The role of electron transfer in DNA building blocks: evaluation of strand breaks and their implications

Disserta����o para obten����o do Grau de Doutor em Engenharia F��sica

Evaluation of pathogenic potential of Aeromonas spp. strains using in vitro methodologies

Dissertation to obtain a Master Degree in Molecular Genetics and Biomedicine

Industrial symbiosis potential of the Sines oil refinery ��� environmental and economic evaluation

Disserta����o para obten����o do Grau de Mestre em Engenharia do Ambiente ��� Perfil Gest��o e Sistemas Ambientais

How training evaluation can be used to potentiate employee development in an organization

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA ��� School of Business and Economics

Evaluation of the effect of hearing aids using electroencephalographic analysis

based on the report for the Doctoral Conference of the PhD programme in Technology Assessment, held at FCT-UNL Campus, Monte de Caparica, July 2013. The PhD thesis has the supervision of Dr. Salom�� Almeida (Central Hospital of Lisbon), and co-supervision of Prof. Manuel Ortigueira (FCT-UNL).

Evaluation of mechanical soft-abrasive blasting and chemical cleaning methods on alkyd-paint graffiti made on carbonate stones

In the context of this dissertation several studies were developed resulting in submission and publication ���Evaluation of mechanical soft-abrasive blasting and chemical cleaning methods on alkyd-paint graffiti made on calcareous stones��� to Journal of Cultural Heritage. (http://dx.doi.org/10.101 /j.culher.2014.10.004)

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

RESUMO: A hipertens��o arterial (HA) �� uma patologia altamente prevalente, embora claramente subdiagnosticada, em doentes com s��ndrome de apneia obstrutiva do sono (SAOS). Estas duas patologias apresentam uma estreita rela����o e a monitoriza����o ambulat��ria da press��o arterial (MAPA), por um per��odo de 24 horas, parece ser o m��todo mais preciso para o diagn��stico de hipertens��o em doentes com SAOS. No entanto, esta ferramenta de diagn��stico para al��m de ser dispendiosa e envolver um n��mero acrescido de meios t��cnicos e humanos, �� mais morosa e, por conseguinte, n��o �� utilizada por rotina no contexto do diagn��stico da SAOS. Por outro lado, apesar da aplica����o de press��o positiva cont��nua nas vias a��reas (CPAP ��� Continous Positive Airway Pressure) ser considerada a terap��utica de elei����o para os doentes com SAOS, o seu efeito no abaixamento da press��o arterial (PA) parece ser modesto, exigindo, por conseguinte, a implementa����o concomitante de terap��utica anti-hipertensora. Acontece que s��o escassos os dados relativos aos regimes de f��rmacos anti-hipertensores utilizados em doentes com SAOS e, acresce ainda que, as guidelines terap��uticas para o tratamento farmacol��gico da HA, neste grupo particular de doentes, permanecem, at�� ao momento, inexistentes. A utiliza����o de modelos animais de hip��xia cr��nica intermitente (CIH), que mimetizam a HA observada em doentes com SAOS, revela-se extremamente importante, uma vez que se torna imperativo identificar f��rmacos 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 f��rmacos neste modelo animal revelam-se insuficientes e, por outro lado, os escassos estudos que testaram f��rmacos anti-hipertensores neste modelo n��o foram desenhados para responder a quest��es de natureza farmacol��gica. Acresce ainda que se torna imprescind��vel garantir a escolha de um m��todo para administra����o destes f��rmacos que seja n��o invasivo e que minimize o stress do animal. Embora a gavagem seja uma t��cnica indiscutivelmente eficaz e amplamente utilizada para a administra����o di��ria de f��rmacos a animais de laborat��rio, ela compreende uma sequ��ncia de procedimentos geradores de stress para os animais e, que podem por conseguinte, constituir um vi��s na interpreta����o dos resultados obtidos. O objectivo global da presente investiga����o translacional foi contribuir para a identifica����o de f��rmacos anti-hipertensores mais efectivos para o tratamento da HT nos indiv��duos com SAOS e investigar mecanismos subjacentes aos efeitos sist��micos associadas �� SAOS bem como a sua modula����o por f��rmacos anti-hipertensores. Os objectivos espec��ficos foram: em primeiro lugar,encontrar novos crit��rios, baseados nas medidas antropom��tricas, que permitam a identifica����o de doentes com suspeita de SAOS, que erroneamente se auto-classifiquem como n��ohipertensos, e desta forma promover um uso mais criterioso do MAPA; em segundo lugar, investigar a exist��ncia de uma hipot��tica associa����o entre os esquemas de f��rmacos antihipertensores e o controle da PA (antes e ap��s a adapta����o de CPAP) em doentes com SAOS em terceiro lugar, avaliar a efic��cia do carvedilol (CVD), um f��rmaco bloqueador ��-adren��rgico n��o selectivo com actividade antagonista ��1 intr��nseca e propriedades anti-oxidantes num modelo animal de hipertens��o induzida pela CIH; em quarto lugar, explorar os efeitos da CIH sobre o perfil farmacocin��tico do CVD; e, em quinto lugar, investigar um m��todo alternativo �� gavagem para a administra����o cr��nica de f��rmacos anti-hipertensores a animais de laborat��rio. Com este intuito, na primeira fase deste projecto, fizemos uso de uma amostra com um n��mero apreci��vel de doentes com SAOS (n=369), que acorreram, pela primeira vez, �� consulta de Patologia do Sono do CHLN e que foram submetidos a um estudo polissonogr��fico do sono, �� MAPA e que preencheram um question��rio que contemplava a obten����o de informa����o relativa ao perfil da medica����o anti-hipertensora em curso. Numa segunda fase, utiliz��mos 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 ��ndice de massa corporal (IMC) e o per��metro do pesco��o (PP) foram identificados como preditores independentes de ���auto-classifica����o err��nea��� da HA em doentes com suspeita de SAOS; em segundo lugar, n��o encontramos qualquer associa����o com significado estat��stico entre os v��rios esquemas de f��rmacos anti-hipertensores bem como o n��mero de f��rmacos inclu��dos nesse esquemas, e o controle da PA (antes e depois da adapta����o do CPAP); em terceiro lugar, apesar das doses de 10, 30 e 50 mg/kg de carvedilol terem promovido uma redu����o significativa da frequ��ncia card��aca, n��o foi observado qualquer decr��scimo na PA no nosso modelo animal; em quarto lugar, as raz��es S/(R+S) dos enanti��meros do CVD nos animais expostos �� CIH e a condi����es de norm��xia revelaram-se diferentes; e, em quinto lugar, a administra����o oral volunt��ria mostrou ser um m��todo eficaz para a administra����o di��ria controlada de f��rmacos anti-hipertensores e que �� independente da manipula����o e conten����o do animal. Em conclus��o, os resultados obtidos atrav��s do estudo cl��nico revelaram que o controle da PA, antes e ap��s a adapta����o do CPAP, em doentes com SAOS �� independente, quer do esquema de f��rmacos anti-hipertensores, quer do n��mero de f��rmacos inclu��dos 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 n��o diagnosticada e com um IMC e um PP acima de 27 kg/m2 e 39 cm, respectivamente, a confirma����o do diagn��stico de HA dever�� ser realizada atrav��s da MAPA, ao inv��s de outros m��todos que com maior frequ��ncia s��o utilizados com este prop��sito. Os resultados obtidos no modelo animal de HA induzida pela CIH sugerem que o bloqueio do sistema nervoso simp��tico, juntamente com os supostos efeitos pleiotr��picos do CVD, n��o parece ser a estrat��gia mais adequada para reverter este tipo particular de hipertens��o e indicam que as altera����es farmacocin��ticas induzidas pela CIH no ratio S/(R+S) n��o justificam a falta de efic��cia anti-hipertensora do CVD observada neste modelo animal. Por ��ltimo, os resultados do presente trabalho suportam ainda a viabilidade da utiliza����o da administra����o oral volunt��ria, em alternativa �� gavagem, para a administra����o cr��nica de uma dose fixa de f��rmacos 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-��1-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.

Essays in health economics: Volume-Outcome Effect, upcoding behaviour and the evaluation of a short-term intervention program

Evidence in the literature suggests a negative relationship between volume of medical procedures and mortality rates in the health care sector. In general, high-volume hospitals appear to achieve lower mortality rates, although considerable variation exists. However, most studies focus on US hospitals, which face different incentives than hospitals in a National Health Service (NHS). In order to add to the literature, this study aims to understand what happens in a NHS. Results reveal a statistically significant correlation between volume of procedures and better outcomes for the following medical procedures: cerebral infarction, respiratory infections, circulatory disorders with AMI, bowel procedures, cirrhosis, and hip and femur procedures. The effect is explained with the practice-makes-perfect hypothesis through static effects of scale with little evidence of learning-by-doing. The centralization of those medical procedures is recommended given that this policy would save a considerable number of lives (reduction of 12% in deaths for cerebral infarction).

Airport pavements evaluation

The airport pavement deteriorates during service due to traffic and climate effects therefore systematic monitoring is required in order to assess their structural and functional condition. The aim of this work is to present the methodologies used nowadays for airport pavement evaluation and to contribute to their improvement in structural analysis area The main aspects that are addressed are the application of the Ground Penetrating Radar (GPR) and the use of the Falling Weight Deflectometer (FWD) tests, for structural evaluation, and the use of the GRIP tester and the measurement of texture depth of the wearing course layer, for the functional evaluation of the runway. Also, freeware computer softwares used to design new runways (FAARFIELD and COMFAA) are presented and examples are given. Case studies are described both for structural and functional evaluation.