Evaluation of antihypertensive drugs in patients with obstructive sleep apnea and in rats submitted to chronic intermittent hypoxia

RESUMO: A hipertensão arterial (HA) é uma patologia altamente prevalente, embora claramente subdiagnosticada, em doentes com síndrome de apneia obstrutiva do sono (SAOS). Estas duas patologias apresentam uma estreita relação e a monitorização ambulatória da pressão arterial (MAPA), por um período de 24 horas, parece ser o método mais preciso para o diagnóstico de hipertensão em doentes com SAOS. No entanto, esta ferramenta de diagnóstico para além de ser dispendiosa e envolver um número acrescido de meios técnicos e humanos, é mais morosa e, por conseguinte, não é utilizada por rotina no contexto do diagnóstico da SAOS. Por outro lado, apesar da aplicação de pressão positiva contínua nas vias aéreas (CPAP – Continous Positive Airway Pressure) ser considerada a terapêutica de eleição para os doentes com SAOS, o seu efeito no abaixamento da pressão arterial (PA) parece ser modesto, exigindo, por conseguinte, a implementação concomitante de terapêutica anti-hipertensora. Acontece que são escassos os dados relativos aos regimes de fármacos anti-hipertensores utilizados em doentes com SAOS e, acresce ainda que, as guidelines terapêuticas para o tratamento farmacológico da HA, neste grupo particular de doentes, permanecem, até ao momento, inexistentes. A utilização de modelos animais de hipóxia crónica intermitente (CIH), que mimetizam a HA observada em doentes com SAOS, revela-se extremamente importante, uma vez que se torna imperativo identificar fármacos que promovam um controle adequado da PA neste grupo de doentes. No entanto, estudos concebidos com o intuito de investigar o efeito anti-hipertensor dos fármacos neste modelo animal revelam-se insuficientes e, por outro lado, os escassos estudos que testaram fármacos anti-hipertensores neste modelo não foram desenhados para responder a questões de natureza farmacológica. Acresce ainda que se torna imprescindível garantir a escolha de um método para administração destes fármacos que seja não invasivo e que minimize o stress do animal. Embora a gavagem seja uma técnica indiscutivelmente eficaz e amplamente utilizada para a administração diária de fármacos a animais de laboratório, ela compreende uma sequência de procedimentos geradores de stress para os animais e, que podem por conseguinte, constituir um viés na interpretação dos resultados obtidos. O objectivo global da presente investigação translacional foi contribuir para a identificação de fármacos anti-hipertensores mais efectivos para o tratamento da HT nos indivíduos com SAOS e investigar mecanismos subjacentes aos efeitos sistémicos associadas à SAOS bem como a sua modulação por fármacos anti-hipertensores. Os objectivos específicos foram: em primeiro lugar,encontrar novos critérios, baseados nas medidas antropométricas, que permitam a identificação de doentes com suspeita de SAOS, que erroneamente se auto-classifiquem como nãohipertensos, e desta forma promover um uso mais criterioso do MAPA; em segundo lugar, investigar a existência de uma hipotética associação entre os esquemas de fármacos antihipertensores e o controle da PA (antes e após a adaptação de CPAP) em doentes com SAOS em terceiro lugar, avaliar a eficácia do carvedilol (CVD), um fármaco bloqueador β-adrenérgico não selectivo com actividade antagonista α1 intrínseca e propriedades anti-oxidantes num modelo animal de hipertensão induzida pela CIH; em quarto lugar, explorar os efeitos da CIH sobre o perfil farmacocinético do CVD; e, em quinto lugar, investigar um método alternativo à gavagem para a administração crónica de fármacos anti-hipertensores a animais de laboratório. Com este intuito, na primeira fase deste projecto, fizemos uso de uma amostra com um número apreciável de doentes com SAOS (n=369), que acorreram, pela primeira vez, à consulta de Patologia do Sono do CHLN e que foram submetidos a um estudo polissonográfico do sono, à MAPA e que preencheram um questionário que contemplava a obtenção de informação relativa ao perfil da medicação anti-hipertensora em curso. Numa segunda fase, utilizámos um modelo experimental de HT no rato induzida por um paradigma de CIH. Do nosso trabalho resultaram os seguintes resultados principais: em primeiro lugar, o índice de massa corporal (IMC) e o perímetro do pescoço (PP) foram identificados como preditores independentes de “auto-classificação errónea” da HA em doentes com suspeita de SAOS; em segundo lugar, não encontramos qualquer associação com significado estatístico entre os vários esquemas de fármacos anti-hipertensores bem como o número de fármacos incluídos nesse esquemas, e o controle da PA (antes e depois da adaptação do CPAP); em terceiro lugar, apesar das doses de 10, 30 e 50 mg/kg de carvedilol terem promovido uma redução significativa da frequência cardíaca, não foi observado qualquer decréscimo na PA no nosso modelo animal; em quarto lugar, as razões S/(R+S) dos enantiómeros do CVD nos animais expostos à CIH e a condições de normóxia revelaram-se diferentes; e, em quinto lugar, a administração oral voluntária mostrou ser um método eficaz para a administração diária controlada de fármacos anti-hipertensores e que é independente da manipulação e contenção do animal. Em conclusão, os resultados obtidos através do estudo clínico revelaram que o controle da PA, antes e após a adaptação do CPAP, em doentes com SAOS é independente, quer do esquema de fármacos anti-hipertensores, quer do número de fármacos incluídos num determinado esquema. Os nossos resultados salientam ainda a falta de validade da chamada self-reported hypertension e sugerem que em todos os doentes com suspeita de SAOS, com HA não diagnosticada e com um IMC e um PP acima de 27 kg/m2 e 39 cm, respectivamente, a confirmação do diagnóstico de HA deverá ser realizada através da MAPA, ao invés de outros métodos que com maior frequência são utilizados com este propósito. Os resultados obtidos no modelo animal de HA induzida pela CIH sugerem que o bloqueio do sistema nervoso simpático, juntamente com os supostos efeitos pleiotrópicos do CVD, não parece ser a estratégia mais adequada para reverter este tipo particular de hipertensão e indicam que as alterações farmacocinéticas induzidas pela CIH no ratio S/(R+S) não justificam a falta de eficácia anti-hipertensora do CVD observada neste modelo animal. Por último, os resultados do presente trabalho suportam ainda a viabilidade da utilização da administração oral voluntária, em alternativa à gavagem, para a administração crónica de uma dose fixa de fármacos anti-hipertensores.---------------------------- ABSTRACT: Hypertension (HT) is a highly prevalent condition, although under diagnosed, in patients with obstructive sleep apnea (OSA). These conditions are closely related and 24-hour ambulatory blood pressure monitoring (ABPM) seems to be the most accurate measurement for diagnosing hypertension in OSA. However, this diagnostic tool is expensive and time-consuming and, therefore, not routinely used. On the other hand, although continuous positive airway pressure (CPAP) is considered the gold standard treatment for symptomatic OSA, its lowering effect on blood pressure (BP) seems to be modest and, therefore, concomitant antihypertensive therapy is still required. Data on antihypertensive drug regimens in patients with OSA are scarce and specific therapeutic guidelines for the pharmacological treatment of hypertension in these patients remain absent. The use of animal models of CIH, which mimic the HT observed in patients with OSA, is extremely important since it is imperative to identify preferred compounds for an adequate BP control in this group of patients. However, studies aimed at investigating the antihypertensive effect of antihypertensive drugs in this animal model are insufficient, and most reports on CIH animal models in which drugs have been tested were not designed to respond to pharmacological issues. Moreover, when testing antihypertensive drugs (AHDs) it becomes crucial to ensure the selection of a non-invasive and stress-free method for drug delivery. Although gavage is effective and a widely performed technique for daily dosing in laboratory rodents, it comprises a sequence of potentially stressful procedures for laboratory animals that may constitute bias for the experimental results. The overall goal of the present translational research was to contribute to identify more effective AHDs for the treatment of hypertension in patients with OSA and investigate underlying mechanisms of systemic effects associated with OSA, as well as its modulation by AHDs. The specific aims were: first, to find new predictors based on anthropometric measures to identify patients that misclassify themselves as non-hypertensive, and thereby promote the selective use of ABPM; second, to investigate a hypothetical association between ongoing antihypertensive regimens and BP control rates in patients with OSA, before and after CPAP adaptation; third, to determine, in a rat model of CIH-induced hypertension, the efficacy of carvedilol (CVD), a nonselective beta-blocker with intrinsic anti-α1-adrenergic activity and antioxidant properties; fourth, to explore the effects of CIH on the pharmacokinetics profile of CVD and fifth, to investigate an alternative method to gavage, for chronic administration of AHDs to laboratory rats. For that, in the first phase of this project, we used a sizeable sample of patients with OSA (n=369), that attended a first visit at Centro Hospitalar Lisboa Norte, EPE Sleep Unit, and underwent overnight polysomnography, 24-h ABPM and filled a questionnaire that included ongoing antihypertensive medication profile registration. In the second phase, a rat experimental model of HT induced by a paradigm of CIH that simulates OSA was used. The main findings of this work were: first, body mass index (BMI) and neck circumference (NC) were identified as independent predictors of hypertension misclassification in patients suspected of OSA; second, in patients with OSA, BP control is independent of both the antihypertensive regimen and the number of antihypertensive drugs, either before or after CPAP adaptation; third, although the doses of 10, 30 and 50 mg/Kg of CVD promoted a significant reduction in heart rate, no decrease in mean arterial pressure was observed; fourth, the S/(R+S) ratios of CVD enantiomers, between rats exposed to CIH and normoxic conditions, were different and fifth, voluntary ingestion proved to be an effective method for a controlled daily dose administration, with a define timetable, that is independent of handling and restraint procedures. In conclusion, the clinical study showed that BP control in OSA patients is independent of both the antihypertensive regimen and the number of antihypertensive drugs. Additionally, our results highlight the lack of validity of self-reported hypertension and suggest that all patients suspected of OSA with undiagnosed hypertension and with a BMI and NC above 27 Kg/m2 and 39 cm should be screened for hypertension, through ABPM. The results attained in the rat model of HT related to CIH suggest that the blockade of the sympathetic nervous system together with the putative pleiotropic effects of carvedilol is not able to revert hypertension induced by CIH and point out that the pharmacokinetic changes induced by CIH on S/(R+S) ratio are not apparently responsible for the lack of efficacy of carvedilol in reversing this particular type of hypertension. Finally, the results here presented support the use of voluntary oral administration as a viable alternative to gavage for chronic administration of a fixed dose of AHDs.

Detection of intestinal parasites on field-grown strawberries in the Federal District of Brazil

Introduction This study evaluated the presence of pathogenic human parasites on field-grown strawberries in the Federal District of Brazil. Methods A total of 48 samples of strawberries and 48 soil samples from 16 properties were analyzed. Results Contaminated strawberries were detected in 56% of the properties. Schistosoma mansoni, Ascaris lumbricoides or Ascaris suum, Balantidium coli, Endolimax nana, and Entamoeba spp. were detected. Soil was contaminated with Entamoeba spp., Entamoeba coli, Strongyloides spp., Ancylostomatidae, and Hymenolepis nana. Conclusions Producers should be instructed on the safe handling of strawberries in order to reduce the incidence of strawberries that are contaminated with enteroparasites.

Basel III new capital requirements, impacts and bank behavior

For some years, researchers could not find a clear effect of capital adequacy on the risk profile of banks, as shareholders could increase the riskiness of the assets (qualitative effect), crowding-out the effect of reduced leverage (volume effect). Some shareholders might have the will to increase the riskiness of the assets, but they may lack the power to do so. Considering only ”powerful” shareholders, definitive conclusions were drawn but with constant ownership profile. In this paper I investigate whether there is a significant change in the type of shareholders in response to regulatory capital shocks and, if so, will the banking system be in the hands of more “desired” shareholders. I find that ownership profile responds to a regulatory shock, changing the risk appetite of the ruling power at the bank. I find more banks and the government in the ownership of undercapitalised banks and much less institutional shareholders and free float. I claim that these new shareholders may not the desired ones, given the objective of the regulatory change, as they are associated with a preference for more leverage. One possible explanation for this crowding-out effect is that regulators are trying to contain idiosyncratic risk (more linked to the riskiness of the assets) with a rule that contains systematic risk (capital adequacy). This has a distorting effect on ownership. Another insight can be drawn from the tests: supervisors should be aware of significant ownership movements that cause the crowding-out.

Mental health and neuroscience. A perspective from the magazine market

Mental health awareness has been rising worldwide, motivated by its social and economic costs. Despite the investment in research in neuroscience in the recent years, little is known about the underlying mechanisms in the brain that are correlated with psychiatric conditions. This project, through two feature articles suitable to be published in magazines, provides perspectives onto mental health research. First it presents an example where psychiatry joins forces with neuroscience and computer science in an interdisciplinary effort to improve the life of those affected by mental disorders. The second article gathers opinions which claim that mental health research priorities should be set by patients themselves, or even that people with lived experience of mental health issues should have an active role in that research. This project was planned and researched while I was an Erasmus student at Nottingham Trent University, in the United Kingdom.

Toxoplasma gondii seropositivity and risk factors in pregnant women followed up by the Family Health Strategy

INTRODUCTION : Toxoplasmosis is a zoonotic infection caused by Toxoplasma gondii. It is transmitted by the ingestion of contaminated water and foods, by soil contaminated with cat feces, especially while handling it, and congenitally via the placenta. The diagnosis of maternal infection is made by serological detection of either IgM or IgG antibodies. This study assessed the seropositivity in pregnant women followed up by the Family Health Strategy (FHS) in Lages, Santa Catarina, Brazil. METHODS: The study was performed in 19 FHS units and included 148 childbearing women. The outcomes evaluated were IgM and IgG seropositivity and behavioral variables. RESULTS: IgG yielded positive results in 16% of the pregnant women, whereas IgM was positive in only 1%. CONCLUSIONS: The 1% IgM positivity rate for T. gondii indicates congenital toxoplasmosis is not common in Lages.

Risk factors for Toxoplasma gondii infection among pregnant women from the State of Tocantins, Northern Brazil

ABSTRACT INTRODUCTION: The prevalence of infection by Toxoplasma gondii and associated risk factors in pregnant women in Tocantins, Northern Brazil were assessed. METHODS: Serological analysis was performed in 338 serum samples and an oral questionnaire was utilized to identify potential risk factors. RESULTS: Anti-IgG antibodies against T. gondii were detected in 71% (240/338) of the pregnant women. Prior contact with cats and meat handling were found to be associated with T. gondii infection. CONCLUSIONS: A considerable percentage (29%) of women living in the Tocantins area remain susceptible to infection by the T. gondii protozoon, representing a serious public health risk.

Cost of drugs manufactured by the University Hospital - role of the Central Pharmacy

The hospital pharmacy in large and advanced institutions has evolved from a simple storage and distribution unit into a highly specialized manipulation and dispensation center, responsible for the handling of hundreds of clinical requests, many of them unique and not obtainable from commercial companies. It was therefore quite natural that in many environments, a manufacturing service was gradually established, to cater to both conventional and extraordinary demands of the medical staff. That was the case of Hospital das Clinicas, where multiple categories of drugs are routinely produced inside the pharmacy. However, cost-containment imperatives dictate that such activities be reassessed in the light of their efficiency and essentiality. METHODS: In a prospective study, the output of the Manufacturing Service of the Central Pharmacy during a 12-month period was documented and classified into three types. Group I comprised drugs similar to commercially distributed products, Group II included exclusive formulations for routine consumption, and Group III dealt with special demands related to clinical investigations. RESULTS: Findings for the three categories indicated that these groups represented 34.4%, 45.3%, and 20.3% of total manufacture orders, respectively. Costs of production were assessed and compared with market prices for Group 1 preparations, indicating savings of 63.5%. When applied to the other groups, for which direct equivalent in market value did not exist, these results would suggest total yearly savings of over 5 100 000 US dollars. Even considering that these calculations leave out many components of cost, notably those concerning marketing and distribution, it might still be concluded that at least part of the savings achieved were real. CONCLUSIONS: The observed savings, allied with the convenience and reliability with which the Central Pharmacy performed its obligations, support the contention that internal manufacture of pharmaceutical formulations was a cost-effective alternative in the described setting.

Blue rubber bleb nevus syndrome: case report

The case of a patient with blue rubber bleb nevus syndrome who is infected by acquired immunodeficiency syndrome virus due to multiple blood transfusions is presented. This case shows that although it is a rare systemic disorder, blue rubber bleb nevus syndrome has to be considered in the differential diagnosis of chronic anemia or gastrointestinal bleeding. Patients should be investigated by endoscopy, which is the most reliable method for detecting these lesions. The patient underwent gastroscopy and enteroscopy via enterotomy with identification of all lesions. Minimal resection of the larger lesions and string-purse suture of the smaller ones involving all the layers of the intestine were performed. The string-purse suture of the lesions detected by enteroscopy proved to be an effective technique for handling these lesions, avoiding extensive intestinal resection and stopping the bleeding. Effective management of these patients demands aggressive treatment and should be initiated as soon as possible to avoid risks involved in blood transfusions, as occurred in this case.

An internationalization strategy

In the present report I intend to study the Chinese higher education market and Chinese students’ rationales behind the selection of a foreign university, so as to propose simple, feasible, effective measures that will ultimately attract more Chinese students to Nova SBE. In order to do so, it was developed a qualitative research that lead to some interesting highlights, namely the fact that parents have a fairly large influence on the foreign school and country the student chooses. Regarding Nova SBE, the research revealed that Chinese students find courses and professors interesting, but they have difficulties in communicating with locals and claim that the school lacks a systematic, coordinated approach to their integration in the university, something that should start earlier in the process.

Livros de artista: gestão da coleção da Biblioteca de Arte da Fundação Calouste Gulbenkian

Os Livros de Artista são obras de arte contemporâneas cujo nascimento se situa no século XX. As coleções deste tipo de documentos encontram‐se em museus e em bibliotecas. Nas bibliotecas os riscos do manuseamento estão mais presentes porque os Livros de Artista são tocados para serem lidos. As particularidades deste tipo de coleções, onde os livros têm tamanhos diversos, formas variadas e materiais díspares, levou‐nos à reflexão sobre o impacto do seu manuseamento nas bibliotecas. A reflexão baseou‐se no estudo das práticas em uso na Biblioteca de Arte da Fundação Calouste Gulbenkian. A observação da gestão do risco do manuseamento em Livros de Artista na instituição e a revisão da literatura permitiram a elaboração de um conjunto de regras. As regras devem ser seguidas pelas instituições que têm à sua guarda coleções de Livros de Artista. Acreditamos que a sua adoção, progressiva e continuada, contribui para a minimização dos efeitos do manuseamento e constitui um auxílio na disponibilização e acessibilidade ao longo do tempo dos Livros de Artista. Não anula, de forma total e absoluta, os efeitos do uso de uma coleção de Livros de Artista. Os Livros de Artista para serem lidos são tocados e, por isso, existirá sempre um dano – o desgaste.

A intervenção da seguradora nas acções propostas contra o segurado

The problem to be discussed results from the relationship established between the insurer and insured by the conclusion of an insurance contract, namely an optional liability insurance contract, to cover the risks taken by the insured resulting from the occurrence of a claim, such as those arising from the emergence of the liability and consequent obligation to compensate damages caused to a third party. This thesis concerns thus the debate between those who consider that, in the optional insurance, the third party may require compliance with the provision to both the insured and the insurer (in the case of voluntary joinder, pursuant to Art. 27 CCP, which corresponds Art. 32 of the New Code of Civil Procedure, Law n. 41/2013 of 26 June, which entered into force on 1 September, hereinafter New Code) - insurance contract on behalf of a third party conception - in the same way that the insured defendant can bring the insurer to intervene as co-defendant in the main process, pursuant al. a) of art. 325 of the CCP (corresponding to art. 316 of the New Code - main intervention caused), and those who argue that the insurer may only intervene in the action as an ancillary party, to assist the defendant, lacking interest, therefore, in necessary or volunteer joinder, with the consequence that the insurer cannot be sued as a main party - only ancillary intervention is justifiable (cf. art. 330 CPC, which corresponds to art. 321 of the New Code).

Contributos para um Plano de Preservação no Arquivo Intermédio da Câmara Municipal de Sintra

Os aquivos municipais preservam a documentação definida legalmente como de conservação permanente, a memória e a experiência da Administração Local e, como tal, são agentes imprescindíveis à preservação dos direitos municipais. A preocupação com a preservação da documentação deve constituir um dos pilares principais do arquivo desde o início da sua criação. E não somente quando a documentação é transferida para o Arquivo Histórico, deve estar presente durante todo o ciclo de vida da documentação. Com a criação do PARAM (Programa de Apoio à Rede de Arquivos Municipais), os arquivos municipais ganham um novo incremento, não só a nível técnico como a nível financeiro, sendo-lhe reconhecido o seu devido valor e importância, na sua dupla dimensão, administrativa e cultural. Uma das funções do arquivo é disponibilizar a documentação que têm à sua guarda e que se encontra armazenada nos depósitos. Para tal é fundamental criar condições a curto, a médio e a longo prazo, implementando toda uma política integrada de preservação, envolvendo os demais serviços da instituição, fazendo-se o controlo do estado de conservação da documentação, aplicando uma metodologia da manipulação de documentos para disponibilizá-los tanto aos clientes internos como externos. O Arquivo Intermédio da Câmara Municipal de Sintra não possui plano de preservação documental, nem ações de preservação extensíveis aos objetos digitais, daí que a presente tese de mestrado pretenda ser um proposta de um contributo de um plano de preservação, que tenha em consideração os demais aspetos desde a localização e construção ou manutenção do edifício onde se encontra o arquivo, questões de segurança, de controlo ambiental, de luz/fotodegradação, o controlo integrado de pragas, danos causados por água, os desastres naturais, a poluição, a limpeza e vigilância na zona de depósitos e armazenamento e manuseamento dos documentos.

Aplicação da teoria das opções reais em análise de projetos estratégicos: um estudo de caso sobre o valor da opção de prosseguir com os investimentos no programa de desenvolvimento de submarinos da Marinha do Brasil

Dissertação de mestrado em Estudos de Gestão

Safest level of tricaine methanesulfonate (ms-222) to induce anesthesia in juveniles of Matrinxã, Brycon cephalus

The use of MS-222 as an anesthetic for matrinxã juveniles was investigated. At dosage of 100 mg/L or lower fish did not achieve a complete anesthesia state. At 150 mg/L, MS-222 induced anesthesia within 36 seconds and recovered from a 10 minutes period of anesthesia within 5.2 min. Higher concentrations (200, 250 and 300 mg/L) anesthetized fish in lesser times, with the offset of mortality (16.7 and 33.3%) at the 200 and 300 mg/L MS-222 doses, respectively. The only significant differences observed in the hematological parameters, was for the glucose values in fish anesthetized with 250 and 300 mg/L. From the results, the recommended dose of MS-222 for handling matrinxã juveniles is 150 mg/L.

O sentido espacial das crianças de 3 e 4 anos

Relatório de estágio de mestrado em Educação Pré-Escolar e Ensino do 1ºCiclo do Ensino Básico