Statistical process control (SPC) is a toolbox to detect changes in the output of a process distribution. It can serve as a valuable resource to maintain high quality in a manufacturing process. This report is based on the work on evaluating and implementing methods for SPC in the process of chromatography instrument manufacturing at GE Healthcare, Umeå. To handle low volume and non-normally distributed process output data, non-parametric methods are considered. Eight control charts, three for for Phase I analysis, and five for Phase II analysis, are evaluated in this study. The usability of the charts are assessed based on ease of interpretation and the performance to detect distributional changes. The later is evaluated with simulations. The result of the project is the implementation of the RS/P-chart, suggested by Capizzi et al (2013), for Phase I analysis. Of the considered Phase I methods (and simulation scenarios), the RS/P-chart has the highest overall probability, of detecting a variety of distributional changes. Further, the RS/P-chart is easily interpreted, facilitating the analysis. For Phase II analysis, the use of two control charts, one based on the Mann-Whitney U statistic, suggested by Chakraborti et al (2008), and one on the Mood test statistic for dispersion, suggested by Ghute et al (2014), have been implemented. These are chosen mainly based on the ease of interpretation. To reduce the detection time for changes in the process distribution, the change-point chart based on the Cramer Von Mises statistic, suggested by Ross et al (2012), could be used instead. Using single observations, instead of larger samples, this chart is updated more frequently. However, this efficiently increases the false alarm rate and the chart is also considered much more difficult to interpret for the SPC practitioner. / Statistisk processkontroll (SPC) är en samling verktyg för att upptäcka förändringar, i fördelningen, hos utfallen i en process. Det kan fungera som en värdefull resurs för att upprätthålla en hög kvalitet i en tillverkningsprocess. Denna rapport är baserad på arbetet med att utvärdera och implementera metoder för SPC i en monteringsprocess av kromatografiinstrument på GE Healthcare, Umeå. Åtta styrdiagram, tre för för fas I analys, och fem för fas II analys, studeras i denna rapport. Användbarheten hos styrdiagrammen bedöms efter hur enkla de är att tolka och förmågan att upptäcka fördelningsförändringar. Den senare utvärderas med simuleringar. Resultatet av projektet är införandet av RS/P-metod, utvecklad av Capizzi et al (2013), för analysen i fas I. Av de utvärderade metoderna, (och simuleringsscenarier), har RS/P-diagrammet den högsta övergripande sannolikheten, för att upptäcka en mängd olika fördelningsförändringar. Vidare är metodens grafiska diagram lätt att tolka, vilket underlättar analysen. För fas II analys, har två styrdiagram, ett baserat på Mann-Whitney's U teststatistika, som föreslagits av Chakraborti et al (2008), och ett på Mood's teststatistika för spridning, som föreslagits av Ghute et al (2014), implementerats. Styrkan i dessa styrdiagram ligger främst i dess enkla tolkning. För snabbare identifiering av processförändringar kan styrdiagrammet baserat på Cramer von Mises teststatistika, som föreslagits av Ross et al (2012), användas. Baserat på enskilda observationer, istället för stickprov, har styrdiagrammet en högre uppdateringsfrekvens. Detta leder dock till ett ökat antal falska larm och styrdiagrammet anses dessutom vara avsevärt mycket svårare att tolka för SPC-utövaren.

Made available in DSpace on 2015-05-14T13:00:08Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1948005 bytes, checksum: 96df7a3d564809417a83d020664df9fc (MD5) Previous issue date: 2014-11-21 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Herpes simplex labialis, one of the most prevalent viral infections worldwide, is a chronic, relapsing incurable disease, persist throughout the lifetime of the host, usually in a latent form. Facing the difficulty of finding an effective therapy to traditional medicine, we seek new possibilities in complementary medicine treatment for this condition. The study aimed to perform non-clinical and clinical phase I and II toxicological tests with topical antiviral celodenina, neoflavonide synthesized from the ethanol extract of the stem bark of Coutarea hexandra (Jacq) K. Shum, topically. Preclinical studies have evaluated the dermal primary skin irritation - acute effect (single dose) and acute eye irritation (single dose) and in both experiments albino rabbits Zealanders, healthy adults were used in number 12, being 6 males and 6 females (control and treated) at a dose of 0.5 g of the cream. The assessment of primary skin irritation demonstrated that the cream does not irritate the skin of rabbits tested in Drug Testing Laboratory of the Federal University of Paraíba, since none showed any degree of erythema and edema throughout the experiment. Regarding eye irritation simple, cream showed low irritant effect, as only 33.3% rabbits showed redness in conjunctiva during the first 24 hours after application of the test substance. Did not identify any changes in the iris and cornea, in any animal throughout the experiment. To investigate the clinical phase I toxicity in humans, the celodenina, 30 volunteers were selected, of both sexes, clinically healthy, aged between 18 and 65 years. Study participants were treated daily, the night shift, by dermal route, with the cream for a period of four weeks and evaluated before the start of the study and after its termination hematology (CBC), biochemical (glucose, urea, creatinine, total cholesterol, AST, ALT, alkaline phosphatase), in order to detect possible changes resulting from use of cream in them, as well as to compare the results before and after the study. No abnormal values for both hematological variables as for biochemical between times and groups were highlighted. During treatment with the cream, some adverse reactions were observed in participants: local dryness (7%), burning (13%), tingling (7%) and erythema (7%), but the number of affected subjects was small, and symptoms and signs reported occurred in the first week of the study, not requiring specific treatment, disappearing spontaneously. Clinical phase II trials were randomized, double-blind, comparing celodenina 4% with placebo in 33 patients with recurrent herpes labialis between 18 and 65 years, who used these substances three times daily for 15 days. Patients were also assessed before and after the study of hematological and biochemical tests, which showed no significant values between times. Few adverse effects were reported, burning (21%) and local dryness (5.3%), both mildly during the first 30 minutes after application in the first five days. Herpes recurrences were evaluated for 30, 60 and 90 days and the participants treated with celodenina 4% had lower percentage of same relative to placebo at all time. These results suggest a low toxicity of the product, satisfactorily efficient control of relapses and indicate that this formulation can be used in Phase III clinical trials, dose and route of administration tested in the treatment of recurrent herpes labialis. / O herpes simples labial, uma das infecções virais mais prevalentes no mundo, é doença crônica, recidivante e incurável, persistindo durante toda a vida do hospedeiro, geralmente sob a forma latente. Frente à dificuldade de se encontrar uma terapia eficaz com a medicina tradicional, busca-se na medicina complementar novas possibilidades de tratamento para esta patologia. O estudo objetivou realizar ensaios toxicológicos, não clínico e clínicos fase I e II, com o antiviral celodenina, neoflavonoide sintetizado, a partir do extrato etanólico das cascas do caule de Coutarea hexandra (Jacq) K. Shum, via tópica. Os estudos dermais não clínicos avaliaram a irritação primária da pele efeito agudo (dose simples) e a irritação ocular aguda (dose simples) e em ambos os experimentos foram utilizados coelhos albinos neozelandeses, sadios, adultos, em número de 12, sendo 6 machos e 6 fêmeas (controle e tratado) para uma dose de 0,5 g do referido creme. A avaliação da irritação primária da pele demonstrou que o creme não é irritante para a pele dos coelhos testados no Laboratório de Ensaios Toxicológicos da Universidade Federal da Paraíba, já que nenhum deles apresentou nenhum grau de eritema e edema durante todo o experimento. Em relação à irritação ocular simples, o creme demonstrou efeito de baixa irritabilidade, porque apenas 33,3% coelhos apresentaram rubor em conjuntiva nas primeiras 24 horas após a aplicação da substância em estudo. Não foi identificada nenhuma alteração na íris e na córnea, em qualquer dos animais em todo o experimento. Para investigar a toxicidade clínica fase I, em seres humanos, da celodenina, foram selecionados 30 voluntários, de ambos os sexos, clinicamente saudáveis, com faixa etária compreendida entre 18 e 65 anos. Os participantes do estudo foram tratados diariamente, no turno da noite, por via dermal, com o creme por um período de 4 semanas e avaliados antes do início do estudo e após o seu término com exames hematológicos (hemograma completo), bioquímicos (glicemia, uréia, creatinina, colesterol total, AST, ALT, fosfatase alcalina), com o objetivo de detectar possíveis alterações decorrentes da utilização do creme nos mesmos, bem como, comparar os resultados antes e após o término do estudo. Não foram evidenciados valores alterados, tanto para as variáveis hematológicas como para as bioquímicas entre os tempos e os grupos. Ao longo do tratamento com o creme, foram observadas algumas reações adversas nos participantes: ressecamento local (7%), ardor (13%), formigamento (7%) e eritema (7%), mas o número de voluntários acometidos foi pequeno, e os sintomas e sinais relatados ocorreram na primeira semana do estudo, não necessitando de tratamento específico, desaparecendo espontaneamente. Os estudos clínicos fase II foi randomizado, duplo-cego, comparando a celodenina 4% com placebo em 33 pacientes portadores de herpes labial recorrente entre 18 e 65 anos, que utilizaram as referidas substâncias 3 vezes ao dia durante 15 dias. Os pacientes também foram avaliados antes e após o término do estudo com exames hematológicos e bioquímicos, os quais não demonstraram valores significativos entre os tempos. Poucos efeitos adversos foram relatados, o ardor (21%) e o ressecamento local (5,3%), ambos, de forma branda, durante os primeiros 30 minutos após a aplicação nos primeiros 5 dias. As recidivas herpéticas foram avaliadas durante 30, 60 e 90 dias e os participantes tratados com celodenina 4% apresentaram menor percentual das mesmas em relação ao placebo em todos os tempos. Estes resultados sugerem a baixa toxicidade do produto, eficiência satisfatória no controle das recidivas e indicam que esta formulação pode ser utilizada para testes clínicos fase III, na dose e via de administração testada no tratamento do herpes labial recorrente.

Made available in DSpace on 2015-05-14T13:00:16Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1932289 bytes, checksum: a18b6ccc194715163ed381d04f52ec3d (MD5) Previous issue date: 2011-02-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The study aimed to perform toxicological tests and preclinical dermal clinical phase I, the hydrogel obtained from the hydroalcoholic extract from the bark of Anacardium occidentale Linn. The dermal preclinical studies have assessed the primary irritation of the skin - acute (single dose) and acute eye irritation (single dose) and in both experiments were used rabbits albino, New Zealand, healthy adults, numbering 12, with 6 males and 6 females (control and treated) for a dose of 0.5 g of the hydrogel obtained from the alcoholic extract of Anacardium occidentale Linn. The evaluation of primary irritation of the skin demonstrated that the hydrogel from the stem bark of Anacardium occidentale Linn is not irritating to the skin of rabbits tested in our laboratory, since only 25% of the rabbits showed barely perceptible erythema in the initial phase of the experiment (first time), and no degree of swelling was observed in rabbits throughout the experiment. In relation to the simple eye irritation, the hydrogel from the stem bark of Anacardium occidentale Linn also did not showed irritant effect, because only 33,3% and 8,3% rabbits showed, respectively, conjunctival redness and swelling in the first 24 hours after application of test substance. Did not present any change in level of the iris and cornea, in any animal throughout the experiment. To investigate the clinical phase I toxicity in humans, hydrogel from the stem bark of Anacardium occidentale Linn, we selected 28 volunteers, clinically healthy, aged between 18 and 25. Study participants were divided into two groups, male and female, with 14 participants each, and treated daily, on the night shift, via dermal, with the hydrogel from the stem bark of Anacardium occidentale Linn by a period of 4 weeks. The volunteers were tested before the start of the study and eight weeks after the study, haematological (CBC) and biochemical (glucose, urea, creatinine, total cholesterol, AST, ALT, alkaline phosphatase), in order to detect possible changes arising from the use of hydrogel in patients, as well as compare the results before and after the study. There was no evidence values changed for both hematology and for biochemical variables between times and groups. During treatment with the hydrogel from the stem bark of Anacardium occidentale Linn, Some adverse reactions were observed in participants: tingling, redness, and stinging, but the number of volunteers affected was small, and the reported symptoms occurred during the first weeks of the study and did not require specific treatment and disappeared spontaneously. Only 3,5% of the female volunteers reported feeling oily skin in three weeks of the study. In contrast, 10,7% (first week) and 3,5% (second week) of male volunteers reported skin feeling soft, "cleaner". These results suggest and the low toxicity of the product and indicate that this herbal formulation can be used by the population, the dose and route of administration tested. / O estudo objetivou realizar ensaios toxicológicos pré-clínicos dermais e clínicos fase I, com o hidrogel obtido a partir do extrato alcoólico das cascas de Anacardium occidentale Linn. Os estudos dermais pré-clínicos avaliaram a irritação primária da pele efeito agudo (dose simples) e a irritação ocular aguda (dose simples) e em ambos os experimentos foram utilizados coelhos albinos neozelandeses, sadios, adultos, em número de 12, sendo 6 machos e 6 fêmeas (controle e tratado) para uma dose de 0,5 g do hidrogel obtido a partir do extrato alcoólico das cascas de Anacardium occidentale Linn. A avaliação da irritação primária da pele demonstrou que o hidrogel das cascas do caule de Anacardium occidentale Linn não é irritante para a pele dos coelhos testados em nosso laboratório, já que apenas 25% dos coelhos estudados apresentaram eritema apenas perceptível, na fase inicial do experimento (primeira hora), e nenhum grau de edema foi observado nos coelhos durante todo o experimento. Em relação à irritação ocular simples, o hidrogel das cascas do caule de Anacardium occidentale Linn demonstrou também efeito não irritativo, porque apenas 33,3% e 8,3% dos coelhos, respectivamente, apresentaram rubor e edema em conjuntiva nas primeiras 24 horas após a aplicação da substância em estudo. Não foi identificada nenhuma alteração na íris e na córnea, em qualquer dos animais em todo o experimento. Para investigar a toxicidade clínica fase I, em seres humanos, do hidrogel das cascas do caule de Anacardium occidentale Linn, foram selecionados 28 voluntários, clinicamente saudáveis, com faixa etária compreendida entre 18 e 25 anos. Os participantes do estudo foram distribuídos em dois grupos, masculino e feminino, com 14 participantes cada um, e tratados diariamente, no turno da noite, por via dermal, com o hidrogel das cascas do caule de Anacardium occidentale Linn por um período de 4 semanas. Os voluntários foram avaliados antes do início do estudo e 8 semanas após o seu término com exames hematológicos (hemograma completo), bioquímicos (glicemia, uréia, creatinina, colesterol total, AST, ALT, fosfatase alcalina), com o objetivo de detectar possíveis alterações decorrentes da utilização do hidrogel nos pacientes, bem como, comparar os resultados antes e após o término do estudo. Não foram evidenciados valores alterados, tanto para as variáveis hematológicas como para as bioquímicas entre os tempos e os grupos. Ao longo do tratamento com o hidrogel das cascas do caule de Anacardium occidentale Linn, foram observadas algumas reações adversas nos participantes: formigamento, hiperemia, e ardência, mas o número de voluntários acometidos foi pequeno, e os sintomas relatados ocorreram nas primeiras semanas do estudo, não necessitando de tratamento específico, desaparecendo espontaneamente. Apenas 3,5% dos voluntários do sexo feminino relatou sensação de pele oleosa nas 3 últimas semanas do estudo. Em contrapartida, 10,7% (primeira semana) e 3,5% (segunda semana) dos voluntários do sexo masculino referiram sensação de pele macia, mais limpa . Estes resultados sugerem a baixa toxicidade do produto e indicam que esta formulação fitoterápica pode ser utilizada pela população, na dose e via de administração testada.

Cette thèse est consacrée à l'inférence de certains modèles statistiques mal spécifiés. Chaque résultat obtenu trouve son application dans une étude sur les facteurs pronostiques dans le cancer du sein, grâce à des données collectées par l'Institut Curie. Dans un premier temps, nous nous intéressons au modèle à risques non proportionnels, et exploitons la connaissance de la survie marginale du temps de décès. Ce modèle autorise la variation dans le temps du coefficient de régression, généralisant ainsi le modèle à hasards proportionnels. Dans un deuxième temps, nous étudions un modèle à hasards non proportionnels ayant un coefficient de régression constant par morceaux. Nous proposons une méthode d'inférence pour un modèle à un unique point de rupture, et une méthode d'estimation pour un modèle à plusieurs points de rupture. Dans un troisième temps, nous étudions l'influence du sous-échantillonnage sur la performance des forêts médianes et essayons de généraliser les résultats obtenus aux forêts aléatoires de survie à travers une application. Enfin, nous présentons un travail indépendant où nous développons une nouvelle méthode de recherche de doses, dans le cadre des essais cliniques de phase I à ordre partiel. / The thesis focuses on inference of statistical misspecified models. Every result finds its application in a prognostic factors study for breast cancer, thanks to the data collection of Institut Curie. We consider first non-proportional hazards models, and make use of the marginal survival of the failure time. This model allows a time-varying regression coefficient, and therefore generalizes the proportional hazards model. On a second time, we study step regression models. We propose an inference method for the changepoint of a two-step regression model, and an estimation method for a multiple-step regression model. Then, we study the influence of the subsampling rate on the performance of median forests and try to extend the results to random survival forests through an application. Finally, we present a new dose-finding method for phase I clinical trials, in case of partial ordering.

Die laufenden Aufrüstungsarbeiten des Large Hadron Colliders haben das Ziel, die Luminosität der Teilchenkollisionen zu erhöhen. Die erhöhte Luminosität liefert zwar neue Möglichkeiten für Präzisionsmessungen und Teilchensuchen, stellt aber gleichzeitig eine große Herausforderung an die beteiligten Experimente. Aus diesem Grund wird auch der ATLAS-Detektor aufgerüstet. Der Fokus ist dabei, eine hohe Effizienz des Triggers sicherzustellen, der die interessanten Physikereignisse in Echtzeit auswählt. Dafür wird das Flüssig-Argon-Kalorimeter des ATLAS-Detektors mit einer neuen Ausleseelektronik ausgerüstet. Um die Funktionsfähigkeit zu testen, wurde ein Demonstrationsaufbau der zukünftigen Ausleseelektronik installiert und von 2014 bis 2018 parallel zur ATLAS- Datennahme betrieben. In dieser Arbeit werden die Daten, die mit dem Aufbau aufgezeichnet wurden, analysiert. Die neue Ausleseelektronik erlaubt es, komplexere Algorithmen zur Erkennung von Signal- und Untergrundereignissen zu nutzen. Es handelt sich dabei um Variablen zur Beschreibung der Form von elektromagnetischen und hadronischen Teilchenschauern im Flüssig-Argon-Kalorimeter. Die Effizienz dieser Variablen wird untersucht. Dabei wird nach Kombination mehrerer Variablen eine Untergrundunterdrückung hadronischer Jets von 75 % bei einer Elektronenerkennungseffizienz von 90 % erreicht. Die zukünftige, erhöhte Luminosität führt dazu, dass sich bei Teilchenkollisionen die Zahl der Ereignisse, die sich sowohl zeitlich als auch räumlich überlappen, erhöht. Der Effekt dieser Überlappereignisse hat Auswirkungen auf die Energierekonstruktion. Daher wird eine Untersuchung der Überlappereignisse durchgeführt, um eine möglichst genaue Kenntnis über diese zu erhalten. Für die Rekonstruktion aus den Signalen der im Detektor deponierten Energie stehen verschiedene digitale Signalfilter zur Auswahl. Die Performanz hinsichtlich der Signalerkennung dieser Algorithmen wird überprüft. Es zeigt sich, dass neue digitale Signalfilter zwar den Effekt des zeitlichen Überlapps von Detektorpulsen reduzieren, jedoch sehr sensitiv auf die genaue Pulsmodellierung sind. / The ongoing upgrade activities at the Large Hadron Collider aim for an increase of the luminosity in the particle collisions. The increased luminosity delivers new capabilities for precision measurements and searches for signatures of new physics. At the same time, challenges arise for the experiments. For this reason, the ATLAS detector is upgraded. The focus is on maintaining the high efficiency of the trigger that selects interesting physics events in real-time. Therefore, the Liquid-Argon calorimeter of the ATLAS detector is upgraded with new readout electronics. To evaluate the performance, a demonstrator readout was installed and operated in parallel to the data taking of the main readout between 2014 and 2018. In this thesis, the data recorded with the demonstrator is analyzed. The new readout electronics allow more sophisticated algorithms to distinguish between signal and background events. They are based on variables that describe electromagnetic and hadronic showers. The proposed shower-shape variables are studied concerning their trigger efficiency and background rejection power. With a combination of the shower-shape variables, a background rejection power of 75 % for hadronic jets is achieved while keeping the electron trigger efficiency at 90 %. The increase in luminosity will lead to an increase in in-time and out-of-time pile-up effects. These have an impact on the energy reconstruction. Therefore, pile-up events are investigated, to gain precise knowledge about their effects. For the energy reconstruction of the detector signals, different digital filter algorithms are available. The signal detection efficiency of these algorithms is examined. While new filter algorithms are capable of reducing the effect of out-of-time pile-up, they depend greatly on the correct phase of the pulse shape.

Dans les Antilles françaises, une proportion anormalement élevée de parkinsonismes atypiques sporadiques – des tauopathies – est observée. Un lien avec la consommation de plantes de la famille des Annonaceae, en particulier Annona muricata L. (corossol) a été démontré. Les acétogénines d’Annonaceae, des inhibiteurs puissants du complexe I de la chaine respiratoire mitochondriale, sont considérées comme des toxines candidates. L’annonacine, une acétogénine représentative, majoritaire dans A. muricata, est neurotoxique in vitro et in vivo. L’Agence Française de Sécurité Sanitaire des Aliments a exprimé ses doutes quant à ce problème de santé publique. Elle insiste sur l’importance d’évaluer l’exposition des consommateurs d’Annonaceae aux acétogénines, et de déterminer les paramètres pharmacocinétiques de ces molécules. Au cours de cette thèse, nous avons cherché à répondre à ces interrogations, avec l’annonacine pour modèle. Après l’analyse structurale d’acétogénines étalons, une méthode de déréplication puissante et innovante a été mise au point par CLHP-ESI-LTQ-Orbitrap® avec infusion post-colonne de lithium. Les profils complets des acétogénines d’extraits bruts issus d’un nectar d’A. muricata et d’un alcool d’Annona cherimolia Mill. (annone, chérimole) ont été élucidés, mettant en évidence une composition plus complexe et plus variée que celle envisagée dans la littérature. A. cherimolia n’avait pas été identifiée comme une source d’exposition jusqu’à maintenant. Des données quantitatives ont été obtenues par CLHP-DAD-MS, à partir d’une quinzaine d’échantillons de produits commerciaux, confirmant une exposition humaine importante à ces molécules par voie alimentaire, via des produits d’origines géographiques, de statuts et de modes d’obtention variés. Des travaux préliminaires d’étude du passage de l’annonacine à travers des membranes biologiques ont été amorcés (modèles de barrières intestinale – Caco-2 – et hémato-encéphalique – hCMEC/D3). Une étude de métabolisation de phase I de l’annonacine sur microsomes de foie de Rat a permis d'identifier 25 métabolites mono-hydroxylés par CLHP-ESI-LTQ-Orbitrap®. Seuls trois d’entre eux sont observés avec des microsomes humains. Ces métabolites ont été obtenus par hémisynthèse (bioconversion, catalyse par porphyrines) et leur structure a été déterminée. Les résultats montrent que cette étape de métabolisation n’est pas cruciale dans le devenir de l’annonacine, et ne peut expliquer de susceptibilité différentielle aux acétogénines. Après la présentation de rappels concernant les Annonaceae, les parkinsonismes et leurs formes atypiques guadeloupéennes et tropicales, puis d’aspects méthodologiques en spectrométrie de masse, nos travaux de phytochimie analytique, d’analyse métabolique, d’hémisynthèse et de détermination structurale sont présentés, et discutés en regard d’un problème de santé publique potentiellement large et préoccupant. / In the French West Indies, an unusually high proportion of atypical sporadic parkinsonisms - tauopathies - is observed. A link between these atypical parkinsonisms and the consumption of plants of the Annonacea family, Annona muricata L. (soursop) was demonstrated. The Annonaceous acetogenins are potent inhibitors of complex I of mitochondrial respiratory chain and are considered to be in vitro toxins candidate. The major acetogenin in Annona muricata, annonacin, is neurotoxic in in vitro and in vivo models. Afssa (Agence Française de Sécurité Sanitaire des Aliments) expressed its concern regarding this public health problem. The Agency reports the importance of assessing consumers ‘exposure to Annonaceous acetogenins, and of determining the pharmacokinetic of these molecules. In this thesis, we sintended to answer these questions, with annonacine as a model. After the structural analysis of acetogenins standards, a powerful and innovative method of dereplication was developed by HPLC-ESI-LTQ-Orbitrap ® with post-column infusion of lithium. Complete acetogenins profile in crude extracts from nectar of A. muricata and from an alcohol of Annona cherimolia Mill. (Annona, cherimoya) were elucidated, revealing a more complex and more varied composition than that proposed in the literature. A. cherimolia had not been identified as a source of exposure to date. Quantitative data were obtained by HPLC-DAD-MS, from fifteen samples of commercial products, confirming an important human exposure to these molecules through food products of varied geographical origins, status and methods. Preliminary works to study ability of annonacin to cross biological membranes have been initiated (intestinal barrier models - Caco-2 - and blood-brain barrier - hCMEC/D3). A study of phase I metabolism of annonacin in rat liver microsomes allowed the identification of 25 mono-hydroxylated metabolites by HPLC-ESI-LTQ-Orbitrap®. Only three of them were observed with human microsomes. These metabolites were obtained by semisynthesis (bioconversion, porphyrin mediated catalysis) and their structure was determined. The results show that phase metabolism is not critical in the becoming of annonacin, and cannot explain a differential susceptibility of acetogenins. After a presentation of the Annonaceae family, of parkinsonism – including atypical and guadeloupean forms then of and methodological aspects of mass spectrometry, analytical phytochemistry of our work, metabolic analysis, semisynthesis and structure determination are proposed, and discussed in the context of a public health problem and potentially broad concern.

Made available in DSpace on 2016-06-02T20:18:19Z (GMT). No. of bitstreams: 1 4875.pdf: 19049146 bytes, checksum: c54256037244fb411763a05e459a625a (MD5) Previous issue date: 2011-02-28 / There are very few published studies evaluating the effect of a protocol of graded exercise of short duration, during phase I cardiac rehabilitation (CR) on the cardiac autonomic modulation in patients after acute myocardial infarction (AMI), thus three investigations were undertaken in order to evaluate the safety of the protocol of cardiovascular therapy (CPT) phase I, as well as observing the behavior of heart rate (HR), blood pressure (BP) and autonomic modulation of HR through HR variability (HRV) in time domain (TD) and frequency (DF) in patients undergoing phase I protocol CPT after the 1st AMI. Physical therapy in phase I of the CR can be initiated 12 to 24 hours after AMI, however, it is common to prolonged bed rest due to fears of instability of the patient. So the goal of the 1st study was to evaluate the hemodynamic and autonomic responses to post-AMI patients undergoing day 1 of phase I protocol of CPT, as well as their safety. We studied 51 patients with first AMI uncomplicated, 5511 years, 76% men and submitted to the 1st day of the protocol CPT Stage I, on average, 24 hours after AMI, consisting of 10 minutes of rest before and after exercises, followed by 4 min of breathing exercises and 5 min of dynamic exercise. The results indicate that the exercise was safe because it caused hemodynamic and autonomic modulation in these patients, without causing any medical complications. The 2nd study aimed to characterize the autonomic and hemodynamic responses to CPT in patients with stage I of an AMI. We studied 21 patients with first uncomplicated AMI, age 5212 years, 81% men, six days a progressive exercise program (phase I CPT), consisting of a daily standard protocol (10 min rest in supine position pre-and post-exercise and 4 min of breathing exercises) and a protocol for dynamic graded exercise, progressing to active-assisted movements of the legs in the first days after AMI, even walking in the last days of hospitalization. The protocol applied CPT promoted hemodynamic and autonomic changes during the course of the year, allowing early mobilization of the patient and gradually preparing to return to their activity of daily living after discharge from hospital, without being observed the presence of any sign and / or symptoms of exercise intolerance. The 3rd study was to evaluate the effects of a progressive exercise protocol used in phase I of RCV on HRV at rest in patients after AMI. We studied thirty-seven patients who were admitted to hospital with first uncomplicated AMI. The treated group (TG) (n= 21, age= 52±12 years) conducted a five-day program of progressive exercises during phase I of the RCV, while the control group (CG) (n= 16, age= 54±11 years) had only breathing exercises. The progressive exercise program performed during the first phase of cardiac rehabilitation associated with clinical treatment increased cardiac vagal modulation and reduced cardiac sympathetic modulation in patients after AMI. Overall Conclusion: The results of the three studies suggest that the protocol is safe when applied CPT started after 24 hours of AMI not complicated, and allows early mobilization of patients and gradually prepare them to return their activity of daily living after discharge, without being observed the presence of any sign and / or symptoms of exercise intolerance. In addition the progressive exercise program that compose the physiotherapy intervention associated with clinical treatment caused an increase in cardiac vagal modulation and reduction of cardiac sympathetic modulation at rest in the patients studied. / Há carência de estudos na literatura que avaliem o efeito de um protocolo de exercício físico progressivo (EFP) de curta duração, durante fase I da reabilitação cardiovascular (RCV), sobre a modulação autonômica cardíaca em pacientes pós-infarto agudo do miocárdio (IAM), deste modo, uma investigação dividida em três partes foi desenvolvida no intuito de avaliar a segurança do protocolo de fisioterapia cardiovascular (FTCV) fase I, bem como, observar o comportamento da frequência cardíaca (FC), da pressão arterial (PA) e da modulação autonômica da FC, por meio da variabilidade da FC (VFC) nos domínios do tempo (DT) e da freqüência (DF), em pacientes submetidos ao protocolo de FTCV fase I após o 1º IAM. A fisioterapia na fase I da RCV pode ser iniciada de 12 a 24 horas após o IAM, no entanto, é comum o repouso prolongado no leito devido ao receio de instabilização do paciente. Assim o objetivo do 1º estudo foi avaliar as respostas autonômicas e hemodinâmicas de pacientes pós-IAM submetidos ao 1º dia de protocolo de FTCV fase I, bem como, sua segurança. Foram estudados 51 pacientes com 1o IAM não-complicado, 5511 anos, 76% homens e submetidos ao 1º dia do protocolo de FTCV fase I, em média, 24 horas pós-IAM, composto de 10 min de repouso pré e pós-exercícios, 4 min de exercícios respiratórios e 5 min de exercícios físicos dinâmicos (EFD) de membros inferiores (MMII). Os resultados obtidos indicam que o exercício realizado foi seguro, pois promoveu alterações hemodinâmicas e na modulação autonômica da FC nestes pacientes, sem ocasionar qualquer intercorrência clínica. O 2º estudo teve como objetivo caracterizar as respostas autonômicas e hemodinâmicas a FTCV fase I em pacientes com 1º IAM. Foram estudados 21 pacientes com 1o IAM não-complicado, idade 5212 anos, 81% homens, durante 6 dias de um programa de EFP (FTCV fase I), composto por um protocolo padrão diário (10 min de repouso na posição supina pré e pós-exercícios e 4 min de exercícios respiratórios) e um protocolo de EFD gradativos, progredindo de movimentos ativo-assistidos de MMII no 1o dia pós-IAM até deambulação nos últimos dias de internação. O protocolo de FTCV aplicado promoveu alterações autonômicas e hemodinâmicas durante a realização do exercício, permitindo a mobilização precoce do paciente e gradativamente o preparando para o retorno a sua atividade de vida diária (AVD) após a alta hospitalar, sem ser observada presença de qualquer sinal e/ou sintoma de intolerância ao esforço. O 3º estudo teve por objetivo avaliar os efeitos de um protocolo de EFP utilizado na fase I da FTCV sobre a VFC de repouso de pacientes pós-IAM. Foram estudados 37 pacientes com 1º IAM não complicado. O grupo tratado (GT) (n=21, idade=52±12 anos) realizou 5 dias de um programa de EFP durante a fase I da FTCV, enquanto o grupo controle (GC) (n=16, idade=54±11 anos) realizou somente exercícios respiratórios. O programa de EFP realizado durante a fase I da FTCV associado ao tratamento clínico aumentou a modulação vagal cardíaca e reduziu a modulação simpática cardíaca em pacientes pós-IAM. Conclusão geral: Os resultados obtidos nas três partes do estudo sugerem que o protocolo de FTCV aplicado é seguro quando iniciado após 24 horas do IAM não complicado, além de permitir a mobilização precoce dos pacientes e gradativamente os preparar para o retorno as suas AVDs após a alta hospitalar, sem ser observada presença de qualquer sinal e/ou sintoma de intolerância ao esforço. Em adição o programa de EFP que compõem a FTCV fase I associado ao tratamento clínico promoveram aumento da modulação vagal cardíaca e redução da modulação simpática cardíaca em repouso nos pacientes estudados.

Made available in DSpace on 2016-06-02T20:19:28Z (GMT). No. of bitstreams: 1 DissMDBS.pdf: 1917686 bytes, checksum: 9d2cd0affae35c5474a851d16fe9b2e0 (MD5) Previous issue date: 2006-03-23 / Universidade Federal de Minas Gerais / The purpose of the present study was to evaluate the effects of physiotherapeutic intervention on the autonomic control of heart rate through heart rate variability (HRV) indices at rest (supine and seated positions), during deep breath test (DBT), during an exercise protocol and during walking, in patients with acute myocardial infarction (AMI) submitted to phase I of cardiac rehabilitation. Second, evaluate the effects of an inspiratory muscle training (IMT) on the maximal inspiratory pressure (PImax) and on the magnitude of respiratory sinus arrhythmia (RSA). Initially, thirty five patients of both genders were studied in the 1st stage of the cardiovascular physiotherapy (CPT), however, only eighteen of them performed all six stages of treatment (mean = 56± 13 year). These patients, who were admitted to the Coronary Care Unit (CCU) (two days) and the ward (four days) of the Santa Casa de Misericórdia de São Carlos with noncomplicated AMI, were hemodynamically stable and used conventional medications. The 1st stage was initiated 22± 5 hours after the CCU admission and the progression to other 5 stages was done based in the daily clinical evolution of each patient. This stage included 10 minutes of rest (pre and post-exercise protocol), 4 minutes of deep breathing test and 5 minutes of exercise protocol (active-assisted low extremities exercises) in the supine position. Furthermore, the 6th stage included 10 minutes of rest in the supine position (pre and post-intervention), 4 minutes of deep breathing test, 5 minutes of rest in the seated position (pre and post-intervention), 5 minutes of active low extremities exercises in the orthostatic position and 15 minutes of walking. The instantaneous heart rate (HR) and the R-R interval (RRi) were acquired by a HR monitor (Polar S810) during all stage and the blood pressure (BP) was measured before and after each stage. Additionally, the PImax was measured (in the seated position) through a manuvacuometer at the pre and post-IMT, which was performed at the 2nd to 6th stages. The intensity of IMT was settled at 40% of PImax pressure load. The HRV was analyzed by time (RMSSD and RMSM indices) and frequency (Fast Fourier Transform) domain methods. The power spectral density was expressed as normalized units (nu) at low (LF) and high (HF) frequencies, and as the LF/HF. Results: The cumulative effect of physiotherapeutic intervention caused increase of AFnu (p<0.05) and decrease of LFnu (p<0.05) when they were evaluated at the rest pre-intervention in the supine position and during exercise protocol of 1st and 6th stages. Additionally, decreased LF/HF was also observed at rest pre-intervention in the supine position. However, no changes were observed for these indices when the 1st and 6th stages were compared to during the RSA, in the rest post-intervention (supine position) and in the rest pre and post-intervention (seated position), and the 4th and 6th stages were compared to during the walking. In the time domain, RMSM and RMSSD diminished at 1st to 6th stages for rest post-intervention in supine position. The IMT augmented the PImax in 46% (P<0.05), but increased PImax and the RSA magnitude did not correlate among them. Conclusion: The CPT realized in the phase I of the cardiac rehabilitation caused increase in the vagal activity and decrease the sympathetic activity during rest and exercises conditions, since the beta-blockade and IECA medications dosages were not altered. Additionally, the intensity used in the IMT was able to improve the PImax, but it did not influence on the RSA magnitude. Financial support: FAPESP (04/05788-6) and CNPq (478799/2003-9). / O presente estudo teve como principal objetivo avaliar a modulação do sistema nervoso autônomo no coração, por meio do comportamento da variabilidade da freqüência cardíaca (VFC) em repouso, supino e sentado, durante manobra para acentuar a arritmia sinusal respiratória (ASR), exercício e deambulação em pacientes com infarto agudo do miocárdio (IAM) antes e após serem submetidos à fisioterapia: fase I da reabilitação cardiovascular. Como objetivo secundário foi avaliada a pressão inspiratória máxima (PImáx) antes e após um programa de treinamento muscular inspiratório (TMI), bem como, a influência do TMI na magnitude da ASR. Foram estudados 35 pacientes na 1ª etapa (controle) e 18 antes e após a fisioterapia cardiovascular (FTCV), com idade média de 56±13 anos, de ambos os sexos, internados na Unidade Coronariana (UCO) (2 dias) e enfermaria da Irmandade Santa Casa de Misericórdia de São Carlos (4 dias) com IAM não complicado. Todos estavam hemodinamicamente estáveis e em uso de medicações convencionais. Foram submetidos a 1ª etapa após 22±5 horas da chegada na UCO e progrediram na FTCV até a 6ª etapa, diariamente, baseado na evolução clínica. A 1ª etapa foi composta de 10 minutos (min) de repouso supino pré (R1) e pós-intervenção (R2), 4 min da manobra para acentuar a ASR (MASR) e 5 min de exercícios ativos-assistidos de membros inferiores (MMII) na postura supina. Já a 6ª etapa foi composta de 10 min de R1 e R2, 4 min da MASR, 5 min de repouso sentado pré (RS1) e pós-intervenção (RS2), 5 min de exercícios ativos de MMII na postura em pé e 15 min de deambulação. Os intervalos R-R (iRR) e a freqüência cardíaca (FC) foram obtidos, batimento a batimento, pelo freqüencímetro Polar® S810i e a pressão arterial (PA) foi aferida antes, durante e após a FTCV. A medida da PImáx foi realizada com um manovacuômetro, na posição sentada, na 2ª etapa e reavaliada na 6ª etapa. O TMI foi realizado, na posição sentada, da 2ª até a 6ª etapa, sendo que a carga pressórica foi de 40% da PImáx obtida na 2ª etapa. A VFC foi analisada nos domínios do tempo (DT - índices RMSSD e RMSM dos iRR em ms) e da freqüência (DF por meio da análise espectral), a qual forneceu as bandas de baixa freqüência (BF) e alta freqüência (AF), expressas em unidades normalizadas (un), e a razão BF/AF. Resultados: Com relação ao efeito cumulativo das seis etapas da FTCV, no DF, houve diminuição da BFun e aumento da AFun no R1 e durante o exercício e diminuição da razão BF/AF no R1 da 1ª para a 6ª etapa, não havendo alterações destas variáveis durante a MASR e no R2 da 1ª para a 6ª etapa, no RS1 e RS2 da 2ª para 6ª etapa e durante a deambulação da 4ª para 6ª etapa. No DT, os índices RMSSD e RMSM diminuíram no R2 da 1ª para a 6ª etapa. Houve aumento de 46% da PImáx com o TMI (p<0,05) e não houve correlação entre o aumento da PImáx e a magnitude de resposta da ASR. Conclusões: A FTCV fase I aplicada aos pacientes com IAM promoveu aumento da atuação vagal e redução da atuação simpática tanto na condição de repouso supino como durante a execução de exercício, uma vez que a dosagem das medicações betabloqueadores e inibidoras da enzima conversora de angiotensina permaneceram inalteradas durante o estudo. Ainda, o TMI promoveu aumento da PImáx na intensidade aplicada, no entanto, não influenciou a magnitude de resposta da ASR Suporte Financeiro: FAPESP Proc. 04/05788- 6, CNPq Proc. 478799/2003-9.

Double sampling procedure is adapted from a statistical branch called acceptance sampling. The first Shewhart-type double sampling monitoring scheme was introduced in the statistical process monitoring (SPM) field in 1974. The double sampling monitoring scheme has been proven to effectively decrease the sampling effort and, at the same time, to decrease the time to detect potential out-of-control situations when monitoring the location, variability, joint location and variability using univariate or multivariate techniques. Consequently, an overview is conducted to give a full account of all 76 publications on double sampling monitoring schemes that exist in the SPM literature. Moreover, in the review conducted here, these are categorized and summarized so that any research gaps in the SPM literature can easily be identified. Next, based on the knowledge gained from the literature review about the existing designs for monitoring the process mean, a new type of double sampling design is proposed. The new charting region design lead to a class of a control charts called a side-sensitive double sampling (SSDS) monitoring schemes. In this study, the SSDS scheme is implemented to monitor the process mean when the underlying process parameters are known as well as when they are unknown. A variety of run-length properties (i.e., the 5th, 25th, 50th, 75th, 95th percentiles, the average run-length (𝐴𝑅𝐿), standard deviation of the run-length (𝑆𝐷𝑅𝐿), the average sample size (𝐴𝑆𝑆) and the average extra quadratic loss (𝐴𝐸𝑄𝐿) metrics) are used to design and implement the new SSDS scheme. Comparisons with other established monitoring schemes (when parameters are known and unknown) indicate that the proposed SSDS scheme has a better overall performance. Illustrative examples are also given to facilitate the real-life implementation of the proposed SSDS schemes. Finally, a list of possible future research ideas is given with hope that this will stimulate more future research on simple as well as complex double sampling schemes (especially using the newly proposed SSDS design) for monitoring a variety of quality characteristics in the future. / Statistics / M. Sc. (Statistics)

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