Diacerhein (DAR) is a slow acting symptomatic drug used to treatment of osteoarthritis. It is available in the Brazilian market as capsules and compounded capsules. There are no official methods for DAR analysis in any of the pharmacopeia. In the present work, methods for the quantification and dissolution evaluation of the drug in capsules and compounded capsules were developed and validated. Spectrophotometry and high-performance liquid chromatography (HPLC) were the methods used for drug determination. In the spectrophotometric method the DAR can be quantified at 277 as well as 502 nm, using 0.1N NaOH as diluent. The HPLC analyses were performed on a C18 column, using a mobile phase composed of triethylamine 0.1%:acetonitrile (65:35, v/v; adjusted to 7.5 with orthophosphoric acid) and UV detection at 250 nm. The methods showed good linearity (r>0.99), precision (RSD<2%) and accuracy (>99%) and the results obtained were not statistically different (P=0.05). The optimization of dissolution test conditions for in vitro quality control of DAR in capsules was evaluated. The use of 900 mL of sodium phosphate buffer at 37.0 ± 0.5 ºC, basket as apparatus, at 100 rpm rotate speed and 30 minutes of test provided satisfactory results for tested products. The percent dissolution of DAR in the established condition was more than 80% and the different evaluated products presented good dissolution efficiency (>85%). The spectrophotometric method that was validated to evaluate the dissolution testing showed to be specific, with no interference of the placebo or shell capsules in the quantification of DAR, linear (0.27 6.66 μg mL-1; r>0.99), precise (RSD<5%) and accurate (>97%). The drug showed satisfactory stability in the selected dissolution medium. / A diacereína (DAR) é um fármaco antiartrósico sintomático de ação lenta. No mercado brasileiro encontra-se disponível na forma de cápsulas e cápsulas manipuladas. Não existem monografias para análise de DAR em nenhuma farmacopéia. No presente trabalho, métodos para quantificação e avaliação da dissolução do fármaco em cápsulas foram desenvolvidos e validados. Os métodos usados para a quantificação do fármaco foram a espectrofotometria e a cromatografia líquida de alta eficiência (CLAE). No método espectrofotométrico DAR pode ser quantificada em 277 ou em 502 nm, utilizando NaOH 0,1N como diluente. As análises por CLAE foram realizadas em coluna C18, utilizando fase móvel composta de trietilamina 0,1%: acetonitrila (65:35, v/v; com pH ajustado para 7,5 com ácido ortofosfórico) com detecção no UV em 250 nm. Os métodos mostraram boa linearidade (r>0,99), precisão (DPR<2%) e exatidão (>99%) e os resultados obtidos não apresentaram diferença estatística significante (P=0,05. A otimização das condições para o teste de dissolução in vitro para DAR em cápsulas foi avaliada. As condições que forneceram resultados satisfatórios para os produtos testados foram 900 mL de tampão fosfato de sódio pH 7,0 com 0,75% de lauril sulfato de sódio, a 37,0 ± 0,5 ºC, aparato cesta, 100 rpm e 30 minutos de teste. A liberação de DAR na condição estabelecida foi superior a 80% e os diferentes produtos analisados demonstraram boa eficiência de dissolução (>85%). O método espectrofotométrico que foi validado para avaliar a dissolução mostrou ser específico, não havendo interferência de excipientes ou do invólucro das cápsulas na quantificação de DAR, linear (0,27 6,66 μg/mL; r> 0,99), preciso (DPR < 5%) e exato (>97%). O fármaco mostrou estabilidade satisfatória no meio de dissolução selecionado.

Made available in DSpace on 2015-05-14T12:59:24Z (GMT). No. of bitstreams: 1 parte1.pdf: 2506854 bytes, checksum: 7b83f48e46031c35dc85c825fdbe1a10 (MD5) Previous issue date: 2010-08-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Resveratrol (cis and trans) and quercetin are important components in ensuring the quality of wine because of the diversity of biological activities that they have. Studies quantifying these constituents in Brazilian wines are rarely reported in the literature, especially in wines from the Vale Submédio do São Francisco. The objectives of this work were to develop and validate a quantification method for cis-resveratrol, trans-resveratrol, total resveratrol and quercetin by HPLC-UV in red wines, to evaluate and correlate the levels of total phenolics by Folin-Ciocalteu method with the anti-radical activity determined usingm the DPPH radical method and to determine the potential for classification of wines from their chromatographic profiles. In the study 45 samples of red wines were analysed. From these, 30 samples were from Brazilian wines:15 of the Vale Submédio do São Francisco, 11 of Serra Gaucha and 4 of Campanha Gaucha. There were 15 samples of imported wines: 5 from Argentina, 5 from Chile and 5 from French. The method developed for quantification of resveratrol (cis and trans) and quercetin was validated andused in the quantification. The results showed that Brazilian wines have about nine times more cis-resveratrol than trans-resveratrol and this relationship is even more pronounced in the Vale do São Francisco, with about 17 times more cis-resveratrol than trans-resveratrol in red wines from this region. The French wines presented quercetin in an amount above the rest of the wine samples. It was also observed that the wines from the Vale do São Francisco had higher levels of total resveratrol, significantly higher than imported wines, with p=0.0381. The total phenolics content was markedly higher in the wines from the Vale do São Francisco in relation to wines from the South, with p=0.001. The study of anti-radical activity against the DPPH radical showed that all wines are active, with EC50<130 μg/mL. In the study of the chromatographic profiles of the wines four distinct groupings among the wines were found, with 87% of the samples from the Vale do São Francisco, 80% of Chileans wines, 60% of the Serra Gaucha wines and 55% of French wines. Taken toghether the results show that Brazilian wines presented high level of phenolics, especially the wines from Vale do Submédio do São Francisco. This is translated into high levels of bioactive substances such as resveratrol (cis and trans) and quercetin, as well the high antioxidant activity. The high intensity of solar light in Brazil, mainly in the Vale do São Francisco, may have been the main factor contributing to the high content of these constituents, thus contributing to the high degree of grouping shown by the wines of this region using multivariate analysis. / O resveratrol (cis e trans) e quercetina são componentes de grande importância na garantia da qualidade do vinho, devido à diversidade de atividades biológicas que eles possuem. Estudos de quantificação destes constituintes em vinhos brasileiros são pouco relatados na literatura, especialmente nos vinhos do Vale Submédio do São Francisco. Os objetivos deste trabalho foram desenvolver e validar um método de quantificação do cis-resveratrol, trans-resveratrol, resveratrol total e quercetina por CLAE-UV/Vis em vinhos tintos, avaliar e correlacionar os teores de fenólicos totais pelo método de Folin-Ciocalteu com a atividade anti-radicalar, frente ao radical DPPH e determinar o potencial de classificação dos vinhos a partir dos perfis cromatográficos. Para execução do trabalho foram analisadas 45 amostras de vinhos tintos, sendo 30 brasileiros das regiões do Vale Submédio do São Francisco (15), Serra Gaúcha (11) e Campanha Gaúcha (4), e 15 importados: argentinos (5), chilenos (5) e franceses (5). O método desenvolvido para quantificação de resveratrol isômeros (cis e trans) e quercetina apresentou dados e características suficientemente bons para ser validado e utilizado no processo de quantificação. Os resultados obtidos demonstraram que os vinhos brasileiros possuem cerca de 9 vezes mais cis-resveratrol que trans-resveratrol, esta relação é ainda mais pronunciada na região do Vale Submédio do São Francisco, sendo cerca de 17 vezes mais cis do que trans. Os vinhos franceses apresentaram quercetina em quantidade superior ao restante dos conjuntos amostrais de vinhos. Foi observado também que os vinhos do Vale Submédio do São Francisco possuem teores de resveratrol total, significativamente superiores aos vinhos importados, com p=0,0381. O teor de fenólicos totais foi marcadamente superior nos vinhos do Vale Submédio do São Francisco em relação aos vinhos da região Sul, com p=0,001. O estudo de atividade anti-radicalar frente ao radical DPPH demonstrou que todos os vinhos são ativos, com CE50 <130 μg/mL. No estudo do perfil cromatográfico dos vinhos foram determinados quatro agrupamentos distintos, sendo 87 % entre os vinhos do Vale Submédio do São Francisco, 80 % entre os chilenos, 60 % entre os da Serra Gaúcha e 55 % entre os vinhos franceses. Os estudos realizados com os vinhos revelaram resultados que posicionam os vinhos brasileiros, especialmente os vinhos da região do Vale Submédio do São Francisco, em um elevado patamar em termos de qualidade. Isto é corroborado pelos elevados teores de substâncias bioativas tais como o resveratrol (isômeros cis e trans) e quercetina, bem como o elevado teor de fenólicos totais e alta atividade anti-radicalar. A alta intensidade de insolação no Brasil, principalmente na região do Vale Submédio do São Francisco, pode ter sido o principal fator a contribuir para elevação do teor destes constituintes, contribuindo, desta forma, para um elevado grau de agrupamento dos vinhos desta região por análise multivariada.

Until recent times, weather forecasts were deterministic in nature. For example, a forecast might state ``The temperature tomorrow will be $20^\circ$C.'' More recently, however, increasing interest has been paid to the uncertainty associated with such predictions. By quantifying the uncertainty of a forecast, for example with a probability distribution, users can make risk-based decisions. The uncertainty in weather forecasts is typically based upon `ensemble forecasts'. Rather than issuing a single forecast from a numerical weather prediction (NWP) model, ensemble forecasts comprise multiple model runs that differ in either the model physics or initial conditions. Ideally, ensemble forecasts would provide a representative sample of the possible outcomes of the verifying observations. However, due to model biases and inadequate specification of initial conditions, ensemble forecasts are often biased and underdispersed. As a result, estimates of the most likely values of the verifying observations, and the associated forecast uncertainty, are often inaccurate. It is therefore necessary to correct, or post-process ensemble forecasts, using statistical models known as `ensemble post-processing methods'. To this end, this thesis is concerned with the application of statistical methodology in the field of probabilistic weather forecasting, and in particular ensemble post-processing. Using various datasets, we extend existing work and propose the novel use of statistical methodology to tackle several aspects of ensemble post-processing. Our novel contributions to the field are the following. In chapter~3 we present a comparison study for several post-processing methods, with a focus on probabilistic forecasts for extreme events. We find that the benefits of ensemble post-processing are larger for forecasts of extreme events, compared with forecasts of common events. We show that allowing flexible corrections to the biases in ensemble location is important for the forecasting of extreme events. In chapter~4 we tackle the complicated problem of post-processing ensemble forecasts without making distributional assumptions, to produce recalibrated ensemble forecasts without the intermediate step of specifying a probability forecast distribution. We propose a latent variable model, and make a novel application of measurement error models. We show in three case studies that our distribution-free method is competitive with a popular alternative that makes distributional assumptions. We suggest that our distribution-free method could serve as a useful baseline on which forecasters should seek to improve. In chapter~5 we address the subject of parameter uncertainty in ensemble post-processing. As in all parametric statistical models, the parameter estimates are subject to uncertainty. We approximate the distribution of model parameters by bootstrap resampling, and demonstrate improvements in forecast skill by incorporating this additional source of uncertainty in to out-of-sample probability forecasts. In chapter~6 we use model diagnostic tools to determine how specific post-processing models may be improved. We subsequently introduce bias correction schemes that move beyond the standard linear schemes employed in the literature and in practice, particularly in the case of correcting ensemble underdispersion. Finally, we illustrate the complicated problem of assessing the skill of ensemble forecasts whose members are dependent, or correlated. We show that dependent ensemble members can result in surprising conclusions when employing standard measures of forecast skill.

abstract: Titanium dioxide (TiO2) nanomaterial use is becoming more prevalent as is the likelihood of human exposure and environmental release. The goal of this thesis is to develop analytical techniques to quantify the level of TiO2 in complex matrices to support environmental, health, and safety research of TiO2 nanomaterials. A pharmacokinetic model showed that the inhalation of TiO2 nanomaterials caused the highest amount to be absorbed and distributed throughout the body. Smaller nanomaterials (< 5nm) accumulated in the kidneys before clearance. Nanoparticles of 25 nm diameter accumulated in the liver and spleen and were cleared from the body slower than smaller nanomaterials. A digestion method using nitric acid, hydrofluoric acid, and hydrogen peroxide was found to digest organic materials and TiO2 with a recovery of >80%. The samples were measured by inductively coupled plasma-mass spectrometry (ICP-MS) and the method detection limit was 600 ng of Ti. An intratracheal instillation study of TiO2 nanomaterials in rats found anatase TiO2 nanoparticles in the caudal lung lobe of rats 1 day post instillation at a concentration of 1.2 ug/mg dry tissue, the highest deposition rate of any TiO2 nanomaterial. For all TiO2 nanomaterial morphologies the concentrations in the caudal lobes were significantly higher than those in the cranial lobes. In a study of TiO2 concentration in food products, white colored foods or foods with a hard outer shell had higher concentrations of TiO2. Hostess Powdered Donettes were found to have the highest Ti mass per serving with 200 mg Ti. As much as 3.8% of the total TiO2 mass was able to pass through a 0.45 um indicating that some of the TiO2 is likely nanosized. In a study of TiO2 concentrations in personal care products and paints, the concentration of TiO2 was as high as 117 ug/mg in Benjamin Moore white paint and 70 ug/mg in a Neutrogena sunscreen. Greater than 6% of Ti in one sunscreen was able to pass through a 0.45 um filter. The nanosized TiO2 in food products and personal care products may release as much as 16 mg of nanosized TiO2 per individual per day to wastewater. / Dissertation/Thesis / M.S. Engineering 2011

Cette thèse porte sur les pratiques et les usages numériques de quantification de soi. Le mouvement Quantified Self est apparu initialement en 2007 dans la Silicon Valley, mais en quelques années ces pratiques ont rapidement évolué pour converger vers les technologies numériques en santé. S’il ressort de la littérature scientifique et académique qu’elles constituent une forme contemporaine de biopouvoir (Lupton, 2016) et qu’elles sont porteuses de nombreux espoirs dans le domaine de la santé, elles ne sont pourtant pas questionnées, ni du point de vue des mutations anthropologiques qu’elles introduisent dans le couplage entre organisme physiologique et données numériques (Simondon, 1958 ; Boullier, 2011 ; Sadin, 2013), ni du point de vue des modèles de conception sous-jacents aux technologies de quantification de soi, essentiellement fondées sur des approches comportementales, privilégiant la persuasion plutôt que la signification. Ce manque de réflexion soulève de nombreuses questions d’ordre éthique quant à la manière de concevoir des dispositifs numériques, en particulier lorsqu’il s’agit de la santé des individus (Lupton, 2013 ; 2016). Dans cette perspective, cette thèse poursuit un double objectif. Le premier est d’apporter un éclairage compréhensif sur les pratiques numériques de quantification de soi. Le second se rapporte à l’instrumentation de ces nouveaux objets technologiques et à leur modélisation en amont de leur conception. Pour ce faire, nous avons choisi le modèle Learning by expanding d’Engeström (1999, 2014) qui permet d’envisager la conception sous l’angle de la médiation. / This thesis concerns the digital practices and uses of self-quantification. The quantified-self movement first appeared in 2007 in Silicon Valley, but in a few years these practices have evolved rapidly to converge on digital health technologies. If it appears from the scientific and academic literature, that they constitute a contemporary form of biopower (Lupton, 2016) and that they carry many hopes in the field of health, they are however not questioned, neither from the perspective of the anthropological changes they introduce in the coupling between body and physiological digital data (Simondon, 1958, Boullier, 2011; Sadin, 2013), nor from the self-quantification technologies models point of view mainly based on behaviorist approaches, favoring persuasion rather than meaning. This lack of thinking raises many ethical questions about how to design a technology, especially when it comes to the health of individuals (Lupton, 2013; 2016).In this perspective, this thesis pursuit a dual purpose. The first is to provide a comprehensive perspective on the digital self-quantification practices. The second objective relates to the instrumentation of these new technological artifacts and to their modeling. To do this, we chose the approach the “Learning by Expanding model” of Engeström (1999, 2014), to model the digital mediations processes involved in the self-quantification practices.

No description available.

Oestrogenic chemicals have become increasingly associated with health effects in wildlife populations and humans. Transgenic animal models have been developed to understand the mechanisms by which these oestrogenic chemicals alter hormonal signalling pathways and how these alterations can lead to chronic health effects. The use of highly informative transgenic animal models will also result in better use and potential reduction of intact animals used in animal testing in line with the principles of the 3Rs. In this thesis work, two novel oestrogen responsive transgenic zebrafish models have been generated to investigate the effects of oestrogenic chemicals, identify their tissue targets and better understand the temporal dynamics of these responses. Both models express the pigment-free ‘Casper’ (a mutant line lacking skin pigment) phenotype, which facilitate identification of responding target tissues in the whole fish in all fish life stages (embryos to adults). The oestrogen response element green fluorescent (ERE-GFP)-Casper model was generated by crossing an established ERE-GFP line with the skin pigment free Casper line. The model generated is highly sensitive to oestrogenic chemicals, detecting responses to environmentally relevant concentrations of EE2, bisphenol A (BPA), genistein and nonylphenol. Use of the ERE-GFP- Casper model shows chemical type and concentration dependence for green fluorescent protein (GFP) induction and both spatial and temporal responses for different environmental oestrogens tested. A semi-automated (ArrayScan) imaging and image analysis system was also developed to quantify whole body fluorescence responses for a range of different oestrogenic chemicals in the new transgenic zebrafish model. The zebrafish model developed provides a sensitive and highly integrative system for identifying oestrogenic chemicals, their target tissues and effect concentrations for exposures in real time and across different life stages. It thus has application for chemical screening to better direct health effects analysis of environmental oestrogens and for investigating the functional roles of oestrogens in vertebrates. The second model generated was an ERE-Kaede-Casper line developed via crossing of the ERE-GFP-Casper line and a UAS-Kaede line and screening subsequent generations for a desired genotype and homozygous expression of the transgenes. Kaede is a photoconvertible fluorescent protein that initially fluoresces green in colour and can be permanently converted to red fluorescence upon short exposure to UV light. The model has a silenced skin pigmentation and high sensitivity to oestrogenic chemicals comparable with the previously developed ERE-GFP-Casper model. Use of this model has identified windows of tissue-specific sensitivity to ethinyloestradiol (EE2) for exposure during early-life (0-48hpf) and illustrated that exposure to oestrogen (EE2) during early life (0-48hpf) can enhance responsiveness (sensitivity) to different environmental oestrogens (EE2, genistein and bisphenol A) for subsequent exposures during development. These findings illustrate the importance of oestrogen exposure history in effects assessments and they have wider implications for the possible adverse effects associated with oestrogen exposure.

Chronic liver diseases, which includes alcoholic liver disease (ALD), are consistently among the top 15 leading causes of death in the United States. ALD is characterized by progression from a normal liver to fatty liver disease (hepatic steatosis), which can lead to cirrhosis, alcoholic hepatitis, and liver failure. We have identified a novel role of phosphohistidine signaling, mediated through phosphohistidine phosphatase 1 (PHPT1), in the onset of hepatic steatosis. We have identified PHPT1 as a target of selective oxidation following acute ethanol exposure as well as being downregulated following chronic ethanol exposure. We mapped the oxidative modification site and developed a mass-spectrometry based phosphohistidine phosphatase assay to determine the impact of PHPT1 oxidative modification during acute ethanol exposure. To further understand the role of PHPT1 and phosphohistidine signaling during chronic ethanol exposure, we have developed PHPT1 overexpression and knockout mouse models. These mouse models were characterized using mass spectrometry-based proteomics. They were then utilized in a 10-day chronic ethanol plus binge model to determine the impact of PHPT1 expression on the onset of ethanol-induced hepatic steatosis. In addition, advanced mass spectrometry-based phenotypic characterization was performed on the treated liver tissues to determine the key regulators and canonical pathways influencing phosphohistidine signaling during chronic ethanol exposure. We have evidence to suggest that PHPT1 overexpression plays a protective role in the onset of hepatic steatosis, the PHPT1 heterozygous model is more susceptible to liver damage, and the complete knockout model is embryonically lethal. Additionally, we have identified novel pathways and regulators involved in phosphohistidine signaling during the development of ethanol-induced hepatic steatosis.

Space missions increasingly require sophisticated guidance, navigation and control algorithms, the development of which is reliant on verification and validation (V&V) techniques to ensure mission safety and success. A crucial element of V&V is the assessment of control system robust performance in the presence of uncertainty. In addition to estimating average performance under uncertainty, it is critical to determine the worst case performance. Industrial V&V approaches typically employ mu-analysis in the early control design stages, and Monte Carlo simulations on high-fidelity full engineering simulators at advanced stages of the design cycle. While highly capable, such techniques present a critical gap between pessimistic worst case estimates found using analytical methods, and the optimistic outlook often presented by Monte Carlo runs. Conservative worst case estimates are problematic because they can demand a controller redesign procedure, which is not justified if the poor performance is unlikely to occur. Gaining insight into the probability associated with the worst case performance is valuable in bridging this gap. It should be noted that due to the complexity of industrial-scale systems, V&V techniques are required to be capable of efficiently analysing non-linear models in the presence of significant uncertainty. As well, they must be computationally tractable. It is desirable that such techniques demand little engineering effort before each analysis, to be applied widely in industrial systems. Motivated by these factors, this thesis proposes and develops an efficient algorithm, based on the cross entropy simulation method. The proposed algorithm efficiently estimates the probabilities associated with various performance levels, from nominal performance up to degraded performance values, resulting in a curve of probabilities associated with various performance values. Such a curve is termed the probability profile of performance (PPoP), and is introduced as a tool that offers insight into a control system's performance, principally the probability associated with the worst case performance. The cross entropy-based robust performance analysis is implemented here on various industrial systems in European Space Agency-funded research projects. The implementation on autonomous rendezvous and docking models for the Mars Sample Return mission constitutes the core of the thesis. The proposed technique is implemented on high-fidelity models of the Vega launcher, as well as on a generic long coasting launcher upper stage. In summary, this thesis (a) develops an algorithm based on the cross entropy simulation method to estimate the probability associated with the worst case, (b) proposes the cross entropy-based PPoP tool to gain insight into system performance, (c) presents results of the robust performance analysis of three space industry systems using the proposed technique in conjunction with existing methods, and (d) proposes an integrated template for conducting robust performance analysis of linearised aerospace systems.

Este trabalho apresenta uma metodologia para análise e monitoração da qualidade da energia elétrica, através da identificação e quantificação dos distúrbios eletromagnéticos. A metodologia utiliza técnicas de processamento digital de sinais, possibilitando a construção de filtros digitais, a detecção de eventos e a estimativa da freqüência dos sinais elétricos analisados. Os principais distúrbios da qualidade definidos pelas normas da ANEEL e do ONS são quantificados através do algoritmo proposto. O programa desenvolvido foi testado usando formas de ondas com distúrbios previamente conhecidos para sua validação. Analisando formas de onda obtidas de medições em campo verificou-se a robustez do algoritmo frente a ruídos e outros fenômenos vinculados à qualidade da energia presentes em medições reais. Esta pesquisa apresenta um programa eficaz e prático que pode ser utilizado no desenvolvimento de um novo equipamento de medição dos distúrbios da QEE. Os resultados obtidos através da análise de dados (sintetizados e medições de campo) validaram o programa proposto. / This dissertation presents a methodology for detection and quantification of power quality disturbances. Digital signal processing (DSP) is applied to simulated and measured disturbances. The use of DSP enables the construction of digital filters for the detection of events, and the estimation of the frequency of voltage and current signals. The disturbances set by ANEEL and ONS standards are quantified by the proposed algorithm. The program developed was tested using simulated disturbance for its validation. Field measurements were used to assess the robustness of the algorithm against signal noise and other disturbances. This research presents effective and practical software that can be used to develop a new device for measuring the disturbances of Power Quality. The results obtained through the analysis of data (simulated and field measurements) validated the proposed algorithm.