Browsing by Subject "Tissues"
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Item An Evaluation of Muscle Biopsies in a Managed Care Organization(2001-05-01) Saad, Jill Moore; S. Dan Dimitrijevich; Roderick HookerSaad, Jill Moore., An Evaluation of Muscle Biopsies in a Managed Care Organization. Master of Science (Biomedical Sciences), May 2001, 16 pp., 7 illustrations, Reference List, 17 titles. Objective: The goal of this study was to assess the use of the percutaneous muscle biopsy in diagnosing inflammatory muscle diseases and to examine the benefit of centralizing inflammatory myopathies under one department-rheumatology-within a large health maintenance organization. Methods: A retrospective review of 363 muscle biopsies and histopathology reports, spanning 25 years, formed the basis of this study. The databases used in this study were the medical record, an institutional rheumatology registry, and histopathology reports. Cytoarchitectural abnormalities, necrosis and regeneration formed the basis of muscle disease classification. The histopathology findings were interpreted against the patient’s clinical history, examination, and clinical tests to develop a final diagnosis. Results: Rheumatologists in this location performed two-thirds of the biopsies percutaneously using an intervertebral rongeur and surgeons performed one-third open biopsies. Over time open biopsies were phased out due to preference for the percutaneous method. The average age of all muscle biopsy patients was 45 (3 months to 88 years old) and 55% were male. Polymyositis was the most frequently identified myositis (62%), followed by dermatomyositis (19%), and inclusion body myositis (7%). Conclusion: The use of percutaneous muscle biopsies using an intervertebral rongeur is the method of choice because of convenience, quality of specimen, low morbidity, and limited discomfort. Centralizing inflammatory muscle diseases within one organization contributes to the efficiency and effectiveness of inflammatory muscle disease management.Item Clinical Internship in the Surgery Department at the University of North Texas Health Science Center: Assessment of Human Antibody Response to Urokinase Part A: Specimin Acquisition Trial for the Assessment of Human Antibody Response to Urokinase in Subjects Treated for Acute Lower-Extremity Ischemia(2003-12-01) Hughes, Telicia A.; Rustin E. ReevesSignificance and Specific Aim of the Study. Significance. FDA has informed Abbott Laboratories of additional concerns related to manufacturing deficiencies for urokinase (Abbokinase). Until these problems are corrected, further distribution of Abbokinase would violate federal laws designed to assure the safety of drugs for patient use. FDA’s concerns about the product relate to serious deficiencies in the manufacturing processes, the testing of the product, and the screening and testing of the donors of the kidney cells used to make Abbokinase. Abbokinase is derived from cultures of human kidney cells from newborns who have died of natural causes, and is approved in the United States to dissolve blood clots in the lungs and heart arteries. It is also approved to help clear intravenous catheters. During inspections of Abbott Laboratories and of BioWittaker, Inc. Abbott’s supplier of human kidney cells, FDA identified numerous significant deviations from current good manufacturing practice (CGMP) regulations designed to assure product safety. Compliance with CGMP is important because products manufactured from human sources have the potential to transmit infectious agents. CGMP for products such as Abbokinase requires important, overlapping safeguards in the production process, including adequate –screening of donors and testing of cells, -controls for proper harvesting, storage, and handling of materials used in all stages of manufacturing, and –processes to remove or inactivate infectious agents from the product. Over the past several months, the firm has reported to FDA that a number of in-process lots of Abbokinase was contained with microorganisms. Six such lots were found to contain various strains of reovirus, a virus that usually results in no symptoms or causes minor respiratory or gastrointestinal symptoms. Association of reovirus infection with other human diseases have been reported, although a causal link has not been established. Another in-process lot was contaminated with mycoplasma, a microorganism that can cause respiratory infections, and, on rare occasions, other infections that may be serious. Abbott has assured FDA that none of these in-process lots were manufactured into final product or distributed. These recent findings of contamination and Abbott’s inability to locate the source of the problem have raised further concerns at FDA about Abbott’s entire manufacturing process for Abbokinase. Abbot’s deviations from CGMP could significantly impact the safety of the product. One FDA concern is that deficiencies in manufacturing practices could also lead to the product being contaminated with microorganisms that have not yet been detected. FDA also obtained additional information regarding the inadequacy of the screening and testing of the mothers and donors of the human kidney cells used to produce Abbokinase. Information was also obtained regarding the seven instances of in-process lots of product being contaminated with reovirus and mycoplasma. In the letter to Abbott, the agency has detailed the steps Abbott needs to take to correct the serious and significant manufacturing deviations. These include: -completing a thorough and adequate investigation of the reovirus and mycoplasma contamination, including the source of the contamination, -manufacturing Abbokinase using human kidney cells that have been obtained, processed, and tested through adequate methods, and –assuring that fully validated methods are used in the manufacturing process to test for infectious agents and remove them. Abbott submitted a supplemental new drug application providing for changes in procurement and processing of neonatal kidney cells, improvements in the manufacture and testing of the drug substance and drug product, revised release specifications for the drug substance and drug product, revised release specifications for the drug substance and drug product, a revised CBER lot release protocol, withdrawal of the “Open-Cath” dosage strengths, and revised labeling. Labeling revisions include updated information regarding product source and adverse reactions, as well as withdrawal of the coronary artery thrombosis and catheter clearance indication. The Department of Health and Human Services completed the review of that supplemental application, as amended, and it was approved based on Abbott’s written commitments, one of which is –To conduct a study to assess the immunogenicity of Urokinase after primary dosing. Urokinase is indicated in adults for the lysis of acute massive pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple segments for the lysis of pulmonary emboli accompanied by unstable hemodynamics, i.e., failure to maintain blood pressure without supportive measures. Therefore, it is important to complete this study, to meet federal requirements, so that Urokinase could be fully marketed and help to improve the quality of life. Specific Aim. 1. To access the human antibody response to Urokinase, a thrombolytic agent in subjects treated for lower extremity ischemia. A.) Technique: All subjects will receive an intra-arterial infusion of a minimum of 240,000 IU of Urokinase (UK). In part A of this study we will obtain serum specimens from subjects receiving UK. These blood specimens will be used in part B of this study for the qualitative/quantitative assessment of antibody response to Urokinase, specifically IgM, IgE, IgG. Antibody directed against the UK drug substance, API, and the inactive peptides/protein in the formulation.Item Effects of Osteopathic Manipulative Treatment on Osteoarthritis(2000-08-01) Pham, Chau N.Osteoarthritis (OA) is the most prevalent form of arthritis in the United States. Of those 65 to 74 years old, 18 per 100 women and 8 out of 100 men will experience OA of the knee. (Towheed and Hochberg, 1997) The Center for Disease Control and Prevention (CDC) reported a high prevalence for disability for person [greater than] 65 years. Arthritis or rheumatism accounts for 7.2 million (17.1%) people ranking above back problems and heart disease. (CDC, 1994) The Framingham epidemiologic study of knee osteoarthritis estimated a 27% prevalence for those 44% of those [greater than] 80 years. Nelson, Naimark, Anderson, Kazis, Castell & Meenan, 1987) This study uses the principles of Osteopathy to treat OA for the elderly as osteopathic manipulative treatment (OMT) specifically addresses the symptoms and signs of OA. The typical symptom of OA is pain stiffness “in and around a joint accompanied by limitation of function.” (Klippel, 1997) Pain from OA may originate from “periostitis at sites of bony remodeling; subchondral microfractures; irritation of sensory nerve endings in the synovium from osteophytes; periarticular muscle spasm; bony angina due to decreased blood flow and/or elevated intraosseous pressure; and synovial inflammation accompanied by release of prostaglandins, leukotrienes, and other cytokine.” (Klippel, 1997) Other symptoms include morning stiffness, gel phenomenon, buckling/instability. The signs of OA are bony enlargements, limitation of range of motion, crepitus, tenderness on pressure, pain, join effusion, malalignment and/or joint deformity. (Hazzard, 1999) Most often, pain and limitation of movement from OA cause signficiant changes in lifestyle for the older adult; functional independence is adversely affected. Decreased functional independence that affects the quality of life makes this the most debilitating illness in the 65 and older population. Studies have shown that patients with osteoarthritis of the hip and knee have comparable number of days with restricted activity as patients rheumatoid arthritis. (Towheed, 1997; Holman & Lorig, 1997). Treatment goals for managing osteoarthritic patients is to control pain subsequently minimizing functional limitation and disability. (Hazzard, 1999) To treat the above dysfunction, current treatments for OA include pharmacologic agents such as NSAIDs, analgesics, intra-articular steroid injections, topical analgesics; glucosamine sulfate and hyaluronic acid; nonpharmacologic measures include weight reduction, therapeutic ultrasound, acupuncture, transcutaneous electrical nerve simulation (TENS), physical therapy, pulsed electrical stimulation, orthotics, hydrotherapy, self management courses, and support groups. (Womheim, 1996; Zizic, 1995; Creamer, 1997; & McNoll, 199*) The primary objective of pharmacologic treatments is to decrease pain resulting in an increased functional capacity and improved quality of life. There are side effects and limitations to pharmacologic regimens. For example, the usage of NSAIDs in the treatment of the elderly can result in gastrointestinal bleeding. (McNoll, 1998) Non-pharmacologic treatments are viable alternatives in treating osteoarthritis; osteopathic manipulative treatment is such an alternative. A primary osteopathic principle dictates that structure and function are reciprocally inter-related. Any change from the “normal” is called somatic dysfunction. Specifically, somatic dysfunction is the altered or impaired function of related components of the somatic (body framework) system-skeletal, arthrodial, and myofascial structures and related vascular, lymphatic, and neural elements. (Greenman, 1989) OMT is used to return the body to its normal state by increasing symmetry and motion thereby improving body balance and reducing inflammation and pain by increasing fluid flow. When considering the physiological causes for OA of the knee coupled with the side effects from pharmacological treatment, health care providers must consider alternative treatments. The principles of osteopathy provide a logical spring board to meet that challenge. This present study provides a preliminary understanding of the efficacy of OMT for OA of the knee.Item Modulation of GABAA Receptor Function by Tyrosine Phosphorylation(1998-05-01) Fang, Mingjun; Glenn Dillon; Thomas Yorio; Eugene E. QuistMingjun, Fang. Modulation of GABAA Receptor Function by Tyrosine Phosphorylation. Master of Science (Biomedical Sciences), May, 1998, 32 pp., 6 illustrations, bibliography, 42 titles. The goal of this study was to determine the modulation of GABAA receptor function by tyrosine kinase phosphorylation, and to detect which subunit is phosphorylated to alter the GABA-induced chloride currents. From previous studies, we suggested that protein tyrosine phosphorylation may maintain GABAA receptor function. Here we tested the hypothesis that tyrosine phosphorylation modulates other GABAA receptor subtypes e.g., α1β2γ2 and α6β2γ2, and subsequently attempted to determine which subunit(s) may be phosphorylated. Our results support the hypothesis that PTK phosphorylation may maintain GABAA receptor function. In addition, we suggest this tyrosine phosphorylation occurs at the γ2 subunit of the receptor.Item Regional Adipose Tissue Deposition, Its Rate of Lipolysis, and Subsequent Effect of Insulin Resistance-in Type II Diabetes Mellitus(1999-06-01) Schalscha, Alan G.; Raven, Peter B.; Downey, H. Fred; Caffrey, James L.Diabetes mellitus is a disease that plagues populations world wide. More than 5 percent of U.S. citizens are afflicted with one or another form of this disease (22). This paper begins by discussing the incidence of this illness as it affects Americans. An explanation of the four forms in which diabetes mellitus itself will be offered, and these will be classified according to etiology. Non-insulin dependent diabetes mellitus (NIDDM), also called type II diabetes mellitus, will be the last of these forms mentioned. Due to its prevalence, NIDDM will be the focus of this paper. The proposed pathophysiology of NIDDM will be discussed, though to researchers it still remains somewhat of a mystery. This paper will then briefly the genetic and environmental interaction responsible for the onset of non-insulin dependent diabetes mellitus. A brief discussion of the interrelationship between decreasing physical activity and a subsequent increase in obesity will follow (38). The location of adipose tissue seems to have adverse effects on certain aspects of NIDDM, including its sensitivity to insulin. This paper proposes that either subcutaneous or visceral adipose deposits specifically reduce insulin sensitivity more than other fat stores. The connection between adipose tissue and insulin sensitivity appears to be mediated by fatty acids released from specific depots and their destination immediately following release.Item Thymic involution perturbs negative selection and leads to chronic inflammation(2015-08-01) Coder, Brandon D.; Dong-Ming Su; Rance E. Berg; Hriday K. DasThe ubiquitous presence of chronic low-level pro-inflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality. The etiology of inflammaging is largely unknown. Recent evidence has identified the persistent activation of immune cells, thought to arise from latent viral infections, as key contributors towards the development of a chronic inflammatory environment. However, the contribution of autoreactive T cells towards the development of inflammaging has yet to be investigated. Another pervasive feature of the aging process is the age-related involution of the thymus gland, which has been linked with a predisposition toward developing autoimmunity. In the present study, we determined how age-related thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging. We utilized a FoxN1 conditional knock-out (FoxN1-cKO) mouse model that mimics thymic involution while maintaining a young periphery and naturally aged C57Bl/6 mice. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by cellular infiltration into non-lymphoid tissues, elevated serum IL-6, and enhanced production of TNFα. Additionally, activated autoreactive T cell clones were detected in the periphery of FoxN1-cKO mice. We determined that a failure of negative selection, facilitated by decreased AIRE expression rather than impaired regulatory T cell (Treg) generation, and led to autoreactive T cell activation in the periphery. Furthermore, we have demonstrated that the young environment can reverse the age-related accumulation of Tregs but not inflammatory infiltration. Together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a source of chronic age-related inflammation (inflammaging).Item Tissue Transglutaminase in Glaucoma(2008-08-01) Tovar-Vidales, Tara; Clark, Abbot F.; Reeves, Rustin E.; Sheedlo, HaroldTovar-Vidales, Tara, Tissue Transglutaminase in Glaucoma. Doctor of Philosophy (Cell Biology and Genetics), August 2008; 113pp; 0 tables, 23 illustrations, 165 bibliography, 25 titles. Primary open-angle glaucoma (POAG) is the second leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is the major risk factor for POAG and is due to resistance of aqueous humor (AH) outflow through the trabecular meshwork ™ and Schlemm’s canal. Transforming growth factor-beta2 (TGF-β2) is elevated in the aqueous humor of glaucomatous eyes compared to normal eyes. Thus, TGF-β2 may play a role in regulating IOP. Tissue transglutaminase (TGM2) is a member of the transglutaminase family involved in cross-linking ECM proteins. In POAG, there are increased cross-linked extracellular matrix proteins (ECM) in the TM, and therefore, may result in elevated AH outflow resistance and elevated IOP. In this study, we examined the differences in both protein expression and enzyme activity of TGM2 between normal and glaucomatous TM cells and tissues. The findings demonstrated the presence of TGM2 in normal and glaucomatous cultured TM cells. We also showed that glaucomatous cultured TM cells and tissues have elevated levels of TGM2. Thus, this data suggest that TGM2 may have a pathogenic role in elevated outflow resistance and elevated IOP. Second, we observed the induction of TGM2 by TGF-β1, β2, and β3 in cultured TM cells, suggesting TGF-β isoforms regulate TGM2 protein levels. Finally, we observed that R-Smads and O38 regulated TGM2 protein levels, suggesting TGF-β2 acts through both its canonical and non-canonical signaling pathway to regulate TGM2.