Browsing by Subject "Cardiovascular System"
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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 Meta-Analysis of the Effects of Chromium on Fasting Blood Glucose, HBA1c, Triglycerdies, LDL-C and HDL-C in Type 2 Diabetes and Impaired Glucose Tolerance(2002-05-01) Evans, Jill E.; Urrutia-Rojas, Ximena; Mains, Doug A.Evans, Jill E., A meta-analysis of the Effects of Chromium on Fasting Blood Glucose, HbA1c triglycerides, LDL-C, and HDL-C in Type 2 Diabetes and Impaired Glucose Tolerance. Master of Public Health, May, 2002, 35 pp., 4 tables, 4 figures, references cited, 23 titles. Objective: To assess the magnitude of chromium’s effect of trivalent chromium (picolinate or chloride) or yeast in type 2 diabetics or subjects with impaired glucose tolerance. Efforts were taken to combine studies with similar doses and treatment periods. Sensitivity analysis was performed. Outcomes Measured: Fasting blood glucose (FBG), HbA1c, triglycerides, high-density cholesterol (HDL-C), and low-density cholesterol (LDL-C). Effect sizes were converted to appropriate units and were reported as “effect size equivalents”. Results: The magnitude of effect of chromium on FPG and HbA1c was negative and generally increased with dosage and duration. Statistically significant effects were observed for typical doses (150-250μg/day) for both outcomes at 1.5-3 months duration, and for HbA1c at 4-6 months; and high dosage (1000 μg/day) at 1.5-3 and 4-6 months for both outcomes. For triglycerides at the typical dose, statistically significant effects (p=0.00) were observed at 1.5-3 months. There was no effect on LDL-C. HDL-C increased with increasing duration of chromium supplementation, with the exception of the 4-6 month duration. Statistically significant effects (p=0.00) were observed for typical dosage at 1.5-3 months. For the studies using yeast with GTF activity, the effect size equivalent for FPG and triglycerides was significantly lowered (p [less than] 0.001 and p=0.00 respectively). When the study using yeast with no GTF activity was included, the pooled fixed effect size equivalent was smaller, yet remained significant. HDL-C was significantly increased (p=0.00). Sensitivity analysis yielded similar results. Conclusion: Meta-analysis of chromium showed a significant reduction in FBG, HbA1C, triglycerides, and LDL-C, while increasing HDL-C in the groups studied. The best available evidence suggests that chromium has a dose and duration-dependent effect on these outcomes.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 Acetoacetate: A Cardioprotective Antioxidant(2002-05-01) Squires, Jeffrey E.; Mallet, Robert T.; Caffrey, James L.; Carroll, JoanSquires, Jeffrey E., Acetoacetate: A Cardioprotective Antioxidant. Master of Science, June 2002, 100 pp., 1 table, 18 illustrations, bibliography, 70 titles. The purpose of this study was to test the effectiveness of acetoacetate and β-hydroxybutyrate as myocardial protectants following peroxide injury and to determine acetoacetate’s ability to potentiate β-adrenergic responsiveness following ischemia-reperfusion injury. This study utilized antegradely perfused isolated working hearts exercised from male guinea pigs and sustained with glucose-fortified Krebs-Henseleit. Hearts were challenged by either 10 min perfusion with 100 μM H2O2 or 45 min of low flow ischemia exacerbated by ι-norepinephrine infusion. H2O2-challenged hearts were treated with 5 mM acetoacetate or β-hydroxybutyrate, whereas hearts injured by ischemia/reperfusion were treated with 5 mM acetoacetate. In the case of the ischemically injured hearts, acetoacetate treatment was combined with 2 nM isoproterenol to delineate acetoacetate’s ability to enhance β-andrenergic responsiveness to submaximal inotropic stimulation. Data were compared to non-injured time control hearts and injured untreated hearts to determine the impact of ketone body treatment. Acetoacetate increased citrate and glucose 6-phosphate content, nearly restored power, and increased the glutathione antioxidant redox potential (GSH/GSSG) by 140% in H2O2-injured myocardium. Although β-hydroxybutyrate increased citrate, an activator of NADPH-generating pathways, and glucose 6-phosphate, the substrate for the hexose monophosphate shunt to the same extent as acetoacetate, β-hydroxybutyrate raised GSH/GSSG by only 60% and did not enhance cardiac power. Therefore, acetoacetate enhances contractile function by augmenting the glutathione redox potential, and does so by additional mechanisms independent of the citrate and hexose monophosphate pathway. In hearts stunned by ischemia/reperfusion, acetoacetate and isoproterenol each increased power and glutathione redox potential three-to-fourfold, but phosphocreatine potential was 70% higher in acetoacetate hearts. Combined, acetoacetate + isoproterenol synergistically increased power and GSH/GSSG 16- and 17- fold respectively, doubled {NADPH/NADP+}, and increased cyclic AMP content 30%. These findings support the conclusion that acetoacetate enhances myocardial sensitivity to β-adrenergic stimulation possibly by enhancing GSH/GSSG.Item Activities of Daily Living and Cardiovascular Risk Factors' Impact on Cardiovascular Disease (CVD) and Cognitive Functioning: A Three Stage Longitudinal Model(2005-05-01) Bozo, Ozlem; Guarnaccia, Charles A.; Hall, James; Kelly, KimberlyBozo, Ozlem, Activities of Daily Living and Cardiovascular Risk Factors’ Impact on Cardiovascular Disease (CVD) and Cognitive Functioning: A Three Stage Longitudinal Model. Doctor of Philosophy (Health Psychology), May, 2005, 122 pp., 23 tables, 4 figures, references, 50 titles. The purpose of this study was to examine the longitudinal relationship of daily living (ADL), cardiovascular risk factors, and cardiovascular diseases to predict the future cognitive functioning of older Americans who are between the ages of 51 and 61 at the time of initial assessment. Three waves of the Health and Retirement Study (HRS) database between the years of 1992 and 2002 were examined with path analysis. The longitudinal hypotheses of the study were that (1) ADLs would positively predict future cognitive functioning, (2) ADLs would negatively predict future cardiovascular risk factors, (3) ADLS would negatively predict future cardiovascular diseases, (5) cardiovascular risk factors would negatively predict future cognitive functioning, (6) cardiovascular disease would negatively predict future cognitive functioning, (7) cardiovascular risk factors would mediate the relationship between ADLS and cardiovascular disease, and (8) cardiovascular disease would mediate the relationship between cardiovascular risk factors and cognitive functioning. The results of the analyses indicate that there was no effect of cardiovascular disease on cognitive functioning; however, there were significant effects of cardiovascular risk factors on cognitive functioning that ranged between B=-/021 and B=-/145. Moreover, it was found that cardiovascular risk factors mediate the relationship between ADLs and cognitive functioning, while cardiovascular disease does not. These results suggest that addressing cardiovascular risk factors may be more important than addressing existing cardiovascular disease to protect future cognitive functioning. This shows the importance of primary/secondary prevention versus tertiary interventions.Item Adenosine Receptor Blockade Increases Lactate and Purine Release But Does Not Affect Functional Recovery in Isolated Rabbit Myocardium(1995-12-01) Wang, Sheng; Downey, H. Fred; He, Miao-Xiang; Mallet, Robert T.Wang, Sheng, Adenosine Receptor Blockade Increases Lactate and Purine Release but does not Affect Functional Recovery in Isolated Rabbit Myocardium Master of Science (Biomedical Sciences), December 1995; 67 pp; 3 tables; 8 figures; bibliography, 121 titles. This study tests the hypothesis that endogenous adenosine mediates recovery of cardiac function in ischemia/reperfused rabbit hearts. Isolated isovolumic rabbit hearts perfused at constant pressure was subjected to mild ischemia (perfusion pressure 50 cm H2) or moderate ischemia (perfusion pressure 30 cm H2O) for 90 min followed by 60 min of reperfusion. In treated hearts, infusion of 100 μM 8-p-sulfophenyl theophylline (SPT) was initiated 20 min before ischemia and maintained throughout the experiment. Adenosine receptor blockade did not affect left ventricular function assessed from pressure-heart rate product (PRP). Lactate release increased to 152 ± 24% of baseline during mild ischemia and 259 ± 26% of baseline during moderate ischemia in untreated hearts. Lactate release was markedly elevated at baseline, ischemia and reperfusion by SPT treatment (p [less than] 0.05 compared to untreated). Purine nucleoside release was 4.1 ±0.7 nmol · min-1 · g-1 in SPT treated group and 1.8 ± 0.24 nmol · min-1 · g-1 in untreated group during moderate ischemia (P [less than] 0.05). Myocardial efficiency was significantly lower in the SPT treated hearts (240 ± 11 mmHg · g=1 · μl-1 O2) compared to untreated hearts (300 ± 22 mmHg · g-1 · μl-1 O2) during reperfusion after moderate ischemia. In conclusion, adenosine receptor blockade stimulates glycolysis in normoxic and ischemic myocardium, but does not affect post-ischemic functional recovery.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 Anatomical Variation of the Inferior Mesenteric Vein’s Drainage Pattern(2015-05-01) Zilaie, Mina; Claire Kirchhoff; Rustin E. Reeves; Patricia A. GwirtzThe purpose of this project is to report the variable drainage pattern of the inferior mesenteric vein (IMV) as reported by medical students’ observations recorded on anatomical variation data sheets (n = 192). A meta-analysis on the drainage pattern of the inferior mesenteric vein as described in various anatomy resources was conducted (n = 40). The inferior mesenteric vein was observed to drain into the splenic vein, the superior mesenteric vein, and the junction between the superior mesenteric vein and the splenic vein. Anatomy resources do not commonly report all three drainage sites. It is imperative that all these common drainage sites of the inferior mesenteric vein are stated in anatomy resources, so that students are taught realistic human anatomy including its common variations.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 Baroreflex Mediated Autonomic Modulation by Acute Pain and Orthostatic Stress(2008-10-01) Raven, Joseph Simon; James Caffrey; Joan Carroll; Robert MalletRaven, Joseph Simon, Baroreflex Mediated Autonomic Modulation by Acute Pain and Orthostatic Stress. Doctor of Philosophy (Integrative Physiology), October 2008, 147 pp.; 23 figures; bibliography; 123 titles. Nociceptive and baroreceptor afferent neurons are implicated as the components responsible for carotid baroreceptor reflex (CBR) resetting. The purpose of this dissertation was to identify the effect of cold induced pain, and cardiopulmonary baroreceptor (CPBR) unloading accompanied by pain, on CBR resetting. First, the relationships between cold induced pain to cardiovascular responses, pain perception, and muscle sympathetic nerve activity (MSNA) were investigated. Questions were addressed through use of the cold pressor test (CPT), finger plethysmography, and microneurography. This study demonstrated perceived pain, MSNA, and blood pressure responses to a cold stimulus were reproducible. Furthermore, graded responses observed in mean arterial pressure (MAP) and MSNA directly correlated to the intensity of the pain stimulus. The next study examined cold induced pain on CBR gain and operational point resetting in healthy normotensive subjects. Using similar experimental methodologies to the previous study, the data demonstrated acute pain shifted the CBR operational point toward the lower limiting value of MSNA. These data also confirmed an upward-rightward shift and increased gain of the CBR function curve during pain. Finally, CBR gain and operational point resetting during simultaneous CPBR unloading and cold induced pain in healthy normotensive subjects was addressed. Using the previous experimental paradigm, this investigation revealed CPBR unloading during acute pain did not abolish the shift of the CBR operational point. Thus, the capacity for hypotensive buffering remained enhanced. This study also determined CPBR unloading during acute pain produced higher prevailing blood pressures compared to periods of CPBR unloading alone. In summary: 1)MSNA and cardiovascular responses were tightly coupled to pain. 2) The CPT was a reliable technique for producing repeated sympathoexcitation within a subject. 3) Acute pain increased CBR gain and induced a shift of the CBR operational point. 4) The CBR operational point shift remained in the presence of CPBR unloading, which precipitated increased MAP during hypotensive stimuli. These findings suggested pain improves blood pressure maintenance during central hypovolemic stress.Item Cardiac Autonomic Response to Hypovolemia --- Effect of Age(1997-08-01) Wang, Hong-Wei; Raven, Peter B.; Shi, Xiangrong; Caffrey, James L.Objective: The beat-to-beat variation in heart rate reflects the dynamic response of the cardiovascular control systems to physiological perturbations such as respiration and postural change. The heart rate variation (HRV) is a part of the rapidly reacting component of cardiovascular homeostasis largely influenced by parasympathetic and sympathetic input. Thus, beat-to-beat variation in heart rate can be used as a measure of cardiac autonomic responses. The standard deviation of R-R interval is a measure of the overall variability in heart rate and has been shown to decrease with aging (9,23). This measure, however, can not identify individual sources of the variation. Spectral analysis reduces a signal to its constituent frequency components and the relative power of these components has been indicated related to parasympathetic mediation, combined sympathetic and parasympathetic mediation, and sympathetic mediation (1, 14, 17). Limited data are available regarding power spectral analysis of heart rate variation to study aging changes under orthostatic stress. An attenuated cardiac sympathetic nerve activity was found in older group vs younger individuals (7, 11, 19) during posture change. However, these studies were carried out using either posture change from to upright or passive head-up tilt. During these posture changes, both cardiopulmonary baroreceptors (i.e., intrathoracic hypovolemia) and arterial baroreceptors (postural hypotension) were unloaded. Therefore, it is unclear whether there is any difference in the HR variability between the young and the elderly during unloading of cardiopulmonary baroreceptors (or low-pressure baroreceptors) alone. In this study, we investigated the age difference in cardiac autonomic modulation of heart rate during unloading of cardiopulmonary baroreceptors with or without systemic arterial hypotension. For the purpose, we examined beat-to-beat heart rate variability in both the time and frequency domain using power spectral analyses in healthy individuals from ages 18 to 68 under basal conditions and in response to graded lower body negative pressure induced central hypovolemia. Not only individual low and high frequency spectral content were analyzed and those parameters were compared in order to find a quantitative evaluation of sympathetic and parasympathetic modulation and under the graded lower body negative pressure.Item Cardiac Parasympathetic Dysfunction in Morphine Addiction(1997-12-01) Napier, Leslie D.; Caffrey, James L.; Raven, Peter B.; Gwirtz, Patricia A.Napier, Leslie D., Cardiac Parasympathetic Dysfunction in Morphine Addiction. Doctor of Philosophy (Biomedical Sciences), December, 1997, 137 pp., 9 tables, 22 figures, references, 163 titles. The effects of chronic morphine treatment on parasympathetic control of the heart and associated cellular mechanisms were examined using a canine model. Vagal bradycardia was significantly blunted in dogs treated for one week with subcutaneous morphine pellets. In a separate group of dogs, heart rate and high frequency fluctuations in heart rate declined during the first three hours of subcutaneous morphine infusion consistent with the vagatonic action of acute morphine. Heart rate remained below baseline on Day 2 of the morphine infusion but had returned to normal by Day 10. Ambient sympathetic tone was increased on Days 2 and 10, and plasma catecholamines were elevated on Day 2. The intrinsic heart rates on Days 2 (160 bpm) and 10 (162 bpm) of morphine treatment were lower than the pre-treatment rate (182 bpm). Suggested mechanisms include a fundamental change in sinoatrial nodal cell function or attenuated tachycardia induced by vasoactive intestinal peptide co-released with acetylcholine from post-ganglionic parasympathetic neurons. The time to 50% maximal bradycardia during vagal nerve stimulation was increased with chronic and acute morphine suggesting an effect on the rate of acetylcholine synthesis, release or degradation. Muscarinic receptor density in left ventricular and right atrial sarcolemmal membranes from dogs treated chronically with morphine were 34% and 17% higher, respectively, than in control animals. Chronic morphine had no effect on basal or MnCl2-stimulated cyclase activity in either region. Similarly, maximal β-adrenergic and muscarinic receptor/G-protein coupling to adenylate cyclase were not altered by chronic morphine. Atrial norepinephrine content was higher than that in the ventricles and was unaltered by morphine. Ventricular norepinephrine was decreased with chronic but not acute morphine treatment. Epinephrine was evenly distributed throughout the myocardium and was reduced in both the atria and the ventricles by either acute or chronic morphine. This pattern suggests that morphine may reduce extraneuronal uptake of catecholamines. Collectively these studies show that chronic morphine treatment and the accompanying persistent vagal activity may reduce parasympathetic function. This attenuated function, however, is short-lived since sympathetic systems adapt with compensatory responses masking, or perhaps reversing, initial parasympathetic deficits.Item Carotid Baroreflex of Leg Vasculature(2004-07-01) Keller, David Melvin; Peter A. Raven; H. Fred Downey; Patricia A. GwirtzKeller, David Melvin, Carotid Baroreflex Control of Leg Vasculature. Doctor of Philosophy (Biomedical Science), July 2004; 110 pp; 5 tables; 10 figures; bibliography. The carotid baroreflex (CBR) exerts control of arterial blood pressure primarily as a result of changes in total vascular conductance. In humans, understanding CBR control of the vasculature supplying a given vascular bed, such as the leg, remains unclear. Furthermore, it appears that metabolic attenuation of sympathetic vasoconstriction may modulate the CBR of the vasculature supplying contracting skeletal muscle during exercise. However, the balance between baroreflex-mediated vasoconstriction and the mechanisms responsible for the metabolic attenuation has not been fully elucidated. Therefore, the purpose of the investigations within this dissertation was to: i) explain CBR control of leg vascular conductance (LVC) and the relationship between changes in LVC and muscle sympathetic nerve activity at rest and during one-legged knee extension exercise, ii) examine the CBR control of the vasculature supplying an exercising leg and a non-exercising leg during exercise, and iii) demonstrate the role of the ATP-sensitive potassium channel in contributing to the metabolic attenuation of CBR-mediated vasoconstriction in the vasculature supplying contracting skeletal muscle. In the first investigation, we demonstrated: i) the stimulus response relationships for CBR control of LVC and MSNA at rest and during two intensities of one-legged knee extension exercise; ii) that CBR control of LVC was preserved during exercise; iii) that the attenuation of CBR-mediated vasoconstriction was no different between 7W and 25W exercise in the vasculature supplying an exercising leg; and iv) that the contribution of changes in LVC to CBR changes in mean arterial pressure was no different from rest to exercise in both the exercising leg and the non-exercising leg. In the second investigation, we examined the role of the ATP-sensitive potassium channel in modulating sympathetically-mediated vasoconstriction at rest and during exercise in the vasculature supplying an exercising leg and a non-exercising leg. The attenuated vasoconstrictor response to the carotid baroreceptor stimulated hypotension observed in the vasculature supplying an exercising leg was partially restored two to four hours after the oral ingestion of glyburide (5mg). This finding indicates that ATP-sensitive potassium channel activation plays a primary role in the effects of functional sympatholysis during leg exercise in humans. We further demonstrated that CBR control of MAP was not altered by oral glyburide administration in healthy subjects.Item Characterization of Recombinant Lecithin: Cholesterol Acyltransferase, Secreted by a Human Lung Cell Line (1069-111) and by Pichia Pastoris Yeast Cells(2004-05-01) Tchedre, Kissaou T.; Caffrey, James L.; Harris, Ben G.; Wu, Ming-ChiTchedre, Kissaou T., Characterization of Recombinant Lecithin: Cholesterol Acyltransferase, Secreted by a Human Lung Cell Line (1069-111) and by Pichia pastoris Yeast Cells (Biomedical Sciences), May, 2004, Lecithin: cholesterol acyltransferase (LCAT) is a key enzyme in mammalian lipoprotein metabolism. Associated with the surface of high-density lipoproteins (HDL), LCAT contributes to the homeostasis of circulating free and esterified cholesterol via the reverse cholesterol transport pathway. The purpose of these studies was to characterize a recombinant form of LCAT, secreted by a human lung cell line (Beta gene 1069/111) and to evaluate a new expression system for LCAT using transformed Pichia pastoris cells. A human lung cell line (Beta gene 1069/111), transfected with pBIISK (Stratagene)+ vector was used as the source of recombinant (rLCAT) for the first stage of characterization studies. Human lung cells were expanded in Dulbecco’s minimal essential medium (DMEM) supplemented with 10% fetal bovine serum for the expression of the recombinant LCAT. At 80 – 90% confluency, the medium was changed to a serum free preparation and the flasks were incubated for 48 hrs at 37°C to facilitate the secretion of the enzyme. Beta gene (1069/111) LCAT was purified from the conditioned medium using phenyl sepharose chromatography. The purified enzyme was characterized according to: carbohydrate composition, and enzyme kinetic parameters. The enzymatic characteristics, of the human lung cell line LCAT had similar Km and Vmax values to other LCAT preparations, isolated from other expression systems and human plasma. Deglycosylation reduced the molecular weight of the enzyme from about 67,000 to about 43,000 suggesting a carbohydrate component of 25-32% of the enzyme’s total mass. Detailed analysis of the carbohydrate structures revealed N-glycan structures in a complex pattern of sialylated and fucosylated tri and tetra-antennary glycosides (8). In addition to the Beta gene expression, a Pichia pastoris yeast expression system was also developed consisting of human LCAT cDNA cloned into pPICZαA vector along with a removable amino-terminal polyhistidine tag. The Pichia pastoris cells were transformed with a vector containing the LCAT gene cDNA and transformants were selected on agar plates containing zeocine (100μg/ml). Polymerase chain reaction (PCR) and reverse transcription polymerase chain reaction (RT-PCR) were used to confirm the correct integration of the LCAT gene cDNA into the pPICZαA vector. The recombinant LCAT produced by the yeast cultures was purified by Talon affinity chromatography, taking advantage of the removable histidine tag. The enzymatic activity was determined using proteoliposome vesicles. The Yeast expression system yielded ~18 mg of enzyme protein/500 ml and thus may provide an appropriate enzyme source for characterization studies via NMR analysis and x-ray crystallography.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 Comparing Site Management of a NIH versus Industry Sponsored Study: CTSN (Surgical Interventions for Moderate Ischemic Mitral Regurgitation) Trial versus DEEP (Dual Epicardial Endocardial Protocol for Persistent and Longstanding Atrial Fibrillation) Trial(2010-12-01) Ong, Jennifer K.; Patricia GwirtzThe management of a clinical trial requires the coordination of a number of tasks concurrently. Every study has its own individual difficulties and concerns that a research team must work around in order to get a study started and begin subject enrollment. The Baylor Research Institute is participating as a research site for both the CTSN and DEEP studies. Each study is funded by a different type of sponsor, which includes the National Institutes of Health and AtriCure. The two studies were followed from the early stage of site selection up until the point of subject enrollment. The CTSN and DEEP trials provided insight as to how to successfully manage the start-up of both types of studies, demonstrating the delays and difficulties that may arise as a clinical trial agreement approaches execution.