Medicine and Health Sciences Commons^™

Obesity Reduces Left Ventricular Strains, Torsion, And Synchrony In Mouse Models: A Cine Displacement Encoding With Stimulated Echoes (Dense) Cardiovascular Magnetic Resonance Study, Sage P. Kramer, David K. Powell, Christopher M. Haggerty, Cassi M. Binkley, Andrea C. Mattingly, Lisa A. Cassis, Frederick H. Epstein, Brandon K. Fornwalt

Pediatrics Faculty Publications

BACKGROUND: Obesity affects a third of adults in the US and results in an increased risk of cardiovascular mortality. While the mechanisms underlying this increased risk are not well understood, animal models of obesity have shown direct effects on the heart such as steatosis and fibrosis, which may affect cardiac function. However, the effect of obesity on cardiac function in animal models is not well-defined. We hypothesized that diet-induced obesity in mice reduces strain, torsion, and synchrony in the left ventricle (LV).

METHODS: Ten 12-week-old C57BL/6 J mice were randomized to a high-fat or low-fat diet. After 5 months on …

Sphingosine-1-Phosphate-Mediated Mobilization Of Hematopoietic Stem/Progenitor Cells During Intravascular Hemolysis Requires Attenuation Of Sdf-1-Cxcr4 Retention Signaling In Bone Marrow, Kasia Mierzejewska, Yuri M. Klyachkin, Janina Ratajczak, Ahmed Abdel-Latif, Magda Kucia, Mariusz Z. Ratajczak

Saha Cardiovascular Research Center Faculty Publications

Sphingosine-1-phosphate (S1P) is a crucial chemotactic factor in peripheral blood (PB) involved in the mobilization process and egress of hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM). Since S1P is present at high levels in erythrocytes, one might assume that, by increasing the plasma S1P level, the hemolysis of red blood cells would induce mobilization of HSPCs. To test this assumption, we induced hemolysis in mice by employing phenylhydrazine (PHZ). We observed that doubling the S1P level in PB from damaged erythrocytes induced only a marginally increased level of mobilization. However, if mice were exposed to PHZ together with the …

Inflammatory Cytokine Gene Expression In Mesenteric Adipose Tissue During Acute Experimental Colitis, William Conan Mustain, Marlene E. Starr, Joseph Daniel Valentino, Donald A. Cohen, Daiki Okamura, Chi Wang, B. Mark Evers, Hiroshi Saito

Markey Cancer Center Faculty Publications

BACKGROUND: Production of inflammatory cytokines by mesenteric adipose tissue (MAT) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Animal models of colitis have demonstrated inflammatory changes within MAT, but it is unclear if these changes occur in isolation or as part of a systemic adipose tissue response. It is also unknown what cell types are responsible for cytokine production within MAT. The present study was designed to determine whether cytokine production by MAT during experimental colitis is depot-specific, and also to identify the source of cytokine production within MAT.

METHODS: Experimental colitis was induced in 6-month-old C57BL/6 …

Transvaginal Ultrasonography In Ovarian Cancer Screening: Current Perspectives, John R. Van Nagell Jr., John T. Hoff

Obstetrics and Gynecology Faculty Publications

Transvaginal ultrasonography (TVS) is an integral part of all major ovarian cancer screening trials. TVS is accurate in detecting abnormalities in ovarian volume and morphology, but is less reliable in differentiating benign from malignant ovarian tumors. When used as the only screening test, TVS is sensitive, but has a low positive predictive value. Therefore, serum biomarkers and tumor morphology indexing are used together with TVS to identify ovarian tumors at high risk for malignancy. This allows preoperative triage of high-risk cases to major cancer centers for therapy while decreasing unnecessary surgery for benign disease. Ovarian cancer screening has been associated …

Self-Reported Juvenile Firesetting: Results From Two National Survey Datasets, Carrie Howell Bowling, Joav Merrick, Hatim A. Omar

Pediatrics Faculty Publications

The main purpose of this study was to address gaps in existing research by examining the relationship between academic performance and attention problems with juvenile firesetting. Two datasets from the Achenbach System for Empirically Based Assessment (ASEBA) were used. The Factor Analysis Dataset (N = 975) was utilized and results indicated that adolescents who report lower academic performance are more likely to set fires. Additionally, adolescents who report a poor attitude toward school are even more likely to set fires. Results also indicated that attention problems are predictive of self-reported firesetting. The National Survey Dataset (N = 1158) …

Can Experienced Observers Differentiate Between Lipoma And Well-Differentiated Liposarcoma Using Only Mri?, Patrick W. O'Donnell, Anthony M. Griffin, William C. Eward, Amir Sternheim, Lawrence M. White, Jay S. Wunder, Peter C. Ferguson

Markey Cancer Center Faculty Publications

Well-differentiated liposarcoma represents a radiographic diagnostic dilemma. To determine the accuracy, interrater reliability, and relationship of stranding, nodularity, and size in the MRI differentiation of lipoma and well-differentiated liposarcoma, MRI scans of 60 patients with large (>5 cm), deep, pathologically proven lipomas or well-differentiated liposarcomas were examined by 10 observers with subspecialty training blinded to diagnosis. Observers indicated whether the amount of stranding, nodularity, and size of each tumor suggested a benign or malignant diagnosis and rendered a diagnosis of lipoma or well-differentiated liposarcoma. The accuracy, reliability, and relationship of stranding, nodularity, and size to diagnosis were calculated for …

Examining The Claim That 80-90% Of Suicide Cases Had Depression, Said Shahtahmasebi

Pediatrics Faculty Publications

No abstract provided.

Clinically Relevant Intronic Splicing Enhancer Mutation In Myelin Proteolipid Protein Leads To Progressive Microglia And Astrocyte Activation In White And Gray Matter Regions Of The Brain, Adam D. Bachstetter, Scott J. Webster, Linda J. Van Eldik, Franca Cambi

Sanders-Brown Center on Aging Faculty Publications

INTRODUCTION: Mutations in proteolipid protein (PLP), the most abundant myelin protein in the CNS, cause the X-linked dysmyelinating leukodystrophies, Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2). Point mutations, deletion, and duplication of the PLP1 gene cause PMD/SPG2 with varying clinical presentation. Deletion of an intronic splicing enhancer (ISEdel) within intron 3 of the PLP1 gene is associated with a mild form of PMD. Clinical and preclinical studies have indicated that mutations in myelin proteins, including PLP, can induce neuroinflammation, but the temporal and spatial onset of the reactive glia response in a clinically relevant mild form of PMD …

Dopaminergic Modulation Of Memory And Affective Processing In Parkinson Depression, Lee X. Blonder, John T. Slevin, Richard J. Kryscio, Catherine A. Martin, Anders H. Andersen, Charles D Smith, Frederick A. Schmitt

Magnetic Resonance Imaging and Spectroscopy Center Faculty Publications

Depression is common in Parkinson's disease and is associated with cognitive impairment. Dopaminergic medications are effective in treating the motor symptoms of Parkinson's disease; however, little is known regarding the effects of dopaminergic pharmacotherapy on cognitive function in depressed Parkinson patients. This study examines the neuropsychological effects of dopaminergic pharmacotherapy in Parkinsonian depression. We compared cognitive function in depressed and non-depressed Parkinson patients at two time-points: following overnight withdrawal and after the usual morning regimen of dopaminergic medications. A total of 28 non-demented, right-handed patients with mild to moderate idiopathic Parkinson's disease participated. Ten of these patients were depressed according …

Ccr3 Inhibition For Ocular Angiogenesis And Macular Degeneration, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Patents

Provided are methods and compositions for the treatment or prevention of ocular angiogenesis and neovascularization. Administration of inhibitors of the CCR3 receptor or its ligands eotaxin (CCL11), eotaxin-2 (CCL24) or eotaxin-3 (CCL26) inhibits ocular angiogenesis.

Amlodipine Reduces Angii-Induced Aortic Aneurysms And Atherosclerosis In Hypercholesterolemic Mice, Xiaofeng Chen, Debra L. Rateri, Deborah A. Howatt, Anju Balakrishnan, Jessica J. Moorleghen, Andrew J. Morris, Richard Charnigo, Lisa A. Cassis, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: The purpose of this study was to determine effects of amlodipine, a dihydropyridine calcium channel blocker, on development of angiotensin II (AngII)-induced vascular pathologies.

METHODS AND RESULTS: Male LDL receptor -/- mice were infused with vehicle, amlodipine (5 mg/kg/d), AngII (1,000 ng/kg/min), or AngII + amlodipine for 4 weeks through osmotic pumps (n=10/group). Mice were fed a saturated fat-enriched diet for 1 week prior to pump implantation and during 4 weeks of infusion. Infusion of amlodipine resulted in plasma concentrations of 32 ± 2 ng/ml and 27 ± 2 ng/ml for mice in saline + amlodipine and AngII + …

Hrs Promotes Ubiquitination And Mediates Endosomal Trafficking Of Smoothened In Drosophila Hedgehog Signaling, Jun-Kai Fan, Kai Jiang, Yajuan Liu, Jianhang Jia

Markey Cancer Center Faculty Publications

In Hedgehog (Hh) signaling, the seven-transmembrane protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation, ubiquitination, and cell surface accumulation. However, it is not clear how Smo cell surface accumulation and intracellular trafficking are regulated. Here, we demonstrate that inactivation of Hrs by deletion or RNAi accumulates Smo in the late endosome that is marked by late endosome markers. Inactivation of Hrs enhances the wing defects caused by dominant-negative Smo. We show that Hrs promotes Smo ubiquitination, deleting the ubiquitin-interacting-motif (UIM) in Hrs abolishes the ability of Hrs to regulate Smo ubiquitination. However, the UIM domain …

Nfkb Disrupts Tissue Polarity In 3d By Preventing Integration Of Microenvironmental Signals, Sabine Becker-Weimann, Gaofeng Xiong, Saori Furuta, Ju Han, Irene Kuhn, Uri-David Akavia, Dana Pe'er, Mina J. Bissell, Ren Xu

Markey Cancer Center Faculty Publications

The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant …

Lpa, Hgf, And Egf Utilize Distinct Combinations Of Signaling Pathways To Promote Migration And Invasion Of Mda-Mb-231 Breast Carcinoma Cells, Susan M. W. Harrison, Teresa Knifley, Min Chen, Kathleen L. O'Connor

Markey Cancer Center Faculty Publications

BACKGROUND: Various pathways impinge on the actin-myosin pathway to facilitate cell migration and invasion including members of the Rho family of small GTPases and MAPK. However, the signaling components that are considered important for these processes vary substantially within the literature with certain pathways being favored. These distinctions in signaling pathways utilized are often attributed to differences in cell type or physiological conditions; however, these attributes have not been systematically assessed.

METHODS: To address this question, we analyzed the migration and invasion of MDA-MB-231 breast carcinoma cell line in response to various stimuli including lysophosphatidic acid (LPA), hepatocyte growth factor …

New Oral Anticoagulants Are Not Superior To Warfarin In Secondary Prevention Of Stroke Or Transient Ischemic Attacks, But Lower The Risk Of Intracranial Bleeding: Insights From A Meta-Analysis And Indirect Treatment Comparisons, Partha Sardar, Saurav Chatterjee, Wen-Chih Wu, Edgar Lichstein, Joydeep Ghosh, Shamik Aikat, Debabrata Mukherjee

Internal Medicine Faculty Publications

PURPOSE: Patients with Atrial Fibrillation (AF) and prior stroke are classified as high risk in all risk stratification schemes. A systematic review and meta-analysis was performed to compare the efficacy and safety of New Oral Anticoagulants (NOACs) to warfarin in patients with AF and previous stroke or transient ischemic attack (TIA).

METHODS: Three randomized controlled trials (RCTs), including total 14527 patients, comparing NOACs (apixaban, dabigatran and rivaroxaban) with warfarin were included in the analysis. Primary efficacy endpoint was ischemic stroke, and primary safety endpoint was intracranial bleeding. Random-effects models were used to pool efficacy and safety data across RCTs. RevMan …

Autonomic Nervous System Function Following Prenatal Opiate Exposure, Matthew Todd Hambleton, Eric W. Reynolds, Thitinart Sithisarn, Stuart J. Traxel, Abhijit R. Patwardhan, Timothy N. Crawford, Marta S. Mendiondo, Henrietta S. Bada

Pediatrics Faculty Publications

In utero exposure to opiates may affect autonomic functioning of the fetus and newborn. We investigated heart rate variability (HRV) as a measure of autonomic stability in prenatal opiate-exposed neonates (n = 14) and in control term infants (n = 10). Electrocardiographic data during both non-nutritive and nutritive sucking were evaluated for RR intervals, heart rate (HR), standard deviation of the consecutive RR intervals (SDRR), standard deviation of the differences of consecutive RR intervals (SDDRR), and the power spectral densities in low and high frequency bands. In controls, mean HR increased significantly, 143-161 per min (p = …

Marijuana: Current Concepts, Donald E. Greydanus, Elizabeth K. Hawver, Megan M. Greydanus, Joav Merrick

Pediatrics Faculty Publications

Marijuana (cannabis) remains a controversial drug in the twenty-first century. This paper considers current research on use of Cannabis sativa and its constituents such as the cannabinoids. Topics reviewed include prevalence of cannabis (pot) use, other drugs consumed with pot, the endocannabinoid system, use of medicinal marijuana, medical adverse effects of cannabis, and psychiatric adverse effects of cannabis use. Treatment of cannabis withdrawal and dependence is difficult and remains mainly based on psychological therapy; current research on pharmacologic management of problems related to cannabis consumption is also considered. The potential role of specific cannabinoids for medical benefit will be revealed …

Firesetting In Childhood And Adolescence, Joav Merrick, Carrie Howell Bowling, Hatim A. Omar

Pediatrics Faculty Publications

Fire is the rapid oxidation of a material in the exothermic chemical process of combustion, releasing heat, light, and various reaction products. Fire is intriguing and therefore something that will attract a curious child from an early age.

In 2010, the United States fire department responded to 44,900 fires started by someone, usually a child, playing with fire. These fires caused 90 civilian deaths, 890 civilian injuries, and $210 million in direct property damage. Preschoolers and kindergartners are most likely to start these fires, while playing with matches or lighters and most likely to die in these fires. Most fire-play …

Human Sexuality And Adolescence, Joav Merrick, Ariel Tenenbaum, Hatim A. Omar

Pediatrics Faculty Publications

No abstract provided.

Retinal Angiogenesis Suppression Through Small Molecule Activation Of P53, Sai H. Chavala, Younghee Kim, Laura Tudisco, Valeria Cicatiello, Till Milde, Nagaraj Kerur, Nidia Claros, Susan Yanni, Victor H. Guaiquil, William W. Hauswirth, John S. Penn, Shahin Rafii, Sandro De Falco, Thomas C. Lee, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Publications

Neovascular age-related macular degeneration is a leading cause of irreversible vision loss in the Western world. Cytokine-targeted therapies (such as anti-vascular endothelial growth factor) are effective in treating pathologic ocular angiogenesis, but have not led to a durable effect and often require indefinite treatment. Here, we show that Nutlin-3, a small molecule antagonist of the E3 ubiquitin protein ligase MDM2, inhibited angiogenesis in several model systems. We found that a functional p53 pathway was essential for Nutlin-3-mediated retinal antiangiogenesis and disruption of the p53 transcriptional network abolished the antiangiogenic activity of Nutlin-3. Nutlin-3 did not inhibit established, mature blood vessels …

Adolescence, Violence, And Public Health, Joav Merrick, Isack Kandel, Hatim A. Omar

Pediatrics Faculty Publications

No abstract provided.

Molecular Signatures In Urologic Tumors, Spencer Larkin, Natasha Kyprianou

Surgery Faculty Publications

Urologic tumors continue to represent a huge fraction of cancer cases in the United States, with over 376,310 estimated new diagnoses in 2013. As with many types of tumors, urologic tumors vary greatly in their phenotype, ranging from minimally invasive to malignancies possessing great metastatic potential. The increasing need for more efficient and less invasive methods of cancer detection, as well as the ability to predict severity of the disease phenotype is readily evident--yet reliable methods remain elusive in a clinical setting today. Comprehensive panels of gene clusters are being developed toward the generation of molecular signatures in order to …

Circulating Micrornas In Alzheimer's Disease: The Search For Novel Biomarkers, Véronique Dorval, Peter T. Nelson, Sébastien S. Hébert

Sanders-Brown Center on Aging Faculty Publications

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. While advancements have been made in understanding the genetic and molecular basis of AD, the clinical diagnosis of AD remains difficult, and post-mortem confirmation is often required. Furthermore, the onset of neurodegeneration precedes clinical symptoms by approximately a decade. Consequently, there is a crucial need for an early and accurate diagnosis of AD, which can potentially lead to strategies that can slow down or stop the progression of neurodegeneration and dementia. Recent advances in the non-coding RNA field have shown that microRNAs (miRNAs) can function as powerful biomarkers …

Reproducibility Of Cine Displacement Encoding With Stimulated Echoes (Dense) Cardiovascular Magnetic Resonance For Measuring Left Ventricular Strains, Torsion, And Synchrony In Mice, Christopher M. Haggerty, Sage P. Kramer, Cassi M. Binkley, David K. Powell, Andrea C. Mattingly, Richard Charnigo, Frederick H. Epstein, Brandon K. Fornwalt

Pediatrics Faculty Publications

BACKGROUND: Advanced measures of cardiac function are increasingly important to clinical assessment due to their superior diagnostic and predictive capabilities. Cine DENSE cardiovascular magnetic resonance (CMR) is ideal for quantifying advanced measures of cardiac function based on its high spatial resolution and streamlined post-processing. While many studies have utilized cine DENSE in both humans and small-animal models, the inter-test and inter-observer reproducibility for quantification of advanced cardiac function in mice has not been evaluated. This represents a critical knowledge gap for both understanding the capabilities of this technique and for the design of future experiments. We hypothesized that cine DENSE …

A Survey Of The Barriers Associated With Academic-Based Cancer Research Commercialization, Nathan L. Vanderford, L. Todd Weiss, Heidi L. Weiss

Markey Cancer Center Faculty Publications

Commercialization within the academic setting is associated with many challenges and barriers. Previous studies investigating these challenges/barriers have, in general, broadly focused on multiple disciplines and, oftentimes, several institutions simultaneously. The goal of the study presented here was to analyze a range of barriers that may be broadly associated with commercializing academic-based cancer research. This goal was addressed via a study of the barriers associated with cancer research commercialization at the University of Kentucky (UK). To this end, a research instrument in the form of an electronic survey was developed. General demographic information was collected on study participants and two …

Positive Youth Development, Life Satisfaction, And Problem Behaviors Of Adolescents In Intact And Non-Intact Families In Hong Kong, Daniel T. L. Shek, Hildie Leung

Pediatrics Faculty Publications

This study investigated whether Chinese adolescents living in intact and non-intact families differed in their positive development, life satisfaction, and risk behavior. A total of 3,328 Secondary 1 students responded to measures of positive youth development (such as resilience and psychosocial competencies), life satisfaction, and risk behavior (substance abuse, delinquency, Internet addiction, consumption of pornographic materials, self-harm, and behavioral intention to engage in problem behavior). Findings revealed that adolescents growing up in intact families reported higher levels of positive developmental outcomes and life satisfaction as compared with adolescents from non-intact families. Adolescents in non-intact families also reported higher levels of …

Calpain-2 Compensation Promotes Angiotensin Ii-Induced Ascending And Abdominal Aortic Aneurysms In Calpain-1 Deficient Mice, Venkateswaran Subramanian, Jessica J. Moorleghen, Anju Balakrishnan, Deborah A. Howatt, Athar H. Chishti, Haruhito A. Uchida

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND AND OBJECTIVE: Recently, we demonstrated that angiotensin II (AngII)-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA) in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2) in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, …

Dose- And Time-Dependent Neuroprotective Effects Of Pycnogenol® Following Traumatic Brain Injury, Mubeen A. Ansari, Kelly N. Roberts, Stephen W. Scheff

Sanders-Brown Center on Aging Faculty Publications

After traumatic brain injury (TBI), both primary and secondary injury cascades are initiated, leading to neuronal death and cognitive dysfunction. We have previously shown that the combinational bioflavonoid, Pycnogenol® (PYC), alters some secondary injury cascades and protects synaptic proteins when administered immediately following trauma. The purpose of the present study was to explore further the beneficial effects of PYC and to test whether it can be used in a more clinically relevant fashion. Young adult male Sprague-Dawley rats were subjected to a unilateral moderate/severe cortical contusion. Subjects received a single intravenous (i.v.) injection of PYC (1, 5, or 10 mg/kg) …

Coupling S100a4 To Rhotekin Alters Rho Signaling Output In Breast Cancer Cells, Min Chen, Anne R. Bresnick, Kathleen L. O'Connor

Markey Cancer Center Faculty Publications

Rho signaling is increasingly recognized to contribute to invasion and metastasis. In this study, we discovered that metastasis-associated protein S100A4 interacts with the Rho-binding domain (RBD) of Rhotekin, thus connecting S100A4 to the Rho pathway. Glutathione S-transferase pull-down and immunoprecipitation assays demonstrated that S100A4 specifically and directly binds to Rhotekin RBD, but not the other Rho effector RBDs. S100A4 binding to Rhotekin is calcium-dependent and uses residues distinct from those bound by active Rho. Interestingly, we found that S100A4 and Rhotekin can form a complex with active RhoA. Using RNA interference, we determined that suppression of both S100A4 and …

Targeting Platelet Thrombin Receptor Signaling To Prevent Thrombosis, Eric L. Wallace, Susan S. Smyth

Gill Heart & Vascular Institute Faculty Publications

Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more comprehensive antithrombotic effects. We review the pathophysiology of atherothrombosis, platelet activation by thrombin, the role of platelet protease activated receptors (PAR), and the clinical data supporting their use.