Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4 roles for cd14, lps-binding protein, and md2 as targets for specificity of inhibition

The generation of reactive oxygen species is a central feature of inflammation that results in the oxidation of host phospholipids. Oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit signaling induced by bacterial lipopeptide or lipopolysac-charide (LPS), yet the mechanisms responsible for the inhibition of Toll-like receptor (TLR) signaling by OxPAPC remain incompletely understood. Here, we examined the mechanisms by which OxPAPC inhibits TLR signaling induced by diverse ligands in macrophages, smooth muscle cells, and epithelial cells. OxPAPC inhibited tumor necrosis factor- production, IB degradation, p38 MAPK phosphorylation, and NF-B-dependent reporter activation induced by stimulants of TLR2 and TLR4 (Pam3CSK4 and LPS) but not by stimulants of other TLRs (poly(I·C), flagellin, loxoribine, single-stranded RNA, or CpG DNA) in macrophages and HEK-293 cells transfected with respective TLRs and significantly reduced inflammatory responses in mice injected subcutaneously or intraperitoneally with Pam3CSK4. Serum proteins, including CD14 and LPS-binding protein, were identified as key targets for the specificity of TLR inhibition as supplementation with excess serum or recombinant CD14 or LBP reversed TLR2 inhibition by OxPAPC, whereas serum accessory proteins or expression of membrane CD14 potentiated signaling via TLR2 and TLR4 but not other TLRs. Binding experiments and functional assays identified MD2 as a novel additional target of OxPAPC inhibition of LPS signaling. Synthetic phospholipid oxidation products 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine inhibited TLR2 signaling from 30 µM. Taken together, these results suggest that oxidized phospholipid-mediated inhibition of TLR signaling occurs mainly by competitive interaction with accessory proteins that interact directly with bacterial lipids to promote signaling via TLR2 or TLR4.

The use of antidepressants to treat attention deficit hyperactivity disorder in adults

There is increasing evidence that children continue to experience attention deficit hyperactivity disorder (ADHD) symptoms into adult life. The two main treatments for ADHD are antidepressants and stimulants. Here, the effectiveness data relating to the use of antidepressants in adults with ADHD are reviewed. Four controlled and six open studies were identified. Although, there is only limited data currently available, antidepressants may offer an effective therapy for adult ADHD. Controlled trials have studied desipramine, atomoxetine and bupropion, with most evidence supporting the efficacy of desipramine. The initial data indicate that atomoxetine is less effective than desipramine. The efficacy of bupropion is unclear. Initial published open data suggest a response rate of 50-78% with venlafaxine. Controlled studies are required to confirm this efficacy. Most of the present data are short-term, therefore long-term effectiveness data are required.

Low-emission vehicle adoption in a UK local authority fleet:economic barriers and air quality benefits

Local air quality was one of the main stimulants for low carbon vehicle development during the 1990s. Issues of national fuel security and global air quality (climate change) have added pressure for their development, stimulating schemes to facilitate their deployment in the UK. In this case study, Coventry City Council aimed to adopt an in-house fleet of electric and hybrid-electric vehicles to replace business mileage paid for in employee's private vehicles. This study made comparisons between the proposed vehicle technologies, in terms of costs and air quality, over projected scenarios of typical use. The study found that under 2009 conditions, the electric and hybrid fleet could not compete on cost with the current business model because of untested assumptions, but certain emissions were significantly reduced >50%. Climate change gas emissions were most drastically reduced where electric vehicles were adopted because the electricity supply was generated by renewable energy sources. The study identified the key cost barriers and benefits to adoption of low-emission vehicles in current conditions in the Coventry fleet. Low-emission vehicles achieved significant air pollution-associated health cost and atmospheric emission reductions per vehicle, and widespread adoption in cities could deliver significant change. © The Author 2011. Published by Oxford University Press. All rights reserved.

The complements towards developing a new risk management framework and Its applicability to the Nigerian power sector

The availability of regular supply has been identified as one of the major stimulants for the growth and development of any nation and is thus important for the economic well-being of a nation. The problems of the Nigerian power sector stems from a lot of factors culminating in her slow developmental growth and inability to meet the power demands of her citizens regardless of the abundance of human and natural resources prevalent in the nation. The research therefore had the main aim of investigating the importance and contributions of risk management to the success of projects specific to the power sector. To achieve this aim it was pertinent to examine the efficacy of risk management process in practice and elucidate the various risks typically associated with projects (Construction, Contractual, Political, Financial, Design, Human resource and Environmental risk factors) in the power sector as well as determine the current situation of risk management practice in Nigeria. To address this factors inhibiting the proficiency of the overarching and prevailing issue which have only been subject to limited in-depth academic research, a rigorous mixed research method was adopted (quantitative and qualitative data analysis). A review of the Nigeria power sector was also carried out as a precursor to the data collection stage. Using purposive sampling technique, respondents were identified and a questionnaire survey was administered. The research hypotheses were tested using inferential statistics (Pearson correlation, Chi-square test, t-test and ANOVA technique) and the findings revealed the need for the development of a new risk management implementation Framework. The proposed Framework was tested within a company project, for interpreting the dynamism and essential benefits of risk management with the aim of improving the project performances (time), reducing the level of fragmentation (quality) and improving profitability (cost) within the Nigerian power sector in order to bridge a gap between theory and practice. It was concluded that Nigeria’s poor risk management practices have prevented it from experiencing strong growth and development. The study however, concludes that the successful implementation of the developed risk management framework may help it to attain this status by enabling it to become more prepared and flexible, to face challenges that previously led to project failures, and thus contributing to its prosperity. The research study provides an original contribution theoretically, methodologically and practically which adds to the project risk management body of knowledge and to the Nigerian power sector.

Efeito imunomodulador e atividade antimicrobiana de heterofucanas de Sargassum filipendula

Fucans, sulphated polysaccharides that contain L-fucose in its constitution, obtained from species of Phaeophyceae of the Sargassum kind, display several biological activities. Heterofucans from Sargassum filipendula are bioactive molecules that contain strong antiproliferative and antioxidant activity. However, their immunomodulatory and antimicrobial activities have not yet been examined. In this context, the aim of this research was to evaluate the heterofucans as for their immunomodulatory capacity and antimicrobial action against Leishmania infantum, Trichomonas vaginalis, Staphylococcus epidermidis and Klebsiella pneumonia (KPC). The five heterofucans obtained from S. filipendula show activities that are distant as stimulants of the immune system and microbial agent. The SF0.5V, SF0.7V amd SF1.0V heterofucans were capable of acting in the activation of murine and human macrophages. In addition to that, SF0.5V has shown antibiofilm activity of S. epidermides and SF0.7V and 1.0V almost completely inhibited the survival of the protozoan T. vaginalis. Results such as this one, reflect the broad range of action of the sulphated polysaccharides obtained from seaweeds, especially from the species S.filipendula

Serious Game no tratamento de obesidade infantil: uma proposta de interação natural com monitoramento remoto

The number of overweight people has increased in the last few years. Factors such as attention to diet and changes in lifestyle are crucial in the prevention and control of obesity and diseases related to it. Experts believe that such actions are most effective when initiated during childhood, and that children raised in an environment that encourages physical activity ultimately become healthier adults. However, to arouse and maintain interest in such activities represent a major challenge, which are initially perceived as repetitive and boring, and, thus, soon abandoned. Computer games, traditionally seen as stimulants to a sedentary lifestyle are changing this perception using non-conventional controls that require constant movement of the player. Applications that combine the playfulness of such games to physical activity through devices, like Microsoft Kinect, might become interesting tools in this scenario, by using the familiarity of Natural User Interfaces along with the challenge and the fun of video games, in order to make attractive exercise routines for schoolchildren. The project carried out consists of an exergame composed of several activities designed and implemented with the participation of a Physical Educator, aimed at children between eight and ten years old, whose performance and progress can be remotely monitored by a professional via web interface. The application arising from this work was accompanied by tests with a group of graduating Physical Education students from the University of Rio Verde GO, and subsequently validated through questionnaires whose results are shown on this work.

Risk Consumption: Children and Online Gaming. The Problem of “Responsible Gambling”

Online gambling is a popular activity among adolescents. However, there has been a notable increase in the number of young people who suffer or are on the verge of pathological gambling. We review the impact of online gambling on young people and discuss the desiderability of the concept of “gambling responsibly” in order to alert of their risks and effectively prevent access to minors. The main factors associated with pathological gambling are the age of start, the family environment, the infl uence of advertising, the consumption of stimulants, and the attitudes of the peer group. Both the government and the gaming industry itself should consider these factors and develop comprehensive plans that ensure a safe and controlled model game. In this context, advertising must take into account criteria of consumer protection knowing that even if they are not allowed, children can easily have access to online gambling. All agents involved, including public and social agents, must provide mechanisms for prevention and awareness of a problem that arouses little social consciousness and excessive carelessness.

Sintomatologia depressiva e sono

Os comportamentos depressivos são cada vez mais evidentes na sociedade atual e ocorrem normalmente, a partir da adolescência, sendo a sua incidência maior nas mulheres. Esses comportamentos, que se traduzem em sintomatologia depressiva interferem com vários aspetos do ser humano, desde a sua imagem corporal, aos seus estados nutricional e psicológico, até ao seu estado de saúde em geral, e ao seu padrão de sono. Este trabalho procura explorar as relações entre os hábitos e a qualidade do sono e a sintomatologia depressiva. Foram avaliados 100 profissionais de saúde com horários de trabalho irregulares e com idades compreendidas entre os 20 e os 65 anos : 54 do sexo feminino e 46 do sexo masculino. Aplicou-se um questionário onde se recolheram os seguintes dados: IMC, horário de trabalho, alimentação, consumo de substâncias estimulantes, sintomatologia depressiva, sonolência diurna e qualidade do sono. Relativamente ao IMC verificou-se que 44% dos inquiridos apresenta excesso de peso e 2% já se encontra em Obesidade grau I. Relativamente ao horário de trabalho, 74 % dos inquiridos referiu o turno da manhã como sendo o seu preferencial e 59% disse que o trabalho por turnos que não era vantajoso. Na avaliação da interferência do horário de trabalho por turnos nas diversas atividades extra profissionais verificou-se que quanto ao tempo de lazer 72 % dos inquiridos disse que interfere muito, na vida social e familiar 78 % dos inquiridos diz que interfere muito, nas atividades pessoais 60 % dos inquiridos disse que interfere muito e na alimentação 83 % dos inquiridos diz que interfere muito. Ainda na alimentação, verificou-se que 52% dos inquiridos acha que o tempo que tem disponível não é adequado a uma boa refeição pelo que se verificou uma frequência das refeições irregular nomeadamente ao pequeno almoço, que apenas 47% disse sempre tomar. Relativamente ao consumo de substâncias estimulantes a mais consumida é o café, uma vez que mais de metade (53%) dos inquiridos diz tomar sempre, segue-se o consumo de tabaco, o qual 44% dos inquiridos disse consumir sempre. Quanto ao exercício físico 68% dos inquiridos disse não praticar. Na presença de sintomatologia depressiva, verifica-se que a maior parte dos inquiridos (68%; n=68) apresenta uma sintomatologia depressiva mínima, 24% apresenta depressão ligeira e 8% (n=8) apresenta depressão moderada. A determinação da sonolência diurna, verifica-se que 28% (n=28) dos inquiridos apresenta pouca sonolência diurna, 65% apresenta moderada sonolência diurna e 7% apresenta Sonolência diurna excessiva. Quanto á qualidade do sono, verifica-se que 18 % dos inquiridos tem uma boa qualidade de sono, 53 % tem sono de má qualidade e 29% dos inquiridos apresenta distúrbio de sono. Estas evidências levaram a concluir que existe uma forte relação ente o sono e a sintomatologia depressiva, e que o horário de trabalho por turnos interfere na qualidade de vida dos indivíduos, sendo que a única forma de intervir está na prevenção, incentivando os trabalhadores a hábitos de vida saudáveis e a um controlo periódico do seu estado de saúde.

A tradução e a sua relevância na indústria farmacêutica

O projeto encontra-se dividido em três partes. Na primeira encontra-se um estudo teórico sobre a importância da tradução médica. A segunda parte apresenta a tradução de dois artigos médicos extraídos de um manual de psiquiatria e a partir desses artigos foi criado um glossário bilingue. Na última parte foi realizada uma reflexão sobre a tradução, detalhando todos os aspetos essenciais da mesma. Os temas abordados nos artigos anteriormente mencionados têm a ver com os antidepressivos e estimulantes, e antipsicóticos, entre os quais se destacam os mecanismos de ação e os efeitos adversos de cada um destes medicamentos.

As salas snoezelen para indivíduos com autismo

Dissertação de Mestrado para obtenção do grau de Mestre em Design de Comunicação, apresentada na Universidade de Lisboa - Faculdade de Arquitectura.

Estudo de composto com propriedades funcionais em flor de cardo submetida a diferentes tratamentos de secagem

O cardo é uma planta que encontra-se associada ao fabrico de queijo, pois é responsável pelo fenómeno da coagulação do leite. No entanto, têm aumentado o número de estudos realizados nesta planta, relacionados com a composição química, de forma a perceber os benefícios para a saúde. O objetivo desta dissertação foi caracterizar a flor de cardo relativamente à sua atividade antioxidante, composição em compostos fenólicos e avaliar a sua estabilidade ao longo do trato digestivo. Para tal, foram estudas amostras de flor de cardo da espécie C. cardunculus spp flavescens, após liofilização e secagem em estufa com convecção forçada a diferentes temperaturas (40ºC, 50ºC e 60ºC). Após cada tratamento, efetuaram-se duas extrações sucessivas com soluções de metanol (98% v/v) e de acetona (60% v/v). Os extratos obtidos foram depois utilizados para quantificar os teores em compostos fenólicos totais, em orto-difenois e em flavonóides. A atividade antioxidante foi determinada utilizando os métodos DPPH e ABTS. Por fim, procedeu-se à avaliação da bioacessibilidade dos compostos presentes submetendo os vários extratos a condições simulantes do trato digestivo. Pela análise dos resultados obtidos foi possível constatar que a quantidade de compostos fenólicos e atividade antioxidante na flor de cardo varia consoante a temperatura de secagem, ocorrendo a diminuição à medida que se aumenta a temperatura. Os resultados obtidos para a bioacessibilidade mostraram um comportamento distinto dos extratos de metanol e de acetona. No entanto, em ambos os casos ocorreu uma diminuição na quantidade de compostos disponíveis para absorção intestinal.

L’art transformateur: Un projet de création avec des jeunes à risque de décrochage scolaire

Méthodologie: Recherche qualitative d’approche heuristique

MicroRNA modulation of aldosterone production in the adrenal gland

Hypertension is the major risk factor for coronary disease worldwide. Primary hypertension is idiopathic in origin but is thought to arise from multiple risk factors including genetic, lifestyle and environmental influences. Secondary hypertension has a more definite aetiology; its major single cause is primary aldosteronism (PA), the greatest proportion of which is caused by aldosteroneproducing adenoma (APA), where aldosterone is synthesized at high levels by an adenoma of the adrenal gland. There is strong evidence to show that high aldosterone levels cause adverse effects on cardiovascular, cerebrovascular, renal and other systems. Extensive studies have been conducted to analyse the role that regulation of CYP11B2, the gene encoding the aldosterone synthase enzyme plays in determining aldosterone production and the development of hypertension. One significant regulatory factor that has only recently emerged is microRNA (miRNA). miRNAs are small non-coding RNAs, synthesized by a series of enzymatic processes, that negatively regulate gene expression at the posttranscriptional level. Detection and manipulation of miRNA is now known to be a viable method in the treatment, prevention and prognosis of certain diseases. The aim of the present study was to identify miRNAs likely to have a role in the regulation of corticosteroid biosynthesis. To achieve this, the miRNA profile of APA and normal human adrenal tissue was compared, as was the H295R adrenocortical cell line model of adrenocortical function, under both basal conditions and following stimulation of aldosterone production. Key differentially-expressed miRNAs were then identified and bioinformatic tools used to identify likely mRNA targets and pathways for these miRNAs, several of which were investigated and validated using in vitro methods. The background to this study is set out in Chapter 1 of this thesis, followed by a description of the major technical methods employed in Chapter 2. Chapter 3 presents the first of the study results, analysing differences in miRNA profile between APA and normal human adrenal tissue. Microarray was implemented to detect the expression of miRNAs in these two tissue types and several miRNAs were found to vary significantly and consistently between them. Furthermore, members of several miRNA clusters exhibited similar changes in expression pattern between the two tissues e.g. members of cluster miR-29b-1 (miR-29a-3p and miR-29b-3p) and of cluster miR-29b-2 (miR-29b-3p and miR-29c- 3p) are downregulated in APA, while members of cluster let-7a-1 (let-7a-5p and let-7d-5p), cluster let-7a-3 (let-7a-5p and let-7b-5p) and cluster miR-134 (miR- 134 and miR-382) are upregulated. Further bioinformatic analysis explored the possible biological function of these miRNAs using Ingenuity® Systems Pathway Analysis software. This led to the identification of validated mRNAs already known to be targeted by these miRNAs, as well as the prediction of other mRNAs that are likely targets and which are involved in processes relevant to APA pathology including cholesterol synthesis (HMGCR) and corticosteroidogenesis (CYP11B2). It was therefore hypothesised that increases in miR-125a-5p or miR- 335-5p would reduce HMGCR and CYP11B2 expression. Chapter 4 describes the characterisation of H295R cells of different strains and sources (H295R Strain 1, 2, 3 and HAC 15). Expression of CYP11B2 was assessed following application of 3 different stimulants: Angio II, dbcAMP and KCl. The most responsive strain to stimulation was Strain 1 at lower passage numbers. Furthermore, H295R proliferation increased following Angio II stimulation. In Chapter 5, the hypothesis that increases in miR-125a-5p or miR-335-5p reduces HMGCR and CYP11B2 expression was tested using realtime quantitative RT-PCR and transfection of miRNA mimics and inhibitors into the H295R cell line model of adrenocortical function. In this way, miR-125a-5p and miR-335-5p were shown to downregulate CYP11B2 and HMGCR expression, thereby validating certain of the bioinformatic predictions generated in Chapter 3. The study of miRNA profile in the H295R cell lines was conducted in Chapter 6, analysing how it changes under conditions that increase aldosterone secretion, including stimulation Angiotensin II, potassium chloride or dibutyryl cAMP (as a substitute for adrenocorticotropic hormone). miRNA profiling identified 7 miRNAs that are consistently downregulated by all three stimuli relative to basal cells: miR-106a-5p, miR-154-3p, miR-17-5p, miR-196b-5p, miR-19a-3p, miR-20b- 5p and miR-766-3p. These miRNAs include those derived from cluster miR-106a- 5p/miR-20b-5p and cluster miR-17-5p/miR-19a-3p, each producing a single polycistronic transcript. IPA bioinformatic analysis was again applied to identify experimentally validated and predicted mRNA targets of these miRNAs and the key biological pathways likely to be affected. This predicted several interactions between miRNAs derived from cluster miR-17-5p/miR-19a-3p and important mRNAs involved in cholesterol biosynthesis: LDLR and ABCA1. These predictions were investigated by in vitro experiment. miR-17-5p/miR-106a-p and miR-20b-5p were found to be consistently downregulated by stimulation of aldosterone biosynthesis. Moreover, miR-766-3p was upregulation throughout. Furthermore, I was able to validate the downregulation of LDLR by miR-17 transfection, as predicted by IPA. In summary, this study identified key miRNAs that are differentially-expressed in vivo in cases of APA or in vitro following stimulation of aldosterone biosynthesis. The many possible biological actions these miRNAs could have were filtered by bioinformatic analysis and selected interactions validated in vitro. While direct actions of these miRNAs on steroidogenic enzymes were identified, cholesterol handling also emerged as an important target and may represent a useful point of intervention in future therapies designed to modulate aldosterone biosynthesis and reduce its harmful effects.