We report here the development of new and more general synthetic pathways for the preparation of allenyl and alkynyl carbonyls. These highly dense functionalized compounds were utilized as key intermediates for the synthesis of [3.2.1] and [3.3.1] bicyclic framework, the motifs found in many natural products. A convenient method described for the dehydration of ketoesters to generate conjugated and deconjugated alkynyl esters and conjugated allenyl esters. This sequential one-pot method involves the formation of a vinyl triflate monoanion intermediate that leads to the selective formation of alkynes or allenes depending on additives and conditions used. Product outcomes appear to be a function of unique monoand dianion mechanisms which are described. Our design of a Morita-Baylis-Hilman (MBH) reaction to include a fast silyl 1,3- Brook rearrangement has enabled the first ever anion-catalysis. This new reaction makes possible the addition of both aliphatic and aromatic aldehydes to s ilylallenes leading to carbinol allenoates. These new MBH reactions products allow for a fasttracked synthesis of [3.2.1] bisoxa-bicycles which make up the framework of many biologically active natural products including Vitisinol D. The development of cyclic addition of hydrazine nitrogen to unactivated alkynes catalyzed by non-metals is reported. Starting from readily accessible silyl allenyl esters, alkynyl hydrazines are prepared in one step and subsequently undergo unprecedented cyclization reactions in the presence of ammonium and phosphonium catalysts leading to dehydro-azaproline products. These heterocycles were also produced in high enantiomeric excesses using chiral ammonium phase transfer catalysts via a kinetic resolution pathway. / The racemic synthesis of fully functionalized bicyclic core of Vitisinol D was achieved using allenyl ester as a key intermediate. The required electron withdrawing group (EWG) at the position was screened for better addition followed by the compatibility towards successive transformation and, finally, the ease of removal. A reductive aldol method to transform lactone-enol to the desired [3.2.1] bicycle was extensively studied to understand the stereoelectronic requirements for the formation of such bicyclic structures. Due to the necessity of selective protection and deprotection of many phenolic and aliphatic hydroxyls as well as ester groups, orthogonal protecting groups were established accordingly. / by Pradip Maity. / Thesis (Ph.D.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

Orientador: Roberto Jorge da S. Franco / Coorientador: Luis Cuadrado Martin / Coorientador: Evelyne Marie Therese Mainbourg / Banca: Pasqual Baretti / Banca: Vanessa dos Santos Silva / Banca: Eduardo Barbosa Coelho / Banca: Marcio Dantas / Resumo: As doenças cardiovasculares representam a primeira causa de morte no Brasil e no mundo. Os poucos estudos biomédicos realizados com grupos indígenas aldeados revelam que obesidade, hipertensão arterial sistêmica e diabetes Mellitus, principais fatores de risco para o desenvolvimento das doenças cardiovasculares, têm sido frequentes. Objetivo: O objetivo deste estudo foi comparar a prevalência dos fatores de risco para as doenças cardiovasculares entre indígenas das etnias do Rio Negro, dos sateré-mawé e de seus vizinhos brancos, pardos/negros que residem na cidade de Manaus. Casuística e Métodos: A amostra foi de 191 sujeitos, sendo 35 (18,3%) indígenas sateré-mawé, 43 (22,5%) indígenas do Rio Negro, 24 (12,6%) brancos e 89 pardos/negros (46,6%). Resultados: Os resultados mostraram que, em todos os grupos, as mulheres foram maioria. A prevalência de HAS foi de 25% entre os pardos/negros, 21% entre os brancos, 11,6% nos indígenas do Rio Negro e 2,3% nos sateré-mawé. A análise de regressão logística mostrou que os indígenas do Rio Negro apresentaram chances semelhantes a dos brancos e pardos/negros para desenvolver HAS, enquanto que os indígenas sateré-mawé apresentaram maior proteção para vir a ter a doença. Por outro lado, os indígenas do Rio Negro apresentaram menor chance de terem triglicerídeos elevados, enquanto que os indígenas sateré-mawé tiveram chances similares aos brancos e pardos/negros. Para todos os grupos, o aumento do IMC, assim como o sedentarismo e atividade física irregular, estiveram associados a níveis de glicemia e triglicerídeos mais elevados. Discussão: Sugere-se que a mudança do estilo de vida e dos hábitos alimentares para os grupos, principalmente os indígenas, tenha influenciado tanto os mecanismos de proteção, como os de maior exposição aos fatores de risco para as DCVs. Conclusão: Entende-se a necessidade de estudos que possibilitem investigar, de forma mais detalhada... / Abstract: Cardiovascular diseases are the leading cause of death in Brazil and worldwide. The few biomedical studies conducted with indigenous groups in villages reveal that obesity, hypertension and diabetes mellitus, major risk factors for the development of cardiovascular diseases, have been frequent. Objective: This study aimed to compare the prevalence of risk factors for cardiovascular diseases among indigenous ethnic groups of the Rio Negro region, the sateré-mawé and their white neighbors, browns / blacks living in the city of Manaus. Methods: The sample consisted of 191 subjects, 35 (18.3%) sateré-mawé natives, 43 (22.5%) natives of the Rio Negro, 24 (12.6%) white and 89 browns / blacks (46.6%). Results: The results showed that in all groups there were mostly women. The prevalence of hypertension was 25% among the browns / blacks, 21% among whites, 11.6% among natives of the Rio Negro and 2.3% in sateré-mawé. The logistic regression analysis showed that the natives of Rio Negro had similar chances to whites and browns / blacks to develop hypertension, whereas the sateré-mawé natives showed greater protection to come to have the disease. On the other hand, the natives of Rio Negro were less likely to have high triglycerides, while the sateré-mawé had similar chances to whites and browns / blacks. For all groups increased BMI, as well as sedentary lifestyles and irregular physical activity, were associated with blood glucose levels and higher triglycerides. Discussion: We suggest that changes in lifestyle and eating habits of these groups, especially indigenous people, have influenced both protection mechanisms, such as increased exposure to risk factors for CVD's. Conclusion: There is need for studies that investigate in more detail, the types and amounts of food consumed by these groups; or there is the hypothesis that saterê-mawé natives have some additional protective factor for hypertension. / Doutor

Furthermore, ACS patients with a high N-terminal pro-B-type natriuretic peptide (NT-proBNP) and a high ROCK activity on admission had a five-fold risk to experience a cardiovascular event, when compared to those with low NT-proBNP and low ROCK activity. In addition, patients with high NT-proBNP and high ROCK activity were also more likely to die or experience a cardiovascular event at two years when comparing to those with high NT-proBNP and low ROCK activity. / In both ACS and CHF study cohorts, all the clinical parameters were recorded and analyzed. / In the first part of this thesis, 176 ACS patients and 51 control subjects were studied. All The patients were enrolled between December 2007 and May 2009 and followed up till 15th March 2010 (mean: 15.4+/-7.6 months, from 0.5 month to 27.5 months). The main outcome measures were all cause mortality, readmission with ACS or congestive heart failure (CHF) at 2 years from presentation. Altogether, there were 23 deaths (13.1%),33 readmissions with ACS (18.8%) and 13 admissions with CHF (7.4%) within 2 years. / Recent studies have shown that ROCK may playa pivotal role in cardiovascular diseases such as vasospastic angina, ischemic stroke, heart failure and metabolic syndrome via its involvement in regulation of vascular tone, endothelial dysfunction, inflammation, and remodeling. Indeed, inhibition of ROCK by statins or other selective inhibitors leads to upregulation and activation of endothelial nitric oxide synthase (eNOS) and reduction of vascular inflammation and atherosclerosis. In this thesis, we hypothesized that ROCK activity is increased in a selected population of patients with acute coronary syndrome (ACS) and congestive heart failure (CHF) and that ROCK activity is able to predict long-term clinical outcomes in these two populations. / Rho/rho-kinase (ROCK) is a serine-threonine protein kinase, which is one of the first immediate downstream targets of RhoA and expressed ubiquitously. ROCK is involved in many cellular functions, such as, cell growth, migration, apoptosis via actin cytoskeleton organization, and gene expression. They regulate cell contraction through serine-threonine phosphorylation of adducin, ezrin-radixin-moesin proteins, LIM kinase, myosin light chain phosphatase, and Sodium-Hydrogen ion (Na/H) exchanger. / The main findings are: ROCK activity was increased in ST elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina (UA) groups when comparing with disease controls and healthy controls. On multivariate analysis, heart failure symptom on presentation, LDL-C level, and number of diseased coronary vessels were independent predictors of ROCK activity in ACS patients. / The ROCK activity in CHF patients was significantly higher than that of the disease control and normal control groups. New York Heart Association (NYHA) class, low left ventricular ejection fraction (LVEF) and high creatinine were independent predictors of the baseline ROCK activity in CHF. In terms of long-term heart failure mortality, ROCK activity was not an independent predictor. However, combining ROCK activity and NT-proBNP provided an incremental value in predicting long-term heart failure mortality over NT-proBNP alone. / Thus, increased ROCK activity is likely involved in cardiovascular diseases and further studies would be helpful to elucidate the potential role of ROCK activity inhibition in cardiovascular diseases. / We also recruited a group of 178 patients with CHF. All the patients were enrolled between December 2007 and January 2009 and followed up until 1st February 2010 (mean: 14.4+/-7.2 months, from 0.5 month to 26 months) or until the occurrence of cardiac death. Forty-five patients died (25.3%) within 2 years follow up. / Dong, Ming. / Adviser: Cheuk Man Yu. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 140-164). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

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Atherosclerotic plaque disruption leading to thrombosis has traditionally been studied as a rupture of a thin fibrous cap over a lipid-laden necrotic core. However, two noteworthy categories of plaques that do not rupture have presented themselves: 1) in mice, plaque rupture is rare if not absent, and 2) in humans, some plaques erode and form a thrombus without rupturing. Current understanding of the biomechanical differences between plaques that rupture and those that do not is incomplete. In this research, we used patient-specific computational biomechanics tools to study differences among these groups. Lesion-specific solid mechanical modeling of murine plaques revealed that the relative distribution of stresses differs considerably between mice and man. In human vulnerable plaques, peak stresses are on the thin fibrous cap over a necrotic core, but in mice the highest stresses are in the media and adventitia, away from the plaque. Whereas atherosclerotic human arteries usually experience neointima formation around the entire circumference of the vessel, mouse plaques tend to be punctate and adjacent lesion-free regions. The difference in mechanical environment suggests that plaque rupture, if possible in mice, is likely not driven by mechanics in the same manner as humans. Similar mechanical modeling of human ruptured and eroded plaques and comparison to histological staining revealed that ruptured plaques exhibit increased levels of inflammatory markers in response to strain in ruptured plaques, but no such response was observed in plaque erosion. This suggests that treatment of inflammation, a current paradigm for care of atherosclerotic patients, may not be an effective approach to mediate plaque erosion. Computational fluid dynamics modeling of patients with plaque erosion revealed no relation between wall shear stress magnitude or direction, further suggesting that the mechanism of plaque erosion differs considerably from that of plaque rupture. Together, these findings suggest that biomechanics can help explain why not all plaques rupture and that different clinical approaches are necessary to address different phenotypes of lesions.

published_or_final_version / Medicine / Master / Master of Research in Medicine

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Cigarette smoke (CS) is a well-established risk factor to cardiovascular health and the most preventable cause of death. Countless studies have demonstrated its harm to health and many more studies investigating its pathogenic mechanisms. While the CS-induced pathogenic mechanism of cardiovascular dysfunction has been mainly attributed to a combination of oxidative imbalance, vascular endothelial dysfunction, inflammation and modification of lipid profile, the focus of the current study was on the mediators of inflammation and the activation of signal pathways. In this study, we investigated the effects of CS on the pro-inflammatory/anti-inflammatory status in the heart and to elucidate the activation of specific signaling pathways in an in vivo rat model. Male Sprague-Dawley rats were divided into groups of CS exposure and sham air (SA) and exposed to 1 hour of respective CS and SA exposure daily for 56 days. The rats were then sacrificed and the ventricular homogenates were examined. Cardiac pro- inflammatory and anti-inflammatory mediators such as C-reactive protein (CRP), interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (CINC-1), transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) and the activation of specific signaling pathways was determined by Western blot analysis. CS caused suppression of cardiac CRP, IL-6, TGF-β1, and IL-10 and elevation of VEGF, revealing the imbalance of pro-inflammatory/anti-inflammatory status. Nuclear factor-κB (NF-κB) was also activated along with the activation of extracellular-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) but not p38 mitogen-activated protein kinase (MAPK) after 56 days of CS exposure. These data suggests the presence of a local adaptive mechanistic response to modulate cardiac pro-inflammatory/anti-inflammatory status via NF-κB/MAPK pathways after exposure to CS. These findings shed insight into the mechanistic pathways of CVD progression, allowing possible identification of selected mediators as biomarkers that could benefit early detection of CVD arisen from cigarette smoking. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

Background Cardiovascular disease (CVD) is the worldwide leading cause of death among non-communicable diseases and results in a huge burden of mortality and morbidity. China, a rapidly growing East Asian country, has the world largest population and is facing an increasing burden. Incidence of CVD is lower in China than in Western countries. There are more strokes, especially hemorrhagic strokes, but less coronary heart disease (CHD) in China than in Western countries. Statin, a first-choice drug for lowering low-density lipoprotein cholesterol (LDL-C), has been shown to be effective in preventing CVD and is widely used in Western countries. However, it is not known whether the same can be applied to Asian countries, where the incidence of CVD is lower and ischemic events are rarer. The aim of this systematic review is to evaluate the effectiveness of statin for prevention of CVD in East Asian populations. Methods A systematic review was conducted by searching for randomized controlled trials from 3 databases (PubMed, MEDLINE and Cochrane Trial) for prevention of CVD comparing statin with usual care or placebo in East Asian population. Data on CVD events (deaths, CHD and cerebrovascular events, rehospitalization and revascularization) and serum lipid levels (total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) were extracted. Risk ratios of CVD events and change in serum lipid level were tabulated. The relationship between change in serum lipid level and mortality and incidence of CVD events were also explored. Results Fourteen studies were included, with most of them (9 studies) done in Japan. Overall, statins did not significantly reduce risk of mortality, CHD events, cerebrovascular events, revascularization and rehospitalization due to CHD. However, statins consistently lowered the risk of angina-related rehospitalization by 53% (95% confidence interval (CI) 23% to 71%) and 64% (95% CI 11% to 86%) respectively in 2 studies. There was a consistent reduced risk of composite CVD events by 34% (95% CI 5% to 55%) to 54% (95% CI 6% to 41%) in 4 studies for secondary prevention. In terms of change in lipid levels, TC and LDL-C were significantly reduced by 8% to 31% and 14% to 41% respectively with statin treatment. Change in HDL-C and TG were not consistent across studies. Lowering of TC and LDL-C level was correlated with the reduction in composite CVD and CHD events. Conclusion The use of statins in East Asian populations to prevent CVD may not be as effective as in Western countries, because of the lower baseline risk and different patterns of CVD. As the prevalence of CVD risk factors increases, the incidence of CVD will increase and the pattern of CVD may change, so careful monitoring is needed. More importantly, most of the studies included had small sample sizes, short follow-up periods and/or low methodological quality, which might contribute to the inconsistent findings. A further large-scale randomized controlled trial should be done to confirm the benefits of statins among Chinese. / published_or_final_version / Public Health / Master / Master of Public Health