Evaluation of: Bangalore S, Steg PG, Deedwania P et al. β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 308(13), 1340–1349 (2012). The number of myocardial infarctions (MIs) in population remains high and this event is a significant predictor of mortality. Information in the literature points to a reduction in mortality, reinfarction and sudden death in first year, especially in patients with high risk, if β-blockers (BBs) are used after MI. In a perspective study, Zuckerman et al. have determined outcome following pharmacotherapy after acute MI in older adults. It is apparent that a number of matters require consideration in evaluation of the effectiveness of BBs. It seems that not all patients benefit equally from treatment with BBs but such an intervention reduces mortality. It is also important to recognize that the beneficial effects of BBs should not be considered in isolation since the biological system is too complex to manipulate with the use of a single class of drugs.

A pretest-posttest experimental study was conducted on 35 music majors at Taylor University, using questionnaires to measure musical performance anxiety and musical performance quality. The study compared the effectiveness of two different treatments: 1) informal practice performance and 2) a coping skills seminar. Though the students attending the seminar averaged less anxiety after treatment, neither treatment was proven statistically to be effective in reducing the level of anxiety or enhancing musical performance quality. / Ed. D.

Controversy exists regarding the effects of beta-blocker medications on functional capacity in cardiac patients and in the effects of disease-related impairments on cardiorespiratory dynamics during exercise testing. Therefore, this study was conducted to examine the exercise responses of 26 subjects (ages 37-66 years) to a graded exercise test. Subjects were divided into three groups based on clinical status: apparently healthy (AH; N=8); cardiacs receiving beta-blockers (C-BB; N=8); cardiacs not receiving beta-blockers (Câ NBB; N=lO). / Master of Science

Radio frequency (RF) receivers are inherently non-linear due to non-linear components contained within the RF front-end such as the low noise amplifier (LNA) and mixer. When receivers operate in the non-linear region, this will affect the system performance due to intermodulation products, and cross-modulation, to name a few. Intermodulation products are the result of adjacent channel signals that combine and create intermodulation distortion of the received signal. We call these adjacent channel signals blockers. Receiving blockers are unavoidable in wideband receivers and their effect must be analyzed and properly addressed. This M.S. Thesis studies the effect of blockers on system performance, specifically the symbol error rate (SER), as a function of the receiver non-linearity figure and the blocking signal power and modulation format. There have been numerous studies on the effect of non-linearity in the probability of true and false detections in spectrum sensing when blockers are present. There has also been research showing the optimal modulation scheme for effective jamming. However, we are not aware of work analyzing the effect of modulated adjacent channel blockers on communication system performance. The approach taken in this paper is a theoretical derivation followed by numerical analysis aimed to quantify the effect of receiver nonlinearity on communication system performance as a function of (1) receiver characteristics, (2) blocking signal powers, (3) signal and blocker modulation format, and (4) phase-synchronized/non-synchronized blocker reception. The work focuses on M-PSK modulation schemes. For high blocker powers and non-linearity, the Es/No (Eb/No) performance loss can be as high as 4.7 dB for BPSK modulated signal and BPSK modulated blockers when received in sync with the desired signal. When blockers have a random phase offset with respect to the desired signal, the performance degradation is about 2 dB for BPSK modulated desired and blocker signals. It was found that for an BPSK transmitted signal with phase-synchronous blockers, the SER (BER) deteriorates the most when the blocking signals are of the same modulation. The effect is reduced, but still significant, as the modulation order of the signal of interest or the blockers, or both increases. / Master of Science / This thesis analyzes the effect of non-linear components in wireless receivers on communication system performance. We consider that two strong radio frequency signals adjacent in frequency to the desired signal enter the receiver and cause signal distortion known as 3rd order intermodulation distortion. We analyze the effect on the symbol error rate (SER) in the presence of two modulated blockers. SER defines the ratio of erroneously detected symbols to the total number of transmitted symbols and is a function of the modulation scheme and radio channel conditions. The SER analysis is done for Phase Shift Keying (PSK) modulated signals and blockers for different receiver types and blocker power levels. This thesis derives the theoretical SER expressions followed by numerical analysis aimed to quantify the effect of receiver non-linearity on communication system performance as a function of (1) receiver characteristics, (2) blocking signal powers, (3) signal and blocker modulation formats, and (4) phase-synchronized/non-synchronized reception of blockers. We justify the need for these new SER expressions and verify them via simulations. The thesis shows that modulated blockers can significantly impact communication system performance if the blockers are strong with respect to the signal of interest and if the device is highly non-linear. The work also shows that the performance degradation is a function of the blocker signal characteristics, but there are ways to overcome this loss by design or management. This has important implications on the management of spectrum in the new shared spectrum bands, where heterogeneous systems and devices will coexist with strong signals coming from nearby transmitters, radars or TV stations, among others.

The sympathetic nervous system plays a key role in the regulation of cardiovascular and ventilatory responses during exercise. The regulation of the heart and peripheral circulation by the autonomic nervous system is accomplished by control centers that receive input from mechanical and chemical receptors through the body. Therefore, the changes in sympathetic and parasympathetic activity allow for rapid responses. <p><p>Exercise is associated with increases of ventilation, heart rate and blood pressure. Ventilation increases adaptedly to increased oxygen uptake (VO2) and carbon dioxide output (VCO2) and eventually to limit metabolic acidosis occurring above the ventilatory threshold. Cardiac output increases to meet the contracting muscles’ requirement for flow. The increase in cardiac output occurs through increases in both heart rate and stroke volume and is regulated by feed-forward mechanisms: central command and exercise pressor reflex. <p><p>Skeletal muscle contraction elicits a reflex increase in sympathetic outflow which causes vasoconstriction contributing to the exercise induced rise in blood pressure. This reflex is triggered by stimulation of metabo- and chemoreceptors. Although the precise stimulus is not known, adrenergic receptor signaling is involved in the cardiovascular and respiratory alterations in response to exercise. <p><p>This thesis has been devoted to a better understanding of the functional aspects of sympathetic nervous system activation during dynamic and resistive exercise, with use of β blocker and β2 stimulant interventions The hypotheses were: 1) that β blocker interventions would decrease aerobic exercise capacity by a limitation of maximal cardiac output, but more so the ventilatory responses to exercise because of a decreased chemosensitivity, thereby decreasing dyspnea, and 2) β2 stimulant interventions would slightly increase aerobic exercise capacity by an increase in maximal cardiac output, but also the ventilatory responses because of an increased chemosensitivity, with possible decrease of the ventilatory reserve at exercise and increased dyspnea. Both interventions could affect maximal muscle strength through central effects.<p><p>Ventilatory responses to hyperoxic hypercapnia (central chemoreflex) and to isocapnic hypoxia (peripheral chemoreflex) were confronted to measurements of ventilatory equivalents for oxygen (O2) and carbon dioxide (CO2) during standard cardiopulmonary exercise test (CPET). Resting 5 measurements of muscle sympathetic nervous activity (MSNA) were obtained in different conditions with and without pharmacological interventions. Muscle metaboreflex and muscle stength measurements were also considered. Drugs with β blocker or β2 stimulant properties were administered in range of doses used in clinical practice for the teatment of cardiovascular or rerspiratory conditions. The results show that β blockade with bisoprolol slightly reduced maximal exercise capacity as assessed by a maximal oxygen uptake (VO2max) or maximal workload (Wmax), with a decreased maximal heart rate, without significant effect on ventilation (VE) or MSNA responses to hypercapnia, hyperoxia or to isometric muscle contraction or ischemia. Both VE/VO2 and VE/VCO2 slopes were decreased during CPET, which was attributable to β blockade-related hemodynamic changes. On the other hand, stimulation of β2 receptors with salbutamol did not affect exercise capacity as assessed by VO2max or Wmax in spite of increased peripheral chemosensitivity with increased VE/VCO2 slopes and early lactic acidosis. MSNA burst frequency, muscle metaboreflex and maximal isokinetic muscle strength were not affected by salbutamol. <p><p>Thus, aerobic exercise capacity in healthy subjects is sensitive to sympathetic nervous system modulation by β blocker or β2 stimulant interventions with drugs at doses prescribed in clinical practice. B blocker intervention has a slight limitation of aerobic exercise capacity and a hemodynamic decrease in ventilation, while β2 stimulant intervention has no change in exercise capacity with associated increased ventilatory responses because of increased chemosensitivity, partly related to early lactic acidosis. None of the studied phamacologic interventions affected MSNA or muscle strength measurements. <p><p>We hope that these results might be useful for the understanding of the effects of revalidation to exercise of patients treated with β blocker or β2 stimulant drugs, document the limited ergogenic properties and also side effects of the intake of these substances in healthy exercising subjects.<p> / Doctorat en Sciences de la motricité / info:eu-repo/semantics/nonPublished

En France, le syndrome coronaire aigu (SCA) représente environ 100 000 hospitalisations par an. Il est recommandé, en prévention secondaire du SCA, un traitement combinant quatre classes médicamenteuses : bêtabloquants, antiagrégants plaquettaires, statines, et inhibiteurs de l’enzyme de conversion ou antagonistes des récepteurs à l’angiotensine II(combinaison BASI). L’objectif de ce travail était l’étude, en situation réelle de soin et en population générale, de l’utilisation et de l’effectivité de la combinaison thérapeutique recommandée en prévention secondaire du SCA. Nous avons d’abord exploré le potentiel représenté par les bases de données médicoadministratives françaises pour cette évaluation. Nous avons ensuite étudié l’utilisation de la combinaison BASI : 42 % des patients étaient traités par la combinaison BASI en post-SCA et 57 % d’entre eux étaient encore traités à deux ans ; la persistance au traitement était plus faible chez les patients âgés, chez ceux ayant d’autres co-morbidités et chez ceux ayant eu un SCA de nature autre qu’un infarctus du myocarde.Nous avons enfin étudié l’effectivité de la combinaison BASI : la combinaison BASI était la combinaison thérapeutique la plus effective à long terme après un SCA chez les patients avec antécédent d’insuffisance cardiaque ; chez les patients sans antécédent de ce type la combinaison sans bêtabloquants n’était pas associée à une augmentation du risque.Ces résultats permettent de reconsidérer l’intérêt à long terme de l’ensemble de la combinaison BASI en post-SCA chez tous les patients et mettent en avant la nécessité de renforcer les stratégies d’éducation thérapeutique. / Acute coronary syndrome (ACS) causes approximately 100,000 hospitalisations per year in France. In secondary prevention of ACS, guidelines advocate pharmacological treatment combining four drug classes: beta-blockers, antiplatelet agents, statins and angiotensin converting enzyme inhibitors or angiotensin receptor blockers (recommended combination).The aim of this work was to study, in real life and among the general population, the use and the effectiveness of the recommended combination for secondary prevention of ACS.Firstly, we explored the potential represented by the French claims databases in this context. Secondly, we studied the use of the recommended combination: 42% of patients were treated with the recommended combination in post-ACS and 57% of them were still treated two years after; persistence to combination was lower in older patients, in those with other comorbidities and those who had an ACS different of myocardial infarction. Thirdly, we studied the effectiveness of the recommended combination: the recommended combination was the most effective combination therapy at long-term in post-ACS patients with history of heart failure; in patients without such history the combination without betablockers was not associated with an increased risk. These results could help reconsidering the long-term interest of the full recommended combination in all ACS patients and highlight the need to strengthen patient education strategies.

OBJECTIVES: To determine the pattern and predictors of use of antiplatelet agents and beta-blockers given in the emergency department (ED) to older adults with acute myocardial infarction (AMI) and its effects on in-hospital mortality and length of hospital stay (LOS) and to determine the effect of computerized ED guideline reminders on their utilization. METHODS: A cross-sectional study using the National Hospital Ambulatory Medical Care Survey (NHAMCS) ED data for years 1992 to 2010 was conducted. Patients were included if they had an admission diagnosis of AMI (ICD-9-CM code 410.xx) and were ≥55 years. Survey logistic regression was used to examine whether there was a trend in the use of antiplatelet agents and beta-blockers across the years and to explore the association between various predictor variables, including ED computerized guideline reminders, and their utilization rates. The chi-square test was used to see whether users of these drugs were different from non-users in their rates of in-hospital mortality. Survey linear regression was used to explore the effect of utilization of these drugs on LOS. All the visits were weighted to get national estimates. All of the analyses were carried out with SAS 9.3 statistical package. RESULTS: A total of 1,771 visits (weighted frequency = 6.1 million) were eligible for this study. Both antiplatelet agents and beta-blockers were shown to have a positive trend across the years. Age, sex, chest pain, triage, using an ambulance, and metropolitan region were all found to be significant predictors of either antiplatelet agent or beta-blocker utilization. Use of beta-blockers was associated with lower in-hospital mortality. Neither drug class had an effect on LOS. Finally, patients who were treated in EDs with computerized guideline reminders were twice as likely to get an antiplatelet agent, but this was not seen with beta-blockers. CONCLUSION: This study displayed a positive pattern across the years in the use of antiplatelet agents and beta-blockers given to older AMI patients. It also showed that age, sex, and other important variables were significant predictors of their utilization. The use of beta-blockers yielded lower in-hospital mortality. Finally, the use of ED reminders increased antiplatelet agent utilization.

Doctor of Philosophy / Department of Chemistry / Stefan Bossmann / Tris-homoleptic ruthenium(II)-quaterpyridyl and quaterpyridinium complexes, with +8 and +14 charge were synthesized by utilizing high pressure reaction pathway. These complexes have diameters ranging from 1.82 to 4.55 nm according to the molecular modeling calculations. These ruthenium complexes are highly luminescent and contain long excited state life times. The novel ruthenium(II)-quaterpyridinium complexes exhibit superior reactivity as sensitizer-relay-assemblies (SRA‟s) in sacrificial systems for water and carbon dioxide reductions, while harvesting the ultraviolet- and most of the visible fraction of the incident solar spectrum. Ru(II)-quaterpyridinium complexes and Pd/TiO2 catalysts were successfully used as the catalytic system for the photo catalytic reduction of water and carbon dioxide to hydrogen and methane respectively. Phosphonate-tethered Ru(II)-quaterpyridinium complexes were synthesized from Ru(II)-tris-quaterpyridyl complexes. These complexes form stable adhesive layers on indium tin oxide (ITO) electrodes. A series of differential pulse voltammetry experiments were carried out to measure the ground state and excited state redox potentials of all the Ru(II)quaterpyridinium complexes. The reductive potentials obtained were compared with the reductive potentials of CO2 to CH4 and H2O to H2 reductions. The measurements obtained from the experiments confirmed that it is possible to thermodynamically oxidize water and reduce CO2 by using phosphonate-tethered Ru(II)-quaterpyridinium complexes. These complexes are successfully utilized as prototypes for mycobacterial channel blockers. The Ru(II) complexes show distinct changes in their luminescence spectra when bound to the porin MspA from M. smegmatis, which is a non-pathogenic relative of M. tuberculosis. By using HPLC, we have determined binding constants of the Ru(II)-complexes to MspA in phosphate buffer (0.05 M, pH = 6.8) ranging from 5.2 x 109 M-1 (Ru-C2) to 1.8 x 109 M-1 (Ru-C4). Our findings indicate that channel blocking is a promising treatment strategy for mycobacterial infections. Poly-N-isopropyl-acrylamide/acetic acid copolymers were synthesized and characterized by elemental analysis and gel permeation chromatography. The average composition of the copolymers determined from CHN analysis is in excellent correlation with the feed composition indicating that the radical polymerization process is indeed statistical. Crosslinking of individual polymer chains permitted the generation of ultraflat layers on Mica surfaces by a simple spin-casting procedure, which are able to host the mycobacterial channel protein MspA, while retaining its channel function.

As concepções de moduladores da dinâmica dos microtúbulos, que levam ao bloqueio do ciclo celular, e de bloqueadores de canais de cálcio tipo L (Cav), tais como o 1,4-di-hidropiridinas e análogos, que diminuem a resistência do organismo humano aos tratamentos quimioterápicos através da inibição da proteína de transmembrana P-gp, são estratégias importantes tanto para terapias antitumorais quanto para leishmanicida. Esta abordagem tem mostrado resultados interessantes na diminuição da resistência à quimioterapia em câncer chamada de MDR (do inglês Multi Drug Resistence), além de também serem uma estratégia importante para controlar a fase inicial da leishmaniose. Diante desse contexto, e baseado no estudo de Ueki 2013 e colaboradores que, a partir de estudos anteriores, os quais relatam a superexpressão das enzimas estona deacetilase (HDAC) e catepsina L (CTSL) em células tumorais, propuseram um pró-fármaco seletivo, planejado a partir de um espaçador de lisina acetilada, que garante a liberação do fármaco seletivamente nas células tumorais, trabalhamos no desenvolvimento de uma nova proposta de pró-fármaco trifuncional. Nossa proposta foi desenvolvida a partir de estudos de triagem virtual, baseados em ligantes e em estrutura, predição das propriedades farmacocinéticas e toxicológicas (ADME/Tox) e também técnicas de bioinformática para a construção de um modelo de canal de cálcio, devido à inexistência de estruturas, do mesmo, que estivessem depositadas no banco de dados de proteínas PDB (Protein Data Bank). Paralelamente, nosso grupo de síntese colaborador sintetizou, através de técnicas de \"Click Chemistry\" e reações de Mitsunobu multicomponentes, uma biblioteca de novos híbridos trifuncionais, os quais, após estudos de atividade biológica, foram avaliados (in silico) frente à estrutura da tubulina, e os compostos mais promissores desta biblioteca serviram de base para novos estudos de triagem virtual. Para a obtenção dos nossos hits, executamos 4 estratégias de triagem virtual, separadas em 2 tarefas. Ao final, selecionarmos um total 59 hits, dos quais, 9 hits apresentam promissoras atividades bloqueadoras do canal de cálcio e 65 hits apresentam promissoras atividades moduladoras da tubulina. Estes hits seguem em estágio de compra e ensaios in vitro e após comprovada a eficácia dos mesmos, estes futuramente farão parte de uma nova proposta de pró-farmaco trifuncional. / The concepts of modulating microtubule dynamics, and calcium channel L-types (CAV) blockers are important strategies for anticancer and antileishmanial therapies. Microtubule modulators that blocks the cell cycle and the calcium channel blockers, such as, 1,4-dihydropyridines and analogues, reduce the resistance of the human body to chemotherapeutic treatments by inhibiting transmembrane P-gp protein. This approach has shown interesting results in reduced resistance to chemotherapy in cancer called MDR (Multi Drug Resistance), and an important strategy for controlling the early stage of leishmaniasis. In this context, we work to develop a new proposal for trifunctional prodrug. We have based on the study of Ueki 2013 and collaborators, which, from earlier studies with reported overexpression of both deacetylase estona enzymes (HDACs) and cathepsin L (CTSL) in tumor cells, proposed a selective prodrug. We considering an acetylated lysine link/spacer, which ensures the release of the drug selectively in tumor cells, have now designed this selective prodrug. Our proposal was developed from virtual screening studies, based on ligands and structure, prediction of pharmacokinetic and toxicological properties (ADME / Tox) and also bioinformatics techniques for the construction of a calcium channel model, due to the inexistence of Structures of the same that were deposited in the database of proteins PDB (Protein Data Bank). At the same time, our collaborating synthesis group synthesized, through Click Chemistry techniques and Mitsunobu multicomponent reactions, a library of new trifunctional hybrids, which, after studies of biological activity, were evaluated (in silico) against the structure of tubulin , And the most promising compounds from this library served as the basis for further virtual screening studies. To obtain our hits, we performed 4 virtual screening strategies, separated into 2 tasks. In the end, we selected 59 hits, of which 9 hits show promising calcium channel blocking activities and 65 hits show promising tubulin modulating activities. These hits follow in vitro purchase and testing, and after proven effectiveness, they will be part of a new tri prodrug proposal.

Orientador: Aparecido Antonio Camacho / Resumo: O uso de betabloqueadores tem mostrado implicações significativas na terapia de neoplasias através do bloqueio de adrenoreceptores em tecidos tumorais. O sistema nervoso autônomo simpático apresenta um perfil pró-inflamatório e por estímulo das catecolaminas ocorre à ativação de macrófagos teciduais com liberação de citocinas inflamatórias. Estudos recentes sugerem que estímulos inflamatórios crônicos podem acelerar a progressão do câncer, fato este relacionado à ativação do sistema beta adrenérgico. Assim, o objetivo do presente estudo foi avaliar a influência do emprego do propranolol sobre a evolução macroscópica dos nódulos mamários assim como a monitoração da função cardíaca. O estudo foi prospectivo, randomizado e longitudinal. Para tanto, 06 cadelas portadoras de tumores de mama (G1) receberam cloridrato de propranolol (0.2 mg/kg/BID, VO, 30 dias) e, outras 08 cadelas também com neoplasia mamária (G0) receberam apenas medicação placebo (BID, VO, 30 dias). Foram realizados exames ecocardiográfico, eletrocardiográficos convencional e Holter, paquimetria tumoral e exame histopatológico. A análise estatística foi baseada em um estudo experimental, cujos resultados foram submetidos à análise de variância (ANOVA) com medidas repetidas no tempo e em seguida Teste de Tukey. O uso do fármaco mostrou segurança sobre os parâmetros cardíacos avaliados e controle sobre o crescimento tumoral quando comparado com o grupo placebo. / Abstract: The use of beta-blockers has shown significant implications in the therapy of neoplasias through the blockade of adrenoreceptors in tumor tissues. The autonomic sympathetic nervous system presents a pro-inflammatory profile and by stimulating the catecholamines occurs to the activation of tissue macrophages with the release of inflammatory cytokines. Recent studies suggest that chronic inflammatory stimuli may accelerate the progression of cancer, a fact related to activation of the beta adrenergic system. Thus, the objective of the present study was to evaluate the influence of the use of propranolol on the macroscopic evolution of the mammary nodes as well as the monitoring of the cardiac function. The study was prospective, randomized, and longitudinal. For this, 06 bitches bearing breast tumors (G1) received propranolol hydrochloride (0.2 mg / kg / BID, VO, 30 days) and another 08 female mammary glanders (G0) received only placebo medication (BID, VO , 30 days). Echocardiographic, conventional electrocardiographic and Holter tests, tumor pachymetry and histopathological examination were performed. The statistical analysis was based on an experimental study, whose results were submitted to analysis of variance (ANOVA) with measures repeated in time and then Tukey's test. The use of the drug showed safety over the evaluated cardiac parameters and control over tumor growth when compared to the placebo group. / Mestre