Browsing by Subject "Cardiology"
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Item A Comparison of Medicare Prospective Payment Systems on P.T.C.A. and Stent Outcomes in an Urban Hospital(2001-05-01) Compton, Ben H.; Doug A. Mains; P. E. HilsenrathCompton, Ben H., A Comparison of Medicare Prospective Systems on P.T.C.A. and STENT Outcomes in an Urban Hospital. Master of Public Health (Health Services Administration), May 2001, 57 pp., 10 tables, 1 graph, bibliography, 51 titles. To determine if differences in outcomes exist between Medicare prospective payment systems when doing percutaneous transluminal coronary angioplasty (PTCA) or STENT surgeries. From January 1999 and December 2000, 146 Medicare patients were identified with 35 being outpatient and 111 inpatient. A separate group of 1-day inpatients was used as a comparison for the outpatient group. Results from the comparison reveal that in the three groups, the majority of patients were white, non-Hispanic males who were about 70 years of age. The 1-day inpatient group had the highest profit of all three with about $3,000 while the inpatient group broke even. The outpatient group had no in-hospital deaths or complications while all three had equal amounts of comorbidities. The conclusion is that losses will probably occur if PTCA and STENTs are done outpatient. Possible solutions are moving to an inpatient setting or determining which costs can be reduced in the outpatient setting.Item A Phase II Clinical Study to Evaluate the Efficacy and Safety of rhThrombin in Subjects Undergoing Arterial Bypass Surgery and AV Graft Formation for Hemodialysis(2004-12-01) Plascencia, Xochitl; Rustin E. Reeves; Della Weis; Don PeskaThe Association of American Medical Colleges Task Force on Clinical Research defines clinical research as a component of medical and health research intended to produce knowledge essential for understanding human disease, preventing and treating illness, and promoting health (Friedman, 1998). A clinical trial is defined as a research study conducted in humans which is designed to answer specific questions using scientifically controlled conditions with specified methodologies and endpoints (Gallin, 2002). Clinical research trials are essential in determining whether or not a drug is safe and effective. There are four phases that investigational drugs go through before they are allowed to be out in the market. Before beginning phase I of a study, there is usually a pre-clinical research and development phase. During this time the initial synthesis of study drug is accomplished and animal testing takes place. Phase I is the initial introduction of an investigational new study drug into humans. Phase I is usually conducted in healthy individuals and the primary goal is to determine the safety profile of the drug. Phase II trials tend to evaluate safety and initial efficacy. Subjects enrolled in this phase tend to have the disease necessary for use of study drug. Phase III studies are conducted to gather additional information about the effectiveness and safety of the drug and to determine the overall benefit-risk relationship of the drug. Finally, phase IV studies are usually referred to as post-marketing studies. During this phase, additional safety information is identified and the drug’s safety during routine use is evaluated. Each phase can range from two to ten years depending on the complexity of the clinical trial (Gallin, 2002). A phase II, randomized, double blind study of the safety and efficacy of topical recombinant human thrombin in patients undergoing peripheral arterial bypass surgery and arterio-venous graft formation for hemodialysis is the focus of the prospective drug study to be carried out in the surgery department at The University of North Texas Health Science Center. The primary objective of this study is to evaluate the safety and efficacy of recombinant human thrombin when used in different types of surgeries. Prior to signing an informed consent, subjects will have to meet inclusion and exclusion criteria set by study protocol. Study specific assessments and procedures will be performed after the informed consent is signed and dated. If bleeding at the anastomosis is found to necessitate intervention, a single application of either rhThrombin or placebo in combination with an absorbable hemostatic sponge to each anastomosis requiring hemostasis will be applied by the surgeon. The safety and efficacy of rhThrombin will be determined by measuring the incidence and severity of adverse events and of laboratory abnormalities. Occurrence of hemostasis within 600 seconds of application of the study drug at the anastomotic surgical site, incidence of anti-rhThrombin product antibodies, and time to hemostasis will also be measured.Item Alterations in Beta-Adrenergic Receptor Density on Human Lymphocytes in Response to Chronic Exercise(2000-12-01) Brittain, Adam K.; Peter B. Raven; Stephen R. Grant; Michael W. MartinA number of cardiovascular adaptations have been shown to occur in healthy individuals as a result from regular, chronic exercise training. These changes include, but are not limited to, a lower resting heart rate, a lower heart rate at any given submaximal workload, an increase in stroke volume, an increase in maximal cardiac output due primarily to an increase in contractility, a decreased peripheral vascular resistance (increased peripheral vascular conductance), an overall increase in vascularity, an increase in left ventricular mass, and an increase in total body oxygen extraction (Raven, 1994). Some of these adaptations are also known to commonly occur in patients with coronary artery disease enabling them to increase their total work capacity. Therefore, exercise apparently adapts the heart to better cope with the adverse affects of coronary artery disease and helps to prevent the aforementioned disease from developing in healthy individuals. The beta-adrenergic receptor (β-AR) is essential for the activation of many aspects of the cardiovascular system during dynamic exercise (1). The catecholamines epinephrine and norepinephrine are released from the adrenal medulla and postganglionic fibers of the sympathetic nervous system respectively in response to dynamic exercise. Epinephrine and other beta-adrenergic receptor agonists bind and activate the β-AR on the cell membrane thus allowing it to couple with the stimulatory GTP-binding regulatory protein Gs. This step initiate the activation of adenylate cyclase and the synthesis of cyclic adenosine 3’,5’ monophosphate (cyclic AMP), a key intracellular second messenger. Cyclic AMP ultimately activates cyclic AMP-dependent protein kinase (PKA), an enzyme that phosphorylates a number of intracellular proteins that subsequently influence cell metabolism and function. Alterations in the activity of the adrenergic system seen in several clinical and physiological situations, including exercise, are directly associated with changes in lymphocytic β-AR density or function (2). Moreover, it has been suggested that the changes in receptor density on lymphocytes correlate closely with cardiovascular responsiveness to catecholamines in humans (3-6). Additionally, changes in catecholamine concentration within the physiological range have a regulatory effect on β-AR density and function (7). One particular study established an inverse relationship between plasma and urine catecholamine concentrations and lymphocytic β-AR density in man (8). It is the intent of this review to describe some of the cardiovascular adaptations that occur as a result of chronic exercise and how these changes could be caused by alterations in β-AR density and responsiveness. Additionally, the comparisons and contradictions between chronic heart failure and chronic exercise will be made. The role of the beta-adrenergic system in mediating the effects of exercise will be introduced. The structure of the β-AR will be described and how its molecular structure dictates its function. A brief synopsis will be presented on the mechanism in which β-AR operates subsequent to ligand binding. Alterations of the β-AR, particularly its expression in the heart, through transgenics will then be reviewed to show how this receptor could be responsive for some of the aforementioned adaptations to chronic exercise. In this, some of the differences between the β1- and β2-AR will be described as well as some of the therapeutic implications that could result from overexpression of the β-AR. Following this, alterations in the density of the β-AR after both short-term and long-term exposure to catecholamines will be examined. Included in this section with be the detailed description of the mechanism of receptor desensitization that precedes receptor down-regulation. A brief review will then be given on the effects of chronic exercise on β-AR density. The use of human lymphocytes as model cells will then be described. Binding theory will be explained as it will be the basis of methodology used in any subsequent studies. Along with this, [125 Iodo] cyanopindolol (125I-CYP) will be introduced and its advantages and disadvantages as a β-AR ligand probe will be discussed.Item An Analysis of Patient Health Outcomes in a Cardiac Rehabilitation Program(2000-12-01) Hall, Cortni K.; Antonio Rene; Raghbir Sandhu; Manuel BayonaHall, Cortni K., An Analysis of Patient Health Outcomes in a Cardiac Rehabilitation Program. Master of Public Health, Epidemiology Track, December 2000, 48 pp., 11 tables, references, 30 titles. This study analyzed the coronary risk factor and quality of life outcome results of 55 patients who participated in a 12 week, phase II cardiac rehabilitation program. Baseline and post cardiac rehabilitation data were analyzed. There was an overall improvement of the coronary risk factor variables with significant improvements in functional capacity (p=0.001), diastolic blood pressure (p=0.01), total cholesterol (p=0.017), and LDL 9p=0.01). Significant improvements in the quality of life variables included physical function (p [less than] 0.01), role-physical (p [less than] 0.01), body pain (p [less than] 0.05), vitality (p [less than] 0.05), and social (p [less than] 0.05). There was also a significant finding of improved knowledge (p [less than] 0.01) after completion of phase II cardiac rehabilitation program.Item Androgens and Cardiovascular Disease(1998-05-01) Dickerman, Rob D.; Walter J. McConathy; Thomas Yorio; Robert GracyDickerman, Rob D., Androgens and Cardiovascular Disease Doctor of Philosophy (Biomedical Sciences), May 1998; 111 pp; 10 tables, bibliography, 197 titles. Anabolic steroids are commonly used by many muscle and strength dependent athletes due to their ability to enhance the hypertrophic effects of resistance training. The use of anabolic steroids by bodybuilders appears to carry significant health risks, most commonly reported are sudden death, myocardial infarction and cardiomyopathy. To investigate the effects of anabolic steroids on cardiovascular risks, a study was designed to analyze the effects of androgens on lipoprotein levels and structure/function of the heart. For the study on lipid-related risk, twelve competitive bodybuilders were recruited for a comprehensive analysis of serum apolipoprotein A-I, B, total cholesterol, HDL-cholesterol, LDL-cholesterol, and testosterone. Serum total cholesterol, HDL- and LDL-cholesterol, apolipoproteins A-I and Be were significantly lower in androgen-users. Consistent with previous reports, androgens were associated with decreases in HDL-cholesterol and apolipoprotein A-I. However, androgens were also associated with reduced serum total cholesterol, LDL-cholesterol and apolipoprotein B. Despite the significantly higher total cholesterol/HDL-cholesterol ratio, the low levels of serum total cholesterol levels (percentile) in the androgen-users raises questions as to whether there is increased risk for cardiovascular disease and the exact role of androgens in cardiovascular risk. To investigate the effects of anabolic steroids in pathologic concentric left ventricular hypertrophy, the effects of androgens on left ventricular size and function were analyzed. Previous investigations conducted on left ventricular size and function have yielded inconclusive results. Problems existing in each of the previous investigations were small body mass, short length of myocardial exposure time to resistance training (years of training), significantly different body mass between steroid-users and steroid-free subjects and monitoring/reporting of steroid use. These problems may have contributed to the discrepancies between studies. Therefore, we selectively recruited eight competitive heavy weight drug-free bodybuilders and eight matched competitive weight bodybuilders on self-directed regimens of anabolic steroids for examination of left ventricular size and function via echocardiography. Increases in left ventricular posterior wall (LVPW) and ventricular septal thickness (VST) were apparent in the steroid-user group (p [less than] 0.05). Ratio of echocardiographic findings to body mass index (BMI) revealed a significantly smaller left ventricular and diastolic dimension (LVDEd/BMI, p [less than] 0.05) in the steroid-user. The smaller LVDEd in steroid-users is coupled with a significantly disproportionate septal and posterior wall thickness in steroid-users. There was no direct evidence of diastolic dysfunction. Thus it appears from these studies that androgens alter lipoproteins leading to a questionable increased risk for cardiovascular disease and may potentiate concentric left ventricular hypertrophy without affecting cardiac function.Item Arterial Baroreflex Control of Muscle Sympathetic Nerve Activity(2000-07-01) Fadel, Paul Joseph; Peter B. Raven; Michael Smith; Patricia GwirtzFadel, Paul Joseph, Jr., Arterial Baroreflex Control of Muscle Sympathetic Nerve Activity. Doctor of Philosophy (Biomedical Science), July 2000; 100 pp; 3 tables; 10 figures; bibliography. Arterial baroreflex control of sympathetic nerve activity is dependent on afferent nerve activity emanating from both the aortic and carotid baroreceptors. While several investigations have reported that the aortic baroreceptor reflex dominates in the baroreflex control of heart rate in humans, the role of carotid and the aortic baroreceptors in the control of sympathetic nerve activity remains unclear. In addition, the effect of exercise and long term endurance training on baroreflex-sympathetic nerve activity responses requires further definition. Therefore, the purpose of the investigations described within this dissertation was to: i) describe carotid baroreflex (CBR) control of muscle sympathetic nerve activity (MSNA) at rest and during exercise, ii) examine the relative contribution of the carotid and aortic baroreflexes to the overall arterial baroreflex control of MSNA during acute hypotension, and iii) determine the effect of fitness on arterial baroreflex control of MSNA. In the first investigation, we constructed stimulus-response relationships for CBR control of MSNA at rest and during dynamic arm cycling and demonstrated that carotid baroreflex control of MSNA was reset to function at the higher arterial pressures induced by exercise without a change in reflex sensitivity. Thus, we concluded that the carotid baroreflex control of MSNA was preserved during dynamic exercise. In the second investigation, acute hypotension was induced non-pharmacologically by releasing a unilateral arterial thigh cuff (300 Torr) following nine minutes of resting ischemia under two conditions: control (aortic and carotid baroreflex deactivation) and suction (aortic baroreflex deactivation alone). The application of neck suction to negate the CBR during cuff release caused a significant attenuation of the MSNA response and a greater decrease in mean arterial pressure; thereby signifying the importance of the CBR in the control of MSNA and maintenance of arterial blood pressure. However, when the drop in carotid sinus pressure was counteracted with neck suction a significant MSNA response was noted, indicating the dominance of the aortic baroreflex control of MSNA. Furthermore, a comparison between high-fit (HF) and average fit (AF) subjects indicated that despite an augmented baroreflex control of MSNA, HF subjects exhibited a greater decrease in mean arterial pressure compared to AF subjects. Thus, it appeared that although the arterial baroreflex appropriately increased the MSNA response to hypotension, the regulation of blood pressure remained attenuated in the HF subjects. We contend that an impaired control of vasomotion hinders blood pressure regulation in high-fit subjects.Item Assessment of Obesity as a Cardiovascular Disease Risk Factor in a Geriatric Rural Texas Community - A Six Month Follow-Up(1999-12-01) Coustasse, Alberto; Antonio Rene; Doug A. Mains; Gilbert RamirezCoustasse, Alberto, Assessment of Obesity as a Cardiovascular Disease Risk Factor in a Geriatric Rural Texas Community – A Six Month Follow-up. Master of Public Health Track, Public Health Administration, December 1999, 22 pp., 9 tables, 9 illustrations, bibliography, 7 titles. The health fair approach was used as a method to establish individual and population health status baselines and to provide a mechanism to follow-up with an elderly population in a rural Texas community. A controlled trial sample of forty-four seniors was initially screened in a primary care clinic in August 1998. Patients were reevaluated at six months and results demonstrated a 46% increase in BMI [Body Mass Index]; 62% remained obese; 62% maintained elevated cholesterol or increased cholesterol values to abnormal values; 61% maintained or increased their BP [blood pressure] to abnormal values. A significant finding was that a change of one unit in the BMI correlated with a change of 19.88 mmHg [millimeter mercury] of SBP [systolic blood pressure] and 18.59 mmHg of DBP [diastolic blood pressure]. The societal economic impact of mortality and morbidity (without the benefit of target interventions) for the initial forty-four seniors was projected at & 74,949. Keywords: Health fairs; obesity; cardiovascular; cost; case management.Item Autonomic nervous control of cardiovascular function during prolonged exercise in humans(2014-05-01) White, Daniel W.; Peter B. RavenThe importance of physical activity is well established as a means to maintain good health. However, under certain conditions and in some individuals, heavy exercise leads to catastrophic failure of the cardiovascular system. This is especially true during early recovery from exercise. This may be due in part to an improper response of the autonomic nervous system; that is, an imbalance of the sympathetic and parasympathetic nervous systems. The purpose of the investigations presented in this dissertation was to: i) re-evaluate the commonly accepted model of autonomic influence on control of heart rate during exercise; ii) study the effects of posture on recovery from heavy exercise; and iii) determine the effect of muscle pump activity on cardiorespiratory control of the cardiovascular system during the transition from active to inactive recovery following heavy dynamic two legged cycling. In the first investigation we examined previously reported and newly collected data and determined a fine balance exists between the sympathetic and parasympathetic nervous systems throughout all intensities of exercise. Our conclusions led to the development of a new model of autonomic balance during exercise. In the second investigation we concluded that unloading of the cardiopulmonary baroreceptors by upright posture significantly increases baroreflex control of heart rate during rest and during recovery from heavy dynamic leg cycling exercise. We also show that steady-state blood pressure and the baroreflex control of blood pressure is not significantly different based on orthostatic posture before or after exercise. In the third investigation we concluded that loading of the cardiopulmonary baroreceptors by muscle pump activity during active recovery from heavy exercise diminishes the respiratory induced changes in cardiovascular function observed during inactive recovery. Overall, these investigations highlight the importance of the autonomic nervous system during exercise and during recovery from heavy exercise. Collectively, these conclusions should influence the decision making process regarding mode of recovery from heavy exercise, especially in an “at risk” population, because recovery is the time when most adverse events take place.Item Barriers to Women's Cardiovascular Risk Knowledge: A Tarrant County Study(2004-05-01) Liewer, Linda J.; Kristine LykensLiewer, Linda J., Barriers to Women’s Cardiovascular Risk Knowledge: A Tarrant County Study. Master of Public Health (Health Management and Policy), May 2004, 71 pp., 19 tables, 6 illustrations, 36 references, 17 titles. Women’s death rate from cardiovascular disease is greater than the death rate from all cancers. Awareness and knowledge of a disease are key to dealing with it, yet many women are still unaware of their CVD risk. The purpose of this study is to identify the barriers to knowledge about cardiovascular disease risk in women in Tarrant County. Interviews with administrative personnel in 10 community organizations confirmed the lack of awareness of CVD. Barriers included: women in caregiver roles advocate effectively for their family members, but less effectively for themselves; physician communication with women regarding CVD is often suboptimal; women fear breast cancer far more than CVD; a program deficiency exists in Tarrant County; lack of a visible woman champion and heart disease is still seen as a man’s disease.Item Bone Morphogenetic Protein 4 inhibits TGF-beta2 Stimulation of Extracellular Matrix Proteins in Optic Nerve Head Cells: Role of Gremlin in ECM Modulation(2005-05-01) Zode, Gulab S.; Wordinger, Robert J.Zode, Gulab Shalikram, Bone Morphogenetic Protein 4 Inhibits TGF-β2 Stimulation of Extracellular Matrix Proteins in Optic Nerve Head Cells: Role of Gremlin in ECM Modulation . Doctor of Philosophy (Cell Biology and Genetics), May 2008; 177pp; 34 figures; bibliography, 192 titles. The glaucomatous neuropathy is caused by irreversible loss of retinal ganglion axons in the optic nerve head (ONH). The extensive remodeling of the extracellular matrix (ECM) in the glaucomatous ONH including increased synthesis and deposition of ECM (increased collagens, basement proteins, and elastin) is associated with loss of axons. Transforming growth factor-beta2 (TGF-β2) is increased in glaucomatous ONH and is thought to be responsible for increased synthesis and deposition of ECM proteins of the ONH. Bone morphogenetic proteins (BMPs) normally maintain the balance of ECM proteins via opposing TGF-β2 stimulated ECM proteins in various cell types. BMP antagonist gremlin inhibits BMPs function, thus may plan an important role in ECM modulation. We previously demonstrated that human ONH expresses BMP-4, BMP receptor and BMP antagonist gremlin. Therefore, we hypothesize that elevated TGF-β2 in the glaucomatous ONH induces gremlin expression that blocks BMP-4 inhibition of TGF-β2 signaling, leading to increased ECM synthesis and deposition. First, we examined whether human ONH tissues and ONH cells express the canonical BMP signaling pathway. This study demonstrated that ONH tissues and ONH cells express BMP-4 and Smad signaling pathway. Treatment of ONH cells with BMP-4 increased phosphorylation of R-Smad/1/58/ phosphorylation and interaction with Co-Smad4 indicating activation of the Smad signaling pathway. Therefore, cells within the human ONH can respond to locally released BMP via activation of Smad signaling. Second, we examined the signaling pathways utilized by TGF-β2 to stimulate ECM in ONH cells. This study demonstrated that TGF-β2 is increased in glaucomatous ONH. Recombinant TGF-β2 increased ECM deposition in ONH cells. TGF-β2 activated phosphorylation of R-smad2/3 but did not alter phosphorylation of ERK1/2, p38, and JNK1/2 in ONH cells. Inhibition of either TGF-β I receptor activity or phosphorylation of R-Smad3 or knockdown of R-Smad2/3 via siRNA reduced TGF-β2 stimulated ECM in ONH cells. Thus, TGF-β2 requires R-Smad2/3 to stimulate ECM proteins in ONH cells. Lastly, we investigated the potential effects of BMP-4 and gremlin on TGF-β2 stimulated ECM in ONH cells. BMP-4 significantly reduced TGF-β2 stimulation of ECM proteins. Addition of gremlin blocked the BMP-4 effect, increasing ECM proteins in ONH cells. Gremlin levels were significantly increased in the human glaucomatous ONH tissues. Interestingly, recombinant gremlin also increased ECM proteins in ONH cells. Gremlin stimulation of ECM proteins required activation of the TGF-β receptor and R-Smad3. TGF-β2 increased gremlin mRNA and protein in ONH cells. Thus, TGF-β2 induced gremlin expression intensifies TGF-β2 effects on ECM metabolism by inhibiting BMP-4 antagonism of TGF-β2 signaling. In conclusion, elevated TGF-β2 and gremlin in the glaucomatous ONH are involved in the pathogenesis of glaucomatous ONH. Elevated TGF-β2 directly increases ECM and also induces gremlin expression, which further aids TGF-β2 to stimulate ECM via inhibiting BMPs antagonism of TGF-β2 signaling, leading to unopposed TGF-β2 stimulated ECM proteins. Interestingly, R-smad3 is required for TGF-β2 or gremlin induced ECM remodeling in ONH cells. Therefore, modulation of R-smad3 provides a novel therapeutic target for preventing ECM remodeling in glaucoma.Item Characterization of the Role of PKN in TGF-Beta 1-Mediated Cell Cycle Regulation of Vascular Smooth Muscle Cells(2005-12-01) Su, Chang; Neeraj Agarwal; Glenn Dillon; Robert MalletChang Su, Characterization of the role of PKN in TGF-beta-1 induced cell cycle inhibition in vascular smooth muscle cells. Doctor of Philosophy (Biomedical Sciences), November 2005, 173 pp, 2 tables, 34 illustrations, 225 references. Mature vascular smooth muscle cells (VSMCs) are unique in that they can switch between proliferative and differentiated phenotypes. Aberrant proliferation of VSMC is regarded as a central feature in vascular diseases such as atherosclerosis and restenosis following balloon angioplasty. Transforming growth factor-β1 (TGF-β1) is known to inhibit smooth muscle cell progression; however, the signaling pathway(s) through which this is accomplished is poorly understood. Entry into mitosis in dividing VSMCs is triggered by Cdc2/cyclin B1 complex, which is tightly controlled by phosphatase Cdc25C that dephosphorylates tyrosine-15 and threonine-14 on Cdc2 at onset of mitosis. A serine/threonine protein kinase, PKN, was recently reported to inhibit Cdc25C activity. PKN has been identified as a downstream target for TGF-β1 signaling in VSMCs. Therefore we hypothesize that PKN mediates TGF-β1-delayed cell cycle progression by inhibiting Cdc25C. In this study, TGF-β1 is shown to delay G2/M phase progression timing in PAC-1 VSMCs. This effect is blocked by pretreatment of cells with either HA1077 of Y-27632, two pharmacological inhibitors of PKN, as well as by reduced expression of PKN by RNA interference (RNAi). Oscillation of PKN activity temporally correlates with G2/M phase progression. Co-immunoprecipitation suggests that Cdc25C and PKN physically associate with each other. Immunocytochemistry demonstrate that PKN and Cdc25C co-localize in the nuclei and peri-nuclear region of only dividing (M phase) cells but not in the interphase cells. Additionally, PKN phosphorylates Cdc25C in PAC-1 cell cultures. Finally, TGF-β1-induced delay of Cdc2 activation is abolished by pretreating the cells with Y-27632. These data suggest that PKN inhibits G2/M progression by directly binding to Cdc25C and inhibiting its activity by phosphorylation. In addition to the PKN-Cdc25C signaling pathway, TGF-β1 strongly induces the transcriptional activity of the Smad-dependent enhancer in PAC-1 cells. This effect is attenuated by blocking PKN function by either chemical inhibitors or RNAi. Active forms of MKK3/6 alone are sufficient to increase the Smad enhancer activity, and co-expression of dominant negative MKK3/6 decreases TGF-β1-induced activation of the Smad enhancer. Lastly, the Smad reporter activity induced by TGF-β1 is also significantly attenuated by SB203580, a highly specific pharmacological inhibitor for p38 MAPK. These data demonstrate a novel mechanism of PKN-MKK3/6-p38 MAPK cascade to cross talk with the Smad pathway in PAC-1 VSMCs. Taken together, findings presented in this dissertation identify components of important intracellular signaling pathways through which TGF-β1 activates PKN to inhibit proliferation and promote differentiation of SMCs. Augmenting PKN-Cdc25C-Cdc2 signaling may provide a potential therapeutic approach to counter abnormal VSMC proliferation, prevent the clinical consequences of atherosclerosis and improve outcomes after angioplasty.Item Control of the Peripheral Vasculature During Exercise: Angiotensin II(2007-04-01) Brothers, Robert Matthew; Peter B. Raven; Michael Smith; Patricia GwirtzBrothers, Robert Matthew, Control of the Peripheral Vasculature During Exercise Angiotesin II. Doctor of Philosophy (Biomedical Science), April 2007, 126 pp; 3 tables; 12 figures; bibliography. Control of the vasculature during exercise is balance between sympathetic vasoconstriction and metabolic vasodilation. There is an exercise intensity dependent reduction in vasoconstriction resulting in a shift towards vasodilation within “metabolically active” muscle and tissues, a phenomena known as “functional sympatholysis”. Previous studies investigating the alpha-receptors during exercise have used intra-arterial infusions of alpha-agonists. These studies indicate that alpha-receptor vasoconstrictionis completely attenuated during mild intensity exercise. When the alpha receptors are pharmacologically blocked the magnitude and onset of “functional sympatholysis” is not as drastic when compared to the agonist infusion studies. Intense exercise also activates the renin-angiotesin-system leading to production of angiotensin II (AngII), which increases exponentially at approximately 55% maximal oxygen uptake (55% VO2max). While the mechanisms of “functional sympatholysis” has been extensively studied less is known about the role of AngII in the control of the vasculature during exercise. Therefore, the purpose of the investigations within this dissertation was to: i)determine if alpha-1- blockade in an exercising human model will identify a greater maintenance of alpha-1 mediated vasoconstriction when compared to agonist infusion studies; ii) to determine if the metabolites produced within the active skeletal muscle will attenuate angiotensin II vasoconstriction; and iii) to determine if AngII vasoconstriction provides a greater percentage contribution to vascular tone as exercise intensity increases. We demonstrated that i) pharmacologic alpha-1-blockade identified a greater maintenance of alpha-1 vasoconstriction during moderately heavy exercise; and ii) this effect decreased as intensity increased in the exercising leg and increased with intensity in the non-exercising leg. In the second investigation we demonstrated that AngII and phenylephrine (PE) mediated vasoconstriction were attenuated to a similar degree during low and mild intensity exercise. In the third investigation we observed that AT1-receptor blockade; 1) attenuated the increases in MAP that occur during high-intensity exercise; ii) did not affect the vasculature in the exercising leg but; iii) we identified that AngII does partially control the vasculature in a “non-metabolically active” muscle group.Item Correlation Between Palpated Pulse Rates Taken by Non-medically Trained Military Reservist and Medically Trained Military Reservist(2004-05-01) Baum, Stephen H.; Laura S. LangBaum, Stephen H., Correlation Between Palpated Pulse Rates Taken by Non-medically Trained Military Reservist and Medically Trained Military Reservist. Masters in Public Health (Social and Behavioral Sciences), May 2004, 41 pp., 9 tables, 4 figures, reference list, 32 titles. The Air National Guard (ANG) is interested in assessing a new fitness testing procedure using the modified Harvard Step Test and "non-medically" trained military reservist to assess peer heart rate/pulse measures before and after participation in the step test. Additionally, the use of "non-medically" trained individuals to provide biometric testing procedures has implications for public health and health promotion practitioners. The purpose of this study was to determine if a statistically significant difference was present between pulse rates taken by "non-medically" and "medically" trained military reservist. The results of this study indicate that no statistically significant difference exists between pulse rates when measured concomitantly by "non-medically" trained or "medically" trained individuals.Item Cross-Bridge Kinetics of Cardiac Myofibrils Carrying Myopathy-Causing Mutation(2007-05-01) Dumka, DishaDumka, Disha., Cross-bridge kinetics of cardiac myofibrils carrying myopathy-causing mutation. Doctor of Philosophy (Biochemistry and Molecular Biology), May 2007, 98 pp., 8 tables, 23 illustrations, and bibliography: 102 titles. Familial hypertrophic cardiomyopathy is a disease characterized by left ventricular hypertrophy and myofibrillar disarray. It is caused by mutations in sarcomeric proteins, including the ventricular isoform of myosin regulatory light chain (RLC). We have focused on one particular mutation of RLC-substitution of glutamic acid (E) at position 22 for lysine (K). The E22k mutation is located in the RLC Ca2+ -binding site. Earlier work has demonstrated that phosphorylation and Ca2+ binding are significantly altered by the E22K mutation. Studies with transgenic (Tg) mice have demonstrated that E22K-RLC mutation increases Ca2+ sensitivity of myofibrillar ATPase activity and steady-state force. However, the mechanisms for the E22K-mutated myocardium that could potentially trigger hypertrophy as seen in human patients harboring this mutation remain unclear. In order to better understand the impact of the E22K-RLC mutation on cardiac muscle contraction, we have studied the three primary parameters which best reflect the mechanism of actomyosin cross-bridge cycling during force generation. Tau one and two (t1 and t2) are the mechanical parameters which measure the dissociation and rebinding time of myosin heads from actin, respectively. Tau three (t3) is an enzymatic parameter which measures the dissociation time of ADP from the active site of myosin. For this study single-turnover contraction experiments were performed on Tg (wild-type and E22K) and non-Tg mouse cardiac myofibrils. Tau one (t1) was statistically greater in Tg-m (Tg-E22K) than in controls indicating that the E22K mutation slows down the rate of cross-bridge dissociation. However, the in-vitro binding experiments showed no difference in binding properties of T g-m vs. Tg-wt myosin to fluorescently labeled actin suggesting that this was a function of genetic manipulation rather than an intrinsic change to muscle. The slight increase in t1 was probably cause by myofibrillar disarray. Tau two (t2) was shorter in Tg-m than in non-Tg, but the same as in Tg-wt indicating that the decrease in Tg hearts was probably caused by replacement of the mouse RLC for the human isoform in the transgenic mice. Tau three (t3) was the same in Tg-m and in controls indicating that the E22K mutation had no effect time of ADP dissociation from the myosin active site. Thus the E22K mutation did not affect the three parameters that were used to study the cross-bridge kinetics of the cardiac muscle from the transgenic mice carrying the E22K-RLC mutation. On extrapolating the results of this study with transgenic mice to humans, it is likely that the change in cross-bridge kinetics is not the primary trigger through which E22K-RLC mutation affects muscle contraction. However one possible limitation of this study is that the Tg-E22K mice did not completely recapitulate the human phenotype of E22K-mutation. Overall, in this study, we successfully followed the mechanical and the enzymatic events in a small population of cross-bridges (~400) in contracting Tg-m cardiac myofibrils. The characterization of motion of a small population of cross-bridges is important because the different steps of cross-bridge cycle do not become obscured and thus it becomes easy to detect any changes in the cross-bridge cycle.Item Differences in the Rates of Cardiovasular Surgical Procedures in Men and Women with Coronary Heart Disease in the State of Texas(2003-02-01) Moreland, Matthew C.; Muriel Marshall; Doug A. MainsMoreland, Mathew, Differences in the rates of cardiovascular surgical procedures between men and women with coronary heart disease in the state of Texas. University of North Texas Health Science Center, School of Public Health, February 2003, 19pp., 3 tables, references, 23 titles. Data for the Texas Health Care Information Council was analyzed to identify the difference in the rates of invasive cardiovascular procedures performed on men and women among 411 Texas hospitals with the diagnosis of coronary heart disease in 1999. In all, 150,361 cases were compared for differences between gender, race, age and type of invasive cardiovascular procedure using chi-square test. Frequencies were tabulated for age, race and gender. Invasive cardiac procedures were differentiated by type: coronary angiography and coronary revascularization. Between the ages of 45 and 79 women were more likely to have angiography performed than men in the same age group. However, young (30-44) and elderly (80+) men were more likely to receive angiographic procedures when presenting with the same symptoms as women. Also, men of all ages and races were more likely to receive revascularization procedures (PTCA, CABG) than women when presenting with coronary heart disease symptomology. Additionally, men between the ages of 35 and 49 received twice the number of revascularization procedures than women. These findings identified patterns of treatment with defined differences between gender which may be attributed to external factors versus a true gender bias.Item Dysfunctional Control of Coronary Blood Flow in Renovascular Hypertension(1999-06-01) Kline, Geoffrey Philip; Gwirtz, Patricia A.; Shi, Xiangrong; Raven, Peter B.Kline, Geoffrey Philip, Dysfunctional Control of Coronary Blood Flow in Renovascular Hypertension Doctor of Philosophy (Biomedical Sciences), June 1999, 98 pp, 2 tables, 10 figures, references, 142 titles. This study was designed to determine the effects of renovascular hypertension (RVH) on coronary vasoreactivity in conscious, chronically instrumented dogs. Six dogs were instrumented to measure left ventricular pressure, +dP/dtmax, heart rate, mean aortic pressure, circumflex blood flow (CBF), and cardiac output. In order to examine endothelial-dependent and independent coronary vasodilation, intracoronary injections of actylcholine (Ach), bradykinin (BDK), and sodium nitroprusside (SNP) were studied before and after induction of RVH in the presence and absence of nitric oxide (NO) blockade. After RVH, resting CBF was significantly reduced (P [less than] 0.05). In the normotensive state, NO-blockade significantly reduced the coronary vasodilation to Ach and BDK (P [less than] 0.05), but not SNP. After RVH, the coronary vasodilation to Ach, BDK, and SNP were reduced (P[less than] 0.05). After RVH, NO-blockade further reduced the coronary vasodilation to BDK (P [less than] 0.05), but not Ach. Thus, RVH resulted in an impairment of both endothelial-dependent and –independent coronary vasodilation. It also appears that during RVH the endothelium retains the ability to produce/release NO to some, but not all, stimuli. In order to examine the possibility that β-adrenergic mediated coronary vasodilation is impaired after RVH, intracoronary injections of norepinephrine (NE), isoproterenol (ISO), and terbutaline (TRB) were administered. These drugs all caused dose dependent increases in CBF before and after RVH. After RVH, the coronary vasodilatory responses to NE, ISO and TRB were significantly reduced (P [less than] 0.05). β1-blockade with intracoronary atenolol (1 mg) reduced the ISO-induced increases in CBF and had no effect on TRB responses (P [less than] 0.05). β2-blockade with intracoronary ICI-118,551 (1 mg) reduced the ISO-induced coronary vasodilation and abolished TRB responses (p[less than] 0.05). During β2-blockade, ISO-induced increases in CBF were not different after RVH. Therefore, these data indicate that β1-adrenergic mediated coronary vasodilation is preserved after RVH, whereas, β2-mediated is not. We conclude that 1) RVH results in an impairment of both endothelial-dependent and –independent coronary vasodilation; 2) RVH results in an impairment of β2-adrenergic mediated coronary vasodilation.Item Gender Differences: Making the Decision to Seek Treatment for Symptoms of Acute Myocardial Infarction(2000-05-01) Borski, Catherine A.; Shelia Reed; Joseph Doster; Claudia CogginBorski, Catherine A., Gender Differences: Making the decision to seek treatment for symptoms of acute myocardial infarction. Masters of Public Health (Health Behavior), May, 2000, 57 pp., reference list, 37 titles. The purpose of this study was to investigate the problem: Do differences in interpretation and response to symptoms of AMI account for additional delay in seeking treatment in women compared with men? The sample consisted of 50 (21 women, 29 men) post-myocardial infarction patients in a large, non-profit, teaching hospital in central Texas. Participants were interviewed within 72 hours of admission using the Revised Response to Symptoms questionnaire. In this study, it was found that there was a statistically significant difference between the cognitive and emotional processes that men and women use when making the decision to seek treatment for symptoms of AMI.Item Hemorrhagic Hypotension Alters Circulating and Myocardial Enkephalins and Catecholamines(1994-11-01) Mateo, Zaira; Caffrey, James; Napier, Leslie; Yoshishige, DariceMateo, Zaira, Hemorrhagic hypotension alters circulating and myocardial enkephalins and catecholamines. Master of Science (Biomedical Sciences). November, 1994. A variety of plasma and intrinsic cardiac enkephalins were extracted, chromatographed and assayed under control conditions and during two hours of hemorrhagic hypotension. The animals were anesthetized, instrumented and sufficient blood was withdrawn as required to reduce mean arterial pressure and maintain it at 40 mmHg. Central venous blood samples were obtained 15 minutes before and at 30 minute intervals during the experiment. Arterial blood gases remained stable throughout the experiment while pH declined from above 7.4 to near 7.1. Heart rate rose gradually by 100 bpm. Plasma catcholamines were unchanged during two hour time-controls. Plasma norepinephrine and epinephrine increased by 6 and 100 fold respectively, during the first hour of hypotension and remained high through the second hour. All eight enkephalin immunoreactivities monitored were unchanged during the time-controls. Plasma met-enkephalin (ME) and Peptide-F both gradually increased by 70-100% during the hypotension. Plasma Met-enkephalin-Arg-Phe (MEAP) and Peptide-B concentrations increased 4-5 fold during the same interval. Proenkephalin and other large enkephalin containing peptids though present, were unchanged during hypotension. Myocardial norepinephrine was preferentially concentrated about 3:1 in the atria. Both atrial and ventricular concentrations were reduced by one third or more following two hours of hypotension. Proenkephalin and peptide-B accounted for 75% of the intrinsic enkephalins and their ventricular concentrations were 3 to 4 times atrial concentrations in the same hearts. Intrinsic cardiac MEAP concentrations were 15-25 times higher than comparable ME concentrations in the same myocardial regions. Hypotension produced a significant increase in Peptide-B and proenkephalin compared to controls. The increase was consistent throughout the heart, thus maintaining the preferential concentration in the ventricles. Myocardial ME, MEAP and Peptide-F were largely unchanged in hypotensives compared to time-controls. The data demonstrate the preferential processing and retention of MEAP rather than ME-immunoreactive enkephalins in heart tissue. The data also indicate the responsiveness of MEAP-ir to changes in the circulatory environment and their subsequent appearance in plasma during hemorrhagic hypotension. Prior data suggests that intrinsic cardiac enkephalins may actively regulate either vagal control of the heart or sympathetic control of vasomotor tone.Item Interaction of Neural and Local Mechanisms in the Control of Skeletal Muscle Blood Flow(2003-12-01) Wray, David Walter; Michael L. SmithWray, David Walter, Interaction of Neural and Local Mechanisms in the Control of Skeletal Muscle Blood Flow. Doctor of Philosophy (Biomedical Science), December, 2003, 181 pp., 1 table, 19 illustrations, references, 139 titles. The current project sought to characterize the interaction of neural and local mechanisms of skeletal muscle blood flow control through exogenous and endogenous α-andrenoreceptor activation. We hypothesized that α1- and α2-adrenoreceptors in the human leg would exhibit differential distribution and responsiveness, and that unilateral knee-extensor exercise would attenuate α-adrenoreceptor-mediated vasoconstriction in an intensity-dependent manner. We also hypothesized that carotid baroreflex (CBR)-mediated sympathoexcitation would provoke less vasoconstriction during exercise than at rest. Intra-arterial infusion of phenylephrine (PE, α1-agonist) or BHT-933 (α2-agonist) reduced femoral blood flow (FBF) by approximately 60% at rest, but during exercise (27W) the degree of vasoconstriction evoked by PE and BHT was significantly reduced. During ramped (7W-37W) exercise, BHT did not reduce FBF at any intensity, while some degree of PE-induced vasoconstriction was evident at all but the highest exercise intensity. Using sinusoidal neck pressure, CBR-mediated changes in heart rate (HR), arterial blood pressure (ABP) muscle sympathetic nerve activity (MSNA), FBF, and tissue oxygenation (TOm) were seen at rest. During 7w exercise, CBR-mediated control of ABP, FBF, and Tom was attenuated. We conclude that exercise attenuates α-adrenergic responsiveness to exogenous and endogenous activation to ensure sufficient muscle blood flow while maintaining systemic ABP homeostasis.Item Interaction of the Exercise Pressor Reflex with Central Command in the Regulation of Blood Pressure During Dynamic Exercise(1996-12-01) Smith, Scott Alan; Peter B. Raven; Patricia A. GwirtzSmith, Scott A., Interaction of the exercise pressor reflex with central command in the regulation of blood pressure during dynamic exercise. Master of Science (Biomedical Sciences, Integrative Physiology), October, 1996, 73 pp., 7 tables, 8 figures, references. Ten subjects, aged 26.5±3.7 years, performed incremental workload cycling exercise to investigate the interaction of skeletal muscle mechano- and metaboreceptors in the regulation of blood pressure. Each subject performed four bouts of exercise: control (exercise with no intervention); exercise with thigh cuff inflation to 90 mmHg (to reduce venous outflow stimulating metaboreceptors); exercise with application of lower body positive pressure (LBPP) to 45 mmHg (to enhance mechanoreceptor activation); and exercise with application of lower body positive pressure (LBPP) to 45 mmHg (to enhance mechanoreceptor activation); and exercise with the application of both LBPP and thigh cuff inflation. Measurements of mean arterial pressure (MAP), heart rate (HR), electromyographic activity (EMG), rate of oxygen uptake (VO2)3 cardiac output (Q), and rating of perceived exertion for both the body (RPEB) and the legs (RPEL) were monitored. Significant mean data is presented. Indices of central command (HR, EMG, and VO2) were not significantly different between the four bouts of exercise indicating that the blood pressure response to central command activity was not altered by the interventions. Significant changes in RPEL from control during inflation of thigh cuffs, application of LBPP, and their combination indicate these stimuli successfully enhanced mechano- and metaboreceptor activation. Results indicate that MAP was significantly elevated from control only with the application of LBPP or the combination of LBPP and thigh cuff inflation. These data suggest that mechanoreceptors are the primary exercise pressor mediator of arterial blood pressure during submaximal dynamic exercise.