Browsing by Subject "Immune System Diseases"
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Item A Review of the Literature on Faith-Based Organization's HIV/AIDs Care and Prevention Efforts in Sub-Saharan Africa(2005-05-01) Rojas, Zeida G.; Lurie, Sue; Urrutia-Rojas, XimenaRojas, Zeida G., A Review of the Literature on Faith-Based Organization’s HIV/AIDS Care and Prevention in Sub-Saharan Africa. Master of Public Health (Community Health), May 2005, 83 pp., 20 diagrams, bibliography, 10 titles. The thesis assesses the role of faith-based organizations (FBOs) involved in HIV/AIDS related care and prevention activities in Sub-Saharan Africa. Do FBOs have the ability to address the multi-faceted syndrome that HIV/AIDS brings to an individual, their family and community? Can FBOs be effective partners to carry out prevention and care initiatives? Faith-based organizations are generally overlooked as potential partners and leaders in the fight against HIV/AIDS. FBOs are often the only genuine nongovernmental organizations in many rural parts of poor countries, or at a minimum, they are the strongest and most influential. Due to their organizational networks, FBOs are able to mobilize people and resources, and to reach rural or isolated areas. Evidence of current FBO efforts demonstrates that FBOs have the ability to address the multifaceted effects of HIV/AIDS and can become indispensable partners for government health agencies and NGOs.Item A Study of Disparities in the Receipt of Anti-Retroviral Drugs, Health Status, and Insurance Coverage Among a Sample of HIV-Positive Adults(2006-12-01) Wittenmyer, Brian F.; Lykens, Kristine; Talbert, Jeffrey; Strawderman, TimWittenmyer, Brian F., A Study of Disparities in the Receipt of Anti-Retroviral Drugs, Health Status, and Insurance Coverage among a Sample of HIV-Positive Adults. Master of Public Health (Health Management and Policy), December 2006, 88 pp., 8 tables, references, 32 titles. Anti-retroviral medications (ARV) are effective at treating HIV/AIDS. Medicare, Medicaid, and ADAP are public programs that supply ARVs to needy patients in the U.S. Studies have documented dispartities in AIDS incidence/prevalence, insurance, and ARV-use. The study described demographic, clinical, and insurance characteristics of a sample of HIV+ persons. The study explored relationships between AIDS diagnosis, health status, and ARV-receipt and demographic, insurance, and clinical variables. Disparities in ARV-receipt, AIDS diagnosis, and health-status were found for gender, age, race, geographic region, and SES. Policy recommendations included: shortening the disability waiting-period for Medicare-eligibility, and relaxing Medicaid’s income-eligibility requirements.Item An Evaluation of Acanthosis Nigricans School Screening Results in Richardson Independent School District to Determine the Association of Acanthosis Nigricans and Other Factors for Type 2 Diabetes Mellitus(2005-05-01) Gardner, Janet E.; Urrutia-Rojas, Ximena; McConathy, Walter J.; Cipher, Daisha J.Gardner, Janet E., An Evaluation of Acanthosis Nigricans School Screening Results in Richardson Independent School District to Determine the Association of Acanthosis Nigricans and Other Risk Factors for Type 2 Diabetes Mellitus. Master of Public Health (Community Health), May 2005, 65 pp., 11 tables, reference list, 47 titles. Cases of Type 2 diabetes mellitus (T2DM) have been increasing at alarming rates in Texas. Identifying underlying factors, such as acanthosis nigricans (AN), elevated body mass index and hypertension, which might contribute to the development for type 2 diabetes, is critical. This study analyzed the relationship of AN with these risk factors of T2DM. Richardson Independent School District screening results for 2003-2004 were analyzed. This study concluded that calculated BMI values yielded the highest association with grades of AN. BMI-for-age percentiles greater than or equal to the 95th percentile and elevated diastolic and/or systolic blood pressures were strongly associated with AN grades.Item Chemokine CXCL8 Mediated Intercellular Interactions in HIV-1 associated Dementia(2013-12-01) Mamik, Manmeet K.; Ghorpade, AnujaThis dissertation explores the role of chemokine CXCL8 during human immune deficiency virus (HIV)-1 infection in the brain. Chemokine CXCL8 is an important neutrophil chemoattractant implicated in various neurodegenerative disorders. It is upregulated in the brains and cerebrospinal fluid of HIV-1 infected individuals suggesting its potential role in HIV-1 associated neuroinflammation. Astrocytes are known to be the major contributors to the CXCL8 pool. Interleukin (IL)-1β activated astrocytes exhibit significant upregulation of CXCL8. In order to determine the signaling pathways involved in CXCL8 regulation in astrocytes, we employed pharmacological inhibitors for non-receptor Src homology-2 domain-containing protein tyrosine phosphatase (SHP) 2 and mitogen-activated protein kinases (MAPK) pathway and observed reduced expression of CXCL8 following IL-1β stimulation. Thus, our findings suggest an important role for SHP2 in CXCL8 expression in astrocytes during inflammation, as SHP2, directly or indirectly, modulates p38 and extracellular signal regulated kinase (ERK) MAPK in the signaling cascade leading to CXCL8 production. In the post-antiretroviral therapy (ART) era, low level of productive replication of HIV-1 in brain is a critical component of neuropathogenesis regulation. HIV-1 replication is a complex mechanism involving both host and viral factors. The majority of viral replication in brain occurs in perivascular macrophages and/or 2 microglia. In this study, we investigated the effect of CXCL8 on productive infection of HIV-1 in human monocytes-derived macrophages (MDM) and primary human microglia. The results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2 and induces HIV-1 long terminal repeat (LTR) promoter activity. Detailed understanding of astrocyte signaling and HIV-1 replication, as presented in the thesis, will be relevant to glial-neuronal interactions, which are central to neuroinflammation in HIV-1 and many other neurodegenerative conditions. Also, modulation of levels of CXCL8 can be a therapeutic strategy for control of productive HIV-1 replication in the brain.Item Evaluation of NK Cell – Astrocyte Interactions: Potential Role in HIV-Associated Neurocognitive Disorders and HIV- Associated Dementia(2015-05-01) Bowen, Kelly E.; Mathew, Porunelloor A.; Mathew, Stephen O.; Hodge, Lisa M.NK cells play important roles in immunity against pathogens and cancer. NK cell functions are regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells. During pathological conditions, NK cells were shown to be recruited to the CNS and could impact CNS physiology by killing glial cells and by secreting IFN-g. Astrocytes are intimately involved in immunological and inflammatory events occurring in the CNS and reactive astrogliosis is a key feature in HIV-associated neurocognitive disorders (HAND). There is little data on NK cell-astrocyte interactions and ligands expressed on astrocytes that could impact NK cell function. This study aimed to identify NK-associated ligands expressed by human astrocytes that confer this NK-directed cytotoxicity of astrocytes and assay the cytotoxicity differences in presence and absence of HIV 3S peptide. Using a fusion protein consisting of the extracellular domain of NKp44 fused to Fc portion of human IgG, we determined the expression of a novel ligand for NKp44 (NKp44L) on astrocytes. Incubation of astrocytes with 3S peptide downregulated NKp44L expression on astrocytes implicating protection from NK mediated killing. Thus, our study demonstrated that NKp44 has a protective effect on astrocytes from NK cell mediated killing during HIV infection. Astrocytes could also secrete cytokines that affect the expression of NK receptors on NK cells. We evaluated the expression of receptors on NK cells after co-culture with astrocytes. CD38 expression was increased on primary NK cells after incubation with astrocytes. CD38 is expressed on both NK cells and astrocytes and has an important implication in HIV-1 infection. Blocking CD38 signaling in our studies decreased astrocyte lysis, suggesting CD38 signaling has important implications in NK-astrocyte interactions. Future studies providing novel insights into the role of NK cells in the pathogenesis of HAND and other brain disorders might result in the development of NK cell based therapies for brain pathologies.Item Immediate Effects of Osteopathic Manipulative Treatments on Immune Function in a Healthy Population: A Pilot Study(2006-05-01) John, Janice Thomas; Stoll, Scott; Simecka, Jerry; Atkinson, BarbaraJanice Thomas, D.O., M.S. Immediate Effects of Osteopathic Manipulative Treatments on Immune Function in a Healthy Population: A Pilot Study. Master of Science (Clinical Research and Education – OMM), May 2006, 75 pp, 3 tables, 5 figures, 66 references, 24 titles. Objectives: The purpose of this pilot study was to investigate the immediate effects of Osteopathic Manipulative Treatment (OMT) on immune function in a healthy population. Methods: This was a randomized, blinded and controlled clinical trial. 50 healthy individuals, ages 18 to 40, were recruited. Subjects were randomly assigned to one of two groups: OMT or Rest (control). Blood and saliva samples were collected pre and post-intervention (thirty minutes of OMT or Rest). Samples were analyzed for a CBC, salivary IgA, and various lymphocyte populations. Results: This study successfully demonstrated the feasibility of this protocol. No statistically significant differences in outcome measures were identified between the two groups, nor were any apparent trends identified. Conclusion: This study established a framework for future research investigating the effects OMT on acute and chronic infection, chronic pain, and immunocompromised populations in human and/or animal populations.Item Intercellular Nef transfer and HIV-1 infection of astrocytes(2015-05-01) Luo, Xiaoyu; He, Johnny J.; Ghorpade, Anuja; Wordinger, Robert J.Acquired immune deficiency syndrome (AIDS) is a pandemic caused by human immunodeficiency virus type 1 (HIV-1). It is a major health issue in many parts of the world ever since its discovery in 1981. The most devastating effect of HIV-1 infection is the graduate loss of CD4+ T cells, which eventually leads to the dysfunction of the immune system, susceptibility to opportunistic infections and cancer. HIV-1 Nef protein is long known as an essential pathogenic factor for HIV-1/AIDS pathogenesis. A few recent studies including ours have demonstrated that Nef can be transferred to neighboring cells and alters the function of these cells. However, the underlying mechanism of intercellular Nef transfer is in dispute. In the first part of our study, we characterized two potential underlying mechanisms for intercellular Nef transfer: direct cell-cell contact and exosomes using several complementary strategies and a panel of exosomal markers. First, we showed that Nef was transferred from Nef-expressing or HIV-infected CD4+ T lymphocytes to CD4+ T lymphocytes and astrocytes, and that the transfer was mainly associated with tunneling nanotube formation. Then we determined that Nef enhanced virological synapse formation and induced cytoskeleton re-arrangement and cell surface protrusions, suggesting that Nef promotes the establishment of intercellular connection and communication between infected cells and uninfected cells. Thirdly, we examined the possibility of Nef transfer through exosomes. In the exosome uptake assay, Nef transfer was undetectable while exosome marker CD81 transferred rapidly. In contrast, Nef was detected in crude exosomes collected from Nef-transfected 293T. In addition, two different populations of exosomes were successfully separated by OptiPrep gradient fractionation and determined as AChE+/CD81low/TSG101low exosomes and AChE- /CD81high/TSG101high exosomes. We determined that Nef was selectively secreted into the AChE+/CD81low/TSG101low population. Lastly, microscopic imaging showed no significant Nef detection in exosomal vesicle-like structures in and out the cell. Taken together, this study shows that Nef transfer requires direct cell-cell contact such as tunneling nanotubes, not cell-free exosomes. In addition, this study reveals existence of two types of exosomes: AChE+/CD81low/TSG101low exosomes and AChE/CD81high/TSG101high exosomes. In the second part, we characterized HIV-1 infection of astrocytes. Astrocytes are the most abundant cells in the central nervous system (CNS) and play important roles in HIV-1/neuroAIDS. Detection of HIV-1 proviral DNA, RNA and early gene products but not late structural gene products in astrocytes in vivo and in vitro indicates that astrocytes are susceptible to HIV-1 infection albeit in a restricted manner. We, as well as others have shown that cell-free HIV-1 is capable of entering CD4- astrocytes through human mannose receptor-mediated endocytosis. In this study, we took advantage of several newly developed fluorescence protein-based HIV-1 reporter viruses and further characterized HIV-1 interaction with astrocytes. First, we found that HIV-1 was successfully transferred to astrocytes from HIV-infected CD4+ T cells in a cell-cell contact- and gp120-dependent manner. In addition, we demonstrated that compared to endocytosis-mediated cell-free HIV-1 entry and subsequent degradation of endocytosed virions, cell-cell contact between astrocytes and HIV-infected CD4+ T cells led to robust HIV-1 infection of astrocytes but retained the restricted nature of viral gene expression. Furthermore, we showed that HIV-1 latency was established in astrocytes. Lastly, we demonstrated that infectious progeny HIV-1 was readily recovered from latently infected astrocytes in a cell-cell contact-mediated manner. Taken together, our studies point to the importance of the cell-cell contact-mediated HIV-1 interaction with astrocytes and provide direct evidence to support the notion that astrocytes are HIV-1 latent reservoirs in the CNS.Item "Is it as Simple as ABC?" -- Applying Uganda's ABC Approach Amongst the Dinka Ethnic Group of Southern Sudan(2007-12-01) Madut, Nyebol B.; Hilsenrath, Peter; Singh, Karan; Stimpson, JimMadut, Nyebol B., “Is it as simple as ABC? – Applying Uganda’s ABC approach amongst the Dinka ethnic group of Southern Sudan. Master of Public Health (Health Management and Policy), December 2007, 127 pp, 23 figures, 23 tables, bibliography, 157 titles. The purpose of this thesis is to explore those activities than can potentially result in a constructive balance of A, B and C activities, which could translate into an effective HIV prevention strategy for Southern Sudan’s largest ethnic group, the Dinka. In other words, the objective of this paper is to examine the local cultural context of southern Sudan’s largest ethnic group, as well as the state of the AIDS epidemic in areas populated by the Dinka; and then determine which public health and/or health management and policy strategies will prove to be the most effective in tailoring an appropriate mix of ABC activities.Item Regulation of TNF-Mediated Cell Death in Breast Cancer Cells(2006-05-01) Lu, Dongmei; Basu, Alakananda; Simpkins, James W.; Wu, Ming-ChiDongmei Lu, Regulation of TNF-mediated cell death in breast cancer cells. Doctor of Philosophy (Biochemistry & Molecular Biology), May 2006, 173 pp., 32 illustrations, 329 references. Protein kinase C-ε (PKCε), a novel PKC, has been shown to attenuate tumor necrosis factor-α (TNF)-induced apoptosis in breast cancer cells. The purpose of this dissertation is to delineate the mechanism(s) by which PKCε exerts its antiapoptotic effect. Comparison of PKCε level in several breast cancer cells revealed that PKCε level alone could not explain sensitivity of breast cancer cells to TNF. Protein kinase B/Akt (Akt) was constitutively active in breast cancer cells resistant to TNF. Inhibition of phosphatidyl-inositol 3-kinase (P13-K0 by Ly294003 increased TNF-mediated apoptosis in MCF-7 cells that overexpress Akt and sensitized BT-20 and SKBR-3 cells that express constitutively active (CA) Akt to TNF. PKC inhibitor bisindolylmaleimide (BIM) also sensitized BT-20 and MCF-7 cells to TNF. Overexpression of CA-Akt in MCF-7 cells attenuated TNF-induced apoptosis. Therefore, both PKCε and Akt are important for deciding TNF sensitivity. The cross-talk between PKCε and Akt was examined in MCF-7 cells. PKCε overexpression increased basal Akt phosphorylation and enhanced TNF-induced Akt activation. Knockdown of PKCε by siRNA decreased TNF-induced Akt activation. Depletion of Akt abolished the antiapoptotic effect of PKCε. Akt was constitutively associated with PKCε and DNA-dependent protein kinase (DNA-PK), and this association was increased by TNF. Knockdown of DNA-PK diminished the effect of PKCε on Akt phosphorylation and increased TNF-mediated apoptosis. These results suggest that PKCε activates Akt via DNA-PK to mediate its antiapoptotic function. We also investigated whether PKCε regulates mitochondrial cell death pathway by inhibiting the proapoptotic function of Bcl-2 family member Bax. Overexpression of wild-type but not dominant-negative PKCε inhibited TNF-mediated mitochondrial depolarization. Depletion of Bax inhibited TNF-induced apoptosis. PKCε overexpression abolished Bax dimerization and translocation to mitochondria, while PKCε depletion had the opposite effect. Bax was associated with PKCε in PKCε-overexpressing cells. These results indicate that PKCε attenuates mitochondrial cell death pathway by inhibiting Bax translocation. These findings demonstrate the PKCε activates Akt via DNA-PK and inhibits proapoptotic Bax to mediate its antiapoptotic effect in breast cancer cells. An understanding of the mechanism(s) by which PKCε inhibits apoptosis in breast cancer cells is important for developing more effective cancer therapies.Item Safety and Efficacy of a Novel Xanthine Oxidase/Xanthine Dehydrogenase Inhibitor in the Treatment of Gout(2003-12-01) Brooks, Molly; Rudick, Victoria; Forman, Mitchell; Jimenez-Williams, CynthiaSummary: The internship report is based on the activities completed during the Internship Practicum at the Department of Internal Medicine, Division of Rheumatology, at the University of North Texas Health Science Center at Fort Worth and at the Rheumatology Clinic at John Peter Smith Hospital. This internship serves as partial training in the area of Clinical Research Management and focuses on studies involving rheumatic diseases, with specific emphasis on Gout. Specific Aims/Hypothesis: Ongoing clinical trials in the Department of Internal Medicine Rheumatology clinic are the bases for the project which focuses on the treatment of gout and a proprietary study on the uses of a novel xanthine oxidase/ xanthine dehydrogenase inhibitor (XOD/XDH inhibitor) to relieve the symptoms of gout. The particular research is a phase three study to assess the safety and efficacy of a novel xanthine oxidase/ xanthine dehydrogenase inhibitor compared to a placebo and an established xanthine oxidase/ xanthine dehydrogenase inhibitor, allopurinol. The hypothesis of the study is that the new XOD/XDH inhibitor will be more effective at lowering uric acid levels and thus will reduce the frequency of gout more effectively and with fewer side effects than traditional treatment or a placebo. Under the direction of the Department of Internal Medicine, subjects who met inclusion/exclusion criteria of the study were randomly assigned to be treated with colchicine in addition to either allopurinol, or the novel compound, which hereafter will be referred to as the novel XOD/XDH inhibitor, or to a placebo. The safety and efficacy of the novel XOD/XDH inhibitor will be compared to the traditional drug of choice allopurinol, a uric acid lowering agent, and to a placebo. The placebo is an inactive pill that is designed to look and taste like either allopurinol or the novel XOD/XDH inhibitor. While the period of the internship is not long enough to complete the study and thereby assess the reliability of the hypothesis, the internship and this report have two specific aims: (1) to perform a literature search of gout and related topics and (2) to understand and perform activities of a clinical research coordinator as they relate to the novel XOD/XDH inhibitor study and to other clinical trials in rheumatology. The literature search focuses on specific areas concerned with details about gout: history, epidemiology, forms, causes, signs and symptoms, clinical diagnosis, differential diagnosis, complications, therapeutics (past, present, and future), prevention, associations, cellular mechanisms involved in hyperuricemia, as well as inflammation. The project also provides a description of the activities involved in clinical research, and discusses specifically the roles of the various personnel: Clinical Trials Coordinator, Principle Investigator, Sub-investigator, Institutional Review Board, and Clinical Trials Monitor as they have been involved in the novel XOD/XDH inhibitor study and other studies in rheumatology. Significance: Finding a new treatment for gout is of significant importance for several reasons. In countries with a high standard of living, such as the United States, prevalence of gout has increased and is probably the second most common form of inflammatory arthritis. Gout can result in significant short-term disability, occupational limitations, and increased utilization of medical services therefore making the disease a significant public health problem. New treatment options could greatly improve the prognosis for patients and in addition reduce the cost of the disease by preventing loss of wages due to patient absence from work, for example. Furthermore, new treatments for gout could provide patients with safer therapeutics alternatives than the traditional treatments.Item Trace amine associated receptor 1 (TAAR1), a novel astrocyte receptor for METH-mediated neurotoxicity in HIV-1-associated neurocognitive disorders (HAND)(2015-05-01) Cisneros, Irma E.; Ghorpade, Anuja; Wordinger, Robert J.; Forster, Michael J.This dissertation explores the role of astrocyte trace amine associated receptor 1 (TAAR1), a novel G-protein coupled receptor (GPCR), in modulating the effects of methamphetamine (METH) on astrocyte-mediated excitotoxicity, thereby exacerbating HIV-associated neurocognitive disorders (HAND). The rising pandemic of methamphetamine (METH) abuse has multiple effects and interactions with HIV-1 in infected individuals, affecting both the periphery and the central nervous system (CNS). Moreover, there is a high prevalence of HIV-1 infection among METH users. Underlying evidence provides insight into the cellular mechanisms associated with METH and HIV-1 neurodegeneration, including the effects and byproducts of glial cells, specifically astrocytes. While indirect effects of METH and HIV-1 have been proposed in astrocytes the direct mechanisms by which they contribute to neurodegeneration and continue to evolve. Particularly, imbalance in glutamate homeostasis plays a vital role in METH- & HIV-1-mediated neurodegeneration. We propose METH activates a novel GPCR, trace amine associated receptor 1 (TAAR1), thereby regulating astrocyte-mediated glutamate uptake via excitatory amino acid transporter-2 (EAAT-2), exacerbating HIV-1-induced excitotoxicity. Importantly, our data demonstrate astrocyte functions leading to neurotoxic outcomes like excitotoxicity can be directly exacerbated through TAAR1 regulation. Additionally, extrinsic regulation of TAAR1 signaling, including cAMP, calcium, PKA and PKC, not only reduce activation of subsequent signaling factors, but also reduce or eliminate METH- and IL-1β-mediated alterations in astrocytes glutamate clearance abilities. Finally, preliminary studies indicate that astrocyte-TAAR1 may be a novel therapeutic target for the common morbidity of METH abuse in HAND