Browsing by Subject "Endocrine System Diseases"
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Item Mechanism of Action and Clinical Efficacy of AL-3789, an Angiostatic Steroid(1996-12-01) Defaller, Joseph M.; Clark, Abbot F.; Quist, Eugene E.; Yorio, ThomasDeFaller, Joseph M., Mechanism of Action and Clinical Efficacy of AL-3789, an Angiostatic Steroid. Doctor of Philosophy (Pharmacology), December, 1996, 115 pp., 11 tables, 31 illustrations, reference list, 115 titles. Angiogenesis, the growth of new blood vessels, is important in cancerous tumor growth, diabetes, and degenerative diseases. During angiogenesis, proliferating vascular endothelial cells from blood vessels secrete proteinases, including urokinase (uPA) and stromelysin-1 (MMP-3), which dissolve the extracellular matrix and allow them to migrate and form new blood vessels. In this investigation the angiostatic effects of AL-3789, an angiostatic steroid, were investigated in in vitro human cell models and human clinical trials. The angiostatic mechanism of action of this agent at 10^-5 molar concentration was demonstrated to include: 1) inhibition of lipopolysaccharide-induced uPA and MMP-3 production by human microvascular endothelial cells (HMVEC-L), 2) dose-dependent inhibition of HMVEC-L proliferation, and 3) alteration in the expression of approximately 1% of HMVEC-L proteins visualized by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). These protein changes are similar in magnitude to those caused by glucocorticoids, which act via an intracellular/intranuclear glucocorticoid receptor. The clinical efficacy of AL-3789 in preventing re-neovascularization and recurrence of malignant pterygia following surgical excision in humans was demonstrated by topical ocular dosing of a 1.0% suspension three times daily in a double-masked, randomized, prospective, placebo-controlled trial. Pterygium is a chronic condition in which neovascularized fibrotic tissue grows over the cornea to eventually obstruct the visual axis in some patients. Computer image analysis of serial photographs for each patient following surgery showed a re-neovascularization growth rate following pterygium excision of 1.58 mm^2/week for patients treated with placebo compared to 0.78 mm^2/week exhibited by the AL-3789 treated group (p [less than] 0.05, ANOVA). Pterygia recurred in 71% of the placebo group compared to 42% of the AL-3789 treated group (p [less than] 0.05, Chi-square contingency test). In conclusion, the angiostatic steroid AL-3789 inhibits neovascularization in part by decreasing vascular endothelial cell proliferation and proteinase (urokinase and stromelysin-1) secretion. AL-3789 treatment significantly inhibits re-neovascularization and recurrence rates following malignant pterygium excision in humans.Item Pre-diabetes Screening Tools for Adults Living in the United States(2014-05-01) Evans, Eva L.; Sterling, David; Fischbach, Lori; Felini, Martha J.Almost 37% of persons living in the US aged [greater than] 18 years have pre-diabetes, Persons with pre-diabetes are at high risk of developing type-2 diabetes (advanced hyperglycemia) and also have a higher risk of cardiovascular disease than those with normal blood glucose levels. Furthermore, results from cross-sectional studies indicate that microvascular complications arising from hyperglycemia may begin at the pre-diabetic stage. There is evidence that progression of pre-diabetes may be halted or even reversed with lifestyle and pharmaceutical interventions. However, less than 10% of US adults with pre-diabetes are aware of their condition, which indicates that current pre-diabetes screening methods are inadequate. US physicians need a comprehensive pre-diabetes screening tool. To this end, non-invasive screening score sets were created to screen for IFG, IGT and elevated HbA1c. Because preliminary analyses indicated that the screening accuracy of the pre-diabetes screening score sets would be enhanced by not restricting the score sets to only the pre-diabetic ranges of hyperglycemia, the pre-diabetes screening tool was designed to screen for hyperglycemia in the pre-diabetic and diabetic ranges. These hyperglycemia screening score sets have been based on a scoring system of non-invasive factors associated with hyperglycemia that are already routinely measured or assessed during a visit to the doctor. These factors were age, gender, smoking status, diabetes family history, history of cardiovascular disease, history of hypertension, height, body mass index, physical activity level (by surrogate measure of fasting heart rate), level of alcohol consumption, history of early menarche (women only), and history of gestational diabetes (parous women only). To boost performance for the non-invasive fasting hyperglycemia score set and the non-invasive elevated HbA1c screening score set, both for use in parous women, the fasting screening score set and the HbA1c screening score set included the factor, ethnicity. The pre-diabetes tools were externally and internally validated and were also compared to other non-invasive methods that might be used to screen for hyperglycemia.Item Store operated calcium entry in glomerular mesangial cells and diabetic nephropathy(2016-08-01) Chaudhari, Sarika; Rong Ma; J. Thomas Cunningham; Robert T. MalletGlomerular mesangial cells (MCs) are the major source of extracellular matrix (ECM). One of the early pathological changes in diabetic nephropathy (DN) is accumulation of ECM in glomeruli. Multifunctional store-operated Ca2+ entry (SOCE) regulates MC function. However, whether and how SOCE in MCs contributes to pathophysiology of DN remains unknown. The aim of the study was to investigate association of SOCE in MCs with ECM protein expression and the underlying mechanism using both in vitro and in vivo systems. Study I was to determine the effect of diabetes on SOCE. In cultured human MCs, we found that prolonged high glucose (HG) treatment (7 days) significantly increased SOCE and membrane currents through store-operated channels (SOC). These responses were abolished by SOC inhibitors. Consistently, prolonged HG treatment also increased the abundance of SOC proteins STIM1 and Orai1. HG also increased STIM1, but not Orai1 mRNA expression. Furthermore, both STIM1 and Orai1 proteins were also increased in the glomeruli/renal cortices of diabetic rats. Study II determined the influence of SOCE in MCs on ECM protein expression. We found that activation of SOC by thapsigargin reduced the abundance of fibronectin and collagen IV while inhibitors of SOC had opposite effects. Knockdown of Orai1 in human MCs increased fibronectin abundance. The HG induced increase in fibronectin was attenuated by SOCE. Using a nanoparticle siRNA delivery system, specific knockdown of Orai1 in MCs in mice increased glomerular fibronectin and collagen IV protein content and mesangial expansion. Study III determined the mechanism for inhibition of ECM protein expression by SOCE. We found that activation of SOC attenuated TGFβ1 mediated phosphorylation and translocation of Smad3, a known fibrotic pathway in MCs. However, there was no change in the production or secretion of TGFβ1 by MCs. Orai1 knockdown in MCs in mice increased the activation of Smad3. Taken together, our results indicate that SOCE in MCs may be increased in the late stage of diabetes, which suppresses ECM protein expression by inhibiting TGFβ1-smad3 pathway.Item Synergy 2008: Annual Research Report(2008-01-01)Item The Association between Health Literacy and Diabetes Outcomes and Self-Management Behaviors among Older Adults in the U.S(2015-08-01) Montoya, Maria F.; Dennis Thombs; Subhash Aryal; Emily Spence-AlmaguerBackground: In the United States an estimated 10.9 million people aged 65 and older are living with diabetes mellitus. Previous research has found that demographic and socioeconomic factors, health status, health behaviors, and interventions are potential determinants of diabetes outcomes. Recent studies have found that limited health literacy may be a potential new determinant of diabetes outcomes. Limited health literacy is common in underrepresented and marginalized groups such as people with low economic status, low educational attainment, new immigrants, the elderly, racial and ethnic minorities, and patients with chronic conditions. Older adults are at higher risk of developing chronic complications from improper diabetes self-management and self-care. Purpose: In this dissertation, we explore the association between health literacy and diabetes outcomes and self-management behaviors among older persons with an imputed health literacy score derived from demographic information. Methods: This study is a secondary analysis of existing cross-sectional data from the National Health & Nutrition Examination Surveys (2009-2010), in the United States. The final sample consisted of 779 participants who were ≥55 years and older and diagnosed with DM by self-report or through bio-marker laboratory testing. The predictor and outcome variables were DAHL proxy health literacy score, categorized as adequate (HL [greater than] 76), marginal (HL 63-75), and inadequate (HLp = 0.66). Proxy health literacy score contributed to the prediction of fasting blood glucose in Block 2, and made a unique contribution (β=−.392; Sig F. change: p = .028) to the full model. The fully adjusted hierarchical regression models for HbA1c showed that HL did not add any variability to the model. The fully adjusted FBG model was not statistically significant. After controlling for covariates, we found that in separate hierarchical logistic regression, health literacy level, was not associated with predicting the odds of the eight indicators of proper diabetes management. Furthermore, the R2 change attributed solely to the addition of health literacy level did not exceed 2.7% for any of the logistic regression models. Conclusion: The present study supports previous findings that found no association between HbA1c, diabetes self-management behaviors and health literacy. This study found that the characteristics of individuals who were not aware of their diabetes status was higher among subjects that were younger, more educated, higher socioeconomic status and not married. More studies are needed to examine factors associated with diabetes self-management behaviors that take into account individual health literacy, diabetes knowledge, and create targeted initiatives that decrease the risk factors associated with diabetes among the aging population.Item The Association of Health Literacy with the Management of Type 2 Diabetes(2017-12-01) Kumar, Samita; Stephen O. Mathew; Caroline A. Rickards; Johnny J. HeIntroduction: Type 2 Diabetes (T2D) is a chronic metabolic disease characterized by high blood glucose levels in the blood. It is associated with microvascular and macrovascular complications which can lead to potential threats such as to amputations and even death. The irony of the disease is that these complications are preventable with appropriate treatment and self-management. The Emergency Medicine Department (ED) at University of Southwestern Medical center conducted this study to assess health literacy Parkland Memorial Hospital patients with T2D. The objective for the research study was to assess the for association of health literacy with management of T2D. Methods: This was a prospective study with collection of personal health information (PHI) and 30 day-follow up for ED recidivism. Eligibility was assessed by pre-screening via EPIC (Electronic Medical Record System for Parkland). The tool for measuring health literacy was the Short Assessment of Health Literacy (SAHL) and data was collected. Results: The total number of subjects enrolled was 23 with ages 18 or above male and females both with Spanish or English speaking only with T2D. Mean age of the subjects was ~50 years with standard deviation of 10 years, males were over half than women. About 74% were white hispanic males. According to the data collected, 30% of the patients demonstrated inadequate health literacy based on SAHL score survey. Since the study could not reach adequate power due to low enrollment, no significant associations could be made from this small sample size. Total number of subjects required to have adequate power was 400. Conclusions: Due to low enrollment period at this time the recommendation would be to continue collecting data to have a larger sample size to afford the observation of statistically relevant associations. If any, statistically significant associations are found, then future studies will focus on improving diabetes outcomes through the development of educational tools at the individual patient’s appropriate literacy level. There are many reasons to improve diabetes care and explore all possible factors that contribute to poor outcomes. Millions of people are living with uncontrolled diabetes and the burden is not only on the patient but also on the community as a whole. Quality care should aim for improved benchmarks for patients with diabetes and their knowledge about the disease, such as 1) obtaining HbA1c levels below 8%, 2) blood pressure in the normal range, 3) having regular foot exams to keep a check on any developing signs of pressure sores and 4) most importantly having dilated eye exam on a regular basis.Item The Role of Fibroblast Growth Factor-2 in the Expansion of Pancreatic Islets IN VITRO(2004-05-01) Ettinger, Eve Sari; S. Dan Dimitrijevich; Julian Borejdo; Richard EasomEttinger, Eve Sari, The Role of Fibroblast Growth Factor-2 in the Expansion of Pancreatic Islets In Vitro. Doctor of Philosophy (Biomedical Sciences, Biochemistry and Molecular Biology), May 2004, 181 pp., 7 tables, 46 figures, 109 references. The focus of these studies was to identify a pool of progenitor cells within the adult islet, which can be expanded in vitro and aggregated into glucose responsive neoislets as a potential source for transplantation in diabetic patients. We hypothesize that normal adult islets contain an unspecialized proliferative progenitor cell population that can be expanded, aggregated by FGF-2 via PKC mechanism in 2-D culture or in a Rotating Wall Vessel Cell Culture System and matured into glucose-sensitive neoislets through the differential expression or activation of one or more PKC isoform(s). It was shown by immunofluorescence that normal adult islets from several species (rat, porcine, human and canine) contain proliferative endocrine precursor (endocrine epithelial) cells, which coexpress insulin, glucagon and somatostatin. These cells also express PDX-1, a marker of mature B cells and endocrine precursors as well as glut 2 and glucokinase, which are necessary components of glucose metabolism. Endocrine epithelial cells were shown to aggregate into neoislets either spontaneously in 2-D culture or via a rotating wall vessel cell culture system in the presence of fibroblast growth factor-2. FGF2 has been implicated in the aggregation of endocrine epithelial cells into neoislets via the FGFR-cadherin-catenin complex or through PKC signal transduction. Due to the variations in islet isolation, Ins-1 cells were used as a model of B cell aggregation. PKC profiles of endocrine epithelial cells, neoislets, native islets, Ins-1 cells and Ins-1 neoislets were determined. PKC-α, BII, ε and ζ were the only isoforms expressed in these cells and are potential targets for modulation in the differentiation of endocrine epithelial cells. Insulin secretion in response to a glucose challenge was examined in normal islets, neoislets, endocrine epithelial cells, and Ins-1 cells. Although endocrine epithelial cells express insulin, show dense secretory granules and contain two critical proteins in the glucose-sensing cascade, they are immature with respect to glucose-responsive insulin secretion. Neoislets show insignificant insulin secretion in response to elevated glucose when compared to normal islets. Aggregation of endocrine epithelial cells may be the first step in differentiation into mature β cells, however glucose-responsive insulin secretion must be achieved in vitro for use as an alternate source of islets for transplantation in diabetic patients.