Digital Commons Network^™

Is Dabigatran Non-Inferior To Warfarin For The Prevention Of Stroke In Those With Atrial Fibrillation?, Brittany Burlakoff

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this systematic review is to determine whether or not dabigatran 150 mg twice daily is non-inferior to warfarin for the prevention of stroke in those with atrial fibrillation with similar rates of bleeding events.

STUDY DESIGN: Review of 3 English language primary studies. All three trials were randomized controlled trials which were blinded for those receiving dabigatran and un-blinded for those receiving warfarin.

DATA SOURCES: Articles were found using PUBMED and COCHRANE databases.

OUTCOME MEASURED: The primary outcomes of these studies were either incidence of stroke or systemic embolism and/or major bleeding events.

RESULTS:The RE-LY …

Is 1.25 Mg Oral Fingolimod Effective In Reducing Relapses In Adults With Relapsing Multiple Sclerosis?, Caitlin M. Cook

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this systematic review is to determine whether or not is 1.25 mg oral fingolimod effective in reducing relapses in adults with relapsing multiple sclerosis.

STUDY DESIGN: Review of three English language primary studies published between 2006 and 2010.

DATA SOURCES: Randomized, double-blind, controlled clinical trials comparing daily 1.25 mg oral fingolimod to either identical placebo capsules or weekly intramuscular interferon beta-1a therapy were found using Pubmed and Cochrane Databases.

OUTCOMES MEASURED: Annualized relapse rate was assessed in all studies. Relapses were confirmed by neurologists and assessed using the Expanded Disability Status Scale (EDSS) to evaluate worsening …

Is Methylphenidate Transdermal System (Daytrana®) Safe And Effective For Managing Attention Deficit Hyperactivity Disorder Symptoms In Children?, Pamela Cassidy

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not methylphenidate transdermal system (Daytrana®) is safe and effective for managing attention deficit hyperactivity disorder symptoms in children.

STUDY DESIGN: A review of three English language studies published from 2006-2010. Includes two randomized, double-blind, controlled trials and one randomized, controlled crossover study.

DATA SOURCES: Randomized, placebo-controlled studies evaluating the effectiveness and safety of methylphenidate transdermal system (MTS) for managing attention deficit hyperactivity disorder (ADHD) symptoms in children were located using the PubMed, CINAHL, and Cochrane Library databases.

OUTCOMES MEASURED: The primary measures of effectiveness used were the …

Mir-145 Directly Targets P70s6k1 In Cancer Cells To Inhibit Tumor Growth And Angiogenesis., Qing Xu, Ling-Zhi Liu, Xu Qian, Qi Chen, Yue Jiang, Dan Li, Lihui Lai, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

MiR-145 can regulate cell apoptosis, proliferation, neural development and stem cell differentiation. Previous studies indicate that miR-145 is downregulated in human colon cancer cells. However, the molecular mechanisms of miR-145 used to regulate colon carcinogenesis and angiogenesis remain to be clarified. Here, we show that the expression of miR-145 is downregulated in colon and ovarian cancer tissues and cell lines. MiR-145 inhibits p70S6K1 post-transcriptional expression by binding to its 3'-UTR. The angiogenic factors hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF), which are downstream molecules of p70S6K1, are decreased by miR-145 overexpression. P70S6K1 rescues miR-145-suppressed HIF-1 and VEGF …

Hiv Rna Suppression And Immune Restoration: Can We Do Better?, Marilia Rita Pinzone, Michelino Di Rosa, Bruno Cacopardo, Giuseppe Nunnari

Department of Microbiology and Immunology Faculty Papers

HAART has significantly changed the natural history of HIV infection: patients receiving antiretrovirals are usually able to control viremia, even though not all virological responders adequately recover their CD4+ count. The reasons for poor immune restoration are only partially known and they include genetic, demographic and immunologic factors. A crucial element affecting immune recovery is immune activation, related to residual viremia; indeed, a suboptimal virological control (i.e., low levels of plasma HIV RNA) has been related with higher levels of chronic inflammation and all-cause mortality. The sources of residual viremia are not yet completely known, even though the most important …

Posttranslational Modification Of Vesicular Stomatitis Virus Glycoprotein, But Not Jnk Inhibition, Is The Antiviral Mechanism Of Sp600125, Sabrina Marozin, Jennifer Altomonte, Sibylle Apfel, Phat X. Dinh, Enrico De Toni, Antonia Rizzani, Andreas Nüssler, Nobuyuki Kato, Roland M. Schmid, Asit K. Pattnaik, Oliver Eberta

School of Veterinary and Biomedical Sciences: Faculty Publications

Vesicular stomatitis virus (VSV), a negative-sense single-stranded-RNA rhabdovirus, is an extremely promising oncolytic agent for cancer treatment. Since oncolytic virotherapy is moving closer to clinical application, potentially synergistic combinations of oncolytic viruses and molecularly targeted antitumor agents are becoming a meaningful strategy for cancer treatment. Mitogenactivated protein kinase (MAPK) inhibitors have been shown to impair liver cell proliferation and tumor development, suggesting their potential use as therapeutic agents for hepatocellular carcinoma (HCC). In this work, we show that the impairment of MAPK in vitro did not interfere with the oncolytic properties of VSV in HCC cell lines. Moreover, the administration …

Identification Of Amino Acid Residues Important For Anti-Ifn Activity Of Porcine Reproductive And Respiratory Syndrome Virus Non-Structural Protein 1, Lalit Beura, Sakthivel Subramaniam, Hiep Vu, Byungjoon Kwon, Asit K. Pattnaik, Fernando A. Osorio

School of Veterinary and Biomedical Sciences: Faculty Publications

The non-structural protein 1 (nsp1) of porcine reproductive and respiratory syndrome virus is partly responsible for inhibition of type I interferon (IFN) response by the infected host. By performing alanine-scanning mutagenesis, we have identified amino acid residues in nsp1α and nsp1β~ (the proteolytic products of nsp1) that when substituted with alanine(s) exhibited significant relief of IFNsuppression. A mutant virus (16-SA, in which residues 16-20 of nsp1β were substituted with alanines) encoding mutant nsp1β recovered from infectious cDNA clone was shown to be attenuated for growth in vitro and induced significantly higher amount of type I IFN transcripts in infected macrophages. …

A Single Amino Acid Change Resulting In Loss Of Fluorescence Of Egfp In A Viral Fusion Protein Confers Fitness And Growth Advantage To The Recombinant Vesicular Stomatitis Virus, Phat X. Dinh, Debasis Panda, Phani B. Das, Subash C. Das, Anshuman Das, Asit K. Pattnaik

School of Veterinary and Biomedical Sciences: Faculty Publications

Using a recombinant vesicular stomatitis virus encoding eGFP fused in-frame with an essential viral replication protein, the phosphoprotein P, we show that during passage in culture, the virus mutates the nucleotide C289 within eGFP of the fusion protein PeGFP to A or T, resulting in R97S/C amino acid substitution and loss of fluorescence. The resultant non-fluorescent virus exhibits increased fitness and growth advantage over its fluorescent counterpart. The growth advantage of the non-fluorescent virus appears to be due to increased transcription and replication activities of the PeGFP protein carrying the R97S/C substitution. Further, our results show that the R97S/C mutation …

Amino Acid Residues In The Non-Structural Protein 1 Of Porcine Reproductive And Respiratory Syndrome Virus Involved In Down-Regulation Of Tnf-Cx Expression In Vitro And Attenuation In Vivo, Sakthivel Subramaniam, Lalit Beura, Byungjoon Kwon, Asit K. Pattnaik, Fernando A. Osorio

School of Veterinary and Biomedical Sciences: Faculty Publications

Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses tumor necrosis factor-alpha (TNF-α) production at both transcriptional and post-transcriptional levels by its non-structural proteins 1α and 1β (Nsp1α and Nsp1β). To identifY the amino acid residues responsible for this activity, we generated several alanine substitution mutants of Nsp1α and Nsp1β. Examination of the mutant proteins revealed that Nsp1α residues Gly90, Asn91 , Arg97, Argl 00 and Arg124 were necessary for TNF-α promoter suppression, whereas several amino acids spanning the entire Nsp1β ~ were found to be required for this activity. Two mutant viruses, with mutations at Nsp1α Gly90 or Nsp1β residues …

Redefining Onyx Hd 500 In The Flow Diversion Era., Richard Tyler Dalyai, Ciro Randazzo, George Ghobrial, L Fernando Gonzalez, Stavropoula I Tjoumakaris, Aaron S Dumont, Robert H Rosenwasser, Pascal Jabbour

Department of Neurosurgery Faculty Papers

We report the largest US case series results using Onyx HD-500 (EV3), a new liquid embolic agent, in the successful treatment of 21 patients with wide-neck intracranial aneurysms (mean size 4.5 mm), which are at increased risk of incomplete occlusion or recanalization with standard endovascular intervention utilizing detachable platinum coils. All aneurysms were located in the anterior circulation, and three aneurysms presented as acute subarachnoid hemorrhages. Complete aneurysm occlusion was present in 19 of 21 patients (90%). On six-month followup, one patient with an initially small residual neck progressed to total occlusion. Aneurysm recanalization was not detected in any patients …

Feasibility Study Of Trans-Cranial Direct Current Stimulation In Presence Of Brain Tumor, Abhilash Nair

Dissertations and Theses

Trans-cranial Direct Current Stimulation has been shown to modulate cortical neuronal activity. Weak constant current is applied to the scalp using electrodes, leading to sub-threshold changes in neuronal membrane potential. Before actual clinical stimulation is performed, such systems are validated by simulating the stimulation and the resulting current flow patterns using finite element solvers. However, the reliability of such models depends upon the accuracy with which the underlying anatomy has been modeled [1]. In earlier studies it has been shown that the current flow patterns within the brain are altered due to the presence of lesioned brain tissues[2]. Here we …

The Role Of C-Reactive Protein In Arthritic Disease, Nicholas Ryan Jones

All ETDs from UAB

C-reactive protein (CRP) is an acute phase protein that is commonly used to evaluate systemic inflammation level. Blood CRP level also correlates very well with rheumatoid arthritis (RA) disease severity. However, CRP has many biological actions that lead one to suspect that it may be playing a role in the development or pathology of the disease. We have directly addressed whether this is the case by the use of novel mouse models (CRP deficiency or transgenic overexpression). We have shown that CRP positively affects collagen-induced arthritis development and progression. In order to thoroughly address the question, we have also reported …

Mycobacterial Iron Acquisition Systems, Christopher M. Jones

All ETDs from UAB

Iron is an essential nutrient for the vast majority of organisms; yet, the availability of iron is limited to microorganisms due to the insolubility of ferric hydroxides and to pathogens by iron withholding strategies of their hosts. Many bacteria produce small, high-affinity iron chelators called siderophores to scavenge iron from the environment. In addition, many bacterial pathogens have evolved mechanisms to steal host iron contained in heme, hemoglobin, or transferrin. Mycobacteria are unique genera of bacteria represented by the notorious pathogens Mycobacterium tuberculosis and Mycobacterium leprae, the causative agents of tuberculosis (TB) and leprosy, respectively. Tuberculosis remains a global health …

A Study Of The Genetic Mechanisms Used To Regulate The Third Complementarity Determining Region Of The Immunoglobulin H Chain, Mohamed Khass

All ETDs from UAB

Developing B cells exhibit sequential changes in the representation of immunoglobulin (Ig) heavy (H) chain sequences with excess hydrophobic or charged amino acids in complementarity determining region 3 (CDR-H3). To begin to elucidate the mechanisms by which this process occurs, we used Bromodeoxy Uridine (BrdU) incorporation and Annexin V binding to quantify B cell turnover and cell cycle progression in developing B cell subsets in the bone marrow, spleen and peritoneal cavity of wild-type BALB/c mice. To magnify the effects of hydrophobicity and charge, we included in this analysis mice limited to the use of an IgH allele with a …

Targeting Mitochondrial Function In Diabetic Nephropathy, Colin Reily

All ETDs from UAB

TARGETING MITOCHONDRIAL FUNCTION IN DIABETIC NEPHROPATHY The incidence of diabetes has increased to epidemic proportions over the last 50 years, due to a complex interaction of lifestyle and dietary factors. Changes in physical activity, caloric intake, and the composition of foods consumed over the last century are thought to interact with metabolic syndrome prone subpopulations leading ultimately to diabetes. It is widely accepted that chronic hyperglycemia in the blood characterizes the diabetic condition. Since the discovery of insulin therapy in the first half of the 20th century, diabetics have extended their lifespan considerably, but at the cost of increased morbitity …

Regulation Of Membrane Traffic By The Big2 Member Of Guanine Nucleotide Exchange Factors, Jason Lowery

All ETDs from UAB

Vesicular transport is an essential cellular process that facilitates the movement of molecules within a cell. The importance of vesicular transport is highlighted by numerous human diseases that result from mutations affecting protein trafficking. The Brefeldin A-inhibited guanine nucleotide exchange factor 2 (BIG2) has emerged as a key regulator of protein trafficking within the late secretory pathway, between the trans-Golgi Network (TGN) and endosomal compartments and within the recycling endosomal pathway. Mutations in BIG2 lead to Autosomal Recessive Periventricular Heterotopia with Microcephly (ARPHM), a disorder characterized by severe brain malformations. BIG2 stimulates nucleotide exchange of GDP for GTP on ADP-ribosylation …

Effects Of Stress On Growth Hormone Receptor Signaling, Ryan Marshall Corrick

All ETDs from UAB

Growth hormone (GH) regulates body composition via stimulation of protein synthesis and catabolism of adipose tissue, generally promoting maintenance of lean body mass. Following severe injury, GH resistance contributes to muscle protein wasting, adversely impacting morbidity and mortality. In this dissertation research, we sought to determine the mechanisms of GH resistance following injury. To accomplish this, we evaluated GH signaling in a mouse model of severe injury. In the first section of this thesis, we demonstrate severe impairments in hepatic GH signaling occurring in association with an apparent, hemorrhage-dependent cleavage of the GH receptor (GHR). In the second section, we …

Neuropharmacology Of The Α2a Adrenergic Receptor In Disorders Of Mood And Cognition, Christopher Cottingham

All ETDs from UAB

Depressive disorders carry relatively high lifetime risks of greater than 10%, and the antidepressant drugs used in the pharmacotherapy of these mood/cognitive disorders are among the most-prescribed pharmacological agents. However, a detailed understanding of both depressive etiology and the pharmacological mechanisms of action for antidepressant drugs remain elusive. The overall goal of this dissertation research is to provide novel in-sights through a detailed study of the neuropharmacology of the α2A adrenergic receptor (AR). α2ARs, as key regulators of noradrenergic neurotransmission, have been broadly understood to have some ill-defined role in both the neurobiology and neuropharmacology of depressive disorders. The studies …

Regulation Of Clc-3 In Human Malignant Glioma, Vishnu Anand Cuddapah

All ETDs from UAB

Malignant gliomas are the most common and deadly form of primary brain cancer afflicting adults. Current treatment regimens, including surgical debulking, radiotherapy, and chemotherapy, have limited efficacy, and median patient survival remains only 14 months. Therefore, novel therapies must target different aspects of glioma biology. Two of the most striking features of this cancer are the unusual ability of glioma cells to robustly proliferate and migrate in the brain, and recent evidence suggests that ClC-3, a voltage-gated Cl- channel/transporter is implicated in both of these processes. We hypothesize that ClC-3 may facilitate proliferation and migration by promoting hydrodynamic shape and …

Scaffold-Mediated Size Determination Of Bacteriophage Capsids By Mobile Genetic Elements, Altaira Davida Dearborn

All ETDs from UAB

Bacteriophage can mediate the transfer of unrelated mobile genetic elements (MGE) from a carrier bacterial cell to the susceptible population around it. This transfer results in the spread of virulence or other accessory genes encoded on the MGE. During viral particle assembly, the MGE can discourage the formation of viable bacteriophage progeny by limiting the size of the particles to those large enough to encapsidate the MGE, but too small to fit the complete bacteriophage genome which is three times larger. Here, I present models for size determination by an external scaffolding protein which is independent of and dominant over …

Modulation Of Capsule Production In Serotype 3 Streptococcus Pneumoniae, Melissa Ellis

All ETDs from UAB

Streptococcus pneumoniae is a Gram-positive pathogen and an important cause of community-acquired pneumonia and meningitis, and it can also cause otitis media and bacteremia. A major virulence factor of S. pneumoniae is its polysaccharide capsule which functions to prevent complement-mediated opsonophagocytosis. At least 93 distinct serotypes that vary in sugar composition and structure exist. S. pneumoniae can asymptomatically colonize the nasopharynx and transition to other body sites such as the lungs and blood causing invasive disease. The ability to regulate capsule production in these vastly different environments is critical for survival as low levels of capsule are necessary for colonization, …

A Role Of Angiogenin In Models Of Parkinson's Disease, Trent Steidinger

All ETDs from UAB

Parkinson's Disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Gene multiplication of alpha-synuclein causes an autosomal dominant inheritance pattern of PD. A mouse model overexpressing alpha-synuclein demonstrates some of the phenotype seen in PD. In a microarray of these mice, a downregulation of angiogenin was observed prior to symptom onset, demonstrating a potential link of angiogenin to pathology in this model. Angiogenin has also been associated with the onset of Amyotrophic Lateral Sclerosis (ALS), and is neuroprotective in models of ALS through activation of the Akt …

The Role Of St6gal-I Sialylation In Fas (Cd95) Death Receptor Function And Tumorigenesis, Amanda F. Swindall

All ETDs from UAB

The golgi glycosyltransferase, ST6Gal-I, adds a negatively-charged sialic acid in an alpha-2-6 linkage to N-linked glycans. ST6Gal-I is upregulated in many cancers, and is associated with increased metastasis and poor patient prognosis. ST6Gal-I expression has been shown to be driven by oncogenic-ras signaling. However, mechanistic details of the role ST6Gal-I plays in tumor initiation and progression are not well defined. Historically, studies have focused on contributions of ST6Gal-I to the malignant cell phenotypes of migration and invasion. Emerging evidence including studies contained in this dissertation have begun to elucidate a role for ST6Gal-I as a regulator of apoptotic signaling by …

Regulatory T Cells In The Fvb.Mdr1a-/- Model Of Colitis, Scott Tanner

All ETDs from UAB

Regulatory T cells (Treg) are necessary for the maintenance of immune homeostasis, and have been implicated in several autoimmune diseases, including inflammatory bowel disease (IBD). Most murine studies focusing on the function of Tregs have been done on the C57BL/6 or BALB/c background, creating a bias towards these two strains. In addition, it has been shown that C57BL/6 and BALB/c Tregs function in different manners. To further investigate potential strain differences in Treg phenotype and function, we chose to analyze FVB/N Tregs. Several differences were observed, including de-creased FVB/N Treg suppression in a non-cell contact dependent manner, decreased FVB/N and …

Glutamate Release And Uptake At Cerebellar Synapses, Ming-Chi Tsai

All ETDs from UAB

Glutamate mediates excitatory synaptic transmission in the central nervous system (CNS). Regulation of glutamate release and uptake shapes the spatiotemporal dynamics of glutamate at and around synapses to influence information transfer between neural cells. This dissertation focuses on the modulation of glutamate release and uptake at excitatory synapses of cerebellar Purkinje cells (PC). In the first project we show that differential expression of PC glutamate transporters controls the amount of glutamate entering the extrasynaptic space, thereby influencing the excitatory responses in surrounding Bergmann glia. This work provides the first evidence that neuronal glutamate uptake affects glial glutamatergic signaling. In the …

Mechanisms Of Lrrk2 Regulation, Philip J. Webber

All ETDs from UAB

Non-synonymous mutations in LRRK2 are the most common known cause of familial and sporadic Parkinson's disease (PD). The dominant inheritance of these mutations in familial PD suggests a gain-of-function mechanism. Increased kinase activity observed in the most common PD associated LRRK2 mutation G2019S suggests that kinase activity is central to disease. However, not all mutations associated with disease are reported to alter kinase activity and controversy exists in the literature about the effects of mutations appearing in the GTPase domain on kinase activity. The studies conducted as a part of this work aim to characterize the mechanisms that regulate LRRK2 …

Finding A Cure For Venezuelan Equine Encephalitis Virus (Veev) Infection: The Search For The Antiviral Genes And Vaccine Development., Svetlana Atasheva

All ETDs from UAB

Venezuelan equine encephalitis virus (VEEV) is a re-emerging virus that causes a severe and often fatal disease in equids and humans. To date, despite a continuous public health threat, no vaccines or antiviral drugs against VEEV infection have been developed for human use. In this study we took advantage of accumulated knowledge of capsid protein function in viral replication, assembly and virus-host interactions. Besides being an integral part of the virion, capsid protein is the major determinant of VEEV pathogenesis. This protein is cytotoxic and induces cellular transcriptional shutoff as a countermeasure to the cellular antiviral response. We introduced targeted …

Myosin Ii Regulates Actin Dynamics Critical For Structural Plasticity And Fear Memory Formation, Cristin Gavin

All ETDs from UAB

Dynamic changes to the actin cytoskeleton are required for synaptic plasticity and long-term memory formation. However, the molecular mechanisms that mediate filamentous actin (F-actin) dynamics during both activity-dependent synaptic potentiation and long-term memory encoding are poorly understood. Myosin II motor proteins are highly expressed in actin-rich growth structures in neurons, including dendritic spines. Recent work demonstrates that these molecular machines mobilize F-actin in response to synaptic stimulation and are required for memory encoding in CA1 hippocampus of rodents. The aims of this project were two-fold. First, we sought to establish if myosin II regulates actin filament polymerization necessary for structural …

Modulation Of Wzy-Dependent Capsule Production In Streptococcus Pneumoniae By The Phosphotyrosine-Specific Phosphatase Cpsb, Kimball Aaron Geno

All ETDs from UAB

Biosynthesis of capsule polysaccharide in the Gram-positive pathogen Streptococcus pneumoniae is regulated in part through the action of a phosphoregulatory system comprised of the products of the capsule biosynthetic operon genes cpsBCD. CpsC and CpsD together comprise an autophosphorylating tyrosine kinase whose homologs are implicated in chain length regulation in other systems in both Gram-positive and Gram-negative organisms. CpsB is the cognate phosphatase for the system. Unlike Gram-negative organisms, which use a low molecular weight phosphotyrosine phosphatase in phosphoregulation of capsule synthesis, Gram-positive organisms utilize a polymerase and histidinol phosphatase (PHP) superfamily phosphatase. Deletion of cpsB has resulted in conflicting …

Regulation Of Neuronal Cell Death By Bh3-Only Proteins, Arindam P. Ghosh

All ETDs from UAB

Apoptosis in metazoan organisms plays critical roles in normal development, tissue homeostasis and immunity, and its disturbed regulation leads to many pathological states, including cancer, autoimmunity, infection and degenerative disorders. Apoptosis can be triggered by the engagement of `death receptors' of the tumor necrosis factor receptor family on the cell surface or by diverse intracellular signals that act upon the BCL2 (B-cell CLL/lymphoma 2) protein family, which controls the integrity of the mitochondrial outer membrane through the complex interactions of family members. Both the pathways lead to cellular demolition by dedicated proteases termed caspases. Different BH3-only proteins (or combinations of …