The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

Achieving optimal dose intensity with adjuvant chemotherapy in elderly breast cancer patients:A 10-year retrospective study in a UK institution

The study was to determine if breast cancer patients aged 65 and above could be given adjuvant chemotherapy safely while achieving an acceptable relative dose intensity of at least 85%. We identified all patients aged 65 and over who received adjuvant chemotherapy over the 10 year period, November 1999 to October 2009, and determined the proportion that achieved a relative dose intensity of at least 85% as well as the tolerability of their treatment. A total of 101 patients were identified, with a median age of 69 years (range 65-78).Of these, 25.7% of patients had at least one major comorbidity, 84.2% had a tumor size of 5 cm or less, 73.3% were node positive and 58.4% were hormone receptor positive. The chemotherapy regimens used were AC (Doxorubicin and Cyclophosphamide), FEC (Fluorouracil, Epirubicin, and Cyclophosphamide), CMF (Cyclophosphamide, Methotrexate, and Fluorouracil) and ECMF (Epirubicin followed by CMF). Seventy-nine patients (78.2%) achieved the relative dose intensity of at least 85%. With respect to toxicity, 11.9% of patients developed febrile neutropenia and 23.8% of patients required hospital admission during the treatment period, but there were no treatment-related deaths in the group. A significant proportion of patients aged 65 and above achieved the intended dose intensity of at least 85% over this 10-year period, with manageable toxicity levels. This supports the use of these regimens as adjuvant chemotherapy for breast cancer in this age group. © 2011 Wiley Periodicals, Inc.

Plasma levels of intermedin (adrenomedullin-2) in healthy human volunteers and patients with heart failure

Intermedin/adrenomedullin-2 (IMD) is a member of the adrenomedullin/CGRP peptide family. Less is known about the distribution of IMD than for other family members within the mammalian cardiovascular system, particularly in humans. The aim was to evaluate plasma IMD levels in healthy subjects and patients with chronic heart failure. IMD and its precursor fragments, preproIMD25–56 and preproIMD57–92, were measured by radioimmunoassay in 75 healthy subjects and levels of IMD were also compared to those of adrenomedullin (AM) and mid-region proadrenomedullin45–92 (MRproAM45–92) in 19 patients with systolic heart failure (LVEF < 45%). In healthy subjects, plasma levels (mean + SE) of IMD (6.3 + 0.6 pg ml−1) were lower than, but correlated with those of AM (25.8 + 1.8 pg ml−1; r = 0.49, p < 0.001). Plasma preproIMD25–56 (39.6 + 3.1 pg ml−1), preproIMD57–92 (25.9 + 3.8 pg ml−1) and MRproAM45–92 (200.2 + 6.7 pg ml−1) were greater than their respective bioactive peptides. IMD levels correlated positively with BMI but not age, and were elevated in heart failure (9.8 + 1.3 pg ml−1, p < 0.05), similarly to MRproAM45–92 (329.5 + 41.9 pg ml−1, p < 0.001) and AM (56.8 + 10.9 pg ml−1, p < 0.01). IMD levels were greater in heart failure patients with concomitant renal impairment (11.3 + 1.8 pg ml−1) than those without (6.5 + 1.0 pg ml−1; p < 0.05). IMD and AM were greater in patients receiving submaximal compared with maximal heart failure drug therapy and were decreased after 6 months of cardiac resynchronization therapy. In conclusion, IMD is present in the plasma of healthy subjects less abundantly than AM, but is similarly correlated weakly with BMI. IMD levels are elevated in heart failure, especially with concomitant renal impairment, and tend to be reduced by high intensity drug or pacing therapy.

A atitude diagnóstica enquanto instrumento de análise de ação educativa

A investigação realizada encontra-se inserida na área das Ciências de Educação, teve como objetivo principal compreender a atitude diagnóstica no quadro das situações educativas e pedagógicas desenvolvidas pelas educadoras de alguns jardins-de-infância, do distrito de Évora e como finalidade construir uma teoria de médio alcance elaborada numa estrutura explicativa do conjunto de fenómenos em contexto. Em educação de infância, o ato de cuidar estabelece-se numa relação de ajuda à criança e orienta-se para objetivos como promover o bem-estar, o conforto e o desenvolvimento em todas as dimensões. Isto implica conhecer e compreender cada criança ou grupo de crianças e as situações educativas e pedagógicas, em contexto. Compreende um exercício prático e para o qual se projeta uma prática de diagnóstico conciliadora da compreensão dos fenómenos sociais, estruturados em comportamentos, ações e atitudes específicas. Verificam-se lacunas quanto à forma como este exercício se cumpre e evolui nas diferentes fases. Repetem-se fragilidades quanto à mobilização de saberes, atitudes e competências a cada momento do agir. Constatam-se conceitos psicologizados e estruturas muito ténues e, por isso, necessitam ser estudadas, documentadas e teorizadas, particularmente numa dimensão praxiológica do conhecimento. O estudo inseriu-se no quadro das metodologias qualitativas, seguiu o paradigma interpretativo e o raciocínio indutivo. O referencial metodológico reuniu os princípios e procedimentos da Grounded Theory. A colheita de dados efetuou-se em jardins-de-infância da rede pública; a amostra teórica envolveu seis educadoras de infância e as crianças com idades compreendidas entre os três e os seis anos. Adotámos o uso de multitécnicas, entre as quais, a observação, a entrevista e a narrativa escrita. Fizemos vinte observações, repartidas pelos dois períodos do dia (manhã e tarde); vinte e seis entrevistas e seis narrativas escritas. Da análise dos dados emergiu a Atitude Diagnóstica como uma predisposição que caracteriza o ato de agir e as suas características foram-se tornando evidentes com o desenvolvimento da caracterização do processo de diagnóstico. Desta emergiu o modelo teórico definido em três eixos fundamentais. O “Processo de avaliação diagnóstica e planeamento” representativo das etapas, segundo as quais o educador desenvolve um conjunto de ações propiciadoras de um conhecimento previamente organizado, visando o bem-estar, o conforto, a segurança e o desenvolvimento. Em concomitância emerge o segundo, “Processo de intervenção educativa e pedagógica”, expressivo do conjunto de ações coerentes e evolutivas, empreendidas com vista à execução dos objetivos do ensino aprendizagem. Trata-se de dois processos sistematizados e perspetivados sob as dimensões diacrónica e sincrónica, compostos por uma sequência de pensamentos, permanentemente averbados pela “Atitude Diagnóstica” que dá um caráter coerente e evolutivo às tomadas de decisão nas ações educativas. Estes dois eixos integrados e entrelaçados são auxiliados por um terceiro, o “Processo de relação” que os harmoniza e dá especificidade a cada situação experienciada. A relação consolida-se e assume-se uma ajuda na confiabilidade necessária para a promoção da confiança entre os pares e o conhecimento vai evoluindo gradualmente em função do tempo e dos compromissos. O educador age com intencionalidade e para cada ator traça objetivos a cada momento do agir. A gestão do tempo, dos sentimentos e emoções funciona como variável importante na relação orientada sob a tríade: educador, criança e família e é concomitante com o Desenvolvimento pessoal e profissional do educador; ### ABSTRACT: The Diagnostic Attitude as an Analysis Instrument in Educational Action The conducted investigation is inserted in the area of Education Sciences. Its main aim was to understand the diagnostic attitude in the frame of the educative and pedagogical activities developed by the educators of some kindergartens in the district of Évora, and its purpose was to build a medium range theory elaborated in a structure explaining the whole of the phenomena in context. In child education, the act of caring is established in a relationship of help towards the child and is oriented towards goals as specific as promoting the well-being, the comfort and the development in all dimensions. This implies knowing and understanding each child or group of children and the educational and pedagogical situations in context. It includes a practical exercise that determines a complex scenario and for which we project a conciliating diagnostic practice towards the understanding of the social phenomena, structured in specific behaviors, actions and attitudes. We recognize some gaps regarding the way how this exercise is fulfilled and evolves in the different phases. Weaknesses regarding the mobilization of knowledge, attitudes and competences in each acting moment are repeated. We notice psichologized concepts and very superficial structures that need thus to be studied, documented and theorized, particularly in a praxeological dimension of knowledge. The study is inserted in the frame of qualitative methodologies, following an interpretative paradigm and an inductive reasoning. The methodological referential has gathered the principles and procedures of the Grounded Theory. The gathering of data was done in public kindergartens; the theoretical sample involved six child educators and children aged between three and six years. Several techniques were used, such as observation, interview and written narrative. We did twenty observations, divided between the two periods of the day (morning and afternoon); twenty-six interviews and six written narratives. The analysis of the data resulted in the Diagnostic attitude, like a predisposition that characterizes the act of acting and its characteristics became evident with the development of the characterization of the diagnostic process. From this rose the theoretical model defined in three fundamental axes. The Process of diagnostic evaluation and planning that represents the stages according to which the educator develops a group of actions that allow the transmission of a previously organized knowledge that aims well-being, comfort, safety and development. Concomitantly arises the second, Process of educative and pedagogic intervention, that expresses a group of coherent and evolving actions, undertaken to reach the goals of the teaching-learning process. These are two systematized processes, perspectivated under the diachronical and synchronical dimensions, composed by a sequence of thought, permanently confirmed by the Diagnostic attitude that gives a coherent and evolving character to the decision making in educative actions. These two integrated and intertwined axis are aided by a third one, Process of relation that harmonizes them and gives specificity to each experienced situation. The relation is consolidated and one assumes a kind of help in the trustworthiness necessary for the promotion of the trust between pairs and the knowledge keeps evolving gradually according to time and commitments. The educator acts with intent and sets goals for each actor at each acting moment. Time, feeling and emotion management works as an important variable in the relation oriented according to the triad educator, child and family, being also concomitant with the Personal and professional development of the educator.

Estudo linguístico dos títulos de imprensa em Portugal: a linguagem metafórica

Além de alguns estudos lexicais, não existe em Portugal nenhuma tradição de análise linguística da imprensa. Entre os aspectos que oferecem especial interesse, incluem-se os títulos das notícias, em parte porque propõem uma gramática diferente da da norma discursiva, mas também devido aos jogos linguísticos, nomeadamente o emprego de linguagem metafórica, a que os redactores recorrem para incentivar a leitura dos textos. O trabalho em curso debruça-se sobre os vários níveis da realização linguística deste tipo textual, partindo de um corpus informatizado de 2.060 títulos de notícia portugueses com linguagem metafórica. Assim, no nível sintáctico, interessou-nos estudar a configuração sintáctica do título e os constituintes que nele correspondem ao veículo metafórico. No nível semântico, identificámos, seguindo um enquadramento teórico subordinado à teoria dos espaços múltiplos de Fauconnier e Turner, as metáforas conceptuais presentes no corpus. No nível fonológico, foi feito um estudo sobre padrões sonoros de aliteração, rima e jogos de palavras concomitantes com a linguagem metafórica do título. O nível gráfico debruçou-se sobre os diversos processos de destacar graficamente o veículo metafórico e suas consequências na descodificação da mensagem. Finalmente, no nível intertextual, apresentou-se uma pesquisa sobre as relações internas do título com outros componentes do co-texto noticioso e as relações externas com textos mais ou menos distantes, mas culturalmente partilhados. Os resultados da pesquisa revelaram os processos através dos quais a linguagem metafórica no título de imprensa permite a verbalização de conceitos, a condensação de significados e motiva à leitura do texto.

Síntese e potenciais aplicações de novas porfirinas β-funcionalizadas

Neste trabalho é descrita a síntese de novos derivados porfirínicos com potencial aplicação em terapia fotodinâmica (PDT) e como quimiossensores para o reconhecimento molecular de catiões metálicos. Os novos compostos foram preparados usando como “template” 2-formil-5,10,15,20-tetrafenilporfirina através de diferentes abordagens sintéticas, tais como, reações de cicloadição 1,3-dipolar ou reações do tipo condensação aldólica. Depois de uma breve introdução sobre porfirinas segue-se no capítulo 2 a descrição dos estudos de formilação de Vilsmeier-Haack dos complexos de Ni(II) e Cu(II) de meso-tetra-arilporfirinas realizados usando irradiação de microondas. Utilizando os complexos de Ni(II) e Cu(II) da 5,10,15,20-tetrafenilporfirina foram considerados vários solventes, potências de irradiação e tempos de reação; as melhores condições encontradas foram aplicadas a outras mesotetra- arilporfirinas. Os derivados formilados resultantes da reação de formilação de Vilsmeier-Haack com irradiação de micro-ondas foram isolados em bons rendimentos e com significativa redução no tempo de reação, que passou de horas, em condiçoes clássicas de aquecimento, para minutos sob irradiação de micro-ondas. O “scale-up” da reação, nas condições estabelecidas, mostrou ser eficiente não sendo a reação afetada pelo aumento da quantidade de porfirina. O capítulo 3 descreve a reação de ciclo-adição 1,3-dipolar de meso-tetraarilporfirinas com iminas de nitrilo, geradas in situ por desidrobromação de hidrazono-α-bromoglioxilatos de etilo na presença de base. A reação de iminas de nitrilo com 5,10,15,20-tetraquis(pentafluorofenil)porfirina, na presença de K2CO3 em tolueno a refluxo, permitiu isolar novas pirazoloclorinas em rendimentos moderados. Foram investigadas as propriedades fotofísicas das novas clorinas e os resultados sugerem que duas delas apresentam potencialidades para serem utilizadas em PDT. Este tipo de reações foi estendida ao complexo 2-vinil-5,10,15,20- tetrafenilporfirinatozinco(II); este complexo reagiu com as iminas de nitrilo obtendo-se os correspondentes derivados porfirina-pirazolina em rendimentos que variaram entre valores de bom e de excelente. A regioquímica dos derivados porfirina-pirazolina formados foi elucidada por RMN e confirmada por difração de raios-X. O tratamento dos derivados porfirina-pirazolina com DDQ proporciona os correspondentes derivados porfirina-pirazol com rendimentos de moderados a excelentes. Quando os derivados porfirina-pirazolina foram submetidos a condições de hidrólise básica, observou-se não só a hidrólise do grupo éster presente no anel pirazolínico mas também a concomitante oxidação desta unidade heterocíclica, isolando-se assim, num único passo reacional, novos derivados de tipo porfirinapirazol com um grupo carboxílico. A descomplexação dos complexos de Zn(II) foi realizada na presença de TFA, tendo-se isolado quantitativamente os respetivos derivados na forma de bases livres.Foram estudadas algumas das propriedades fotofísicas de todos os compostos obtidos, quer na forma de complexos de Zn(II), quer na forma de base livre. Duma forma geral, todos os compostos preparados mostraram ser bons geradores de oxigénio singleto, o que os torna interessantes para possível utilização como fotossensibilizadores em PDT. No capítulo 4 é descrita a reação de 2-formil-5,10,15,20-tetrafenilporfirina com aril-cetonas e acetato de amónio, na presença de La(OTf)3, o que permitiu isolar novas benzoporfirinas e 2-(2,6-diarilpiridina-4-il)porfirinas. Esta metodologia foi utilizada para preparar, pela primeira vez, uma 2-(2,2':6,2''- terpiridin-4-il)porfirina. As estruturas de duas das 2-(2,6-diarilpiridin-4- il)porfirinas foram confirmadas por difração de raios-X de cristal único. A metodologia descrita permite ainda preparar novos derivados de tipo porfirinacalcona, apenas com pequenos ajustes nas condições reacionais através de uma reação do tipo condensação aldólica. Os derivados do tipo porfirinacalcona foram posteriormente usados para preparar derivados do tipo porfirinapirazol 1,3,5-tri-substituídos em bons rendimentos, através de reação de condensação com fenil-hidrazina. Em cada um dos capítulos é descrito os procedimentos experimentais e a caracterização espectroscópica (RMN, UV-vis e massa) dos novos compostos isolados. Em alguns casos foi necessário o recurso a técnicas de RMN bidimensionais como COSY, NOESY, HSQC e HMBC. Os compostos preparados neste trabalho foram ainda objecto de estudos de avaliação das respetivas potencialidades para actuarem como quimiossensores para o reconhecimento de catiões metálicos, nomeadamente, Cu(II), Ag(I), Zn(II), Cd(II) e Hg(II). Assim no capítulo 5 é descrita a caracterização fotofísica dos compostos preparados no capítulo 4 e, os estudos destes como potenciais quimiossensores. Os estudos para verificar a potencialidade dos compostos como quimiossensores foram efectuados: i) em solução, através de titulações espectrofotométricas e espectrofluorimétricas, ii) no estado sólido, recorrendo à preparação de filmes de PMMA dopados com os ligandos porfirínicos em estudo e, iii) na fase gasosa, seguindo as titulações dos ligandos com metais por espectrometria de massa (MALDI-TOF-MS). Os compostos estudados mostraram ter capacidade para atuarem como quimiossensores de catiões metálicos capazes de distinguirem entre os iões Zn(II) e Hg(II).

Estudo da ansiedade em alunos do ensino superior utilizando o Biofeedback

A ansiedade é reconhecidamente um fator que interfere no sucesso académico tendo implicações ao nível da saúde física e mental dos indivíduos. A literatura tem revelado a necessidade de intervir preventivamente de forma a minimizar a ocorrência de perturbações mais complexas com elevado impacto pessoal e social. Em Portugal são reduzidos os estudos que englobem a intervenção específica na ansiedade em contexto do ensino superior, pelo que o pretendemos com o nosso contributo colmatar uma lacuna especificamente ao nível da avaliação da ansiedade com instrumentos de medida psicofisiológicos. A presente investigação pretende: 1) caracterizar os estudantes quanto aos seus níveis de ansiedade, fatores de stresse e bem-estar e a relação destes com variáveis sociodemográficas e académicas (estudo tipo transversal); 2) avaliar a eficácia da intervenção na gestão da ansiedade, com programa de Biofeedback (BFB) e comparar com a Terapia Cognitivo Comportamental - TCC (Estudo do tipo quasi-experimental); 3) estudar e avaliar a intervenção específica com BFB. A amostra global envolveu 310 estudantes do 1º ano de áreas de saúde repartidos por três estudos. Os instrumentos utilizados foram o State Trait Anxiety Inventory (STAI), o Inventário de Stresse nos Estudantes Universitários (ISEU) e o Teste de Orientação de Vida (LOT, de Life Orientation Test), Patient’s Health Questionnaire (PHQ-9) e os Termómetros Emocionais (TE). Como instrumento de avaliação das variáveis psicofisiológicas foi usado o Biofeedback 2000x-pert. No primeiro estudo foi feita a caracterização dos níveis de ansiedade, de stresse e de bem-estar dos estudantes do primeiro ano da Escola Superior de Saúde da Universidade de Aveiro, os quais identificaram níveis elevados de ansiedade e de stress. O segundo estudo, a partir dos elementos encontrados no primeiro, incluiu uma intervenção comparativa entre o BFB e a TCC na gestão da ansiedade. No terceiro estudo, focalizado na avaliação da eficácia do Biofeedback, os resultados mostraram que o BFB é particularmente eficaz na redução desses níveis nos estudantes com níveis elevados de ansiedade e stresse. As conclusões desta investigação sugerem que o BFB apresenta possibilidades interessantes para ser utilizado num programa de redução do stresse e da ansiedade em estudantes do ES. São referidas implicações para o futuro, estratégias de intervenção que permitam potenciar o desempenho académico dos estudantes.

Evaluation of the matabolic response of osteosarcoma cells to conventional and new anticancer drugs by NMR metabolomics

The main scope of this work was to evaluate the metabolic effects of anticancer agents (three conventional and one new) in osteosarcoma (OS) cells and osteoblasts, by measuring alterations in the metabolic profile of cells by nuclear magnetic resonance (NMR) spectroscopy metabolomics. Chapter 1 gives a theoretical framework of this work, beginning with the main metabolic characteristics that globally describe cancer as well as the families and mechanisms of action of drugs used in chemotherapy. The drugs used nowadays to treat OS are also presented, together with the Palladium(II) complex with spermine, Pd2Spm, potentially active against cancer. Then, the global strategy for cell metabolomics is explained and the state of the art of metabolomic studies that analyze the effect of anticancer agents in cells is presented. In Chapter 2, the fundamentals of the analytical techniques used in this work, namely for biological assays, NMR spectroscopy and multivariate and statistical analysis of the results are described. A detailed description of the experimental procedures adopted throughout this work is given in Chapter 3. The biological and analytical reproducibility of the metabolic profile of MG-63 cells by high resolution magic angle spinning (HRMAS) NMR is evaluated in Chapter 4. The metabolic impact of several factors (cellular integrity, spinning rate, temperature, time and acquisition parameters) on the 1H HRMAS NMR spectral profile and quality is analysed, enabling the definition of the best acquisition parameters for further experiments. The metabolic consequences of increasing number of passages in MG-63 cells as well as the duration of storage are also investigated. Chapter 5 describes the metabolic impact of drugs conventionally used in OS chemotherapy, through NMR metabolomics studies of lysed cells and aqueous extracts analysis. The results show that MG-63 cells treated with cisplatin (cDDP) undergo a strong up-regulation of lipid contents, alterations in phospholipid constituents (choline compounds) and biomarkers of DNA degradation, all associated with cell death by apoptosis. Cells exposed to doxorubicin (DOX) or methotrexate (MTX) showed much slighter metabolic changes, without any relevant alteration in lipid contents. However, metabolic changes associated with altered Krebs cycle, oxidative stress and nucleotides metabolism were detected and were tentatively interpreted at the light of the known mechanisms of action of these drugs. The metabolic impact of the exposure of MG-63 cells and osteoblasts to cDDP and the Pd2Spm complex is described in Chapter 6. Results show that, despite the ability of the two agents to bind DNA, the metabolic consequences that arise from exposure to them are distinct, namely in what concerns to variation in lipid contents (absent for Pd2Spm). Apoptosis detection assays showed that, differently from what was seen for MG-63 cells treated with cDDP, the decreased number of living cells upon exposure to Pd2Spm was not due to cell death by apoptosis or necrosis. Moreover, the latter agent induces more marked alterations in osteoblasts than in cancer cells, while the opposite seemed to occur upon cDDP exposure. Nevertheless, the results from MG-63 cells exposure to combination regimens with cDDP- or Pd2Spm-based cocktails, described in Chapter 7, revealed that, in combination, the two agents induce similar metabolic responses, arising from synergy mechanisms between the tested drugs. Finally, the main conclusions of this thesis are summarized in Chapter 8, and future perspectives in the light of this work are presented.

Teacher education in the United Kingdom post devolution: convergences and divergences

This paper examines the roles of research in teacher education across the four nations of the United Kingdom. Both devolution and on-going reviews of teacher education are facilitating a greater degree of cross-national divergence. England is becoming a distinct outlier, in which the locus for teacher education is moving increasingly away from Higher Education Institutions and towards an ever-growing number of school-based providers. While the idea of teaching as a research-based profession is increasingly evident in Scotland, Northern Ireland and Wales, it seems that England, at least in respect of the political rhetoric, recent reforms and explicit definitions, is fixed on a contrastingly divergent trajectory towards the idea of teaching as a craft-based occupation, with a concomitant emphasis on a (re)turn to the practical. It is recommended that research is urgently needed to plot these divergences and to examine their consequences for teacher education, educational research and professionalism.

Perceived positive and negative consequences after surviving cancer and their relation to quality of life

Surviving childhood cancer has multiple implications on both physical and psychological domains of the individual. However, its study and possible effects on health-related quality of life (HRQoL) outcomes of adolescent survivors has been understudied. The objective of this study was twofold; to assess positive and negative cancer-related consequences (psychosocial and physical) in a sample of adolescent cancer survivors and to explore their relationship with HRQoL outcomes. Forty-one participants answered two questions about positive and negative consequences in the aftermath of cancer and filled in the KIDSCREEN-52 self-reported version. Data were analysed using mixed methods approach. 87.8% of the sample identified positive consequences and 63.4% negative consequences in survivorship. Four positive categories and five negative categories with regard to cancer-related consequences were found. Changed perspectives in life narratives seem to be the positive consequence more related to HRQoL (physical well-being, mood & emotions, autonomy, social support & peers), followed by useful life experience (physical well-being, autonomy, social support & peers). Psychological impact was the most referred negative consequence with a significant detrimental effect on social support and peers HRQoL dimension. Even if the majority of survivors reported benefit finding in the aftermath of cancer, concomitant positive and negative consequences have been found. However, findings only reveal a significant relationship between positive narratives and HRQoL, and negative consequences do not seem to have a significant influence on overall HRQoL in survivorship.

In vitro and in vivo insulinotropic properties of the multifunctional frog skin peptide hymenochirin-1B: a structure–activity study

Hymenochirin-1b (Hym-1B; IKLSPETKDNLKKVLKGAIKGAIAVAKMV.NH2) is a cationic, α-helical amphibian host-defense peptide with antimicrobial, anticancer, and immunomodulatory properties. This study investigates the abilities of the peptide and nine analogues containing substitutions of Pro5, Glu6, and Asp9 by either l-lysine or d-lysine to stimulate insulin release in vitro using BRIN-BD11 clonal β cells or isolated mouse islets and in vivo using mice fed a high-fat diet to produce obesity and insulin resistance. Hym-1B produced a significant and concentration-dependent increase in the rate of insulin release from BRIN-BD11 cells without cytotoxicity at concentrations up to 1 µM with a threshold concentration of 1 nM. The threshold concentrations for the analogues were: [P5K], [E6K], [D9K], [P5K, E6K] and [E6K, D9k] 0.003 nM, [E6K, D9K] and [D9k] 0.01 nM, [P5K, D9K] 0.1 nM and [E6k] 0.3 nM. All peptides displayed cytotoxicity at concentrations ≥1 µM except the [P5K] and [D9k] analogues which were non-toxic at 3 µM. The potency and maximum rate of insulin release from mouse islets produced by the [P5K] peptide were significantly greater than produced by Hym-1B. Neither Hym-1B nor the [P5K] analogue at 1 µM concentration had an effect on membrane depolarization or intracellular Ca2+. The [P5K] analogue (1 µM) produced a significant increase in cAMP concentration in BRIN-BD11 cells and stimulated GLP-1 secretion from GLUTag cells. Down-regulation of the protein kinase A pathway by overnight incubation with forskolin completely abolished the insulin-releasing effects of [P5K]hym-1B. Intraperitoneal administration of the [P5K] and [D9k] analogues (75 nmol/kg body weight) to high-fat-fed mice with insulin resistance significantly enhanced glucose tolerance with a concomitant increase in insulin secretion. We conclude that [P5K]hym-1B and [D9k]hym-1B show potential for development into anti-diabetic agents.

L'adoption d'une innovation technopédagogique par une communauté enseignante universitaire

Résumé: L'adoption d'une innovation technopédagogique par une communauté enseignante universitaire La thèse traite de l'adoption d'une innovation technopédagogique par une communauté enseignante universitaire. Cette étude longitudinale, réalisée dans le cadre d'une recherche-action, vise à comprendre la dynamique globale du processus d'adoption d'une innovation. Le cadre de réflexion théorique de l'étude provient de la recherche en management, en systèmes d'information et en éducation. Il tient à la fois compte des motivations et des besoins des individus (dimension individuelle), de la compatibilité des technologies de l'information selon les théories usuelles de l'apprentissage (dimension pédagogique) et du type de soutien à offrir aux utilisatrices-utilisateurs (dimension organisationnelle). Le modèle d'accompagnement émergeant de cette recherche se compose de cycles itératifs au cours desquels un groupe définit et résout un problème, puis réfléchit successivement aux enjeux émergents d'un cycle à l'autre. Le modèle tient explicitement compte des trois éléments clés suivants: l'individu, la pédagogie et l'organisation qui forment une dynamique systémique indissociable et en interaction les unes les autres pendant toute la durée du processus d'adoption de l'innovation. Il met aussi en lumière la nécessité de stimuler une réflexion critique grâce au concours de ressources externes crédibles pour déterminer la compatibilité des technologies à partir d'expériences concrètes. Une telle démarche participative systématique permet d'accroître la cohésion des idées du groupe par le dialogue et les débats d'opinions_ Par ailleurs, la proximité avec notre milieu de recherche sur une période de deux ans offre la possibilité de saisir plusieurs facettes de la dynamique organisationnelle. Lorsque l'on réalise une étude longitudinale qui met en évidence l'incidence d'événements concomitants, on constate la fragilité du processus et la réversibilité de la décision d'adoption. L'intention d'adoption évolue constamment au gré des expériences des individus et du contexte qui évolue lui-même. L'établissement de relations partenariales avec les groupes intéressés représente une activité essentielle pour pallier ou neutraliser les effets indésirables d'événements concomitants.||Abstract: This thesis deals with a university teaching community adopting a technological/pedagogical innovation. This longitudinal study--part of an action-research study--aims at gaining understanding of the overall dynamics involved in adopting an innovation. The study's conceptual framework derives from management, information-systems, and teaching research. It takes into account the motivations and needs of individuals (individual dimension), the compatibility of information technologies according to current learning theories (pedagogical dimension), and the type of support to be offered to users (organizational dimension). The companion model issuing from this research work comprises iterative cycles during which a group defines and solves a problem and then successively reflects on the issues emerging from one cycle to the next. The model takes explicit account of three key elements: the individual, pedagogical approach, and organization form an indissociable system dynamic in which all dimensions interact during the entire process of adopting innovation. It also sheds light on the need to stimulate critical reflection about the combination of credible external resources so that tangible experiences can be used to determine technology compatibility. This kind of systematic participative process yields greater cohesiveness of group ideas through dialogue and discussion. Moreover, the proximity to our research setting over two years provides the opportunity to seize the many facets of organizational dynamics. During the course of a longitudinal study that highlights the incidence of concomitant events, the fragility of the process and reversibility of the adoption decision become apparent. The adoption intention constantly fluctuates through the experiences of individuals and the context, which also changes. Establishing partnership relations with interested groups stands out as an essential activity in attenuating or counteracting the undesirable effects produced by concomitant events.

Colonoscopia virtual e DNA fecal : estudo de viabilidade como testes de rastreio do cancro colorretal

Tese de doutoramento, Cirurgia Geral (Medicina), Universidade de Lisboa, Faculdade de Medicina, 2014

Biological membranes : biophysical properties and aquaporin function

Tese de doutoramento, Farmácia (Bioquímica), Universidade de Lisboa, Faculdade de Farmácia, 2014

Role of plasmodium translationally repressed gene products in malaria transmission

Tese de doutoramento, Ciências Biomédicas (Microbiologia e Parasitologia), Universidade de Lisboa, Faculdade de Medicina, 2015