Thesis (M.Sc.). / Written for the Dept. of Biochemistry. Title from title page of PDF (viewed 2009/06/25). Includes bibliographical references.

Thesis (Ph.D.)--Bioengineering, Georgia Institute of Technology, 2007. / Committee Co-Chair: Litt, Brian; Committee Co-Chair: Vachtsevanos, George; Committee Member: Butera, Robert; Committee Member: Frazier, Bruno; Committee Member: Gerstenfeld, Edward; Committee Member: Hunt, William.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Description based on contents viewed June 24, 2007; title from title screen. Includes bibliographical references (p. 76-80).

Η εκφυλιστική στένωση της αορτικής βαλβίδας και τα οξέα στεφανιαία σύνδρομα αποτελούν τις σημαντικότερες αιτίες θανάτου από καρδιαγγειακά νοσήματα. Είναι τεκμηριωμένο ότι ο ρόλος της ασβεστοποίησης στην παθοφυσιολογία των ανωτέρω νοσημάτων είναι σημαντικός και αναμφισβήτητος. Μέχρι πρόσφατα θεωρούταν ότι η ασβεστοποίηση αποτελεί παθητική διαδικασία εναπόθεσης αλάτων ασβεστίου σε ιστούς που έχουν υποστεί κάποιου βαθμού βλάβη. Ωστόσο τελευταία δεδομένα υποδεικνύουν ότι πρόκειται για ενορχηστρωμένη διαδικασία που έχει ως αποτέλεσμα την κυτταρική διαφοροποίηση και την ενεργοποίηση μεταγραφικών παραγόντων που σχετίζονται με τον οστίτη ιστό. Προκειμένου να τεκμηριώσουμε την άποψη ότι η ασβεστοποίηση των αορτικών βαλβίδων και στεφανιαίων αρτηριών στηρίζεται σε μία ενεργό διαδικασία που περιλαμβάνει την ενεργοποίηση χονδρο – οστεογενών οδών, μελετήσαμε ανοσοϊστοχημικά για πρώτη φορά την έκφραση των παραγόντων NFATc1 και Osterix. Επιπρόσθετα, διερευνήσαμε άλλα χαρακτηριστικά του προγράμματος οστεογενούς και χονδρογενούς διαφοροποίησης όπως την έκφραση των παραγόντων OPG, RANKL, RANK, Runx2 και Sox9 καθώς και τη συμμετοχή της φλεγμονής, της νεοαγγείωσης και της υπερπλασίας κυττάρων που εκφράζουν α - SMA. Στην παρούσα ερευνητική εργασία τεκμηριώνεται για πρώτη φορά η συμμετοχή των βασικών ρυθμιστικών παραγόντων των οστών NFATc1 και Osterix στη διαδικασία ασβεστοποίησης των αορτικών βαλβίδων και των στεφανιαίων αρτηριών στον άνθρωπο. Επιπρόσθετα, επιβεβαιώνεται η συμβολή των παραγόντων Runx2 και Sox9 στη δημιουργία αποτιτανώσεων στους συγκεκριμένους ιστούς. Οι αλλαγές στην έκφραση του συμπλέγματος OPG/RANKL/RANK σχετίζονται με την ασβεστοποίηση της αορτικής βαλβίδας. Αντίθετα, το προφίλ έκφρασης του συμπλέγματος δεν είναι σταθερό στις στεφανιαίες αρτηρίες επιβεβαιώνοντας αντικρουόμενα αποτελέσματα προηγούμενων μελετών. Τέλος, επιβεβαιώνεται η συμμετοχή της φλεγμονής, της νεοαγγείωσης και της υπερπλασίας των κυττάρων με συσταλτικό φαινότυπο στην εξέλιξη της παθοφυσιολογικής διεργασίας. Από την παρούσα μελέτη διαπιστώνουμε ότι η διαδικασία της ασβεστοποίησης στις αορτικές βαλβίδες και τις στεφανιαίες αρτηρίες παρουσιάζει αρκετές ομοιότητες με την οστεογένεση. Αυτό συνεπάγεται ευοίωνες προοπτικές για δυνητική γονιδιακή παρέμβαση σε πρώιμα στάδια που θα μπορούσε να οδηγήσει σε αναστροφή της παθοφυσιολογικής διαδικασίας εναπόθεσης ασβεστίου. / Degenerative aortic stenosis and acute coronary syndromes constitute major causes of cardiovascular morbidity. There is evidence that calcification plays significant role in pathophysiology of these diseases. Until recently, calcification was considered to be a passive process of calcium deposition in injured tissue. However, recent data suggest that calcification of aortic valves and coronary arteries is an active process related to cellular differentiation and transcription of bone regulators. In order to provide further evidence that aortic valve and coronary artery calcification is an active process involving chondro-osteogenic pathways, we investigated using immunohistochemistry the expression of NFATc1 and Osterix in human calcified aortic valves and coronary arteries, which to the best of our knowledge has not been reported previously. Additionally, we investigated in our specimens other features of chondro/osteogenic differentiation program such as the expression of OPG, RANKL, RANK, Runx2 and Sox9, and the participation of inflammation, neovessel formation and hyperplasia of α - SMA positive cells in calcification process. Our results provide evidence for the involvement of bone regulatory factors NFATc1 and Osterix in aortic valve and coronary artery calcification process in human. In addition, we confirm Runx2 and Sox9 expression in diseased specimens. Expression pattern of OPG / RANKL / RANK system is related to aortic valve calcification. Consistently with previous reports, the role of OPG / RANKL / RANK system in coronary artery calcification is not clear. Finally, our study confirms involvement of inflammation, neovessel formation and hyperplasia of α - SMA positive cells in calcification process. Present study demonstrates that aortic valve and coronary artery calcification is actually an active process sharing features with developmental osteogenesis. This fact implies promising prospects for potential genetic intervention in early stages that could lead to inhibition of calcification process.

Το πεδίο έρευνας της παρούσας διδακτορικής διατριβής είναι η υπολογιστική καρδιολογία και συγκεκριμένα η μέτρηση όγκου δεξιάς κοιλίας με χρήση υπερήχων σε καθετήρα πνευμονικής αρτηρίας (ΚΠΑ) για την αποτελεσματικότερη διαχείριση των βαριά πασχόντων ασθενών. Μέχρι τώρα ο ΚΠΑ μετράει μόνο τις πιέσεις ενδοκοιλοτικά. Τα αποτελέσματα από τη χρήση του δεν είναι επαρκώς ενθαρρυντικά. Έχει βρεθεί ότι για την καλύτερη αντιμετώπιση των βαριά πασχόντων στην μονάδα εντατικής θεραπείας (ΜΕΘ), ή στην μονάδα εμφραγμάτων, ή ακόμα και κατά την προετοιμασία ή τη διάρκεια μιας σοβαρής χειρουργικής επέμβασης, σημαντική παράμετρος πέρα από την πίεση είναι ο τελοσυστολικός και ο τελοδιαστολικός όγκος της δεξιάς κοιλίας. Αυτές οι παράμετροι συνδυαζόμενες με τις πιέσεις, προσφέρουν σαφώς καλύτερη εκτίμηση και αποτελεσματικότερη αιμοδυναμική διαχείριση των βαριά πασχόντων ασθενών με απώτερο στόχο την ελάττωση της νοσηρότητας και θνησιμότητας. Γι’ αυτό το λόγο μοντελοποιήθηκε σύστημα μέτρησης όγκου δεξιάς κοιλίας από εικόνες MRI (μαγνητικού συντονισμού) με προσομοίωση υπερήχων. Επίσης το γεγονός ότι δεν υπάρχει μέθοδος υπολογισμού όγκου ενδοκοιλιακά που να συνδυάζεται με τον δεξιό καθετηριασμό, καθιστά την παρούσα διατριβή ως καινοτόμα αφ’ ενός στον υπολογισμό του όγκου της δεξιάς κοιλίας και αφ’ ετέρου στην διαχείριση της αιμοδυναμικής κατάστασης των βαριά πασχόντων. / The research field of this PhD thesis is the computational cardiology and more specifically the right ventricle’s volume measurement using ultrasound technology on the pulmonary artery catheter (PAC) for the effective management of critically ill patients. Hitherto, right cardiac catheterization with a pulmonary artery catheter provides only intracavity pressure measurements. Several studies showed that the use of PAC in critically illness does not make any effect in patient management. It was found that for the reliable management of critical ill patients in intensive care unit (ICU), or in infarctions unit, or even during serious surgery, pressures, is the right ventricle end-diastolic and end-systolic volume. The combination of those parameters with pressures, provides obviously better estimation and effective hemodynamic management of critically ill patients seeking in mortality and morbidity reduction. For that reason, a right ventricle’s volume measurement system was modeled from cardiac MRIs with ultrasound simulation. The fact that there is not any intraventricular volume calculation method combined with right catheterization, makes this PhD thesis innovative as the right ventricle’s volume and the hemodynamic management of critically ill patients regards.

Trata-se de estudo transversal sem modelo de intervenção, que tem como objeto a atenção à saúde na prevenção secundária da doença coronariana a pacientes com ou sem tratamento ambulatorial especializado. O objetivo primário foi: Avaliar se há diferença na atenção à saúde entre pacientes portadores de doença arterial coronariana em sua forma aguda ou crônica com ou sem acompanhamento ambulatorial especializado. Os objetivos secundários foram: a) apresentar o perfil de cada grupo de pacientes a partir de dados sócio-demográficos e econômicos; b) descrever as característica clínicas dos pacientes e identificar a que fatores de risco cada grupo de pacientes está exposto; c) descrever a regularidade na utilização de medicamentos e como se dá o acesso à mesma; d) identificar o tipo e principais dificuldades enfrentadas pelo paciente para seguir o tratamento. Para a coleta de dados foi utilizado formulário desenvolvido e previamente testado para atender os objetivos propostos para o estudo, além de informações coletadas diretamente do prontuário do paciente. A coleta de dados foi realizada em três unidades públicas de saúde localizadas no município do Rio de Janeiro. A amostra selecionada foi composta por 112 pacientes divididos igualmente entre os dois grupos existentes na pesquisa. Os dados foram transcritos para planilha do programa Statistic Package for the Social Science e análise realizada através dos testes estatísticos de diferença entre proporção, odds-ratio e qui-quadrado. Quanto ao perfil sócio-demográfico e econômico verificou-se diferença estatística significativa quanto ao grau de instrução entre os grupos I e II, com predomínio de pacientes de nível fundamental incompleto para o grupo I e médio completo no grupo II (p=0,0434), foi também verificada diferença significativa entre os grupos relacionada ao rendimento mensal, embora o maior percentual encontrado em ambos os grupos tenha sido observado na faixa de dois salários mínimos, uma vez que o grupo II apresentou maior concentração de renda entre a faixa de dois a três salários mínimos (p=0,0044). Ao que se refere aos fatores de risco para doença coronariana, observou-se diferença estatística entre os grupos para a variável tabagismo (p= 0,0001) e sedentarismo (p=0,0025). Verificou-se para pacientes do grupo I valor estatístico significativo quanto a regularidade em utilizar medicamentos (p=0,0010). Concluiu-se, portanto, que o acompanhamento de pacientes pós-síndrome coronariana aguda em ambulatório especializado de coronariopatias apresentou benefícios significativos quando comparado ao grupo de pacientes não cobertos por este tipo de assistência. Verificou-se ainda que o enfermeiro poderá contribuir e atuar amplamente para a prevenção secundária da doença coronariana, enquanto membro da equipe multidisciplinar. / This transverse study has been made without an intervention model and its subject is the health attention level throughout the secondary prevention of the coronary artery disease in patients with and without specialized outpatient treatment. The primary objective was: assessing the difference in the treatment given to acute and chronicle patients with coronary artery disease who are with or without specialized outpatient treatment follow-up. The secondary objectives were: a) presenting the profile of each group of patients, considering their socio-demographic and economic data; b) describing the patients clinical characteristics and identifying to which risk factors each group of patients is exposed to; c) describing the regularity in the use of medicines and how one can access it; d) identifying type and main difficulties found by patients to follow their treatment. Data collection has been done through a specially created and previously tested form so as to attend the proposed objectives of this study, besides through information directly collected from the patients record table. This data collection has been made in three municipal public health treatment unities located in Rio de Janeiro. The selected sample has been composed of 112 patients equally divided into the two existing groups in the research. The data has been transcribed into the Statistic Package for the Social Science table and the analysis has been made through statistical tests of difference among proportion, odds-ratio and chi-square. Concerning the socio-demographic and economic profile, a significant statistical difference has been considered according to the education level between the groups I and II, with a predominant number of patients with incomplete basic educational level in group I and with complete college education in group II (p=0,0434). A significant difference concerning monthly income between the groups has also been proved, although the highest percentage found in both groups was observed in the range of two minimum wages, group II had a higher concentration of income among the range of two to three minimum wages (p = 0.0044). Regarding risk factors for coronary disease, there was a statistical difference between groups for the variables smoking (p = 0.0001) and lack of exercise (p = 0.0025). It was found that, for patients in Group I as statistically significant value in using medication regularly (p = 0.0010). It was concluded therefore that the monitoring of patients after acute coronary syndrome in the specialized coronary artery disease outpatient treatment showed significant benefits when compared to patients not covered by this type of assistance. It was also found that nurses can contribute and act widely for the secondary prevention of coronary disease, as a member of the multidisciplinary team.

TÍTULO: Associação entre Distúrbios Respiratórios do Sono, Estresse Oxidativo e Doença Arterial Coronariana. INTRODUÇÃO: Evidências sugerem associação entre a doença arterial coronariana (DAC) e os distúrbios respiratórios do sono (DRS), porém o mecanismo que explica essa associação é incerto. Episódios repetitivos de hipóxia e reoxigenação vivenciados pelos indivíduos com DRS levam ao aumento de espécies reativas de oxigênio (ERO). ERO no interior dos eritrócitos podem ser detoxificadas pelas enzimas antioxidantes glutationa peroxidase (GPx), catalase (CAT) e superóxido dismutase (SOD). Ainda no citoplasma as ERO podem ser detoxificadas pela vitamina C ou ácido úrico. O estresse oxidativo é caracterizado por um desequilíbrio entre os níveis de ERO e antioxidantes. Este desequilíbrio promove lesão oxidativa em biomoléculas, mecanismo este associado à fisiopatologia da DAC. OBJETIVOS: Verificar a relação entre o índice de apnéia hipopnéia (IAH) e a presença de DAC. Verificar a associação entre IAH, DAC e a atividade das enzimas antioxidantes: SOD, CAT, GPx e antioxidantes não enzimáticos, ácido úrico e vitamina C. Avaliar a relação entre IAH, DAC e os produtos de danos oxidativos em lipídios, proteínas. Entre os marcadores de estresse oxidativo identificar preditores para DAC. MATERIAIS E MÉTODOS: Estudo transversal. Entre junho de 2007 e maio de 2008 na Hemodinâmica do Hospital de Clínicas de Porto Alegre, triamos consecutivamente 519 indivíduos encaminhados para angiografia diagnóstica ou terapêutica. Incluímos 14 pacientes com DAC (≥ 50% diminuição do lúmen da coronária) e 30 controles com < 50% de obstrução. O IAH foi mensurado por meio de polissonografia portátil. Verificamos presença de DAC através da angiografia coronariana. A quantificação dos grupos carbonil no hemolisado e no plasma e as atividades das enzimas antioxidantes SOD, CAT e GPx foram verificadas por método espectrofotométrico. Mensuramos malondialdeído (MDA) e vitamina C por cromatografia líquida de alta eficiência. RESULTADOS: Este é o primeiro trabalho que evidencia correlação entre IAH e o aumento de carbonilação de proteínas eritrocitárias. Além disso, os resultados obtidos mostram que os indivíduos portadores de DAC apresentam níveis maiores de grupos carbonil no hemolisado quando comparados aos indivíduos controles. Em um modelo de regressão multivariado ajustado para idade, sexo e índice de massa corporal, buscando verificar preditores para DAC, verificamos que o aumento de uma unidade de carbonil aumenta 1,7% o risco para desenvolvimento de DAC, já uma unidade do IAH aumenta em 3,9% o risco de desenvolvimento de DAC. Não foi encontrada correlação entre IAH e os marcadores MDA, carbonil no plasma e os antioxidantes: SOD, CAT, GPx vitamina C e ácido úrico. Não verificamos correlação entre DAC e os marcadores MDA, carbonil no plasma e entre os antioxidantes SOD, CAT , GPx e ácido úrico. Pacientes com CAD significativa apresentaram níveis menores de vitamina C. Correlação positiva foi observada entre os níveis de vitamina C e a concentração de proteínas carboniladas no plasma. CONCLUSÃO: Foi evidenciado que a carbonilação de proteínas eritrocitárias e o IAH tem importância na fisiopatologia da DAC. Da mesma forma a vitamina C parece ter importância na prevenção da DAC. / INTRODUCTION: Evidences suggest association between Coronary Artery Disease (CAD) and Sleeping Disordered Breathing (SDB), however the mechanism is uncertain. Repetitive episodes of hypoxia and reoxygenation experienced by individuals with SDB lead to an increase of Reactive Oxygen Species (ROS). ROS inside the erythocytes may be scavenging by glutathione peroxidase antioxidants enzymes (GPx), catalase (CAT) and superoxide dismutase (SOD). In the cytoplasm ROS may be inhibited by vitamin C, or uric acid. Oxidative stress is characterized by an unbalance between ROS and antioxidants. These unbalance promotes oxidative damage in biomolecules, this mechanism is associated to the CAD physiopathology . OBJECTIVE: Verify the relation between apnea hypopnea index (AHI) and CAD. Verify association between AHI, CAD and antioxidants enzymes activity: SOD, CAT, GPx and non enzymatic antioxidants, uric acid, and vitamin C. Evalute the relation between AHI, CAD and oxidative damage products in lipids and proteins. Among the oxidative stress markers identify the predictors for CAD. MATERIALS AND METHODS: Cross sectional study. Between June and May 2008 in the hemodinamic ward of Clinicas Hospital of Porto Alegre, we consecutively screened 519 individuals sent for diagnostic or therapeutic angiography. We included 14 cases with CAD (≥ 50% narrowing of coronary lumen) and 30 controls with < 50% narrowing. The AHI was measured by portable polisomnography. We found the presence of CAD through coronary angiography. Carbonyl groups quantification in the hemolysed and plasma and antioxidants enzyme activities of SOD, CAT and GPx were verified by spectophotometric method. Malondyaldeyde (MDA) and vitamin C were measured by HPLC. RESULTS: This work is the first one that shows correlation between AHI and increased erythrocytes protein carbonylation. In the same way evidences that individuals with significant CAD compared to controls present higher levels of carbonyl groups in the hemolysates. In a multivaried regression model adjusted to age, gender and body mass index to verify predictors for CAD, we verified that the carbonyl unit increased 1.7% the risk for development of CAD, while one unit of IAH increased in 3.9% the risk to develop CAD. We did not find correlation between AHI and the markers MDA, plasma carbonyl and the antioxidants: SOD, CAT, GPx vitamin C and uric acid. We didn’t verify correlation between CAD and the markers MDA, plasma carbonyl and the others antioxidants SOD, CAT , GPx and uric acid. Patients with significant CAD had lower levels of vitamin C. Positive correlation was observed between vitamin C and erythrocyte carbonyl concentration. CONCLUSION: We evidenced that erythrocytes protein carbonylation and AHI are important in the physiopathology of CAD. In the same way vitamin C appears important factor in CAD prevention.

Made available in DSpace on 2015-12-06T23:05:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2005 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundo de Auxílio aos Docentes e Alunos (FADA) / Objetivo: Este estudo piloto procurou revisar a metodologia e discutir a aplicação da Terapia por Contensão Induzida (TCI) nos pacientes com acidente vascular cerebral isquêmico (AVCI) crônico, em um centro de reabilitação brasileiro. Método: Uma ampla revisão da literatura médica foi realizada para adaptar esta técnica em nosso meio. Foram selecionados 10 pacientes que se submeteram a 6 horas de tratamento por duas semanas consecutivas. Entre os critérios de seleção destacam-se AVCI em território da artéria cerebral média. Nestes 14 dias os pacientes foram submetidos a atividades motoras repetitivas utilizando o membro superior parético, enquanto o membro não parético era mantido com um dispositivo de contenção. Resultados: Houve melhora significativa no déficit motor do membro superior parético e concomitante melhora na resposta ao Teste de Função Motora de Wolf. Conclusão: Esta nova técnica de reabilitação específica para pacientes com déficit motor moderado em membro superior parético é viável em nosso país. Nosso estudo sugere que a dominância e tempo de lesão têm um efeito modificador sobre o tratamento em pacientes com lesão isquêmica crônica no território da artéria cerebral média. / Purpose: The purpose of this pilot study is to review evidence and discuss the aplly of Constraint Induced Movement Therapy (CIMT) protocol in a brazilian center of rehabilitation in chronic patients with isquemic stroke. Methods: A wide revision of the medical literature was accomplished to adapt this technique for our population. Ten patients were selected and submitted at 6 hours of treatment for 2 weeks. Among the selection criteria they stand out schemic stroke in the middle cerebral artery territorry. On these 14 days the patients were submitted to repetitive motor activities using the paretic upper-limb while the unaffected limb was maintained with a constraint device. Results: There was a significant improvement of function of the affected upper-limb in the motor deficit of the paretic upper-limb and concomitant improvement in the answer to the Wolf Motor Function Test. Conclusions: This new technique of specific rehabilitation for patients with moderate motor deficit in paretic upper limb is feasible in Brazil. Our study suggest that the dominance and the time of lesion have a modifier effect on the treatment in patients with chronic schemic lesion in the middle cerebral artery territory. / BV UNIFESP: Teses e dissertações

FDA approval of drug-eluting stents (DES) in 2002, was based on data obtained from several pivotal, short-term (< one year) randomized control trials that evaluated their efficacy in reducing in-stent restenosis when used in treatment of coronary artery lesions compared with bare metal stents (BMS). These trials excluded patients with complex coronary lesions. When the FDA approved use of DES in treatment of coronary artery lesions, the on-label indications only applied to a very limited subset of simple lesions. Immediate advantages of DES were observed in clinical practice for on-label indications, specifically in their ability to significantly reduce in-stent restenosis after PCI. The increased short-term safety and efficacy seen in on-label clinical cases soon led clinicians to expand the use DES to more complex lesions. These complex indications, not included in the pivotal FDA trials, are considered off-label. Off-label indications include bifurcation lesions, ostial lesions, lesions greater in length and diameter than those approved by the FDA, implantation in saphenous vein grafts, and lesions in the left main coronary artery. Currently, DES use for treatment of lesions presenting off-label indications may comprise as much as 60% of clinical cases. However, early evidence that DES may play a role in adverse safety outcomes, has led many to question the use of DES outside their on-label indications. This paper sought to evaluate some of the current research investigating first generation DES use in four different off-label indications: coronary artery bypass graft lesions, saphenous vein graft lesions, ostial lesions, and chronic total coronary occlusions. In particular, it looked at studies, which compared the efficacy and clinical outcomes of DES and BMS treatment of each of the different lesion types. The results of this evaluation were very promising in that of the four specific off-label indications evaluated, all of them showed to be superior in reduction of neointimal growth and subsequent in-stent restenosis. Additionally, DES treatment of left main coronary artery lesions, saphenous vein graft lesions, and chronic total coronary occlusions showed to be superior in reducing the incidence rate of major adverse cardiac events and target vessel revascularization over various follow-up durations. The only scenario that DES did not prove to be superior to BMSs was the treatment of ostial lesions. Long-term randomized control trials with large study populations should be performed to further elucidate the effects of DES treatment of specific off-label lesions.

Magister Sport, Recreation and Exercise Science - MSRES / The work demands involved in fire-fighting place significant stress on the cardiovascular system. Cardiovascular disease is the leading cause of on-duty death among fire fighters and is a major cause of morbidity. This study investigated the prevalence of coronary artery disease risk factors among career fire fighters in the Western Cape.