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Noninvasive Assessment Of Cardiac Abnormalities In Experimental Autoimmune Myocarditis By Magnetic Resonance Microscopy Imaging In The Mouse, Chandirasegara Massilamany, Vahid Khalilzad-Sharghi, Arunakumar Gangaplara, David Steffen, Shadi F. Othman, Jay Reddy

School of Veterinary and Biomedical Sciences: Faculty Publications

Myocarditis is an inflammation of the myocardium, but only ~10% of those affected show clinical manifestations of the disease. To study the immune events of myocardial injuries, various mouse models of myocarditis have been widely used. This study involved experimental autoimmune myocarditis (EAM) induced with cardiac myosin heavy chain (Myhc)-α 334-352 in A/J mice; the affected animals develop lymphocytic myocarditis but with no apparent clinical signs. In this model, the utility of magnetic resonance microscopy (MRM) as a non-invasive modality to determine the cardiac structural and functional changes in animals immunized with Myhc-α 334-352 is shown. EAM and healthy mice …

Intricacies Of Cardiac Damage In Coxsackievirus B3 Infection: Implications For Therapy, Chandirasegara Massilamany, Arunakumar Gangaplara, Jay Reddy

School of Veterinary and Biomedical Sciences: Faculty Publications

Heart disease is the leading cause of death in humans, and myocarditis is one predominant cause of heart failure in young adults. Patients affected with myocarditis can develop dilated cardiomyopathy (DCM), a common reason for heart transplantation, which to date is the only viable option for combatting DCM. Myocarditis/DCM patients show antibodies to coxsackievirus B (CVB)3 and cardiac antigens, suggesting a role for CVB-mediated autoimmunity in the disease pathogenesis; however, a direct causal link remains to be determined clinically. Experimentally, myocarditis can be induced in susceptible strains of mice using the human isolates of CVB3, and the disease pathogenesis of …

Direct Staining With Major Histocompatibility Complex Class Ii Dextramers Permits Detection Of Antigen- Specific, Autoreactive Cd4 T Cells In Situ, Chandirasegaran Massilamany, Arunakumar Gangaplara, Ting Jia, Christian Elowsky, Guobin Kang, Jean-Jack Riethoven, Qingsheng Li, You Zhou, Jay Reddy

School of Veterinary and Biomedical Sciences: Faculty Publications

We report here the utility of major histocompatibility complex (MHC) class II dextramers for in situ detection of self-reactive CD4 T cells in two target organs, the brain and heart. We optimized the conditions for in situ detection of antigen-specific CD4 T cells using brain sections obtained from SJL mice immunized with myelin proteolipid protein (PLP) 139–151; the sections were costained with IA^s/PLP 139–151 (specific) or Theiler’s murine encephalomyelitis virus (TMEV) 70–86 (control) dextramers and anti-CD4. Analysis of sections by laser scanning confocal microscope revealed detection of cells positive for PLP 139–151 but not for TMEV 70–86 dextramers …

Influence Of Iron And Aeration On Staphylococcus Aureus Growth, Metabolism, And Transcription, Nagender Ledala, Bo Zhang, Javier Seravalli, Robert Powers, Greg Somerville

School of Veterinary and Biomedical Sciences: Faculty Publications

Staphylococcus aureus is a prominent nosocomial pathogen and a major cause of biomaterial-associated infections. The success of S. aureus as a pathogen is due in part to its ability to adapt to stressful environments. As an example, the transition from residing in the nares to residing in the blood or deeper tissues is accompanied by changes in the availability of nutrients and elements such as oxygen and iron. As such, nutrients, oxygen, and iron are important determinants of virulence factor synthesis in S. aureus. In addition to influencing virulence factor synthesis, oxygen and iron are critical cofactors in enzymatic and …

Sjl Mice Infected With Acanthamoeba Castellanii Develop Central Nervous System Autoimmunity Through The Generation Of Cross-Reactive T Cells For Myelin Antigens, Jay Reddy, Chandirasegaran Massilamany, Francine Marciano-Cabral, Bruno Da Rocha-Azevedo, Melissa Jamerson, Arunakumar Gangaplara, David Steffen, Rana Zabad, Zsolt Illes, Raymond Sobel

School of Veterinary and Biomedical Sciences: Faculty Publications

We recently reported that Acanthamoeba castellanii (ACA), an opportunistic pathogen of the central nervous system (CNS) possesses mimicry epitopes for proteolipid protein (PLP) 139–151 and myelin basic protein 89–101, and that the epitopes induce experimental autoimmune encephalomyelitis (EAE) in SJL mice reminiscent of the diseases induced with their corresponding cognate peptides. We now demonstrate that mice infected with ACA also show the generation of crossreactive T cells, predominantly for PLP 139–151, as evaluated by T cell proliferation and IAs/dextramer staining. We verified that PLP 139–151-sensitized lymphocytes generated in infected mice contained a high proportion of T helper 1 cytokineproducing cells, …

Using Quantitative Disease Dynamics As A Tool For Guiding Response To Avian Influenza In Poultry In The United States Of America, K. M. Pepin, E. Spackman, J. D. Brown, K. L. Pabilonia, Lindsey P. Garber, J. Todd Weaver, D. A. Kennedy, Kelly A. Patyk, K. P. Huyvaert, Ryan S. Miller, Alan B. Franklin, Kerri Pedersen, T. L. Bogich, P. Rohani, Susan A. Shriner, Colleen T. Webb, S. Riley

United States Department of Agriculture Wildlife Services: Staff Publications

Wild birds are the primary source of genetic diversity for influenza A viruses that eventually emerge in poultry and humans. Much progress has been made in the descriptive ecology of avian influenza viruses (AIVs), but contributions are less evident from quantitative studies (e.g., those including disease dynamic models). Transmission between host species, individuals and flocks has not been measured with sufficient accuracy to allow robust quantitative evaluation of alternate control protocols. We focused on the United States of America (USA) as a case study for determining the state of our quantitative knowledge of potential AIV emergence processes from wild hosts …

Endocannabinoid Involvement In Impulsivity And Decision-Making, Christopher P. Norris

Theses and Dissertations (Comprehensive)

Problem gambling is a widespread phenomenon with a prevalence estimate of 2.3% globally (Williams, Volberg, & Stevens, 2012). Although little is known about the neurochemistry underlying this pathological behaviour, evidence suggests that dysregulation of the brain’s endocannabinoid (eCB) system may be implicated in impulsivity and decision-making. For example, chronic cannabis users exhibit impulsive behaviour and impaired decision-making on the Iowa Gambling Task (IGT). The present study sought to further examine the role of the eCB system in problem gambling-related decision-making in laboratory rats using the five-choice serial reaction time task (5-CSRTT), and a recently-developed rodent analogue of the IGT called …

Fluid Flow Shear Stress Over Podocytes Is Increased In The Solitary Kidney., Tarak Srivastava, Gianni E. Celsi, Mukut Sharma, Hongying Dai, Ellen T. Mccarthy, Melanie Ruiz, Patricia A. Cudmore, Uri S. Alon, Ram Sharma, Virginia A. Savin

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Glomerular hyperfiltration is emerging as the key risk factor for progression of chronic kidney disease (CKD). Podocytes are exposed to fluid flow shear stress (FFSS) caused by the flow of ultrafiltrate within Bowman's space. The mechanism of hyperfiltration-induced podocyte injury is not clear. We postulated that glomerular hyperfiltration in solitary kidney increases FFSS over podocytes.

METHODS: Infant Sprague-Dawley rats at 5 days of age and C57BL/6J 14-week-old adult mice underwent unilateral nephrectomy. Micropuncture and morphological studies were then performed on 20- and 60-day-old rats. FFSS over podocytes in uninephrectomized rats and mice was calculated using the recently published equation …

Clinical Manifestations, Complications, And Treatment Of Brucellosis: Evaluation Of 72 Cases, Şükran Köse, Süheyla Seri̇n Senger, Gülgün Akkoçlu, Lütfi̇ye Kuzucu, Yildiz Ulu, Gürsel Ersan, Fi̇li̇z Oğuz

Turkish Journal of Medical Sciences

Brucellosis is an important disease in developing countries. We aimed to determine the epidemiologic, clinical, and laboratory characteristics of brucellosis, which still has a high morbidity in Turkey. Materials and methods: Seventy-two patients with brucellosis, monitored at our clinic from January 2004 to July 2010, were reviewed retrospectively. Results: The average age was determined to be 44.8 ± 18 years, and 40 of the patients were female (55.6%). The most frequent transmission route was the use of raw milk and dairy products, in 45 of the patients (62.5%). The most frequent complaints were joint pain, high fever, weakness, low back …

Efficacy Of Resuscitation With Intralipid In A Levobupivacaine-Induced Cardiac Arrest Model, Murat Karcioğlu, Kasim Tuzcu, Fati̇h Sefi̇l, Işil Davarci, Suzan Aydin, Ali̇ Sari, Akin Aydoğan, Rai̇f Özden

Turkish Journal of Medical Sciences

Cardiac toxicity due to the administration of local anesthetics may be fatal. In this study, we evaluated the efficacy of a 20% lipid solution combined with epinephrine in a levobupivacaine-induced cardiac arrest model. Materials and methods: A total of 14 New Zealand rabbits were sedated and mechanically ventilated. Asystole was induced with intravenous levobupivacaine injection. The rabbits were randomized into groups receiving the same volume of either 0.9% saline (CR group) or a 20% lipid solution (LE group) along with a 100 µg/kg epinephrine bolus, which were administered immediately upon asystole. Standard advanced cardiac life support protocols were performed. Results: …

Immunohistochemical Investigation Of Galectin-3 In The Skin Of Mice Applied With Origanum Hypericifolium Essential Oil And Irradiated With Ultraviolet B, Pinar İli̇, Nazan Keski̇n

Turkish Journal of Medical Sciences

To demonstrate galectin-3-immunoreactivity in the undiluted essential oil of Origanum hypericifolium when applied to the ultraviolet B (UVB) irradiated skin of mice. Materials and methods: Female BALB/c mice were allocated to 4 groups, each comprising 6 mice (Group 1: control; Group 2: UVB irradiated control; Group 3: undiluted O. hypericifolium essential oil applied; Group 4: undiluted O. hypericifolium essential oil applied before UVB irradiation). One week prior to UVB irradiation, the undiluted O. hypericifolium essential oil was applied to the shaved dorsal skin of mice 3 times a week. Subsequently, the mice were irradiated 3 times per week with UVB …

Effects Of Linoleic Acid On Generalized Convulsive And Nonconvulsive Epileptic Seizures, Fati̇h Eki̇ci̇, Gönül Gürol, Nurbay Ateş

Turkish Journal of Medical Sciences

To comparatively investigate the effects of linoleic acid on convulsive and nonconvulsive epileptic seizures. Materials and methods: Rats were divided into 3 groups: convulsive epileptic rats receiving only pentylentetrazole (PTZ) injections (group 1), convulsive epileptic rats receiving PTZ and linoleic acid (group 2), and Wistar Albino Glaxo rats from Rijswijk with genetic absence epilepsy receiving linoleic acid (group 3). The duration and severity of convulsive activity were determined in groups in which convulsive seizures were induced by PTZ. In group 3, intravenous linoleic acid was administered after 1-h baseline electroencephalography (EEG) recordings. The EEG recordings were analyzed. Results: When groups …

Actions Of Grape Seed Extract In Rodent Brain And Differences In Metabolism Of Its Polyphenols In A Rodent Model Of Menopause, John Kenneth Cutts

All ETDs from UAB

Grape seed extract (GSE), a dietary supplement, has potential in the treatment and prevention of human chronic age-related diseases including cancers, cardiovascular diseases, and neurodegenerative diseases. GSE and adult hippocampal neurogenesis, independently, have enhanced learning and memory in rodents. We hypothesized that GSE enhances learning and memory, at least partially, by enhancing hippocampal neurogenesis. However, adult mice given GSE did not exhibit increased number of progenitor cells or new neurons, established markers of neurogenesis, in the dentate gyrus (DG). Also, 26-day-old pups whose mother was given GSE only while nursing had fewer new neurons in the DG compared to control …

Targeting Tau-Mediated Nmdar Hypofunction Reverses Deficits In A Mouse Model Of Frontotemporal Dementia, Brian Andrew Warmus

All ETDs from UAB

Frontotemporal dementia (FTD) is a rapidly progressive and lethal disease, with no disease-modifying treatments. It is known that tau mutations cause FTD, but the underlying neurobiology is undefined. We sought to identify how tau affects the neurobiology in order to find potential treatment targets. Here, we address this question using a new mouse model expressing human tau with an FTD-associated mutation. We studied behavior, physiology, biochemistry, and neuropathology in several cohorts of mice at different ages. These mutant tau mice had abnormal repetitive behavior characteristic of FTD and synaptic deficits selectively in regions associated with FTD (ventral striatum and insula). …

Modulation Of Neocortical Gabaergic Interneurons By Voltage-Gated Ion Channels, Sidney B. Williams

All ETDs from UAB

GABAergic interneurons provide the main source of inhibition in the neocortex and are important in regulating neocortical network activity. In the presence of the K+ channel blocker 4-AP and the glutamate receptor blockers, CNQX and D-APV, large amplitude evoked and spontaneous depolarizing responses are observed in the neocortex. These large propagating responses are blocked by GABAA receptor antagonists indicating that these events are due to synchronized activity of GABAergic interneurons. Cortical GABAergic networks are comprised of several types of interneurons, each with its own protein expression pattern, receptor profile, firing properties, synaptic targets and role in network activity. Voltage-gated ion …

Copper Homeostasis In Mycobacteria, Jennifer L. Rowland

All ETDs from UAB

Mycobacterium tuberculosis, the causative agent on tuberculosis in humans, is a globally important pathogen. In 2013, nearly 1.2 million people died from tuberculosis. Drug treatments and effective vaccines are lacking for this pathogen. A better understanding of the basic physiology of M. tuberculosis is required to improve disease outcomes. Upon inhalation into the lungs, M. tuberculosis is taken up by macrophages, in a process called phagocytosis, which normally destroys invading bacteria. As the phagosome inside the macrophage matures, bactericidal mechanisms are activated including: lowering pH, and introducing reactive oxygen and nitrogen species and hydrolytic enzymes to degrade bacterial cell walls. …

Rhodopsin As A Model For Gpcr Trafficking And Its Role In Outer Segment Formation, Joshua D. Sammons

All ETDs from UAB

Rhodopsin is a prototypical G-protein coupled receptor whose biological function has been well worked out, yet little is known about the mechanism by which it is so efficiently transported to the rod outer segment (ROS) after synthesis. If rhodopsin is not efficiently transported to the ROS, rod cells will apoptose leading to cone cell apoptosis as well which results in the blinding disease retinitis pigmentosa. Work has begun to elucidate proteins responsible for transporting rhodopsin to the ROS using Xenopus laevis as a model since the photoreceptors of this amphibian are large and transgenic animals are relatively easy to prepare. …

Protein O-Glcnac Modification In Diabetic Vascular Calcification, Jack Heath

All ETDs from UAB

Vascular calcification is prevalent in patients of diabetes mellitus, which represents an independent risk factor that positively correlated with morbidity and mortality in these patients. Vascular calcification is now recognized as a cell-regulated process of osteogenic differentiation of vascular smooth muscle cells (VSMC) in response to stress, such as hyperglycemia and oxidative stress. Both hyperglycemia and oxidative stress have been shown to induce protein modification by O-linked ß-N-acetylglucosamine modification (O-GlcNAcylation), which is also elevated in diabetes. The present studies aimed to determine the effects of protein O-GlcNAcylation on vascular calcification in diabetes, and uncover the underlying molecular mechanisms. With the …

The Expression And Function Of Icam-2 In Neuroblastoma, Joseph Feduska

All ETDs from UAB

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for 15% of all childhood cancer deaths. At the time of initial diagnosis, the majority of patients present with NB that has already metastasized. While initial remission is often achieved following treatment, roughly 50% of these patients will relapse and die from the development of intractable metastatic progression. Intercellular adhesion molecule-2 (ICAM-2) is a transmembrane glycoprotein, normally expressed only in endothelial cells and subsets of leukocytes. ICAM-2 expression in cancer cells had not been previously investigated, until our lab recently reported the novel finding of endogenous ICAM-2 expression …

Evidence Of Altered Ampa Receptor Localization And Regulation In Schizophrenia, Jana Drummond

All ETDs from UAB

Although the glutamate hypothesis of schizophrenia posits altered glutamatergic transmission is occurring in this illness, the precise mechanisms be-hind these proposed changes in schizophrenia brain remain elusive. Recent evidence from our laboratory supports a model of altered forward trafficking of glutamate receptors to synaptic membranes in schizophrenia, which could contribute to changes in neurotransmission. The AMPA subtype of ionotropic glutamate receptor (AMPAR), is the main facilitator of fast, excitatory neurotransmission in the brain, and changes in AMPAR number at synapses may control synaptic strength and plasticity. One mechanism that could alter AMPAR trafficking to synapses is abnormal expression of AMPAR …

Elucidating The Role Of Gsk3 In Synaptic And Cognitive Deficits In Fragile X Syndrome, Aimee Vinson Franklin

All ETDs from UAB

Fragile X Syndrome (FX) is the most common inherited form of mental retarda-tion. Prominent characteristics of FX are mimicked in a mouse model with deleted fmr1 including hyperactivity, anxiety, developmental delay and social deficits. Additionally, FX mice display deficits in n-methyl-d-aspartate receptor (NMDAR) dependent long-term potentiation (LTP) at medial perforant path synapses onto dentate granule cells (MPP-DGC synapses). Because LTP is a cellular correlate of learning and memory, defi-cits in LTP at this synapse are thought to underlie impairments in pattern separation, a form of learning and memory dependent on proper DG function. Identifying the patho-logical mechanisms that cause impaired …

Tumorgraft Models As A Platform For Molecular Characterization And Drug Evaluation In Pancreaticobiliary Malignancies, Patrick Lee Garcia

All ETDs from UAB

arribada nesting behavior. The first chapter addresses the potential effects of a nest’s

Innate Immune Defense Against The Fungal Pathogen Aspergillus Fumigatus, Melissa Ann Gessner

All ETDs from UAB

The opportunistic fungal pathogen Aspergillus fumigatus is a ubiquitous mold that causes severe, invasive life-threatening infections in patients that are severely immunocompromised. Major risk factors include neutropenia, neutrophil dysfunction and immunosuppressive therapies. Recently, however, rising incidences of colonizing A. fumigatus have been reported in patients without classical risk factors. We sought out to elucidate non-classical pre-disposing conditions that may render a lung environment susceptible to fungal colonization as well as mechanisms involved in immune defense against the invading fungal pathogen. Further defining a role for Dectin-1 in an Aspergillus fumigatus infection, we demonstrated a critical role for Dectin-1 dependent interleukin-22 …

The Role Of Il-7 And C-Kit Signaling Pathways In Specification Of B Lymphocytes, Oleg Kolupaev

All ETDs from UAB

B-lymphocyte commitment from common lymphoid progenitors (CLP) is orchestrated by a number of transcription factors and extracellular developmental cues. Most prominently, IL-7 signaling acts as a critical factor for promotion of B cell differentiation through its role in upregulation of the B-cell commitment factor, Ebf1, by activation of Jak-Stat5 signaling. Other cytokines and growth factors secreted by bone marrow stromal cells, such as Flt3 ligand, are known to modulate developmental outcomes by regulating the IL-7R-Jak-Stat5 pathway. The role of stem cell factor (SCF), the ligand of the receptor tyrosine kinase (RTK) c-Kit, and the mechanism by which it affects cell …

Osteomimmunology Of Bone Fracture Healing And Cell And Gene Therapy Approaches For Nonunion Bone Defects, Seth G. Levy

All ETDs from UAB

Despite the body's ability to repair bone fractures under normal circumstances, up to 10% of the 7.9 million fractures suffered in the United States each year do not achieve bony union. Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis are known to work in concert to control many stages of this process, but when one is impaired it leads to failure of bone healing, referred to as a nonunion. Such nonunion fractures often result from critical-size defects that will not completely heal over the natural lifetime of the animal. Based on this …

Assessing The Active Kinome Of Influenza Virus Infected A549 Cells, Colm Atkins

All ETDs from UAB

Influenza A Virus is a respiratory pathogen of the family Orthomyxoviridae and causes significant worldwide morbidity and mortality during seasonal epidemics and periodic pandemics. As with all viruses, influenza's limited coding capacity requires the use of host proteins and processes in its replication and release cycle. Phosphorylation, mediated by cellular kinases and phosphatases, represents a significant mechanism of post-translational modification of cellular products, and is responsible for regulating the activi-ty, lifespan and localization of many lipids and proteins in host-cells. Several cellular kinases have been associated with various steps of the Influenza lifecycle, including PKC-ßII (viral entry), PKR (host defense), …

Il-8 Is Necessary And Sufficient For X-Ray Radiation Enhanced Endothelial Adhesion., Stephen Kyle Babitz

All ETDs from UAB

Ionizing radiation (IR) is a potent inflammatory stimulus to the human body. In the vasculature, inflammation is a major contributing factor for atherosclerosis. In addition, radiation from several sources has been linked with increased risk for multiple cardiovascular complications. A key compnent of radiation associated inflammation is an increase in the adhesiveness of the endothelium which leads to a pathogenic accumulation of leukocytes in the vascular wall. This is one of the initial steps in vascular inflammation and leads to a number of adverse complications such as heart disease and stroke. The molecular mechanisms behind radiaton enhanced endothelial adhesion have …

Targeted Delivery Of Osteoinductive Peptides To Bone Graft Utilizing A Calcium Binding Domain To Enhance The Regenerative Potential, Jennifer Leigh Bain

All ETDs from UAB

Bone grafting procedures are common practice. Autogenous bone is considered optimal, however, complications associated with bone harvesting often lead clinicians to use off-the-shelf materials that have limited osteoinductivity. Alternatively, bioactive factors passively adsorbed onto various carriers are available. These materials, while effective, are expensive to produce, require supraphysiological doses, and have adverse side effects due to dissemination from the graft site. This dissertation aims to reintroduce osteoinductive factors to bone grafts to enhance regenerative capacity. Specifically, we utilized negatively-charged calcium-binding domains (polyglutamate) to anchor two osteoinductive peptides bone graft materials including an allograft, xenograft, alloplast, and bone cement. The peptides …

Effects Of Storage On The Red Blood Cell And Its Implications For Transfusion, Ryan D. Stapley

All ETDs from UAB

Transfusion with red blood cells (RBC) remains a frontline therapy in critically ill patients. Recent studies have documented an association between storage duration and an increased incidence of transfusion-related toxicities. This transfusion-related toxicity is characterized by both a pro-inflammatory state and a microcirculatory dysfunction and is associated with changes that occur to the RBC and its media during storage referred to as the storage lesion. These changes that occur to the RBC include an increase in cell-free hemoglobin, heme, free iron, microparticles, as well as changes to the RBC itself. This thesis explores how these elements could contribute to transfusion-related …

Translocation Of Shed Syndecan-1 To The Nucleus: A Novel Mechanism Of Tumor-Host Crosstalk, Mark Stewart

All ETDs from UAB

Multiple myeloma is a hematological malignancy of plasma cells that disseminates throughout the body. Crosstalk between myeloma and host cells is critical to the establishment of a microenvironment conducive to tumor growth and progression. An important mediator of this crosstalk is syndecan-1, a heparan sulfate proteoglycan. Syndecan-1 is proteolytically shed from the surface of myeloma cells and is abundant in the bone marrow microenvironment and serum of myeloma patients. Shed syndecan-1 facilitates tumor-host crosstalk within the microenvironment to drive tumor growth, angiogenesis, and metastasis. We now report for the first time that shed syndecan-1 can be taken up by a …