Estima-se que a adesão dos pacientes à farmacoterapia anti-hipertensiva varie entre 50 - 70%. A baixa adesão ou não adesão ao tratamento farmacológico anti-hipertensivo constituem problemas de saúde pública e devem ser compreendidos como um dos maiores obstáculos para o sucesso do tratamento da hipertensão arterial. A elevada prevalência desta condição clínica e seqüelas devastadoras no controle inadequado da pressão arterial tem sido freqüentemente relacionadas à mortes precoces. Este estudo tem como objetivo estudar a adesão ao tratamento farmacológico em pacientes hipertensos seguidos nos Núcleos de Saúde da Família I, III, IV e V do município de Ribeirão Preto - SP. Foram entrevistados 109 pacientes, utilizando-se o Teste de Morisky- Green para mensurar o grau de adesão ao tratamento farmacológico e foram estudadas variáveis que possam estar relacionadas ao grau de adesão, como: características sócio-econômicas; fatores relacionados à equipe e ao serviço de saúde; fatores relacionados à terapia; nível de conhecimento sobre a doença e fatores relacionados ao paciente. A análise dos dados foi realizada utilizando-se o programa estatístico Epi-Info versão 6.0 e o software SAS. Observou-se predomínio do sexo feminino em 84,4%, idade média de 61,4 anos, 56% casados, 81,7% de cor branca, 65,2% apresentavam baixa escolaridade e 45% eram do lar. A adesão dos pacientes foi verificada utilizando-se os critérios 1 e 2 do Teste de Morisky e Green. Através do Critério 1 do TMG, 79,8% dos pacientes foram classificados como \"mais aderentes\" e 20,2% como \"menos aderentes\". Utilizando-se o Critério 2, 43,1% dos pacientes foram \"mais aderentes\" e 56,9% \"menos aderentes\". Em relação às possíveis causas da não adesão ao tratamento, identificou-se associações estatisticamente significantes entre as variáveis \"confiança no médico\" e \"quantidade de medicamentos para HAS que utiliza\" com o grau de adesão pelo Critério 2 do TMG. O farmacêutico é um profissional de saúde que, através da Atenção Farmacêutica vem estudando e identificando as causas da baixa adesão ao tratamento e implementando estratégias, junto ao paciente, para resolvê-las. / It is estimated that patients\' adherence to medicine treatment against high blood pressure varies between 50 and 70%. The low adherence or non-adherence to high blood pressure medicine treatment is a public health problem and should be considered one of the main obstacles to a successful high blood pressure treatment. The high prevalence of such condition and devastating consequences resulting from the disease due to inadequate control of blood pressure have been frequently related to untimely deaths. The present study aims to analyze the adherence to medicine treatment of high blood pressure patients followed at the Family Health Centers I, III, IV and V in the city of Ribeirão Preto - SP. 109 patients were interviewed by using the Morisky-Green Test to measure the level of adherence to medicine treatment. Several conditions which could be related to the level of adherence were studied as well, such as: social-economic conditions, factors related to the health center\'s team and service, factors related to the therapy itself, level of knowledge about the disease and factors related to the patient. The analysis of data was accomplished by using the statistics program Epi-Info version 6.0 and the software SAS. We observed a predominance of 84% of the female sex, average age 61.4, 56% married, 81.7% white, 65.2% having low scholarity and 45% housewives. The patients\' adherence was checked by using criteria 1 and 2 of the Morisky-Green Test. According to criterion 1 of the test, 79.8% of the patients were classified as more adherent and 20.2% as less adherent. According to criterion 2, 43.1% of the patients were more adherent and 56.9% less adherent. In regard to the possible causes of non-adherence to treatment, we identified statistically important associations between the conditions \"doctor reliability\" and \"quantity of high blood pressure medicines used\" with the level of adherence, according to criterion 2 of the Morisky-Green Test. The pharmacist is a health care professional who, by means of Pharmaceutical Care has been studying and identifying the causes of low adherence to treatments and also implementing strategies in order to solve this problem in collaboration with the patients.

The rare disease pulmonary arterial hypertension (PAH) results in high blood pressure in the lung caused by narrowing of lung arteries. Genes causative in PAH were discovered through family studies and very often harbour rare variants. However, the genetic cause in heritable (31%) and idiopathic (79%) PAH cases is not yet known but are speculated to be caused by rare variants. Advances in high-throughput sequencing (HTS) technologies made it possible to detect variants in 98% of the human genome. A drop in sequencing costs made it feasible to sequence 10,000 individuals including 1,250 subjects diagnosed with PAH and relatives as part of the NIHR Bioresource - Rare (BR-RD) disease study. This large cohort allows the genome-wide identification of rare variants to discover novel causative genes associated with PAH in a case-control study to advance our understanding of the underlying aetiology. In the first part of my thesis, I establish a phenotype capture system that allows research nurses to record clinical measurements and other patient related information of PAH patients recruited to the NIHR BR-RD study. The implemented extensions provide a programmatic data transfer and an automated data release pipeline for analysis ready data. The second part is dedicated to the discovery of novel disease genes in PAH. I focus on one well characterised PAH disease gene to establish variant filter strategies to enrich for rare disease causing variants. I apply these filter strategies to all known PAH disease genes and describe the phenotypic differences based on clinically relevant values. Genome-wide results from different filter strategies are tested for association with PAH. I describe the findings of the rare variant association tests and provide a detailed interrogation of two novel disease genes. The last part describes the data characteristics of variant information, available non SQL (NoSQL) implementations and evaluates the suitability and scalability of distributed compute frameworks to store and analyse population scale variation data. Based on the evaluation, I implement a variant analysis platform that incrementally merges samples, annotates variants and enables the analysis of 10,000 individuals in minutes. An incremental design for variant merging and annotation has not been described before. Using the framework, I develop a quality score to reduce technical variation and other biases. The result from the rare variant association test is compared with traditional methods.

The apelin system is an evolving transmitter system consisting of the G protein coupled apelin receptor and two endogenous peptide ligands, apelin and elabela. It is implicated as a potential therapeutic for a number of diseases; however, the endogenous peptides are limited by half-life and bioavailability. This study aims to identify and pharmacologically characterise apelin agonists in vitro and in vivo and to evaluate their therapeutic potential in pulmonary arterial hypertension as a model disease. CMF-019 was identified as the first G protein biased apelin agonist. To date, suitable small molecule apelin agonists as experimental tool compounds have been limited and CMF-019 represents an important advance. CMF-019 was active in vivo, producing an increase in cardiac contractility and vasodilatation, similar to apelin. These effects were achieved without receptor desensitisation, supporting the remarkable G protein bias observed in vitro. Furthermore, it was disease-modifying in vitro in an endothelial cell apoptosis assay but despite this, did not prevent pulmonary arterial hypertension in a monocrotaline rat model of the disease. An apelin mimetic peptide possessing an unnatural amino acid, MM202, conjugated chemically via a polyethylene glycol linker to an anti-serum domain antibody (AlbudAb) was also characterised. The product MM202-AlbudAb represents the first time an AlbudAb has been conjugated chemically to an unnatural peptide mimetic, providing protection from proteolysis and glomerular filtration. Importantly, it retained binding to albumin and demonstrated in vitro and in vivo activity at the apelin receptor. In conclusion, this thesis has identified and pharmacologically characterised two novel apelin agonists that possess significant advantages over the endogenous peptides. CMF-019 is suitable as an experimental tool compound and, as the first G protein biased small molecule, provides a starting point for more suitable therapeutics. In addition, MM202-AlbudAb proves that unnatural peptides can be conjugated to AlbudAb, supporting use of this technology in other small-peptide ligand transmitter systems.

An important cause of pulmonary arterial hypertension (PAH) in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To gain a better understanding of the disease process, the changes in biochemical pathways and metabolism of pulmonary arterial smooth muscle cells (PASMCs) were studied using a unique surgical ovine model of increased pulmonary blood flow. PASMCs isolated from 4-week-old lambs with increased PBF (shunt) showed lower oxygen consumption rates and lower extracellular acidification rates linked to glutamine metabolism when compared to controls. Shunt and control PASMCs both exhibited a switch into the reverse tricarboxylic acid (TCA) cycle, while only shunt cells showed a decrease of glucose being transformed into Acetyl CoA to enter the forward TCA cycle. Shunt PASMCs also demonstrated increased levels of yes-associated protein 1 (YAP1) expression in the nucleus. These results indicate changes in glutamine metabolism, glucose metabolism, and protein signaling cascades associated with increased mechanical forces in the setting of increased PBF, as seen in PAH in children with CHD.

The overall objective of the research presented in this dissertation was to investigate molecular risk factors of susceptibility to estrogenic chemicals, polychlorinated biphenyls (PCBs), hormone replacement therapy, and oral contraceptives and how that leads to the development of pulmonary arterial hypertension (PAH). Environmental and molecular risk factors for PAH are not clearly understood. This is a major hurdle for the development of new therapy against PAH as well as understanding individual susceptibility to this disease. Gender has been shown to impact the prevalence of PAH. Although controversial, estrogens have been implicated to be a risk factor for PAH. Thus, we hypothesize that women exposed to estrogenic chemicals are at increased risk of developing PAH when endocrine disrupting chemicals interact with unopposed estrogen to worsen pulmonary arterial disease. In support of this hypothesis, we have accomplished the following: Microarray data on PAH were collected and subsequent meta-analysis was conducted using genome-wide association and environment-wide association approaches on published studies as well as GEO and NHANES data. All PCB geometric mean concentrations found higher levels in people at risk of PAH than people not at risk of PAH. The sum of non-dioxin-like PCBs and the sum of dioxin-like PCBs were significantly higher in people at risk of PAH than people not at risk of PAH. Also, different levels of LOD (including PCBs concentration >LOD, > 50th percentile, 50th-75th percentile, and ≥75th percentile) were significantly higher in people at risk of PAH than people not at risk of PAH. We reported that females used estrogen pills and oral contraceptive were associated with risk of PAH. However, females used progestin and estrogen/progestin pills were not at risk of PAH. Molecular risk factor analysis using machine learning approaches revealed that VAMP2, LAMA5, POLR2C, VEGFB, and PRKCH genes are causal genes of PAH pathogenesis. Gene ontology and pathway analysis of PAH showed that genes involved in the apoptosis pathway, p53 pathway, Ras Pathway, T-cell activation, TGF-beta pathway, VEGF pathway, and Wnt pathway appear to be significantly associated with PAH. Documenting the exposure to estrogenic chemicals among the general U.S. population, and identifying agents and molecular risk factors associated with PAH have the potential to fill research gaps and facilitate our understanding of the complex role environmental chemicals play in producing toxicity in the lungs.

No description available.

<p>Diss. (sammanfattning) Umeå : Umeå universitet, 2003</p> / digitalisering@umu

Made available in DSpace on 2014-06-11T19:23:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-25Bitstream added on 2014-06-13T18:50:43Z : No. of bitstreams: 1 cezar_mdm_me_botfm.pdf: 590654 bytes, checksum: 33eb8534bd0be27d262392bb6adb637d (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A hipertensão arterial sistêmica é uma das principais causas de insuficiência cardíada (IC). No processo do desenvolvimento da hipertrofia miocárdica e a evolução pra IC, decorrente da sobrecarga pressórica, a ativação dos sistemas nervoso simpático e renina-angiotensina-aldosterona exerce papel fundamental, e a aldosterona tem sido responsabilizada por muitos desses efeitos. Diversos estudos clínicos e experimentais mostraram que o bloqueio da aldosterona atenua a remodelação ventricular na IC avançada. Considerando os efeitos adversos da aldosterona, o bloqueio de seus receptores, na fase mais precoce ao desenvolvimento da IC, poderá ser também benéfico atenuando a progressão da remodelação cardíaca. Para investigar essa questão, foram utilizados ratos espontaneamente hipertensos, com 16 meses de idade, divididos em dois grupos experimentais: controle (CTL) e tratado com espironolactona 20 mg/kg/dia (ESP) por seis meses. A pressão arterial sistólica (PAS) foi medida no início e no final do experimento. A avaliação estrutural e funcional cardíaca in vivo foi realizada por ecocardiograma. O estudo funcional in vitro foi realizado pela técnica do músculo papilar do ventrículo esquerdo (VE). A reserva contrátil foi avaliada após o aumento da concentração de cálcio extracelular, contração pós-pausa e estimulação por β-agonista isoproterenol. Para análise estrutural in vitro foram medidos os pesos do VE, ventrículo direito, átrios, pulmão e amostra de fígado, e calculada a razão peso úmido/peso seco desses órgãos. Amostras do VE foram obtidas para análise histológica, com a finalidade de medira área seccional dos cardiomiócitos (hematoxilina e eosina) e a área ocupada pelo colágeno (picrosirius red), para quantificação de hidroxiprolina e realização da técnica do RT-PCR em tempo real... / Arterial hypertension is one of the main causes of heart failure (HF). In the process of myocardial hypertrophy and HF development due to pressure overload, activation of sympathetic nervous system and renin-angiotensin system plays a fundamental role. Several clinical and experimental studies have been shown that aldosterone blockade attenuates ventricular remodeling in advanced HF. Considering the aldosterone deleterious effects, we hypothesized that the blockade of its receptors in the early phase of HF development can attenuate the progression of cardiac remodeling. To investigate this issue, 16 month-old spontaneously hypertensive rats were used. Rats were separated into two groups: control (CTL) and spironolactone treated (SPR, 20 mg/kg/day) for six months. Systolic arterial pressure (SAP) was measured at the beginning and the end of the experiment. In vivo cardiac structural and functional evaluation was performed by echocardiogram. In vitro myocardial function was analyzed in left ventricular (LV) papillary muscles under isometric contractions. Contractiel reserve was evaluated after extracellular calcium concentration increase, post-pause contractions, and β-agonist isoproterenol stimulation. In vitro structural analysis was done bay measuring LV, right ventricle, and atria weight, and the wet-to-dry weight ratio of these organs and also lung and liver samples. LV samples were stored for histological analysis (cardiomyocyte cross-sectional area and myocardial collagen fraction), measurement of hydroxyproline concentration, and quantification of gene expression of proteins related to cardiac remodeling by real-time RT-PCR. According to sample distribution, normal or non-normal, Student's t test or Mann-Whitney test was used to compare the groups. Mortality rate was analyzed by log-rank test (Kaplan Meier curve). Statistical analysis... (Complete abstract click electronic access below)

Systemic sclerosis (SSc) is a rare connective tissue disease affecting skin and internal organs. The pathogenesis of SSc is multifactorial and includes autoimmunity, inflammation and vasculopathy. Pulmonary arterial hypertension (PAH) is among the most serious of SSc complications and is characterized by augmented vasoconstriction, neointimal remodeling and occlusion of small arteries in lung. Elevated pulmonary arterial blood pressure and volume overload in the right heart eventually lead to death from heart failure. Pre-existing elevated pro-fibrotic signaling, systemic vasculopathy and chronic inflammation are additional factors that likely contribute to the more severe PAH manifestation in SSc patients, whose response to existing therapies is suboptimal. The aim of my thesis research was to investigate the pathological role of altered transcriptional regulation of endothelium in pulmonary vasculature, as well as testing potential novel therapies for SSc-PAH in vivo. I found that endothelial downregulation of GATA6 promotes increased production of reactive oxygen species (ROS) by suppressing enzymatic machinery responsible for ROS clearance. Increased ROS production triggered ER stress and inflammation, exacerbating endothelial dysfunction and vascular injury both in vitro and in vivo. Another discovery is that simultaneous depletion of two ETS-family factors, ERG and FLI1 synergistically activates interferon signaling in pulmonary endothelial cells and promotes inflammation in lung in vivo. Based on observed pathological contribution of oxidative stress and inflammation to vasculopathy and fibrosis I tested an anti-oxidative and anti-inflammatory agent- dimethyl fumarate (DMF) in mouse models of PAH, as well as lung and skin fibrosis. DMF efficiently ameliorated increased pulmonary artery pressure and vascular remodeling, as well as fibrotic changes in lung and skin. Mechanistically, I found that DMF promotes a proteasomal, βTRCP-dependent degradation of pro-fibrotic mediators TAZ/YAP, β-catenin and Sp1. In conclusion, I characterized new elements of pathological mechanism that promote vasculopathy and fibrosis, as well as provided an insight into anti-inflammatory and anti-fibrotic DMF therapy. Importantly, elucidating the novel mechanism of DMF action and recognizing the pathological role of Hippo and Wnt signaling in fibrosis might help to design more specific and effective pharmacological intervention in SSc-PAH patients.

Em média, 50% dos pacientes com doença crônica em países desenvolvidos não aderem a tratamento farmacológico, o que caracteriza problema mundial. A não-adesão é afetada por diversos fatores, sendo que, dentre eles, sugere-se que esteja o baixo desempenho cognitivo. Assim, foi realizada análise secundária de ensaio clínico randomizado, com o objetivo de investigar hipótese de que função cognitiva, ansiedade e desordens psiquiátricas associam-se a adesão ao tratamento, em hipertensos não-controlados. A amostra foi constituída por 56 pacientes adultos, com pressão arterial não controlada sob tratamento farmacológico, que participaram de todos os encontros do ensaio clínico randomizado Pharmaceutical care program for patients with uncontrolled hypertension. Capacidade cognitiva e memória foram mensuradas por meio de Mini Exame do Estado Mental (Mini-mental), spans de dígitos e palavras, testes das silhuetas de torres e igrejas e da pequena estória e metamemória. Ansiedade e desordens psiquiátricas foram avaliadas, respectivamente, por Inventário de Ansiedade Traço Estado (IDATE) e Self-Report Questionnaire (SRQ 20). Os participantes foram classificados como tendo adesão ao tratamento farmacológico ou não, segundo identificação dos níveis plasmáticos de hidroclorotiazida. Todos os pacientes pertencentes ao grupo de não-adesão ao tratamento (n=12) apresentaram pelo menos um teste de memória com escore alterado. Os participantes que obtiveram escores insatisfatórios em Mini-mental e span de palavras para memória recente apresentaram riscos, respectivamente, cinco e nove vezes maiores de não aderir a tratamento, em relação àqueles com escores normais (RR=5,42; IC95%: 1,62 - 18,14; P=0,006; e RR=8,89; IC95%: 0,98 - 80,61; P=0,052). Os presentes achados suportam a hipótese de que alterações de função cognitiva e memória estão associadas à menor adesão a tratamento, em pacientes hipertensos não-controlados. Tal associação não foi encontrada para ansiedade e desordens psiquiátricas. Os dados sugerem um novo olhar sobre a prática farmacêutica, podendo representar um avanço para a determinação de estratégias efetivas de intervenção. O farmacêutico, por meio da prática da Atenção Farmacêutica, pode utilizar Mini-mental e span de palavras como instrumentos no screening de não-adesão a tratamento. A partir dessa determinação, pacientes com prejuízo cognitivo ou de memória devem receber abordagem educacional diferenciada quanto à utilização de medicamentos, buscando superar a influência daqueles problemas sobre a adesão ao tratamento. / Mean of 50% of patients with chronic disease have no adherence to pharmacological treatment in developed countries, characterizing a world problem. The non-adherence is affected by several factors, being the low cognitive performance one of them. Then it was performed secondary analysis of a randomized clinical trial, aiming to investigate the hypothesis that cognitive function, memory and psychiatric disorders are associated with adherence to treatment in patients with uncontrolled hypertension. The sample included 56 adult patients with uncontrolled blood pressure under pharmaceutical treatment who participated of all meetings of the randomized clinical trial Pharmaceutical care program for patients with uncontrolled hypertension. Cognitive function and memory were measured by the Mini Mental State Examination (Mini-mental), digit and word spans of memory, tower and church shadow test, short story test and metamemory. Anxiety and psychiatric disorders were evaluated by the State Trace Anxiety Inventory (STAI) and the Self-Report Questionnaire (SRQ), respectively. The participants were classified as being adherent or non-adherent to the treatment, according to the identification of plasmatic hydrochlorothiazide levels. All of the non-adherent patients (n=12) had at least one memory test with altered score. The participants who obtained an unsatisfactory score in the Mini-mental and word span test for short-term memory had, respectively, five and nine-fold higher risks of not adhering to treatment than those with a normal score (RR=5.42; CI 95%: 1.62 - 18.14; P=0.006; and RR=8.89; IC 95%: 0.98 - 80.61; P=0.052). The current findings support the hypothesis that alterations of cognitive function and memory are associated to low adherence to treatment in patients with uncontrolled blood pressure. This association was not found for anxiety and psychiatric disorders. Data suggest a new view for the pharmaceutical practice, representing a progress towards the determination of effective intervention strategies. Through the practice of pharmaceutical care, the pharmacist can use the mini-mental and word span test as instruments for the screening of non-adherence to treatment. According to this determination, the patients with cognitive or memory impairments should receive a differentiated educational approach, regarding minimizing the influence of these problems upon non-adherence to the treatment.