Posterior Elbow Arthroscopy, Srinath Kamineni, David Anthony Hamilton Jr.

Orthopaedic Surgery and Sports Medicine Faculty Publications

Elbow arthroscopy has increased in popularity in the past 10 years for both diagnostic and therapeutic purposes. A major limiting factor faced by the elbow arthroscopist is the close proximity of the neurovasculature to the working field, with the risk of iatrogenic injury. Many arthroscopic procedures are less extensive than their open equivalents because of an inability to consistently and safely eliminate the risk of neural and vascular injury. Many open procedures in the posterior compartment of the elbow joint are not routinely performed arthroscopically. The primary reason for this restriction in arthroscopic practice is the locality of the posteromedially …

Atovaquone Ameliorate Gastrointestinal Toxoplasmosis Complications In A Pregnancy Model, Helieh S. Oz, Thomas Tobin

Physiology Faculty Publications

Background: Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of choice but not approved for use in congenital Toxoplasmosis. We hypothesized atovaquone to be safe and effective against feto-maternal Toxoplasmosis.

Material/Methods: Programmed pregnant mice were i.p. infected with 50–2400 Tachyzoites from Type II strain (clone PTG). Dams were treated daily with atovaquone or sham and monitored for pain, and complications.

Results: Dams developed pain related abdominal hypersensitivity (allodynia) to mechanical stimuli in a Tachyzoites dose dependent manner. Infected dams were anemic and exhibited ascities and …

Sarcopenia, Obesity, And Natural Killer Cell Immune Senescence In Aging: Altered Cytokine Levels As A Common Mechanism, Charles T. Lutz, Lebris S. Quinn

Pathology and Laboratory Medicine Faculty Publications

Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all-cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue …

Transcriptional Repression Of Sodium-Iodide Symporter In Thyroid Carcinoma, Kenneth B. Ain, Wei Li

Internal Medicine Faculty Patents

The present disclosure relates to a sodium iodide symporter (NIS)-repressor binding site (NRBS) consisting of a DNA molecule spanning from −645 to −605 nucleotides (SEQ ID NO:4) or from −648 to −620 nucleotides (SEQ ID NO:5) upstream from the translation start site of human NIS gene. The disclosure further relates to a method of restoring iodide transport to a human thyroid carcinoma cell, including: the steps of: i) contacting the cell expressing and forming a NIS repressor protein complex capable of binding to the NRBS of the disclosure with a modulator of said complex, and ii) administering to the cell …

Reflective Journals Of Students Taking A Positive Youth-Development Course In A University Context In Hong Kong, Daniel T. L. Shek, Florence K. Y. Wu

Pediatrics Faculty Publications

To promote the holistic development of university students, a course entitled "Tomorrow's Leaders" was developed and offered at The Hong Kong Polytechnic University. Based on a case study approach, reflective journals of five outstanding students of the course are presented and analyzed (i.e., thick description), with several themes emerging from the reflection. First, the students liked the course, and they identified many positive attributes. Second, the students appreciated the instructors. Third, the students viewed that the course contributed to different aspects of their development. Fourth, some areas of improvements were proposed. In conjunction with other evaluation mechanisms, the present findings …

Subjective Outcome Evaluation Of The Project P.A.T.H.S. (Extension Phase) Based On The Perspective Of Program Implementer, Daniel T. L. Shek, Lu Yu

Pediatrics Faculty Publications

A total of 231 schools participated in the Project P.A.T.H.S. in 2009/2010 school year. After completion of the Tier 1 Program, subjective outcome evaluation data were collected from 3,259 program implementers. Based on the consolidated data with schools as units, results showed that participants had positive perceptions of the program, implementers, and benefits of the program. More than four-fifth of the implementers regarded the program as helpful to the program participants. Multiple regression analyses revealed that perceived qualities of the program and the program implementers predicted perceived effectiveness of the program. Similar to previous studies, compared to implementers' perception about …

Morphological And Genetic Activation Of Microglia After Diffuse Traumatic Brain Injury In The Rat, Tuoxin Caou, Amanda M. Lisembee, Kelley D. Hall, James R. Pauly, Jonathan Lifshitz

Kaleidoscope

Traumatic brain injury (TBI) survivors experience long, term post-traumatic morbidities. In diffuse brain injured rats, a chronic sensory sensitivity to whisker stimulation models agitation in brain injury survivors and provides anatomical landmarks across the whisker-barrel circuit to evaluate traumatic neuropathology. As a consequence of TBI, acute and chronic microglial activation can contribute to degenerative and reparative events underlying post-traumatic morbidity. Here, we hypothesize that delayed microglial activation is concomitant with neuroplastic change after diffuse brain injury in the rat, by examining differential microglial activation states and neuroplasticity through gene and protein expression. Adult male, Sprague-Dawley rats were subjected to a …

Hormonal Induction Of Polo-Like Kinases (Plks) And Impact Of Plk2 On Cell Cycle Progression In The Rat Ovary, Feixue Li, Misung Jo, Thomas E. Curry, Jing Liu

Obstetrics and Gynecology Faculty Publications

The highly conserved polo-like kinases (Plks) are potent regulators of multiple functions in the cell cycle before and during mitotic cell division. We investigated the expression pattern of Plk genes and their potential role(s) in the rat ovary during the periovulatory period. Plk2 and Plk3 were highly induced both in intact ovaries and granulosa cells in vivo after treatment with the luteinizing hormone (LH) agonist, human chorionic gonadotropin (hCG). In vitro, hCG stimulated the expression of Plk2 in granulosa cells, but not Plk3. This induction of Plk2 expression was mimicked by both forskolin and phorbol 12 myristate 13-acetate (PMA). Moreover, …

Family And Personal Adjustment Of Economically Disadvantaged Chinese Adolescents In Hong Kong, Daniel T. L. Shek, Pik Fong Tsui

Pediatrics Faculty Publications

This study attempted to examine the relationship between poverty and adolescent developmental outcomes in the family and personal domains in 3,328 Chinese secondary school students in Hong Kong. Developmental outcomes included positive youth development constructs, problem behaviors, perceived family interaction, and parental parenting. Results showed that adolescents experiencing poverty did not differ from nonpoor adolescents in terms of risk behavior and in most indicators of positive youth development. On the other hand, adolescents with economic disadvantage displayed lower levels of positive identity, family interaction, and perceived paternal parenting than did those without economic disadvantage.

Subjective Outcome Evaluation Of The Project P.A.T.H.S. In Different Cohorts Of Students, Daniel T. L. Shek, Cecilia M. S. Ma

Pediatrics Faculty Publications

The project P.A.T.H.S. is an indigenously developed positive youth development program in Hong Kong. In the extension phase (2009/2010 school year), subjective outcome evaluation data were collected from 231 schools involving 89,068 participants after completion of the curricula-based Tier 1 Program. With schools as the units of analysis, results showed that participants generally had positive perceptions of the program content and implementers, with over four-fifth of the participants regarded the program as helpful to them. There were some significant grade differences in the subjective outcome evaluation findings, although the related effect size was not strong. Multiple regression analyses revealed that …

Student Classroom Misbehavior: An Exploratory Study Based On Teachers' Perceptions, Rachel C. F. Sun, Daniel T. L. Shek

Pediatrics Faculty Publications

This study aimed to examine the conceptions of junior secondary school student misbehaviors in classroom, and to identify the most common, disruptive, and unacceptable student problem behaviors from teachers' perspective. Twelve individual interviews with teachers were conducted. A list of 17 student problem behaviors was generated. Results showed that the most common and disruptive problem behavior was talking out of turn, followed by nonattentiveness, daydreaming, and idleness. The most unacceptable problem behavior was disrespecting teachers in terms of disobedience and rudeness, followed by talking out of turn and verbal aggression. The findings revealed that teachers perceived student problem behaviors as …

Postlecture Evaluation Of A Positive Youth Development Subject For University Students In Hong Kong, Daniel T. L. Shek

Pediatrics Faculty Publications

The purpose of this study was to examine the postlecture evaluation by the students taking a course (Tomorrow's Leaders) that attempted to promote their leadership qualities and intrapersonal competencies at The Hong Kong Polytechnic University in Hong Kong. Except for the last lecture, students were invited to respond to a 12-item postlecture questionnaire after each lecture. Results showed that the students had positive perceptions of the subject, class, and teacher attributes, and they had positive global evaluation of the teacher and the subject. The postlecture evaluation questionnaire was found to possess good psychometric properties. Multiple regression analyses showed that subject, …