Medicine and Health Sciences Commons^™

Metabotropic Glutamate Receptor 5 In The Medial Prefrontal Cortex: Role In Cocaine Sensitization And Addiction, Kristin Marie Timmer

Theses and Dissertations (ETD)

Cocaine sensitization is associated with cocaine-induced hyperexcitability of pyramidal projection neurons within the medial prefrontal cortex (mPFC). Such hyperexcitability presumably results in increased glutamatergic input to reward-affiliated brain regions such as the ventral tegemental area (VTA) and nucleus accumbens (NAc), consequently facilitating drugseeking behavior. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in cocaine addiction and demonstrated to increase neuronal excitability, therefore, the aim of the present study was to investigate the effect of intra-mPFC mGluR5 manipulation on behavioral and neurochemical sensitization and drug-seeking. Bilateral cannulae were implanted into the mPFC of male Sprague-Dawley rats and mGluR5 antagonist MTEP (15 …

N200 And P300 Evoked By Stimuli Straddling Category Boundary In Lexical Context, Ji Young Lee

Theses and Dissertations (ETD)

Background and Objectives: Event-related potentials (ERPs) like N200 and P300 have been reported to reflect the categorical perception of speech. The purpose of the present study is to explore whether these ERP components reflect the influence of lexical context on categorical perception. Findings may provide evidence for bottom-up or top-down processing of speech. Methods: On a seven step series of the /bi/-/pi/ continuum, a two-forced choice labeling test was administered in two conditions: /bi/ context (e.g. bee sting) and /pi/ context (e.g. pea soup). From the labeling results, Stimulus 1which is a prototypical /bi/ was selected for standard stimuli, and …

Mrp4 Is A Crucial Regulator Of Testosterone Biosynthesis, Jessica Ann Morgan

Theses and Dissertations (ETD)

The physiological role of multidrug resistance protein 4 (Mrp4) in the testes is unknown. It was discovered that Mrp4 is expressed primarily in mouse and human Leydig cells; however, there is no current evidence that Mrp4 regulates testosterone biosynthesis. The role of Mrp4 was investigated in Leydig cells where testosterone production is regulated by cAMP, an intracellular second messenger formed when the luteinizing hormone (LH) receptor (Lhr) is activated. As Mrp4 regulates cAMP, we compared testosterone levels in our Mrp4 WT and KO mice. Prepubertal KO mice had significantly reduced testicular testosterone, impaired gametogenesis, and disrupted cAMP homeostasis, resulting in …

Anti-Apoptotic Mcl-1 Localizes To The Mitochondrial Matrix And Couples Mitochondrial Fusion To Respiration, Rhonda Perciavalle

Theses and Dissertations (ETD)

MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, I report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, a MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to …

How Theories Evolved Concerning The Mechanism Of Action Of Barbiturates, Wolfgang Löscher, Michael A. Rogawski

Michael A. Rogawski

The barbiturate phenobarbital has been in use in the treatment of epilepsy for 100 years. It has long been recognized that barbiturates act by prolonging and potentiating the action of γ-aminobutyric acid (GABA) on GABA-A) receptors and at higher concentrations directly activating the receptors. A large body of data supports the concept that GABA-A) receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the β3 GABA-A)-receptor subunit exhibit diminished sensitivity to the sedative and immobilizing actions of the anesthetic barbiturate pentobarbital. Although phenobarbital is only modestly less potent …

Paradoxical Results Of Adaptive False Discovery Rate Procedures In Neuroimaging Studies, Philip T. Reiss, Armin Schwartzman, Feihan Lu, Lei Huang, Erika Proal

Philip T. Reiss

Adaptive false discovery rate (FDR) procedures, which offer greater power than the original FDR procedure of Benjamini and Hochberg, are often applied to statistical maps of the brain. When a large proportion of the null hypotheses are false, as in the case of widespread effects such as cortical thinning throughout much of the brain, adaptive FDR methods can surprisingly reject more null hypotheses than not accounting for multiple testing at all—i.e., using uncorrected p-values. A straightforward mathematical argument is presented to explain why this can occur with the q-value method of Storey and colleagues, and a simulation study shows that …

Ccpa Regulates Arginine Biosynthesis In Staphylococcus Aureus Through Repression Of Proline Catabolism., Austin S. Nuxoll, Steven M. Halouska, Marat Sadykov, Mark L. Hanke, Kenneth W. Bayles, Tammy Kielian, Robert Powers, Paul D. Fey

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a leading cause of community-associated and nosocomial infections. Imperative to the success of S. aureus is the ability to adapt and utilize nutrients that are readily available. Genomic sequencing suggests that S. aureus has the genes required for synthesis of all twenty amino acids. However, in vitro experimentation demonstrates that staphylococci have multiple amino acid auxotrophies, including arginine. Although S. aureus possesses the highly conserved anabolic pathway that synthesizes arginine via glutamate, we demonstrate here that inactivation of ccpA facilitates the synthesis of arginine via the urea cycle utilizing proline as a substrate. Mutations within putA, rocD, …

Investigating A Model For Fetal Alcohol Damage In Caenorhabditis Elegans, Lindsay Kondo

Theses and Dissertations

Alcohol use and abuse has many harmful effects, especially to children exposed prenatally, including fetal alcohol spectrum disorders (FASDs). The disabilities due to fetal alcohol exposure continue throughout life and cause major financial burdens to society. The molecular mechanisms underlying FASDs are not well understood. We have taken a genetic approach to characterize ethanol’s effect on changing a discrete cell fate decision during embryogenesis in the nematode, Caenorhabditis elegans (C. elegans). Our preliminary data suggest that ethanol can affect the development of AWC neurons, a pair of olfactory neurons in C. elegans. We suggest that lipids can protect AWC neurons …

Role Of Tyrosyl-Dna Phosphodiesterase (Tdp 1) On Repair Of 3′-Phosphoglycolate (3′- Pg) Terminated Dna Double-Strand Breaks (Dsbs) And In Response To Oxidative Stress, Tong Zhou

Theses and Dissertations

DNA DSBs are most toxic to cells because they can lead to genomic rearrangements and even cell death. Most DSBs induced by ionizing radiation or radiomimetic drugs such as calicheamicin and bleomycin, bear 3′-phosphate or 3′- PG moieties that must be removed to allow subsequent gap filling and ligation. DSBs can be repaired by two main pathways: the homologous recombination (HR) pathway and the non-homologous end-joining (NHEJ) pathway, NHEJ is the primary repair pathway in mammalian cells. While HR repairs single strand breaks (SSBs) or DSBs accurately by using an undamaged copy of the sequence mostly at late S phase …

Pharmacokinetics And Brain Uptake In The Rhesus Monkey Of A Fusion Protein Of Arylsulfatase A And A Monoclonal Antibody Against The Human Insulin Receptor, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui, Rachita K. Sumbria, William M. Pardridge

Pharmacy Faculty Articles and Research

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder of the brain caused by mutations in the gene encoding the lysosomal sulfatase, arylsulfatase A (ASA). It is not possible to treat the brain in MLD with recombinant ASA, because the enzyme does not cross the blood-brain barrier (BBB). In the present investigation, a BBB-penetrating IgG-ASA fusion protein is engineered and expressed, where the ASA monomer is fused to the carboxyl terminus of each heavy chain of an engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, …

Lack Of P53 Affects The Expression Of Several Brain Mitochondrial Proteins: Insights From Proteomics Into Important Pathways Regulated By P53, Ada Fiorini, Rukhsana Sultana, Eugenio Barone, Giovanna Cenini, Marzia Perluigi, Cesare Mancuso, Jian Cai, Jon B. Klein, Daret K. St. Clair, D. Allan Butterfield

Chemistry Faculty Publications

The tumor suppressor protein p53 has been described "as the guardian of the genome" for its crucial role in regulating the transcription of numerous genes responsible for cells cycle arrest, senescence, or apoptosis in response to various stress signals. Although p53 promotes longevity by decreasing the risk of cancer through activation of apoptosis or cellular senescence, several findings suggest that an increase of its activity may have deleterious effects leading to selected aspects of the aging phenotype and neurodegenerative diseases. There is the link between p53 and oxidative stress, the latter a crucial factor that contributes to neurodegenerative processes like …

Systematic Review Of Tst Responses In People Living With Hiv In Under-Resourced Settings: Implications For Isoniazid Preventive Therapy., Andrew D. Kerkhoff, Katharina Kranzer, Taraz Samandari, Jessica Nakiyingi-Miiro, Christopher C. Whalen, Anthony D. Harries, Stephen D. Lawn

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

People living with HIV (PLWH) who have positive tuberculin skin tests (TST) benefit from isoniazid preventive therapy (IPT) whereas those testing TST-negative do not. Revised World Health Organization guidelines explicitly state that assessment of TST is not a requirement for initiation of IPT. However, it is not known what proportions of patients will benefit from IPT if implemented without targeting according to TST status. We therefore determined the proportions of PLWH who test TST-positive.

Methodology/Principal Findings

We systematically reviewed the literature published between January 1990 and February 2012 to determine the proportions of patients without active tuberculosis attending HIV …

Over Prescription Of Antibiotics For Adult Pharyngitis Is Prevalent In Developing Countries But Can Be Reduced Using Mcisaac Modification Of Centor Scores: A Cross-Sectional Study., Amber Hanif Palla, Rafeeq Alam Khan, Anwar H. Gilani, Fawziah Marra

Department of Biological & Biomedical Sciences

Background

Although Group A beta hemolytic streptococcus (GABHS) can cause bacterial pharyngitis, the most common etiology is viral; despite this viral etiology, antibiotics are commonly prescribed for this infection in industrialized countries. We investigated the prevalence of GABHS in adult pharyngitis patients from lower socioeconomic settings in Karachi, Pakistan, how often antibiotics are prescribed for pharyngitis and if appropriate agents were used in a developing world setting. Finally, we wanted to see the usefulness of modified McIsaac scores in predicting positive cultures.

Methods

Adult patients were recruited from three local hospital outpatient dispensaries (OPDs). All patients aged 14–65 years who …

A 'Snip' In Time: What Is The Best Age To Circumcise?, Brian J. Morris, Jake H. Waskett, Joya Banerjee, Richard G. Wamai, Aaron A. R. Tobian, Ronald H. Gray, Stefan A. Bailis, Robert C. Bailey, Jeffrey D. Klausner, Robin J. Willcourt, Daniel T. Halperin, Thomas E. Wiswell, Adrian Mindel

Richard G. Wamai

Background Circumcision is a common procedure, but regional and societal attitudes differ on whether there is a need for a male to be circumcised and, if so, at what age. This is an important issue for many parents, but also pediatricians, other doctors, policy makers, public health authorities, medical bodies, and males themselves. Discussion We show here that infancy is an optimal time for clinical circumcision because an infant's low mobility facilitates the use of local anesthesia, sutures are not required, healing is quick, cosmetic outcome is usually excellent, costs are minimal, and complications are uncommon. The benefits of infant …

Biochemical Pathways In Cancer, Eun-Kyoung Yim Breuer, Mandi M. Murph, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

No abstract.

The Role Of P62 In Osteoclastogenesis And Paget’S Disease Of Bone, Tamer Hadi

Theses and Dissertations

Paget’s disease (PDB) is the second most common metabolic bone disease after osteoporosis, affecting up to 3% of adults over age 55. It is characterized by focal lesions of bone resorbed by hyperactive osteoclasts coupled with rapid formation of highly disorganized, low quality bone formed by osteoblasts. Such lesions cause skeletal deformity, fractures, and other symptoms that significantly decrease quality of life. In 2001, mutations in the SQSTM1/p62 gene were found in a subset of Paget’s patients. The work summarized in this dissertation sought to answer two broad questions: what is the function of p62 in normal bone homeostasis and …

Effect Of Testosterone On Inflammatory Markers In The Development Of Early Atherogenesis In The Testicular-Feminized Mouse Model, Daniel Kelly, Donna Sellers, M. Woodroofe, T. Jones, Kevin Channer

Donna Sellers

Background: Low levels of serum testosterone in men are associated with cardiovascular disease. Clinical studies show that testosterone replacement therapy (TRT) can improve symptoms of cardiovascular disease and reduce the inflammatory burden evident in atherosclerosis.

Aim: We used an in vivo animal model to determine whether testosterone influences mediators of vascular inflammation as part of its beneficial effects on atherogenesis.

Methods: Testicular-feminized (Tfm) mice, which express low endogenous testosterone and a non-functional androgen receptor (AR), were used to assess the effect of androgen status on atheroma formation, serum lipids, and inflammatory mediators. Tfm mice were fed a high-cholesterol diet, received …

Embryonic Stem Cell Derived Neural Precursor Grafts For Treatment Of Temporal Lobe Epilepsy, Janice R. Naegele

Janice R Naegele

Temporal Lobe Epilepsy (TLE). For many TLE patients, there is an initial traumatic head injury that is the precipitating cause of epilepsy. Severe TLE can be associated with neuropathological changes, including hippocampal sclerosis, neurodegeneration in the dentate gyrus, and extensive reorganization of hippocampal circuits. Learning disabilities and psychiatric conditions may also occur in patients with severe TLE for whom conventional anti-epileptic drugs are ineffective. Novel treatments are needed to limit or repair neuronal damage, particularly to hippocampus and related limbic regions in severe TLE and to suppress temporal lobe seizures. A promising therapeutic strategy may be to restore inhibition of …

Gene And Stem Cell Therapies For Treating Epilepsy., Janice Naegele, Xu Maisano

Janice R Naegele

No abstract provided.

Trekking Through The Telencephalon: Hepatocyte Growth Factor-Mediated Guidance For Parvalbumin-Expressing Interneurons, Janice R. Naegele

Janice R Naegele

No abstract provided.

The Impact Of Post-Mastectomy Radiation Therapy On Male Breast Cancer Patients--A Case Series, Edward Yu, Hiromichi Suzuki, Jawaid Younus, Tarek Elfiki, Larry Stitt, Gary Yau, Olga Vujovic, Francisco Perera, Michael Lock, Patricia Tai

Michael Lock

OBJECTIVE: To assess the impact of radiation management on male breast cancer (MBC) at London Regional Cancer Program (LRCP).

METHODS AND MATERIALS: Men with a diagnosis of breast cancer referred to LRCP were reviewed. The seventh American Joint Committee on Cancer staging system was used. Patients treated with and without post-mastectomy radiation therapy (PMRT) were analyzed. Disease-free survival (DFS) was defined as time duration from diagnosis to first recurrence. Overall survival (OS) was defined as time duration from pathologic diagnosis to death or last follow-up with any death defined as an event. Survival estimates were obtained using Kaplan-Meier methodology.

RESULTS: …

Technology Assessment Of Automated Atlas Based Segmentation In Prostate Bed Contouring, Jeremiah Hwee, Alexander Louie, Stewart Gaede, Glenn Bauman, David D'Souza, Tracy Sexton, Michael Lock, Belal Ahmad, George Rodrigues

Michael Lock

BACKGROUND: Prostate bed (PB) contouring is time consuming and associated with inter-observer variability. We evaluated an automated atlas-based segmentation (AABS) engine in its potential to reduce contouring time and inter-observer variability.

METHODS: An atlas builder (AB) manually contoured the prostate bed, rectum, left femoral head (LFH), right femoral head (RFH), bladder, and penile bulb of 75 post-prostatectomy cases to create an atlas according to the recent RTOG guidelines. 5 other Radiation Oncologists (RO) and the AABS contoured 5 new cases. A STAPLE contour for each of the 5 patients was generated. All contours were anonymized and sent back to the …

Role Of X-Rays In Rhinology, Balasubramanian Thiagarajan

Balasubramanian Thiagarajan

X-rays in the present day context is considered to be outdated by Rhinologists. CT scan images have replaced conventional x-ray imaging. Current concensus is that still x-rays have a role in the field of rhinology. Its inherent advantages like easy availability, cost effectiveness makes this investigation still relevant in the present day scenario. Bony lesions involving nose and sinuses, can be evalutated with reasonable degree of accuracy by performing conventional radiographs. Air present inside the paranasal sinuses serve as excellent contrast medium for plain x-ray evaluation. Pathologies involving paranasal sinuses encroach upon these air spaces causing alterations in their translucency.

The Role Of Magl Inhibition In Nicotine Withdrawal And Reward, Pretal Muldoon

Theses and Dissertations

ROLE OF MAGL INHIBITION IN NICOTINE WITHDRAWAL AND REWARD. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by Pretal Ishvarlal Patel Muldoon Director: M. Imad Damaj, PhD Professor, Department of Pharmacology and Toxicology Tobacco use is one of the leading causes of preventable deaths worldwide. Nicotine, the main psychoactive component of tobacco, sustains and initiates tobacco addiction. Cessation of nicotine induces a dependence withdrawal syndrome. Recent in vivo studies indicate that the endocannabinoid (EC) system modulates both nicotine reward and withdrawal. The purpose of this proposal is to …

Inla Promotes Dissemination Of Listeria Monocytogenes To The Mesenteric Lymph Nodes During Food Borne Infection Of Mice, Elsa N. Bou Ghanem, Grant S. Jones, Tanya Myers-Morales, Pooja D. Patil, Achmad N. Hidayatullah, Sarah E. F. D'Orazio

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Intestinal Listeria monocytogenes infection is not efficient in mice and this has been attributed to a low affinity interaction between the bacterial surface protein InlA and E-cadherin on murine intestinal epithelial cells. Previous studies using either transgenic mice expressing human E-cadherin or mouse-adapted L. monocytogenes expressing a modified InlA protein (InlA(m)) with high affinity for murine E-cadherin showed increased efficiency of intragastric infection. However, the large inocula used in these studies disseminated to the spleen and liver rapidly, resulting in a lethal systemic infection that made it difficult to define the natural course of intestinal infection. We describe here a …

Targeting Astrocytes Ameliorates Neurologic Changes In A Mouse Model Of Alzheimer's Disease, Jennifer L. Furman, Diana M. Sama, John C. Gant, Tina L. Beckett, M. Paul Murphy, Adam D. Bachstetter, Linda J. Van Eldik, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific …

Immune Correlates Of Aging In Outdoor-Housed Captive Rhesus Macaques (Macaca Mulatta), Elizabeth S. Didier, Chie Sugimoto, Lisa C. Bowers, Imtiaz A. Khan, Marcelo J. Kuroda

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Questions remain about whether inflammation is a cause, consequence, or coincidence of aging. The purpose of this study was to define baseline immunological characteristics from blood to develop a model in rhesus macaques that could be used to address the relationship between inflammation and aging. Hematology, flow cytometry, clinical chemistry, and multiplex cytokine/chemokine analyses were performed on a group of 101 outdoor-housed captive rhesus macaques ranging from 2 to 24 years of age, approximately equivalent to 8 to 77 years of age in humans.

Results

These results extend earlier reports correlating changes in lymphocyte subpopulations and cytokines/chemokines with increasing …

Muc4 And Muc1 Expression In Adenocarcinoma Of The Stomach Correlates With Vessel Invasion And Lymph Node Metastasis: An Immunohistochemical Study Of Early Gastric Cancer., Yukihiro Tamura, Michiyo Higashi, Sho Kitamoto, Seiya Yokoyama, Masahiko Osako, Michiko Horinouchi, Takeshi Shimizu, Mineo Tabata, Surinder K. Batra, Masamichi Goto, Suguru Yonezawa

Journal Articles: Biochemistry & Molecular Biology

We have previously reported that MUC4 expression is a poor prognostic factor in various carcinomas. Our previous study also showed that MUC1 expression in gastric cancers, including the early and advanced stages is a poor prognostic factor. In the present study, the expression profiles of MUC4 and MUC1 were examined by immunohistochemistry (IHC) using two anti-MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8, and anti-MUC1 MAb DF3 in 104 gastrectomy specimens of early gastric adenocarcinoma with submucosal invasion (pT1b2), including 197 histological subtype lesions. Before the IHC study of the human specimens, we evaluated the specificity of the two MAbs by …

Regulation Of Contractile Proteins And Protein Translational Signaling In Disused Muscle, Hua Liu, Eric Blough, Ravi Arvapalli, Yeling Wang, Peter Reiser, Satyanarayana Paturi, Anjaiah Katta, Robert Harris, Niraj Nepal, Miaozong Wu

Ravi K. Arvapalli

Background/Aims: Muscle disuse can lead to muscle atrophy and impaired skeletal muscle function. How skeletal muscle modulates protein translational signaling in response to prolonged muscle disuse is not well understood. Using the hindlimb unloading (HU) model of muscle atrophy we examined how hindlimb unweighting affects protein translational signaling, including the activation of Akt/mTOR/p70S6K/S6 signaling and the inhibitory association of 4EBP1 with translation initiation factor eIF4E. Methods: Male F344BN rats were randomized into baseline control, or subjected to HU for 3, 7 or 14 days. Body weight, gastrocnemius muscle, and individual myofiber cross-sectional area were measured to evaluate the degree of …

Aging-Associated Dysfunction Of Akt/Protein Kinase B: S-Nitrosylation And Acetaminophen Intervention, Miaozong Wu, Anjaiah Katta, Murali Gadde, Hua Liu, Sunil Kakarla, Jacqueline Fannin, Satyanarayana Paturi, Ravi Arvapalli, Kevin Rice, Yeling Wang, Eric Blough

Ravi K. Arvapalli

Background: Aged skeletal muscle is characterized by an increased incidence of metabolic and functional disorders, which if allowed to proceed unchecked can lead to increased morbidity and mortality. The mechanism(s) underlying the development of these disorders in aging skeletal muscle are not well understood. Protein kinase B (Akt/PKB) is an important regulator of cellular metabolism and survival, but it is unclear if aged muscle exhibits alterations in Akt function. Here we report a novel dysfunction of Akt in aging muscle, which may relate to S-nitrosylation and can be prevented by acetaminophen intervention. Principal Findings: Compared to 6- and 27-month rats, …