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.

Leprosy in Buriticupu, state of Maranh��o: active search in the general population

INTRODUCTION: This study was developed to evaluate the situation of leprosy in the general population of the municipality of Buriticupu, State of Maranh��o, Brazil. METHODS: We used the method of active search to identify new cases from 2008 to 2010. Bacilloscopy of intradermal scrapings was performed in all patients with skin lesions compatible with leprosy, and histopathological examination in those who had doubts on the definition of the clinical form. RESULTS: The study included 19,104 individuals, with 42 patients diagnosed with leprosy after clinical examination, representing a detection rate of 219.84 per 100,000 inhabitants. The predominant clinical presentation was tuberculoid with 24 (57.1%) cases, followed by borderline with 11, indeterminate with four, and lepromatous with three cases. The study also allowed the identification of 81 patients with a history of leprosy and other skin diseases, such as pityriasis versicolor, dermatophytosis, scabies, vitiligo, and skin carcinoma. The binomial test showed that the proportion of cases in the headquarters was significantly higher than that in the villages (p = 0.04), and the generalized exact test showed that there was no association between age and clinical form (p = 0.438) and between age and gender (p = 0.083). CONCLUSIONS: The elevated detection rate defines the city as hyperendemic for leprosy; the active search for cases, as well as the organization of health services, is an important method for disease control.

What hides behind the fixed-term contracts wage gap?

In Portugal, about 20% of full-time workers are employed under a fixed-term contract. Using a rich longitudinal matched employer-employee dataset for Portugal, with more than 20 million observations and covering the 2002-2012 period, we confirm the common idea that fixed-term contracts are not desirable when compared to permanent ones, by estimating a conditional wage gap of -1.7 log points. Then, we evaluate the sources of that wage penalty by combining a three way high-dimensional fixed effects model with the decomposition of Gelbach (2014), in which the three dimensions considered are the worker���s unobserved ability, the firm���s compensation wage policy and the job title effect. It is shown that the average worker with a fixed-term contract is less productive than his/her permanent counterparts, explaining -3.92 log points of the FTC wage penalty. Additionally, the sorting of workers into lower-paid job titles is also responsible for -0.59 log points of the wage gap. Surprisingly, we found that the allocation of workers among firms mitigates the existing wage penalty (in 4.23 log points), as fixed-term workers are concentrated into firms with a more generous compensation policy. Finally, following Figueiredo et al. (2014), we further control for the worker-firm match characteristics and reach the conclusion that fixed-term employment relationships have an overrepresentation of low quality worker-firm matches, explaining 0.65 log points of the FTC wage penalty.

Interven����o educativa junto de um grupo de enfermeiros de um servi��o de medicina : impacto na pr��tica da terap��utica inalat��ria

RESUMO: O presente estudo, enquadra-se, no dom��nio do exerc��cio profissional dos enfermeiros e na forma����o em servi��o destes profissionais e teve por objectivo avaliar, num grupo de enfermeiros de um servi��o de medicina, o impacto de uma interven����o educativa na melhoria dos procedimentos a executar na pr��tica da terap��utica inalat��ria. A amostra do estudo (amostra por conveni��ncia) foi constitu��da por oito enfermeiros do servi��o de medicina do Hospital Curry Cabral (idades compreendidas entre os 24 a 43 anos de idade), sem anterior forma����o espec��fica na ��rea da terap��utica inalat��ria, mas com experiencia profissional pr��via com doentes respirat��rios. O estudo decorreu em dois momentos de avalia����o: avalia����o 0 (antes da interven����o educativa) e avalia����o 1 (ap��s a interven����o educativa). Entre estes dois momentos, foi ministrada, a todos os enfermeiros, uma ac����o de forma����o sobre terap��utica inalat��ria, com componente te��rico-pr��tica. Antes e depois da interven����o educativa foram aplicados dois instrumentos: para avalia����o dos conhecimentos te��ricos, construi-se e aplicou-se, um question��rio de auto-avalia����o de conhecimentos sobre terap��utica inalat��ria ao grupo dos enfermeiros, e para avalia����o dos conhecimentos pr��ticos e execu����o de procedimentos, uma grelha de observa����o da demonstra����o da t��cnica de inala����o com tr��s dispositivos inalat��rios: MDI, MDI com c��mara expansora ACE e DPI turbohaler��. Os resultados do estudo mostraram que o grupo dos enfermeiros da nossa amostra detinha j�� alguns conhecimentos de car��cter te��rico, de ��mbito geral, sobre a terap��utica inalat��ria, mas conhecimentos pouco s��lidos, nomeadamente no que concerne aos f��rmacos utilizados por via inalat��ria. Verificou-se, ainda, um deficiente dom��nio de conte��dos de car��cter mais espec��fico e pr��tico sobre terap��utica inalat��ria, por exemplo a import��ncia de determinados procedimentos - agita����o do inalador, tempo de pausa entre cada inala����o, cuidados de manuten����o da c��mara expansora, higieniza����o da cavidade bucal ap��s a inala����o dos corticoster��ides. Quanto �� observa����o da t��cnica de inala����o, o grupo dos enfermeiros revelou algumas lacunas, quer relativamente �� t��cnica de inala����o com MDI, quer do MDI com c��mara expansora, observando-se a execu����o de passos incorrectos e mesmo omiss��o de passos por parte dos enfermeiros, antes da interven����o educativa.N��o nos foi poss��vel realizar a observa����o da t��cnica de inala����o com dispositivo de p�� seco turbohaler��, dado que nenhum dos enfermeiros da nossa amostra se sentiu capaz de manusear de forma correcta este dispositivo, antes e ap��s a forma����o. Em termos globais, achamos que a forma����o dada sobre terap��utica inalat��ria, mostrou melhorar os conhecimentos te��ricos e pr��ticos dos enfermeiros neste ��mbito. Esta melhoria ficou claramente demonstrada no aumento do n��mero de respostas correctas dadas pelos enfermeiros no question��rio efectuado, ap��s a forma����o. Do mesmo modo, ap��s a forma����o, registou-se uma melhoria consider��vel dos conhecimentos espec��ficos e pr��ticos, no que concerne �� import��ncia de determinados procedimentos na pr��tica da terap��utica inalat��ria - agita����o do inalador, tempo de pausa entre cada inala����o, cuidados de manuten����o da c��mara expansora, higieniza����o da cavidade bucal ap��s a inala����o dos corticoster��ides - observando-se, um maior n��mero de respostas correctas assinaladas no question��rio. Em contrapartida, os conhecimentos sobre f��rmacos administrados por via inalat��ria, ficaram um pouco aqu��m das expectativas, pois o n��mero de respostas correctas dadas pelos enfermeiros ap��s a forma����o n��o foi significativo. Poderemos mesmo dizer que, a ac����o de forma����o com maior grau de especificidade sobre f��rmacos n��o se revelou eficaz e gerou at�� alguma ���confus��o��� neste grupo de enfermeiros, parecendo que os conhecimentos anteriores sobre f��rmacos por via inalat��ria n��o estariam consolidados antes da forma����o. De igual modo, ap��s a forma����o, registou-se no grupo dos enfermeiros do estudo uma melhoria na performance da t��cnica de inala����o com o MDI e MDI com a c��mara expansora. Os enfermeiros do estudo, n��o s�� corrigiram os passos ou itens de avalia����o da t��cnica inalat��ria, anteriormente executados incorrectamente, mas tamb��m, mostraram um melhor conhecimento dos passos ou itens de avalia����o da t��cnica de inala����o, com menor n��mero de passos ou itens de avalia����o omissos, ap��s a forma����o. Em contrapartida, a ac����o de forma����o, no que diz respeito ao dispositivo de p�� seco turbohaler��, n��o cumpriu o seu objectivo, dado que nenhum dos enfermeiros da amostra foi capaz de demonstrar a t��cnica de inala����o com este dispositivo, antes e ap��s a forma����o. Poderemos dizer que, n��o sendo um dispositivo da sua pr��tica cl��nica, os enfermeiros n��o sentiram necessidade de adquirir estes conhecimentos. Em s��ntese, podemos concluir que na sua globalidade, a forma����o dada (com informa����o actualizada sobre as orienta����es mais adequadas neste dom��nio) e o treino formal dos enfermeiros neste ��mbito, foi bastante proveitoso, uma vez que, mostrou melhorar os conhecimentos te��ricos e pr��ticos na pr��tica da terap��utica inalat��ria do grupo de enfermeiros doservi��o de medicina. Real��a-se, no entanto, a import��ncia de uma forma����o adequada, sentida como ��til pelos enfermeiros, faseada, ligada �� pr��tica dos profissionais e alternando com momentos de exerc��cio profissional. Os conhecimentos e os procedimentos dos enfermeiros dever��o ainda ser monitorizados e avaliados ao longo do tempo, para a detec����o de eventuais desvios que a rotina pode introduzir e para levantamento de novas necessidades de forma����o.-------------------ABSTRACT: This study fits in the domain of in-service training of professional nurses. It was aimed to assess the impact of an educational intervention and the consequent improvement of the practice of inhalation therapy in a group of nurses from a medical service The study sample (convenience sample) was consituted by eight nurses from the medical service, Hospital Curry Cabral (aged 24-43 years) without previous special training in the field of inhalation therapy, but with prior experience with patients with respiratory diseases. The study ran in two moments of evaluation: evaluation 0 (before the educational intervention) and evaluation 1 (post-intervention). Between these two moments, a training program about therapeutic inhalation was administered to all nurses, with a double component of theory and practice. Before and after the educational intervention two evaluation tools were applied: for the assessment of theoretical knowledge, the nurses had to fill a self-assessment questionnaire and in order to evaluate their knowledge related to procedural skills as well as their performance, they were observed (and their behaviour recorded on a check-list) during a demonstration of three inhalation techniques with devices: metered dose inhaler, metered dose inhaler with a spacer device ACE�� and device turbohaler�� The study results showed that the group of nurses in our sample had already some knowledge of theoretical nature (general scope of the inhalation therapy) but little solid knowledge, particularly in regard to drugs used in inhalation. In fact, a relatively weaker knowledge was registerd in what concerns specific and practical knowledge about inhalation therapy, for example, the importance of certain procedures - shaking the inhaler, pause between each inhalation, maintenance care of spacer device, mouth cavity hygiene after inhalation of corticosteroids. As for the observation of the inhaler technique, it was found that the group of nurses had a poor inhalation technique, in what concerns inhalation technique with MDI or MDI with spacer device, with a performance with several incorrect steps, or even omission of steps by nurses before the educational intervention. Finally, as the observation technique of the dry powder device turbohaler ��, we were unable to analyze the observation concerning this device, since none of the nurses in our sample, wast able to handlle it correctly, before and after training.In general terms, we found that the training given on inhalation therapy had a positive impact either in the theorical or the pratical knowledge on inhalation therapy (higher number of correct answers after training). Similarly, after training, there was the considerable improvement of specific and practical skills, namely the importance of certain procedures in the practice of inhalation therapy - shaking the inhaler, pause time between each inhalation, maintenance care of spacer device, sanitizing the buccal cavity after inhalation of corticosteroids. In contrast, knowledge about drugs administered by inhalation, were slightly below expectations, showing a lower number of correct answers given by the nurses after training. The training seemed to be a factor of "confusion" for this group of nurses, whose prior knowledge in this domais was not probably very solid to begin with. After training, the group of nurses in the study improved the performance of inhalation technique with MDI and MDI with spacer device. They not only correcty performed the steps or itens for the assessment of inhalation technique, previously performed incorrectly, but also showed a better understanding of the steps or itens for assessing the inhalation technique, with fewer steps missing (after training). In contrast, training with regard to the device turbohaler �� dry powder, was also below expectations, given that none of the nurses in the sample was able to demonstrate inhaler technique with this device before and after training. This was probably due to the fact that, the nurses did not feel the need to acquire this knowledge and the related practice. In summary, we can say that, overall, the training (with updated information on the appropriate policies in this field) showed an improvement in knowledge and performance in the practice of inhalation therapy. It is however crucial to underline the importance of in-service adequate training programmes, perceived as useful by the nurses, developped in different phases, linked to the nurses��� practice and combining with professional practices. The nurses��� knowledge and skills should also be further monitorized and evaluated in order to detect deviations introduced by the rotinization of procedures and to identify new training needs.

Estigma e percep����es dos m��dicos de Cl��nica Geral sobre a doen��a mental e o suic��dio

RESUMO: INTRODU����O: A OMS (2001) revela que cerca de 450 milh��es de pessoas sofrem de perturba����es mentais ou comportamentais em todo o mundo, mas apenas uma pequena minoria tem tratamento, ainda que elementar. Transformam-se em v��timas por causa da sua doen��a e convertem-se em alvos de estigma e discrimina����o. O suic��dio �� considerado como um grande problema de sa��de p��blica em todo o mundo, �� uma das principais causas de morte de jovens adultos e situa-se entre as tr��s maiores causas de morte na popula����o entre 15-34 anos (OMS, 2001). As perturba����es mentais aumentam o risco de suic��dio. A depress��o, esquizofrenia, e a utiliza����o de subst��ncias incrementam o risco de suic��dio. Estudos (Sartorius, 2002; Magliano et al., 2012) mostram que os profissionais de sa��de, tal como o p��blico em geral, podem ter atitudes negativas e estigma em rela����o ��s pessoas com perturba����es mentais, podendo agir em conformidade, uma vez feito e conhecido o diagn��stico psiqui��trico. Os cl��nicos gerais s��o os receptores das perturba����es mentais e tentativas de suic��dio nas principais portas de entrada no acesso a cuidados de sa��de. As cren��as, conhecimentos e contacto com a doen��a mental e o suic��dio, podem influenciar a aten����o cl��nica. OBJECTIVOS: Avaliar o estigma e as percep����es dos m��dicos de cl��nica geral em rela����o ��s tentativas de suic��dio, o suic��dio e perturba����es mentais bem como os poss��veis factores associados a estes fen��menos. MATERIAIS E M��TODOS: Estudo do tipo transversal, combinando m��todos quantitativos e qualitativos. A amostra �� constitu��da por 125 sujeitos, m��dicos de cl��nica geral. Utilizaram-se as vers��es adaptadas dos seguintes instrumentos: Question��rio sobre Percep����es e Estigma em Rela����o �� Sa��de Mental e ao Suic��dio (Liz Macmin e SOQ, Domino, 2005) e a Escala de Atitudes sobre a Doen��a Mental (Amanha Hahn, 2002). Para o tratamento estat��stico dos dados usou-se a estat��stica 1) descritiva e 2) An��lise estat��stica das hip��teses formuladas (Qui Quadrado - ���2) a correla����o entre vari��veis (Spearman: ��, rho). Os dados conectados foram limpos de inconsist��ncias com base no pacote inform��tico e estat��stico SPSS vers��o 20. Para a aferi����o da consist��ncia interna foi usado o teste de Alfa de Cronbach. RESULTADOS: Uma boa parte da amostra (46.4%) refere que n��o teve forma����o formal ou informal em sa��de mental e (69.35%) rejeitam a ideia de que ���grupos profissionais como m��dicos, dentistas e psic��logos s��o mais suscept��veis a cometer o suic��dio���. J�� (28.0%) t��m uma perspectiva pessimista quanto a possibilidade de recupera����o total dos sujeitos com perturba����o mental. Sessenta e oito(54.4%) associa sujeitos com perturba����o mental, a comportamentos estranhos e imprevis��veis, 115 (92.0%) a um baixo QI e 35 (26.7%) a poderem ser violentas e e perigosas. Os dados mostram uma associa����o estatisticamente significativa (p���0.001) entre as vari��veis: tempo de servi��o no SNS, recear estar perto de sujeitos com doen��a mental e achar que os sujeitos com doen��a mental s��o mais perigosos que outros. Em termos estat��sticos, existe uma associa����o estatitisticamente significativa entre as duas vari��veis(X2=9,522; p���0.05): percep����o de que ����� vergonhoso ter uma doen��a mental��� e os conhecimentos em rela����o �� doen��a mental. Existe uma correla����o positiva, fraca e estatisticamente significativa entre os conhecimentos dos cl��nicos gerais(beneficiar-se de forma����o em sa��de mental) e a percep����o sobre os factores de risco (������0,187; P���0,039). DISCUSS��O E CONCLUS��ES: A falta de conhecimento sobre as causas e factores de risco para os comportamentos suicid��rios, op����es de interven����o e tratamento, particularmente no ��mbito da doen��a mental, podem limitar a procura de ajuda individual ou dos pr��ximos. Percep����es negativas como o facto de n��o merecerem prioridade nos servi��os, mitos (fr��geis e cobarde, sempre impulsivo, chamadas de aten����o, problemas espirituais) podem constituir-se como um indicador de que os cl��nicos gerais podem sofrer do mesmo sistema de estigma e cren��as, de que sofre o p��blico em geral, podendo agir em conformidade (atitudes de afastamento ereceio). As atitudes s��o influenciadas por factores como a forma����o, cultura e sistema de cren��as. Sujeitos com boa forma����o na ��rea da sa��de mental t��m uma percep����o positiva e optimista sobre os factores de risco e uma atitude positiva em rela����o aos sujeitos com doen��a mental e comportamentos suicid��rios.-------------ABSTRACT: INTRODUCTION: The WHO (2001) reveals that about 450 million people suffer from mental or behavioral disorders worldwide, but only a small minority have access to treatment, though elementary. They become victims because of their disease and they become the targets of stigma and discrimination. Suicide is seen as a major public health problem worldwide, is a leading cause of death for young adults and is included among the three major causes of death in the population aged 15-34 years (WHO, 2001). Mental disorders increase the risk of suicide. Depression, schizophrenia, and the substances misuse increase the risk of suicide. Studies (Sartorius, 2002; Magliano et al, 2012) show that health professionals, such as the general public, may have negative attitudes and stigma towards people with mental disorders, and can act accordingly after psychiatric diagnosis is known. General practitioners are the main entry points of mental disorders and suicide attempts in the health sistem. Beliefs, knowledge and contact with mental illness and suicide, may influence clinical care. OBJECTIVES: To assess stigma and perceptions of general practitioners in relation to suicide attempts, suicide and mental disorders as well as possible factors associated with these phenomena. MATERIAL AND METHODS: This was a descriptive cross-sectional study, combining quantitative and qualitative methods. The sample consisted of 125 subjects, general practitioners. We used adapted versions of the following instruments: Questionnaire of Perceptions and Stigma in Relation to Mental Health and Suicide (Liz Macmin and SOQ, Domino, 2005) and the Scale of Attitudes on Mental Illness (Tomorrow Hahn, 2002). For the statistical treatment of the data we used: 1) descriptive (Data distribution by absolute and relative frequencies for each of the variables under study (including mean and standard deviation measures of central tendency and deviation), 2) statistical analysis of hypotheses using (Chi Square - ���2, a hypothesis test that is intended to find a value of dispersion for two nominal variables, evaluating the association between qualitative variables) and the correlation between variables (Spearman ��, rho), a measure of non-parametric correlation, which evaluates an arbitrary monotonic function can be the description of the relationship between two variables, without making any assumptions about the frequency distribution of the variables). For statistical analysis of the correlations were eliminated subjects who did not respond to questions. The collected data were cleaned for inconsistencies based on computer and statistical package SPSS version 20. To measure the internal consistency was used the Cronbach's alpha test. RESULTS: A significant part of the sample 64 (46.4%) reported no formal or informal training in mental health and 86 (69.35%) reject the idea that "professional groups such as doctors, dentists and psychologists are more likely to commit suicide." On the other hand, 42 (28.0%) have a pessimistic view of the possibility of full recovery of individuals with mental disorder. Sixty-eight ( 54.4 % ) of them associates subjects with mental disorder to strange and unpredictable behavior, 115 ( 92.0 % ), to low IQ, 35 ( 26.7 % ) and even to violent and dangerous behavior, 78 ( 62.4 % ) The data show a statistically significant (p = 0.001) relationship between the following variables: length of service in the NHS, fear of being close to individuals with mental illness and considering individuals with mental illness more dangerous than others. In statistical terms, there is a dependency between the two variables (X2 = 9.522, p> 0.05): the perception that "it is shameful to have a mental illness" and knowledge regarding mental illness. There is a positive and statistically significant weak correlation between knowledge of general practitioners (benefit from mental health training) and the perception of the risk factors (������0,187; P���0,039). DISCUSSION AND CONCLUSIONS: The lack of knowledge about the causes and risk factors for suicidal behavior, intervention and treatment, particularly in the context of mental illness options, may decreaseseeking for help by individual and their relatives. Negative perceptions such as considering that they dont deserve priority in services, myths (weak and cowards, always impulsive, seeking for attentions, spirituals problems) may indicate that general practitioners, may suffer the same stigma and beliefs systems as the general public, and can act accordingly (withdrawal and fear attitudes). Attitudes are influenced by factors such as education, culture and belief system. Subjects with good training in mental health have a positive and optimistic perception of the risk factors and a positiveattitude towards individuals with mental illness and suicidal behaviour.

A logical foundation for session-based concurrent computation

Linear logic has long been heralded for its potential of providing a logical basis for concurrency. While over the years many research attempts were made in this regard, a Curry-Howard correspondence between linear logic and concurrent computation was only found recently, bridging the proof theory of linear logic and session-typed process calculus. Building upon this work, we have developed a theory of intuitionistic linear logic as a logical foundation for session-based concurrent computation, exploring several concurrency related phenomena such as value-dependent session types and polymorphic sessions within our logical framework in an arguably clean and elegant way, establishing with relative ease strong typing guarantees due to the logical basis, which ensure the fundamental properties of type preservation and global progress, entailing the absence of deadlocks in communication. We develop a general purpose concurrent programming language based on the logical interpretation, combining functional programming with a concurrent, session-based process layer through the form of a contextual monad, preserving our strong typing guarantees of type preservation and deadlock-freedom in the presence of general recursion and higher-order process communication. We introduce a notion of linear logical relations for session typed concurrent processes, developing an arguably uniform technique for reasoning about sophisticated properties of session-based concurrent computation such as termination or equivalence based on our logical approach, further supporting our goal of establishing intuitionistic linear logic as a logical foundation for sessionbased concurrency.

Changes in prescribing patterns of benzodiazepines after training of general practitioners

RESUMO: Introdu����o: As benzodiazepinas s��o os f��rmacos ansiol��ticos e hipn��ticos mais utilizados. O elevado consumo destes f��rmacos tem representado uma preocupa����o devido aos efeitos secund��rios do seu uso prolongado e depend��ncia. Portugal tem a maior utiliza����o de benzodiazepinas na Europa. Este estudo pretende analisar a altera����o do padr��o de prescri����o de benzodiazepinas ap��s uma interven����o com cl��nicos gerais. M��todos: A interven����o consistiu numa sess��o educacional a um grupo de cl��nicos gerais. Foi comparado o padr��o de prescri����o de benzodiazepinas dos m��dicos intervencionados com o de um grupo de m��dicos n��o intervencionado da mesma regi��o e com o de um grupo de m��dicos n��o intervencionados de outra regi��o. Analisaram-�����se as prescri����es de 12 meses antes e depois da interven����o. A an��lise do padr��o de prescri����o utilizou como metodologia a Dose Di��ria Definida (DDD) e a Dose Di��ria Definida por 1000 pacientes por dia (DHD). A an��lise estat��stica recorreu a m��todos de regress��o segmentada. Resultados: Houve uma diminui����o no padr��o de prescri����o de benzodiazepinas no grupo intervencionado ap��s a interven����o (p=0.005). Houve tamb��m uma redu����o no padr��o de prescri����o no grupo n��o intervencionada da mesma regi��o (p=0.037) e no grupo n��o-intervencionado da regi��o diferente (p=0.010). Analisando por g��nero, prescritores do g��nero feminino prescrevem uma quantidade maior de benzodiazepinas. Os cl��nicos gerais do g��nero feminino intervencionados tiveram a maior redu����o na prescri����o ap��s a interven����o (p=0.008). Discuss��o: Os dados demonstraram que a interven����o reduziu a prescri����o de benzodiazepinas ap��s a interven����o. A diminui����o geral do padr��o de prescri����o poder�� ser explicada pelo efeito de Hawthorne ou pela contamina����o entre os tr��s grupos de cl��nicos gerais. Os dados dispon��veis n��o explicam as diferen��as nos padr��es de prescri����o por g��nero. Conclus��o: Este estudo demonstra como uma ��nica interven����o tem um impacto positivo na melhoria dos padr��es de prescri����o. A replica����o desta interven����o poder�� representar uma oportunidade para alterar a prescri����o de benzodiazepinas em Portugal. -----------------------------ABSTRACT: Introduction: Benzodiazepines are the most utilized anxiolytic and hypnotic drugs. The high consumption of benzodiazepines has been a concern due to the reported side effects of long-�����term use and dependence. Portugal has the highest benzodiazepine utilisation in Europe. This study aims to analyse the change in General Practitioners��� (GPs) benzodiazepine prescription pattern after na intervention period. Methods: An educational session was delivered to a group of intervened GPs. The benzodiazepine prescription pattern of the intervened group was compared to the pattern of a non-�����intervened matched group from the same region, and to the pattern of another non-�����intervened matched group from a diferente region. The research time frame was 12 month before and after intervention. The analysis of the prescription trends used the Defined Daily Dose (DDD) and Defined Daily Dose per 1000 patients per day (DHD) methodology. The statistical methods consisted of segmented regression analysis. Results: There was a decrease in benzodiazepine prescription pattern of intervened GPs after intervention (p=0.005). There was also a decrease in benzodiazepine prescription pattern for the non-�����intervened group from the same region (p=0.037) and for the non-����� intervened group from a diferente region (p=0.010). Concerningthe analysis by gender, female gender prescribed a higher amount of benzodiazepines. The intervened female gender prescribers presented the highest decrease in prescription trend after intervention (p=0.008). Discussion: The data demonstrated that the intervention was effective in reducing benzodiazepine prescription after intervention. The general decrease in prescription trend might be explained by a Hawthorne effect or a contamination effect between the three groups of GPs. The available data couldn��t explain the diferences in prescription patterns by gender. Conclusion: This study demonstrates how a single intervention has a positive impact on improving prescription trends. The replication of this intervention might be an opportunity to changing the worrying benzodiazepine utilisation in Portugal.

O impacto do diagn��stico de dem��ncia no casal

RESUMO: A experi��ncia de viver com dem��ncia ocorre, frequentemente, num contexto de uma rela����o conjugal duradoura. A qualidade da rela����o e o sentido de coer��ncia (conjunto de caracter��sticas pessoais que permite compreender, gerir e integrar os factores de stress de forma construtiva) apresentam-se como factores promotores e protectores da sa��de, no contexto de experi��ncias adversas, nomeadamente de doen��a. Provavelmente, o mesmo poder�� acontecer nos quadros demenciais. O presente estudo teve como objectivo principal analisar o impacto do diagn��stico, no contexto das fases iniciais de dem��ncia, em casais de pessoas idosas, explorando o papel da qualidade da rela����o conjugal e do sentido de coer��ncia na confronta����o com o diagn��stico e na experi��ncia de viver com a doen��a. Realiz��mos um estudo observacional de seis casais de pessoas idosas (pessoas com dem��ncia e respectivos c��njuges prestadores de cuidados), com recurso a entrevistas individuais e conjuntas como suplemento metodol��gico central, suportado pela utiliza����o dos instrumentos: Orientation to Life Questionnaire - SOC (Antonovsky, 1987) e Quality of Carer-Patient Relationships ��� QCPR (Spruytte et al. 2000). Os resultados sugerem que a qualidade da rela����o e um sentido de coer��ncia mais elevado podem facilitar uma adapta����o bem-sucedida aos desafios, promover a adop����o de estrat��gias para refor��ar os aspectos positivos da experi��ncia de cuidar e atenuar os negativos (sobrecarga e sofrimento ps��quico do cuidador), encorajar padr��es positivos no acesso e na utiliza����o dos cuidados formais e adiar a institucionaliza����o precoce da pessoa com dem��ncia.----------------------- ABSTRACT: In couples, caregiving experiences in dementia usually occur within long-standing relationships preceding the onset of the illness and evolving as it progresses. The quality of relationship (QR) and Antonovsky���s salutogenic construct of sense of coherence (SOC) are assumed to promote and protect health in stressful situations, such as dementia. SOC refers to the extent to which a person considers his/her life as comprehensible, manageable and meaningful. We aim to uncover the role of QR and SOC as moderator or mediator in the ability of patients and their partners to cope with the impact of dementia We studied six couples in which one spouse had been diagnosed with dementia. We used a qualitative research approach (combining in-depth individual and joint interviews), triangulated with the measures Orientation to Life Questionnaire - SOC scale (Antonovsky, 1987) and the Quality of Carer-Patient Relationships ��� QCPR (Spruytte et al. 2000). The method was informed by a literature review on the role of RQ and SOC within dementia. Results highlight the importance of listening to both spouses, in a dyadic perspective, while acknowledging the voice of PwD themselves despite methodological challenges. Aspects of prior relationship impact on caregiving dynamics and on how the care-giver and care-recipient roles are experienced. At the same time, the experience of living with dementia impacts on the relationship, often causing change or loss which is difficult to accept or adjust to. Diagnosis played an important role on the SOC���s comprehensibility component (life makes sense). Good pre-caregiving and current relationship was associated with carers��� ability to cope, namely on SOC���s manageability (problems will be bearable) and meaningfulness (life is viewed as a challenge). Our findings suggest that an understanding of QR and SOC prior to diagnosis may encourage positive patterns of care, foster successful adaptation to changing needs, and support in-home arrangements as long as possible.

Effects of ocean acidification on the swimming ability, development and biochemical responses of sand smelt larvae

Ocean acidification, recognized as a major threat to marine ecosystems, has developed into one of the fastest growing fields of research in marine sciences. Several studies on fish larval stages point to abnormal behaviours, malformations and increased mortality rates as a result of exposure to increased levels of CO2. However, other studies fail to recognize any consequence, suggesting species-specific sensitivity to increased levels of CO2, highlighting the need of further research. In this study we investigated the effects of exposure to elevated pCO2 on behaviour, development, oxidative stress and energy metabolism of sand smelt larvae, Atherina presbyter. Larvae were caught at Arr��bida Marine Park (Portugal) and exposed to different pCO2 levels (control: ~600��atm, pH=8.03; medium: ~1000��atm, pH=7.85; high: ~1800��atm, pH=7.64) up to 15days, after which critical swimming speed (Ucrit), morphometric traits and biochemical biomarkers were determined. Measured biomarkers were related with: 1) oxidative stress - superoxide dismutase and catalase enzyme activities, levels of lipid peroxidation and DNA damage, and levels of superoxide anion production; 2) energy metabolism - total carbohydrate levels, electron transport system activity, lactate dehydrogenase and isocitrate dehydrogenase enzyme activities. Swimming speed was not affected by treatment, but exposure to increasing levels of pCO2 leads to higher energetic costs and morphometric changes, with larger larvae in high pCO2 treatment and smaller larvae in medium pCO2 treatment. The efficient antioxidant response capacity and increase in energetic metabolism only registered at the medium pCO2 treatment may indicate that at higher pCO2 levels the capacity of larvae to restore their internal balance can be impaired. Our findings illustrate the need of using multiple approaches to explore the consequences of future pCO2 levels on organisms.

Essays on bounded rationality: Individual decision and strategic interaction

Economics is a social science which, therefore, focuses on people and on the decisions they make, be it in an individual context, or in group situations. It studies human choices, in face of needs to be fulfilled, and a limited amount of resources to fulfill them. For a long time, there was a convergence between the normative and positive views of human behavior, in that the ideal and predicted decisions of agents in economic models were entangled in one single concept. That is, it was assumed that the best that could be done in each situation was exactly the choice that would prevail. Or, at least, that the facts that economics needed to explain could be understood in the light of models in which individual agents act as if they are able to make ideal decisions. However, in the last decades, the complexity of the environment in which economic decisions are made and the limits on the ability of agents to deal with it have been recognized, and incorporated into models of decision making in what came to be known as the bounded rationality paradigm. This was triggered by the incapacity of the unboundedly rationality paradigm to explain observed phenomena and behavior. This thesis contributes to the literature in three different ways. Chapter 1 is a survey on bounded rationality, which gathers and organizes the contributions to the field since Simon (1955) first recognized the necessity to account for the limits on human rationality. The focus of the survey is on theoretical work rather than the experimental literature which presents evidence of actual behavior that differs from what classic rationality predicts. The general framework is as follows. Given a set of exogenous variables, the economic agent needs to choose an element from the choice set that is avail- able to him, in order to optimize the expected value of an objective function (assuming his preferences are representable by such a function). If this problem is too complex for the agent to deal with, one or more of its elements is simplified. Each bounded rationality theory is categorized according to the most relevant element it simplifes. Chapter 2 proposes a novel theory of bounded rationality. Much in the same fashion as Conlisk (1980) and Gabaix (2014), we assume that thinking is costly in the sense that agents have to pay a cost for performing mental operations. In our model, if they choose not to think, such cost is avoided, but they are left with a single alternative, labeled the default choice. We exemplify the idea with a very simple model of consumer choice and identify the concept of isofin curves, i.e., sets of default choices which generate the same utility net of thinking cost. Then, we apply the idea to a linear symmetric Cournot duopoly, in which the default choice can be interpreted as the most natural quantity to be produced in the market. We find that, as the thinking cost increases, the number of firms thinking in equilibrium decreases. More interestingly, for intermediate levels of thinking cost, an equilibrium in which one of the firms chooses the default quantity and the other best responds to it exists, generating asymmetric choices in a symmetric model. Our model is able to explain well-known regularities identified in the Cournot experimental literature, such as the adoption of different strategies by players (Huck et al. , 1999), the inter temporal rigidity of choices (Bosch-Dom enech & Vriend, 2003) and the dispersion of quantities in the context of di cult decision making (Bosch-Dom enech & Vriend, 2003). Chapter 3 applies a model of bounded rationality in a game-theoretic set- ting to the well-known turnout paradox in large elections, pivotal probabilities vanish very quickly and no one should vote, in sharp contrast with the ob- served high levels of turnout. Inspired by the concept of rhizomatic thinking, introduced by Bravo-Furtado & C��rte-Real (2009a), we assume that each per- son is self-delusional in the sense that, when making a decision, she believes that a fraction of the people who support the same party decides alike, even if no communication is established between them. This kind of belief simplifies the decision of the agent, as it reduces the number of players he believes to be playing against { it is thus a bounded rationality approach. Studying a two-party first-past-the-post election with a continuum of self-delusional agents, we show that the turnout rate is positive in all the possible equilibria, and that it can be as high as 100%. The game displays multiple equilibria, at least one of which entails a victory of the bigger party. The smaller one may also win, provided its relative size is not too small; more self-delusional voters in the minority party decreases this threshold size. Our model is able to explain some empirical facts, such as the possibility that a close election leads to low turnout (Geys, 2006), a lower margin of victory when turnout is higher (Geys, 2006) and high turnout rates favoring the minority (Bernhagen & Marsh, 1997).

The role of individual ability and structural embeddedness on entrepreneurial success

In the present thesis I analyse the roles of individual ability and structural embeddedness on entrepreneurial success. The results retrieved from a matched employer-employee longitudinal data set show prior worker productivities and environmental embeddedness to have a persistent positive impact on the size and growth rates of new firms. What is more, embeddedness facilitates the impact of ability on start-up performance with outsiders of comparable abilities starting smaller and slower growing firms. Those in higher ability categories are more likely to transfer and also, albeit to a lesser extent, close their ventures, an effect attributed to the higher opportunity costs associated with the group. Firms managed by embedded agents enjoy longer longevities and have better chances of finding a new owner after the departure of the previous one. Finally, higher ability types show evidence of specialisation in serial entrepreneurship.

Rifapentine for latent tuberculosis infection treatment in the general population and human immunodeficiency virus-positive patients: summary of evidence

AbstractLatent tuberculosis infection (LTBI) and human immunodeficiency virus (HIV)-coinfection are challenges in the control of tuberculosis transmission. We aimed to assess and summarize evidence available in the literature regarding the treatment of LTBI in both the general and HIV-positive population, in order to support decision making by the Brazilian Tuberculosis Control Program for LTBI chemoprophylaxis. We searched MEDLINE, Cochrane Library, Centre for Reviews and Dissemination, Embase, LILACS, SciELO, Trip database, National Guideline Clearinghouse, and the Brazilian Theses Repository to identify systematic reviews, randomized clinical trials, clinical guidelines, evidence-based synopses, reports of health technology assessment agencies, and theses that investigated rifapentine and isoniazid combination compared to isoniazid monotherapy. We assessed the quality of evidence from randomized clinical trials using the Jadad Scale and recommendations from other evidence sources using the Grading of Recommendations, Assessment, Development, and Evaluations approach. The available evidence suggests that there are no differences between rifapentine + isoniazid short-course treatment and the standard 6-month isoniazid therapy in reducing active tuberculosis incidence or death. Adherence was better with directly observed rifapentine therapy compared to self-administered isoniazid. The quality of evidence obtained was moderate, and on the basis of this evidence, rifapentine is recommended by one guideline. Available evidence assessment considering the perspective of higher adherence rates, lower costs, and local peculiarity context might support rifapentine use for LTBI in the general or HIV-positive populations. Since novel trials are ongoing, further studies should include patients on antiretroviral therapy.

Can body traits, other than wings, reflect the flight ability of Triatominae bugs?

Abstract: INTRODUCTION : Insects of the subfamily Triatominae are vectors of Trypanosoma cruzi , the Chagas disease parasite, and their flying behavior has epidemiological importance. The flying capacity is strikingly different across and within Triatominae species, as well as between sexes or individuals. Many Triatoma infestans individuals have wings but no flying muscles. In other Triatominae species, no clear relationships were found between wing length and flying behavior. If wing presence or size is not reflective of the flying behavior, which other parts of the body could be considered as reliable markers of this important function? METHODS : The genus Mepraia has exceptional characteristics with invariably wingless females and wingless or winged males. We calculated the porous surface exposed to odorant molecules to estimate the olfactory capacity of Mepraia spinolai . The head shape and thorax size were estimated using the geometric morphometric approach and traditional morphometric techniques, respectively. RESULTS : Alary polymorphism in M. spinolai was significantly associated with consistent modification of the thorax size, head shape, and notable change in the estimated olfactory capacity. The macropterous individuals had a larger olfactory surface and thorax size and significantly different head shape compared to those of the micropterous individuals. CONCLUSIONS: We concluded that these structural changes could be associated with the flying potential of Triatominae. Thus, morphological attributes not found on wings could help determine the likely flying potential of the bugs.

Perfil imunol��gico de gr��vidas at��picas versus gr��vidas saud��veis

RESUMO: A preval��ncia das doen��as at��picas tem vindo a aumentar, em especial ao n��vel dos pa��ses ocidentalizados. V��rios fatores t��m sido apontados para justificar este aumento de preval��ncia,destacando-se o reduzido tamanho das fam��lias, o elevado uso de antibi��ticos, a melhoria das condi����es sanit��rias, bem como a diminui����o quer das infe����es de helmintas, quer da contamina����o orofecal. Alguns estudos t��m tamb��m avaliado a influ��ncia do ambiente pr��-natal no desenvolvimento de atopia e asma. Da an��lise da literatura, parece ineg��vel a import��ncia deste per��odo para o desenvolvimento do sistema imunit��rio. Neste ��mbito, a transmiss��o de atopia �� descend��ncia em mulheres at��picas, e concretamente com asma al��rgica, poder�� ser moldada desde este per��odo. A possibilidade de identificar marcadores de risco precoces para o desenvolvimento de atopia poder�� ser o primeiro passo para o desenvolvimento de estrat��gias de preven����o para os indiv��duos em risco. Este trabalho pretendeu abordar o sistema imunit��rio materno de forma a enriquecer a sua carateriza����o desde o terceiro trimestre da gravidez at�� ao fim do puerp��rio. Para al��m da explora����o de perfis celulares e citoc��nicos maternos (nos quais se incluiu sobretudo a avalia����o de diferentes popula����es de c��lulas T e B, com fun����es efetoras e reguladoras), foi tamb��m considerada a sua eventual rela����o com o desenvolvimento de atopia nas crian��as. Foram recrutadas 135 mulheres com crit��rios para serem inclu��das num dos 4 grupos do estudo: gr��vidas at��picas ��� GA (n=24), n��o gr��vidas at��picas ��� NGA (n=32), gr��vidas saud��veis ��� GS (n=44) e n��o gr��vidas saud��veis ��� NGS (n=35). Foram caraterizadas por Citometria de Fluxo popula����es de leuc��citos e linf��citos, com particular interesse nos perfis maturativos de linf��citos T e B, bem como nas subpopula����es de c��lulas T e B reguladoras. Foi ainda efetuada uma an��lise funcional, para avaliar a capacidade de produ����o de citocinas pelos linf��citos T e B. Foram igualmente avaliadas as concentra����es de citocinas s��ricas por ensaios imunoenzim��ticos. Estes par��metros imunol��gicos maternos foram acompanhados desde o terceiro trimestre de gesta����o, at�� depois do puerp��rio (primeiras 6 semanas p��s parto), e aos seis meses de idade, foi efetuada uma avalia����o cl��nica das crian��as. As mulheres n��o gr��vidas at��picas apresentaram contagens celulares mais elevadas para a generalidade das popula����es leucocit��rias e linfocit��rias (em rela����o a mulheres n��o gr��vidas saud��veis). Destaca-se ainda uma maior presen��a de eosin��filos nas mulheres NGA (p=0,0009; teste de Mann-Whitney U), que tinham igualmente os seus compartimentos linfocit��rios T e B mais ricos em c��lulas de mem��ria, em rela����o ��s mulheres NGS. Para os perfis de regula����o, verificou-se que as c��lulas T reguladoras se encontravam percentualmente aumentadas (p���0,003; teste de Mann-Whitney U), tal omo as c��lulas T produtoras de IL10 ap��s estimula����o (p���0,03; teste de Mann-Whitney U) em mulheres NGA. Tamb��m se observou uma maior express��o de Foxp3 (p=0,0002; teste de Mann-Whitney U), e ainda a diminui����o dos n��veis s��ricos de IFN-�� nas mulheres NGA (p=0,0019; teste de Mann-Whitney U), em rela����o a mulheres NGS. De um modo geral, as altera����es verificadas nos par��metros imunol��gicos de mulheres gr��vidas at��picas no terceiro trimestre da gravidez foram semelhantes ��s observadas em mulheres gr��vidas saud��veis. Comparadas com mulheres NGA, nas mulheres gr��vidas at��picas ocorreu uma altera����o substancial da f��rmula leucocit��ria, com um importante incremento de neutr��filos (p<0,0001; teste de Mann-Whitney U) e diminui����o dos valores das restantes popula����es leucocit��rias. A diminui����o nas contagens de linf��citos totais estendeu-se a grande parte das subpopula����es linfocit��rias caraterizadas. Nos compartimentos linfocit��rios T e B foi poss��vel observar uma diminui����o das subpopula����es de c��lulas de mem��ria. Verificou-se igualmente na gravidez uma menor express��o de Foxp3 em mulheres GA (p<0,0001; teste de Mann-Whitney U) e ainda menos c��lulas B CD24HiCD38Hi circulantes (p=0,0012; teste de Mann-Whitney U). Ocrreu ainda uma diminui����o relativa das c��lulas T CD4 produtoras de IFN-�� em mulheres GA (p���0,024; teste de Mann-Whitney U), e uma maior presen��a de c��lulas T CD8 produtoras de IL17 (p=0,0172; teste de Mann-Whitney U), em rela����o ao observado em mulheres NGA. Depois do puerp��rio, no compartimento T de mulheres do grupo GA, verificou-se um aumento das popula����es de c��lulas de mem��ria. Em compara����o com a gravidez, ap��s o puerp��rio o compartimento B, apresentou nas mulheres GA um aumento significativo da subpopula����o de c��lulas B de transi����o (p<0,0001; teste de Wilcoxon). Verificou-se, igualmente em mulheres GA ap��s o puerp��rio, uma maior express��o de Foxp3 nas c��lulas T reguladoras (p<0,0001; teste de Wilcoxon) e o aumento das popula����es de c��lulas T circulantes produtoras de IFN-�� (p���0,0234; teste de Wilcoxon). As modula����es das popula����es T e B desde a gravidez at�� depois do puerp��rio ocorreram de forma semelhante nas mulheres dos grupos GA e GS. Apesar de as mulheres GA manterem um perfil imunol��gico pr��ximo do das mulheres GS depois do puerp��rio, aconteceu tamb��m neste per��odo um processo de reaproxima����o ao perfil observado nas mulheres NGA. As mulheres GA com manifesta����es de risco para atopia na descend��ncia (comparadas com mulheres GA sem manifesta����es de risco para atopia na descend��ncia at�� aos 6 meses de vida) apresentaram uma maior propor����o de c��lulas T e menor propor����o de c��lulas B, percentagens mais elevadas de c��lulas T CD8 de mem��ria efetoras, de c��lulas B de transi����o e de c��lulas B CD24HiCD38Hi, e contagens mais baixas de c��lulas B de mem��ria. Na avalia����o destes par��metros como marcadores de risco para o desenvolvimento de atopia verificou-se que o par��metro com melhor desempenho foi a percentagem de c��lulas B de transi����o, com uma Odds-Ratio de 54,0 [IC 95%: 4,2-692,9; (p=0,0005)], sensibilidade de 90,0% [IC 95%: 55,5 ��� 99,8] e especificidade de 85,7% [IC 95%: 57,2 ��� 98,2]. Este estudo foi pioneiro em Portugal, e no mundo, no que se refere ao acompanhamento do compartimento linfocit��rio B circulante, abordando o seu perfil de matura����o, e em particular as c��lulas B com fun����es reguladoras, desde a gravidez at�� ao fim do puerp��rio, em mulheres at��picas e n��o at��picas. A este n��vel, encontram-se estudos na literatura a documentar a altera����o do compartimento B durante a gravidez. O presente trabalho reporta agora que altera����es, como a diminui����o do n��mero de c��lulas B em circula����o, s��o impostas tamb��m na mulher at��pica. Em suma, demonstrou-se a exist��ncia de um perfil imunol��gico carater��stico em mulheres at��picas, que sofre altera����es significativas durante a gravidez, tendendo os par��metros imunol��gicos a normalizar ap��s o puerp��rio. O compartimento T, para o qual a literatura �� mais rica em estudos e abordagens, demonstrou tamb��m neste trabalho oscila����es carater��sticas entre o per��odo pr�� e p��s-natal. Verificaram-se sobretudo varia����es nos compartimentos de c��lulas T de mem��ria, sem grandes altera����es ao n��vel das c��lulas Treg no que se refere �� sua presen��a em circula����o. Apenas a registar a menor express��o de Foxp3 nas c��lulas Treg durante a gesta����o observada em mulheres at��picas, tal como em mulheres saud��veis (como tamb��m j�� foi relatado em estudos anteriores). Apesar de muitos dos dados se encontrarem em concord��ncia com a literatura, quer no que se refere ��s subpopula����es de c��lulas de mem��ria, quer no que se refere ��s c��lulas Treg, tamb��m se encontram resultados discordantes, por exemplo documentando varia����es num��ricas nas c��lulas Treg em circula����o em mulheres at��picas e mulheres at��picas gr��vidas. A import��ncia de harmonizar protocolos e fen��tipos, parece crucial na abordagem de estudos futuros. Ao n��vel do risco para a atopia na descend��ncia de mulheres at��picas, acrescentou-se ainda a possibilidade de definir marcadores n��o invasivos para a crian��a, em particular as c��lulas B de transi����o. Estas c��lulas, cuja maior presen��a em circula����o no rec��m-nascido foi recentemente associada com manifesta����es al��rgicas subsequentes, s��o agora apontadas j�� na mulher at��pica, gr��vida do terceiro trimestre, como um elemento de risco para o desenvolvimento de atopia. Os marcadores de risco descritos, para al��m de facilmente poderem vir a ser englobados no ��mbito dos normais rastreios maternos durante a gravidez, apresentam ainda a vantagem da precocidade do diagn��stico, permitindo n��o s�� a possibilidade de preven����o p��s-natal, mas estendendo esta possibilidade ao per��odo gestacional.----------------------------ABSTRACT: The prevalence of atopic diseases has been increasing, especially in Westernized countries. Several factors have been suggested to justify this increase in prevalence, as the small size of families, the high use of antibiotics, the improvement in sanitation conditions, as well as the reduction of both helminth infections, and orofecal contamination. A few studies have adressed the influence of prenatal environment on the development of atopy and asthma. From literature, it seems undeniable the importance of the prenatal period for the development of the immune system. In this context, the transmission of atopy to the progeny in atopic women, and specifically in women with allergic asthma, can be modulated from this period on. The ability to detect early risk markers for the development of atopic diseases may be the first step in the development of prevention strategies for individuals at risk. This study aimed to approach the maternal immune system in order to enrich its characterization from the third trimester of pregnancy until the end of the puerperium period. In addition to the evaluation of the maternal cellular profiles (in which, mostly, diferente populations of T and B cells with effector and regulatory functions were included) and citokines, the relation between these profiles and the development of atopy in the progeny was also assessed. 135 women were recruited for this study, and fullfiled the inclusion criteria necessary to be included in one of the four groups preset: atopic pregnant women - GA (n = 24), atopic nonpregnant women - NGA (n = 32), healthy pregnant women - GS (n = 44) and healthy nonpregnant women - NGS (n = 35). Populations of leukocytes and lymphocytes, and particularty maturation profiles of T and B lymphocytes, as well as subpopulations of T and B cells with regulatory functions, were characterized by flow cytometry. Functional assays were also performed, to assess the ability of cytokine production by T and B lymphocytes. Serum cytokine concentrations were assessed as well by enzymatic immunoassays. These maternal imune parameters were monitored since the third trimester of pregnancy until the end of the puerperium period (first six weeks after delivery). A clinical evaluation of all the newborn children was performed at the age of six months. Non-atopic pregnant women presented higher cell counts for most leukocyte and lymphocyte populations (compared to healthy non-pregnant women). We should also highlight the increased presence of eosinophils in NGA women (p = 0,0009; Mann-Whitney U test). Again compared to NGS women, NGA women showed increased memory cells within the circulating T and B lymphocyte compartments. Considering the regulatory profiles, NGA women presented higher percentages of regulatory T cells (p���0,003; Mann-Whitney U test) and IL10 producing T cells after stimulation (p���0,03; Mann Whitney U), as well as increased expression of Foxp3 (p = 0,0002; Mann-Whitney U test), and also decreased serum levels of IFN-�� (p = 0,0019; test Mann-Whitney U test) compared to NGS women. In general, the changes observed in immune parameters of atopic pregnant women in the third trimester of gestation were similar to those observed in healthy pregnant women. Comparing pregnant and non-pregnant atopic women, an important change in leukocyte subsets was observed, with a significant increase of neutrophils (p <0,0001; Mann-Whitney U test) and the consequent diminution of the remaining leukocyte populations in the GA group. The decrease in total lymphocyte counts was extended to most of the lymphocyte subsets characterized. It was possible to detect a decrease in memory cell subsets within the T and B lymphocyte compartments, also. During pregnancy, a lower expression of Foxp3 was reported in GA women (p <0,0001; Mann-Whitney U test) and, besides, lesser CD24HiCD38Hi B cells were present in circulation in these women, compared to NGA women (p = 0,0012; Mann-Whitney U test). There was still a decrease in the percentages of IFN-��-producing CD4 T cells in GA women (p���0,024; Mann-Whitney U test) and a greater presence of IL17-producing CD8 T cells (p = 0,0172; Mann-Whitney U test), compared to the levels observed in NGA women. At the end of the puerperium, there was an increase in memory cell subpopulations within the T cell compartment of GA women. Compared with the pregnancy evaluation, after puerperium, the B cell compartment showed a significant increase in the transitional subpopulation (p<0,0001; Wilcoxon test), in GA women. Moreover, after puerperium, GA women exhibited a greater expression of Foxp3 in Treg cells (p <0,0001; Wilcoxon test) and there was an increase in circulating IFN-��-producing T cells (p���0,0234; Test Wilcoxon). The modulations of T and B cell subpopulations from pregnancy until the end of puerperium were similar in women of GA and GS groups. Although at the end of puerperium, GA women still kept an immune profile close the one observed in GS women, at this time point, there were also signs of rapprochement between the immune profiles observed in women of GA and NGA groups. GA women with atopic manifestations in the offspring (compared to GA women without atopic manifestations in the offspring at the age of 6 months) presented higher proportions of T cells and lower proportions of B cells, higher percentages of effector memory CD8 T cells, transitional B cells and CD24HiCD38Hi B cells, and, finally, lower absolute counts of memory B cells. In the evaluation of these parameters as risk markers for the development of atopy, the parameter which presented the best performance was the percentage of transitional B cells, with an Oddsratio of 54,0 [95% CI: 4,2 to 692,9; (p = 0,0005)], sensitivity of 90,0% [95% CI: 55,5 to 99,8] and a specificity of 85,7% [95% CI: 57,2 to 98,2]. This study was a pioneer in Portugal, and in the world, in what concerns the monitoring of the circulating B cell compartment, addressing not only the maturation profile, but, in particular, B cells with regulatory functions, from pregnancy untill after puerperium, in atopic and non-atopic women. Literature presents evidence of a typical change in circulating B cells during pregnancy. This study now reports that changes, such as the decrease in the number of circulating B cells,/ are also imposed by pregnancy in atopic woman. In brief, it demonstrated the existence of a characteristic immune profile in atopic women, which undergoes significant alterations during pregnancy, tending to normalize after the puerperium. As for the T cell compartment, for which the literature is richer in studies and approaches, this study also showed characteristic fluctuations between the pre- and postnatal periods. There were variations mostly in the memory subsets within the T cell compartment, without major changes in regulatory T cells regarding their presence in circulation. Only the expression of Foxp3 in Treg cells presented lower levels during pregnancy, in both atopic and healthy women (as previously reported in other studies). Although much of the data now reported are in agreement with literature, regarding either memory cell subsets or regulatory T cells, there are also conflicting results, for example documenting changes in the numbers of regulatory T cells circulating in atopic pregnant and atopic non-pregnant women. The importance of harmonizing protocols and phenotypes seems crucial for the establishement of future studies. Considering the risk for atopy in the offspring of atopic women, this study added the possibility to define non-invasive markers for the child, in particular transitional B cells. These cells, whose greater presence in circulation in newborns has recently been associated with subsequent allergy development, are here identified in atopic pregnant women in the third trimester of gestation as a risk factor in the development of atopy in their progeny. The risk factors described, besides having the capacity to easily become integrated within the normal maternal screening protocols during pregnancy, also have the advantage of an early diagnosis, allowing not only the possibility of postnatal prevention but extending this possibility to the prenatal period.

Sodium serum levels in hypoalbuminemic adults at general medical wards

Hypoalbuminemia may cause interstitial edema and hemodilution, which we hypothesized may influence serum sodium levels. Our purpose was to compare serum sodium levels of hospitalized adults with or without hypoalbuminemia. All sodium and albumin serum levels of 142 adults hospitalized at general medical wards over a six-month period were searched at a University Hospital mainframe computer. Relevant laboratory data and clinical details were also registered. Hypoalbuminemia was defined by serum albumin concentration < 3.3 g/dl Fisher, Mann-Whitney, and Student's t tests were applied to compare groups with or without hypoalbuminemia. Ninety-nine patients, classified as hypoalbuminemic, had lower blood hemoglobin (10.68 �� 2.62 vs. 13.54 �� 2.41), and sodium (135.1 �� 6.44 vs. 139.9 �� 4.76mEq/l) and albumin (2.74 �� 0.35 vs. 3.58 �� 0.28g/dl) serum levels than non-hypoalbuminemic (n=43). Pearson's coefficient showed a significant direct correlation between albumin and sodium serum levels (r=0.40) and between serum albumin and blood hemoglobin concentration (r=0.46). Our results suggest that hypoalbuminemic adults have lower serum sodium levels than those without hypoalbuminemia, a phenomenon that may be at least partially attributed to body water retention associated with acute phase response syndrome.