Estudo sobre o insight em pessoas com psicose

Para al��m das vari��veis cl��nicas e sociodemogr��ficas existem concerteza importantes componentes individuais que desempenham um contributo importante no n��vel de insight apresentado por cada pessoa doente, por exemplo, o n��vel de intelig��ncia, personalidade, cultura, experi��ncias passadas, mem��ria, etc. A natureza cl��nica, emocional e/ou intelectual do termo ajuda-nos a compreender a complexidade da dificuldade que existe na sua tradu����o e, inclusive, na sua compreens��o. Da�� que as defini����es atribu��das ao conceito sejam muito distintas e variem consoante a forma����o te��rica do autor/investigador. Pretende-se, a partir dessa identifica����o/compreens��o, promover a qualidade de vida destas pessoas atrav��s do desenvolvimento de novas aprendizagens que possibilitem uma coopera����o activa. �� igualmente fundamental ir ao encontro das capacidade intactas de maneira a possibilitar a aquisi����o de novos(s) comportamento(s) que tenham um impacte positivo nas queixas, sinais, sintomas, incapacidade e disfuncionalidade apresentados pelo/a utente. Uma vez que a pr��pria conceptualiza����o do termo traduzir�� aquilo que se pretende avaliar,ser�� efectuada uma reflex��o detalhada acerca dos instrumentos e defini����es que t��m sido mais utilizadas para explorar o insight nas psicoses.Procurei, no meu trabalho de investiga����o, real��ar e promover a import��ncia que cada sujeito, alvo de interven����o, desempenha ao longo do seu processo de recupera����o e na preven����o de reca��das. No seguimento dos objectivos acima descritos, para al��m da revis��o te��rica efectuada ao fen��meno em termos de conceptualiza����o e estudos desenvolvidos na ��rea de investiga����o, foi,neste estudo, realizada a contribui����o para a valida����o do instrumento ���Assessment of Insight in Psychosis: a re-standartization of a New Scale��� de Markov�� & Berrios (2003).O fen��meno de insight escolhido pela Insight Scale, relata menos as mudan��as vividas em rela����o �� doen��a mental, e mais a actual consci��ncia e articula����o de tais mudan��as. Tendo como base uma abordagem psicopedag��gica, o fen��meno do insight aqui explorado assentou numa perspectiva reabilitativa, actual e multidimensional, que fosse para al��m das dimens��es cl��nicas tradicionais. Neste sentido �� apresentada uma escala original, intitulada ���Escala de Avalia����o do Insight e Identifica����o das Necessidades em Pessoas com Psicose���, bem como um modelo de interven����o psicopedag��gico breve, assente nos pressupostos descritos ao longo do trabalho.-----------------------------------------ABSTRACT: The importance of insight in people with mental illnesses was first studied in psychiatry, in the first decades of the 20th century, by people as important as Lewis (1934) and Jaspers (1959). However, this field of investigation was left unexplored for many years. Only in the last decade has this phenomenon become the object of numerous scientific investigations, having been given special attention by its investigators. For this reason a significant number of instruments for evalauting insight in psychotic disorders were developed. Since then many papers have been published, which has allowed for a more in depth knowledge on the subject. Therefore, in recent years, the concept of insight has been developed in an attempt to clarify its compexity. A once dichotomic phenomenon, described in terms of presence or absence, became considered multidimensional, which made the identification of different levels of insight and different dimensions possible. Current concepts categorize insight into five dimensions: the awareness of the patient in relation to his/her mental illness, the awareness of the patient in relation to the social consequences of his/her illness, the awareness of the need for treatment, the awareness of the symptoms and the explanation of those symptoms in relation to the illness. The lack of insight in psychiatry, in general terms, and as this phenomenon has been described, the lack of awareness of having a mental illness, represents one of the most common symptoms of schizophrenia and affects a big part of the population that suffer from this illness. It is estimated that bewteen 50 and 80 per cent of patients with schizophrenia do not believe that they are ill, which, consequently has a big impact in the process of adherence to treatment. It is still not possible, however, to identify all the factors that determine the lack of insight in schizophrenics. There are psychological, social and cultural influences that almost certainly play their role in the lack of insight registered in this pathology.Since the impact of scizophrenia is felt in many aspects of the individual���s life, its effective treatment should be directed at various levels, including the improvement of insight. One of the objectives of this study is to explore the relationship between the level of insight in psychosis and the clinical and sociodemographic variables, the psychopathology and its global functioning. As well as the clinical and sociodemographic variables, there are of course important individual components that contribute to the level of insight seen in each patient, for example, their level of inteligence, personality, culture, past experiences, memory, etc. The clinical, emotional and/or intelectual nature of the term helps us understand the difficulty that lies in its interpretation as well as in its comprehension. Therefore, the definitions attributed to the term are very different and vary according to the theoretical training of the investigator. It is intended, from this identification/understanding, to promote the quality of life of these people through the development of new findings that might enable an active cooperation. It is equally fundamental to observe their unimpaired capacities in order to enable the acquisition of new behaviour(s) that have a positive impact on the complaints, signs, symptoms, incapacity and disfunctioning seen in the patient.As the actual comprehension of the term explains what we intend to evaluate, a detailed reflection is made on the instruments and definitions that have been used the most to explore insight in psychosis.In this investigation I tried to underline and promote the importance that each subject, undergoing medical intervention, plays during his/her process of recovery and prevention of relapses. Considering the above mentioned objectives, as well as a theoretical review of the phenomenon in terms of conceptualization and investigative studies developed, this study contributed to the validation of the instrument.The insight phenomenon chosen by the ���Insight Scale���, records less changes experienced in relation to the mental illness and more actual awareness and articulation of these changes. Based on a psychopedagogical approach, the insight phenomenon explored here settled on a rehabilitation, current and multidimensional perspective that would go beyond the traditional clinical dimensions. For this reason an original scale entitled ���Insight Evaluation Scale and Need Identification in Psychosis Patients��� is presented, as well as a psychopedagogical intervention model soon to be used with admitted patients based on the presuppositions described in this study.

Exploring the experience of stigma in severe mental illness : a Portuguese contribution to the validation of a psychometric instrument

RESUMO: Fizemos uma an��lise da evolu����o do conceito de estigma, das suas correla����es e das suas consequ��ncias e analis��mos os instrumentos psicom��tricos utilizados para estudar experi��ncias pessoais de estigma. Revimos os principais estudos de investiga����o sobre estigma em Portugal. Revimos, igualmente, os estudos relevantes utilizando o ���Consumer Experiences of Stigma Questionnaire��� (CESQ) e as propriedades psicom��tricas j�� documentadas. O nosso estudo teve como objetivos: explorar as experi��ncias de estigma numa amostra portuguesa de pessoas com perturba����o mental grave e contribuir para a documenta����o das propriedades psicom��tricas do ���Consumer Experiences of Stigma Questionnaire��� e para a valida����o da sua vers��o portuguesa. Fizemos um estudo transversal, descritivo e anal��tico, recolhemos dados sociodemogr��ficos e cl��nicos e medimos as experi��ncias de estigma e o funcionamento global. A frequ��ncia das respostas da sec����o de estigma foi semelhante �� dos restantes estudos utilizando a CESQ. A frequ��ncia das respostas na sec����o de discrimina����o foi ligeiramente inferior �� reportada noutros estudos. Verific��mos a exist��ncia de uma associa����o entre a pontua����o da subescala de discrimina����o, o sexo masculino e o facto de se viver na comunidade. A pontua����o da subescala de discrimina����o est�� tamb��m correlacionada de forma positiva com o funcionamento global. Os alfas de Cronbach para a CESQ e para as suas subescalas foram considerados bons. Os coeficientes de correla����o intraclasse foram igualmente considerados igualmente bons. Utilizando t��cnicas de an��lise fatorial, verific��mos que a maior parte dos itens da CESQ se enquadrava em dois fatores, correspondendo sensivelmente ��s subescalas definidas previamente. Conclu��mos que o presente estudo explorou com sucesso a quest��o do estigma em Portugal, contribuindo em simult��neo para a valida����o do ���Consumer Experiences of Stigma Questionnaire.--------------ABSTRACT: We reviewed the evolution of concept of stigma, its correlates and consequences, and analysed psychometric instruments that were used to study personal experiences of stigma. We provided an insight over research of stigma in Portugal. We reviewed relevant studies that use Consumer Experiences of Stigma Questionnaire and documented psychometric properties of this instrument. Our study aimed both to explore experiences of stigma in a Portuguese sample of people with severe mental illness and to contribute to the assessment of the psychometric properties of Consumer Experiences of Stigma Questionnaire and to the validation of its Portuguese translation. We performed a cross sectional descriptive and analytic study, collected socio-demographic data and measured experiences of stigma and global functioning. Frequency of responses regarding stigma section of CESQ matched previous studies using that scale. Frequency of responses in discrimination section was slightly lower than previously reported studies. We found an association between the discrimination score of CESQ and both male gender and living in the community. The discrimination score also positively correlated with global functioning. Cronbach alphas for CESQ and its subscales were good. Intraclass correlation coefficients for CESQ and stigma subscale were also good. Using factor analysis we found most of the items in CESQ would fit 2 factors, grossly corresponding to the previously defined subscales. We conclude that this study successfully explored stigma in Portugal, contributing in simultaneous to the validation of Consumer Experiences Questionnaire.

Thomsen-Friedenreich antigens in bladder cancer: evaluation of their prognostic value

RESUMO: Introdu����o. O cancro de bexiga �� uma patologia comum que representa o 6�� e o 5�� cancro mais incidente em Portugal e na It��lia, respetivamente. Em mais de metade dos casos ocorre reincid��ncia durante o primeiro ano, requerendo acompanhamento cl��nico ao longo da vida. A instila����o intravesical de Bacillus Calmette-Gu��rin (BCG) (uma estirpe atenuada do Mycobacterium bovis) representa uma imunoterapia eficaz no combate ao cancro de bexiga, no entanto, muitos aspetos da intera����o de BCG com as c��lulas tumorais bem como com as c��lulas do sistema imunit��rio permanecem por desvendar. As c��lulas tumorais de bexiga expressam frequentemente as formas sialiladas dos antig��nios de Thomsen-Friedenreich (TF), i.e., sialil-T (sT) e sialil-Tn (sTn). Contudo ainda se desconhece o significado da sua express��o na malignidade tumoral e se afeta a efic��cia da terap��utica BCG. Objetivo do estudo. Investigar o papel dos antig��nios sT e sTn no fen��tipo maligno de c��lulas de cancro de bexiga bem como na resposta mediada pelo sistema imunit��rio �� terapia com BCG. Metodologia. Para tal, foram utilizadas as linhas celulares de cancro da bexiga HT1376 e MCR, geneticamente modificadas por transdu����o com vetores codificantes para as sialiltransferases ST3GAL1 ou ST6GALNAC1, de forma a expressar homogeneamente os antig��nios sT ou sTn respetivamente. Estes modelos celulares foram estudados ap��s confronto com BCG. O n��vel de BCG internalizado foi avaliado por citometria de fluxo. O perfil global de express��o gen��tica dos modelos celulares antes e ap��s incuba����o com BCG foi analisado pela tecnologia de microarray. O perfil de citocinas secretadas pelos modelos celulares ap��s incuba����o com BCG, bem como de macr��fagos estimulados pelo secretoma de c��lulas de cancro de bexiga que por sua vez foram estimuladas previamente por BCG, foi estudado pelo sistema multiplex de ���imuno-esferas���. Resultados. A an��lise do transcritoma dos modelos celulares revelou que grupos de genes envolvidos em fun����es espec��ficas foram modulados em paralelo nos dois modelos celulares, ap��s transdu����o, independentemente da sialiltransferase expressa. Ou seja, em c��lulas que expressavam a sialiltransferase ST3GAL1 ou ST6GALNAC1, os genes envolvidos na regula����o da segrega����o cromoss��mica e na repara����o do DNA foram consistentemente regulados negativamente. Genes descritos na literatura como marcadores para o cancro de bexiga foram tamb��m modulados. A incuba����o com BCG resultou numa tend��ncia ao aumento da express��o de genes relevantes na preserva����o e estabilidade gen��mica e menor malignidade, no entanto, apenas em c��lulas que expressavam sT ou sTn. Entre as dez citocinas testadas, apenas a IL-6 e IL-8 foram expressas pelas linhas celulares de cancro da bexiga, com indu����o destas ap��s estimula����o com BCG, e principalmente em c��lulas que expressavam ST3GAL1 ou ST6GALNAC1. Em macr��fagos, citocinas inflamat��rias, tais como IL-1��, IL-6 e TNF��, e a citocina anti-inflamat��ria IL-10, foram induzidas apenas pelo secretoma de c��lulas de cancro da bexiga confrontadas com BCG, com maior relev��ncia quando estas expressavam ST3GAL1 ou ST6GALNAC1, prevendo a estimula����o de macr��fagos semelhantes aos de tipo M1 e uma melhor resposta �� terapia com BCG. Conclus��es. O efeito geral da express��o destas sialiltransferases e dos produtos enzim��ticos sT ou sTn nas c��lulas de cancro de bexiga conduz a um fen��tipo de maior malignidade. Contudo, a maior avidez de estas na produ����o de citocinas inflamat��rias ap��s confronto com BCG, bem como a maior capacidade de estimula����o de macr��fagos, predir�� uma resposta �� terapia com BCG mais eficaz em tumores que expressem os antig��nios de TF sialilados. Tais conclus��es s��o totalmente concordantes com os nossos mais recentes dados cl��nicos obtidos em colabora����o, que mostram que em doentes com cancro de bexiga que expressam sTn respondem melhor a terapia BCG. ----------ABSTRACT: Background. Bladder cancer is a common malignancy representing the 6th and the 5th most incident cancer in Portugal and in Italy, respectively. More than half of the cases relapse within one year, requiring though a lifelong follow-up. Intravesical instillation of Bacillus Calmette-Gu��rin (BCG) (an attenuated strain of Mycobacterium bovis) represents an effective immunotherapy of bladder cancer, although many aspects of the interaction of BCG with cancer cells and host immune cells remain obscure. Bladder cancer cells often express the sialylated forms of the Thomsen-Friedenreich (TF), i.e., sialil-T (sT) e sialil-Tn (sTn). However, it���s still unknown the sense of such expression in tumour malignancy and in the BCG therapy efficacy. Aim of the study. To investigate the role of the sT and sTn antigens on the malignant phenotype of bladder cancer cells and the immune mediated response to BCG therapy. Experimental. We have utilized populations of the bladder cancer cell lines HT1376 and MCR, genetically modified by transduction with the sialyltransferases ST3GAL1 or ST6GALNAC1 to express homogeneously sT or sTn antigens. The level of BCG internalized was assessed by flow cytometry. The whole gene expression profile of BCG-challenged or unchallenged bladder cancer cell lines was studied by microarray technology. The profile of cytokines secreted by BCG-challenged bladder cancer cells and that of macrophages challenged by the secretome of BCG-challenged bladder cancer cells was studied by multiplex immune-beads assay. Results. Transcriptome analysis of the sialyltransferase-transduced cells revealed that groups of genes involved in specific functions were regulated in parallel in the two cell lines, regardless the sialyltransferase expressed. Namely, in sialyltransferase-expressing cells, genes involved in the proper chromosomal segregation and in the DNA repair were consistently down-regulated, while genes reported in literature as markers for bladder cancer were modulated. BCG-challenging induced a tendency to up-regulation of the genes preserving genomic stability and reducing malignancy, but only in cells expressing either sT or sTn. Among the ten cytokines tested, only IL-6 and IL-8 were expressed by bladder cancer cell lines and up-regulated by BCG-challenging, mainly in sialyltransferases-expressing cells. In macrophages, inflammatory cytokines, such as IL-1��, IL-6 and TNF��, and the antinflammatory IL-10 were induced only by the secretome of BCG-challenged bladder cancer cells, particularly when expressing either sialyltransferase, predicting the stimulation of M1-like macrophages and a better response to BCG therapy. Conclusions. The general effect of the expression of the two sialyltransferases and their products in the bladder cancer cells is toward a more malignant phenotype. However, the stronger ability of sialyltransferase expressing cells to produce inflammatory cytokines upon BCG-challenging and to stimulate macrophages predicts a more effective response to BCG in tumours expressing the sialylated TF antigens. This is fully consistent with our recent clinical data obtained in collaboration, showing that patients with bladder cancer expressing sTn respond better to BCG therapy.

M��todos estat��sticos aplicados �� modela����o de dados oncol��gicos

RESUMO: A estrutura demogr��fica portuguesa �� marcada por baixas taxas de natalidade e mortalidade, onde a popula����o idosa representa uma fatia cada vez mais representativa, fruto de uma maior longevidade. A incid��ncia do cancro, na sua generalidade, �� maior precisamente nessa classe et��ria. A par de outras doen��as igualmente lesivas (e.g. cardiovasculares, degenerativas) cuja incid��ncia aumenta com a idade, o cancro merece relevo. Estudos epidemiol��gicos apresentam o cancro como l��der mundial na mortalidade. Em pa��ses desenvolvidos, o seu peso representa 25% do n��mero total de ��bitos, percentagem essa que mais que duplica noutros pa��ses. A obesidade, a baixa ingest��o de frutas e vegetais, o sedentarismo, o consumo de tabaco e a ingest��o de ��lcool, configuram-se como cinco dos fatores de risco presentes em 30% das mortes diagnosticadas por cancro. A n��vel mundial e, em particular no Sul de Portugal, os cancros do est��mago, recto e c��lon apresentam elevadas taxas de incid��ncia e de mortalidade. Do ponto de vista estritamente econ��mico, o cancro �� a doen��a que mais recursos consome enquanto que do ponto de vista f��sico e psicol��gico �� uma doen��a que n��o limita o seu raio de a����o ao doente. O cancro ��, portanto, uma doen��a sempre atual e cada vez mais presente, pois reflete os h��bitos e o ambiente de uma sociedade, n��o obstante as caracter��sticas intr��nsecas a cada indiv��duo. A ado����o de metodologia estat��stica aplicada �� modela����o de dados oncol��gicos ��, sobretudo, valiosa e pertinente quando a informa����o �� oriunda de Registos de Cancro de Base Populacional (RCBP). A pertin��ncia �� justificada pelo fato destes registos permitirem aferir numa popula����o espec��fica, o risco desta sofrer e/ou vir a sofrer de uma dada neoplasia. O peso que as neoplasias do est��mago, c��lon e recto assumem foi um dos elementos que motivou o presente estudo que tem por objetivo analisar tend��ncias, proje����es, sobreviv��ncias relativas e a distribui����o espacial destas neoplasias. Foram considerados neste estudo todos os casos diagnosticados no per��odo 1998-2006, pelo RCBP da regi��o sul de Portugal (ROR-Sul). O estudo descritivo inicial das taxas de incid��ncia e da tend��ncia em cada uma das referidas neoplasias teve como base uma ��nica vari��vel temporal - o ano de diagn��stico - tamb��m designada por per��odo. Todavia, uma metodologia que contemple apenas uma ��nica vari��vel temporal �� limitativa. No cancro, para al��m do per��odo, a idade �� data do diagn��stico e a coorte de nascimento, s��o vari��veis temporais que poder��o prestar um contributo adicional na caracteriza����o das taxas de incid��ncia. A relev��ncia assumida por estas vari��veis temporais justificou a sua inclus��o numaclasse de modelos designada por modelos Idade-Per��odo-Coorte (Age-Period-Cohort models - APC), utilizada na modela����o das taxas de incid��ncia para as neoplasias em estudo. Os referidos modelos permitem ultrapassar o problema de rela����es n��o lineares e/ou de mudan��as s��bitas na tend��ncia linear das taxas. Nos modelos APC foram consideradas a abordagem cl��ssica e a abordagem com recurso a fun����es suavizadoras. A modela����o das taxas foi estratificada por sexo. Foram ainda estudados os respectivos submodelos (apenas com uma ou duas vari��veis temporais). Conhecido o comportamento das taxas de incid��ncia, uma quest��o subsequente prende-se com a sua proje����o em per��odos futuros. Por��m, o efeito de mudan��as estruturais na popula����o, ao qual Portugal n��o �� alheio, altera substancialmente o n��mero esperado de casos futuros com cancro. Estimativas da incid��ncia de cancro a n��vel mundial obtidas a partir de proje����es demogr��ficas apontam para um aumento de 25% dos casos de cancro nas pr��ximas duas d��cadas. Embora a proje����o da incid��ncia esteja associada a alguma incerteza, as proje����es auxiliam no planeamento de pol��ticas de sa��de para a afeta����o de recursos e permitem a avalia����o de cen��rios e de interven����es que tenham como objetivo a redu����o do impacto do cancro. O desconhecimento de proje����es da taxa de incid��ncia destas neoplasias na ��rea abrangida pelo ROR-Sul, levou �� utiliza����o de modelos de proje����o que diferem entre si quanto �� sua estrutura, linearidade (ou n��o) dos seus coeficientes e comportamento das taxas na s��rie hist��rica de dados (e.g. crescente, decrescente ou est��vel). Os referidos modelos pautaram-se por duas abordagens: (i)modelos lineares no que concerne ao tempo e (ii) extrapola����o de efeitos temporais identificados pelos modelos APC para per��odos futuros. Foi feita a proje����o das taxas de incid��ncia para os anos de 2007 a 2010 tendo em conta o g��nero, idade e neoplasia. �� ainda apresentada uma estimativa do impacto econ��mico destas neoplasias no per��odo de proje����o. Uma quest��o pertinente e habitual no contexto cl��nico e a que o presente estudo pretende dar resposta, reside em saber qual a contribui����o da neoplasia em si para a sobreviv��ncia do doente. Nesse sentido, a mortalidade por causa espec��fica �� habitualmente utilizada para estimar a mortalidade atribu��vel apenas ao cancro em estudo. Por��m, existem muitas situa����es em que a causa de morte �� desconhecida e, mesmo que esta informa����o esteja dispon��vel atrav��s dos certificados de ��bito, n��o �� f��cil distinguir os casos em que a principal causa de morte �� devida ao cancro. A sobreviv��ncia relativa surge como uma medida objetiva que n��o necessita do conhecimento da causa espec��fica da morte para o seu c��lculo e dar-nos-�� uma estimativa da probabilidade de sobreviv��ncia caso o cancro em an��lise, num cen��rio hipot��tico, seja a ��nica causa de morte. Desconhecida a principal causa de morte nos casos diagnosticados com cancro no registo ROR-Sul, foi determinada a sobreviv��ncia relativa para cada uma das neoplasias em estudo, para um per��odo de follow-up de 5 anos, tendo em conta o sexo, a idade e cada uma das regi��es que constituem o registo. Foi adotada uma an��lise por per��odo e as abordagens convencional e por modelos. No ep��logo deste estudo, �� analisada a influ��ncia da variabilidade espa��o-temporal nas taxas de incid��ncia. O longo per��odo de lat��ncia das doen��as oncol��gicas, a dificuldade em identificar mudan��as s��bitas no comportamento das taxas, popula����es com dimens��o e riscos reduzidos, s��o alguns dos elementos que dificultam a an��lise da varia����o temporal das taxas. Nalguns casos, estas varia����es podem ser reflexo de flutua����es aleat��rias. O efeito da componente temporal aferida pelos modelos APC d��-nos um retrato incompleto da incid��ncia do cancro. A etiologia desta doen��a, quando conhecida, est�� associada com alguma frequ��ncia a fatores de risco tais como condi����es socioecon��micas, h��bitos alimentares e estilo de vida, atividade profissional, localiza����o geogr��fica e componente gen��tica. O ���contributo���, dos fatores de risco ��, por vezes, determinante e n��o deve ser ignorado. Surge, assim, a necessidade em complementar o estudo temporal das taxas com uma abordagem de cariz espacial. Assim, procurar-se-�� aferir se as varia����es nas taxas de incid��ncia observadas entre os concelhos inseridos na ��rea do registo ROR-Sul poderiam ser explicadas quer pela variabilidade temporal e geogr��fica quer por fatores socioecon��micos ou, ainda, pelos desiguais estilos de vida. Foram utilizados os Modelos Bayesianos Hier��rquicos Espa��o-Temporais com o objetivo de identificar tend��ncias espa��o-temporais nas taxas de incid��ncia bem como quantificar alguns fatores de risco ajustados �� influ��ncia simult��nea da regi��o e do tempo. Os resultados obtidos pela implementa����o de todas estas metodologias considera-se ser uma mais valia para o conhecimento destas neoplasias em Portugal.------------ABSTRACT: mortality rates, with the elderly being an increasingly representative sector of the population, mainly due to greater longevity. The incidence of cancer, in general, is greater precisely in that age group. Alongside with other equally damaging diseases (e.g. cardiovascular,degenerative), whose incidence rates increases with age, cancer is of special note. In epidemiological studies, cancer is the global leader in mortality. In developed countries its weight represents 25% of the total number of deaths, with this percentage being doubled in other countries. Obesity, a reduce consumption of fruit and vegetables, physical inactivity, smoking and alcohol consumption, are the five risk factors present in 30% of deaths due to cancer. Globally, and in particular in the South of Portugal, the stomach, rectum and colon cancer have high incidence and mortality rates. From a strictly economic perspective, cancer is the disease that consumes more resources, while from a physical and psychological point of view, it is a disease that is not limited to the patient. Cancer is therefore na up to date disease and one of increased importance, since it reflects the habits and the environment of a society, regardless the intrinsic characteristics of each individual. The adoption of statistical methodology applied to cancer data modelling is especially valuable and relevant when the information comes from population-based cancer registries (PBCR). In such cases, these registries allow for the assessment of the risk and the suffering associated to a given neoplasm in a specific population. The weight that stomach, colon and rectum cancers assume in Portugal was one of the motivations of the present study, that focus on analyzing trends, projections, relative survival and spatial distribution of these neoplasms. The data considered in this study, are all cases diagnosed between 1998 and 2006, by the PBCR of Portugal, ROR-Sul.Only year of diagnosis, also called period, was the only time variable considered in the initial descriptive analysis of the incidence rates and trends for each of the three neoplasms considered. However, a methodology that only considers one single time variable will probably fall short on the conclusions that could be drawn from the data under study. In cancer, apart from the variable period, the age at diagnosis and the birth cohort are also temporal variables and may provide an additional contribution to the characterization of the incidence. The relevance assumed by these temporal variables justified its inclusion in a class of models called Age-Period-Cohort models (APC). This class of models was used for the analysis of the incidence rates of the three cancers under study. APC models allow to model nonlinearity and/or sudden changes in linear relationships of rate trends. Two approaches of APC models were considered: the classical and the one using smoothing functions. The models were stratified by gender and, when justified, further studies explored other sub-models where only one or two temporal variables were considered. After the analysis of the incidence rates, a subsequent goal is related to their projections in future periods. Although the effect of structural changes in the population, of which Portugal is not oblivious, may substantially change the expected number of future cancer cases, the results of these projections could help planning health policies with the proper allocation of resources, allowing for the evaluation of scenarios and interventions that aim to reduce the impact of cancer in a population. Worth noting that cancer incidence worldwide obtained from demographic projections point out to an increase of 25% of cancer cases in the next two decades. The lack of projections of incidence rates of the three cancers under study in the area covered by ROR-Sul, led us to use a variety of forecasting models that differ in the nature and structure. For example, linearity or nonlinearity in their coefficients and the trend of the incidence rates in historical data series (e.g. increasing, decreasing or stable).The models followed two approaches: (i) linear models regarding time and (ii) extrapolation of temporal effects identified by the APC models for future periods. The study provide incidence rates projections and the numbers of newly diagnosed cases for the year, 2007 to 2010, taking into account gender, age and the type of cancer. In addition, an estimate of the economic impact of these neoplasms is presented for the projection period considered. This research also try to address a relevant and common clinical question in these type of studies, regarding the contribution of the type of cancer to the patient survival. In such studies, the primary cause of death is commonly used to estimate the mortality specifically due to the cancer. However, there are many situations in which the cause of death is unknown, or, even if this information is available through the death certificates, it is not easy to distinguish the cases where the primary cause of death is the cancer. With this in mind, the relative survival is an alternative measure that does not need the knowledge of the specific cause of death to be calculated. This estimate will represent the survival probability in the hypothetical scenario of a certain cancer be the only cause of death. For the patients with unknown cause of death that were diagnosed with cancer in the ROR-Sul, the relative survival was calculated for each of the cancers under study, for a follow-up period of 5 years, considering gender, age and each one of the regions that are part the registry. A period analysis was undertaken, considering both the conventional and the model approaches. In final part of this study, we analyzed the influence of space-time variability in the incidence rates. The long latency period of oncologic diseases, the difficulty in identifying subtle changes in the rates behavior, populations of reduced size and low risk are some of the elements that can be a challenge in the analysis of temporal variations in rates, that, in some cases, can reflect simple random fluctuations. The effect of the temporal component measured by the APC models gives an incomplete picture of the cancer incidence. The etiology of this disease, when known, is frequently associated to risk factors such as socioeconomic conditions, eating habits and lifestyle, occupation, geographic location and genetic component. The "contribution"of such risk factors is sometimes decisive in the evolution of the disease and should not be ignored. Therefore, there was the need to consider an additional approach in this study, one of spatial nature, addressing the fact that changes in incidence rates observed in the ROR-Sul area, could be explained either by temporal and geographical variability or by unequal socio-economic or lifestyle factors. Thus, Bayesian hierarchical space-time models were used with the purpose of identifying space-time trends in incidence rates together with the the analysis of the effect of the risk factors considered in the study. The results obtained and the implementation of all these methodologies are considered to be an added value to the knowledge of these neoplasms in Portugal.

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.

Development of a global IT charging model for BASF Group

With ���GS Strategy 2025��� BASF Business Services GmbH was formed to centrally steer all IT related topics of BASF group. Thus, a global charging system has to be designed, which complies to international transfer price regulations and the strategy of BASF SE. This work project develops a charging system with a following evaluation. The direct charging system benefits from its cost transparency upsides but comes with a higher administrative effort due to volume-based charging. In contrast, the indirect charging system convinces because of easy handling, which is the result of the application of suitable allocation keys. Regarding the complex group structure of BASF SE with more than 300 legal entities in 80 countries, the lower administrative effort of the indirect charging system outweighs the benefits of the direct charging model and should be used by BASF group.