<p>The nasal passages are constantly exposed to both air- and bloodborne foreign compounds. In particular, the olfactory mucosa is demonstrated to be susceptible to a variety of drugs and chemicals. In this thesis, mechanisms involved in tissue-selective toxicity in the olfactory mucosa of rodents have been investigated using the olfactory toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO₂) as a model compound. Comparative studies were performed with the non-toxic 2,5-dichlorophenyl methylsulphone (2,5-diClPh-MeSO₂) and the reasons for the strikingly different toxicity were investigated. </p><p>A strong bioactivation and protein adduction of 2,6-diClPh-MeSO₂ in olfactory microsomes and S9-fractions of rodents was demonstrated. In contrast, no significant metabolic activation of 2,5-diClPh-MeSO₂ was observed and the bioactivation in the liver for both chlorinated isomers was negligible. <i>In vitro</i> studies with recombinant yeast cell microsomes expressing mouse cytochrome P450 2A5 (CYP2A5) demonstrated a metabolic activation of 2,6-diClPh-MeSO₂. The 2,6-diClPh-MeSO₂-induced lesions and CYP2A5 expression preferentially occurred in Bowman’s glands and sustentacular cells of the olfactory mucosa. A significant depletion of glutathione (GSH) in the olfactory mucosa was demonstrated <i>in vivo</i>, while no changes were observed in the liver. There was a rapid induction of the endoplasmic reticulum (ER)-specific chaperone Grp78, activation of the ER-specific caspase-12 and the downstream caspase-3 in the Bowman’s glands. Electron microscopy revealed swelling of ER and mitochondria and a lost integrity of the Bowman’s glands. </p><p>Based on these results, the proposed mechanism for 2,6-diClPh-MeSO₂-induced toxicity in the olfactory mucosa is bioactivation by CYP2A5 into a reactive intermediate causing protein adduction and GSH-depletion. This is initiating a sequence of downstream events of ER-stress, changes in ion homeostasis, ultrastructural organelle disruption and apoptotic signalling. In spite of the initial apoptotic signals, the terminal phase of apoptosis seemed to be blocked and necrotic features occurred. The predominant expression of CYP2A5 in the olfactory mucosa is proposed to play a key role for the tissue- and cell-specific toxicity induced by 2,6-diClPh-MeSO₂.</p>

The nasal passages are constantly exposed to both air- and bloodborne foreign compounds. In particular, the olfactory mucosa is demonstrated to be susceptible to a variety of drugs and chemicals. In this thesis, mechanisms involved in tissue-selective toxicity in the olfactory mucosa of rodents have been investigated using the olfactory toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) as a model compound. Comparative studies were performed with the non-toxic 2,5-dichlorophenyl methylsulphone (2,5-diClPh-MeSO2) and the reasons for the strikingly different toxicity were investigated. A strong bioactivation and protein adduction of 2,6-diClPh-MeSO2 in olfactory microsomes and S9-fractions of rodents was demonstrated. In contrast, no significant metabolic activation of 2,5-diClPh-MeSO2 was observed and the bioactivation in the liver for both chlorinated isomers was negligible. In vitro studies with recombinant yeast cell microsomes expressing mouse cytochrome P450 2A5 (CYP2A5) demonstrated a metabolic activation of 2,6-diClPh-MeSO2. The 2,6-diClPh-MeSO2-induced lesions and CYP2A5 expression preferentially occurred in Bowman’s glands and sustentacular cells of the olfactory mucosa. A significant depletion of glutathione (GSH) in the olfactory mucosa was demonstrated in vivo, while no changes were observed in the liver. There was a rapid induction of the endoplasmic reticulum (ER)-specific chaperone Grp78, activation of the ER-specific caspase-12 and the downstream caspase-3 in the Bowman’s glands. Electron microscopy revealed swelling of ER and mitochondria and a lost integrity of the Bowman’s glands. Based on these results, the proposed mechanism for 2,6-diClPh-MeSO2-induced toxicity in the olfactory mucosa is bioactivation by CYP2A5 into a reactive intermediate causing protein adduction and GSH-depletion. This is initiating a sequence of downstream events of ER-stress, changes in ion homeostasis, ultrastructural organelle disruption and apoptotic signalling. In spite of the initial apoptotic signals, the terminal phase of apoptosis seemed to be blocked and necrotic features occurred. The predominant expression of CYP2A5 in the olfactory mucosa is proposed to play a key role for the tissue- and cell-specific toxicity induced by 2,6-diClPh-MeSO2.

The overall aim of this thesis on congenital clubfoot was to estimate the incidence with a national perspective, analyse residual deformities and their management, and evaluate patient reported long-term quality of life and foot function. Paper I was a prospective, nationwide sampling of 280 children with congenital clubfoot during 1995-96. The average incidence was 1.4‰. There was regional heterogeneity but no seasonal variation. Paper II evaluated ultrasonography on 54 newborn, prospectively followed up to 12 months of age. Significant increase of medial malleolus to navicular distance (MM-N-distance) and of soft tissue thickness with increasing age was seen and with acceptable reliability. Paper III assessed 35 children (47 feet) after previous posterior release, mean age of 4.5 years, and the MM-N-distance was shorter in unilateral clubfeet (21 patients) than in contralateral normal feet. No association between navicular position and forefoot adduction (FFA) was determined. Smaller FFA yielded better subjective and functional outcome. Paper IV reviewed distraction treatment with Ilizarov External Fixator in seven patients (10 feet), 6-15 years of age, with relapsed deformities. All patients, except one, reported satisfaction with the overall result but less stiffness was experienced in only 4/10 feet. Paper V evaluated self-estimated outcome in 83 patients (63 males, 20 females), mean age of 64 years, through SF-36 and EQ-5D, and through AAOS foot and ankle score. Age and gender adjusted norm groups were used. Female patients scored worse than male patients did. Both males and females reported negative influence on foot and ankle function. Conclusion: The incidence of congenital clubfoot in Sweden is higher than in previous Scandinavian studies. Ultrasonography is reliable for describing pathoanatomy of the talo-navicular joint in clubfeet and can detect "spurious" (false) correction. Distraction treatment with the Ilizarov External Fixator yields subjective improvement but stiffness remains. Long-term influence on daily life activities is limited to foot and ankle function for both genders, but only female patients report negative influence on physical aspects of quality of life.

Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2013-04-10T17:55:55Z No. of bitstreams: 1 Luiz.pdf: 5892404 bytes, checksum: 4fdceae3cd45c4ee27c8b376fbaacefb (MD5) / Approved for entry into archive by Rodrigo Meirelles(rodrigomei@ufba.br) on 2013-04-22T19:26:19Z (GMT) No. of bitstreams: 1 Luiz.pdf: 5892404 bytes, checksum: 4fdceae3cd45c4ee27c8b376fbaacefb (MD5) / Made available in DSpace on 2013-04-22T19:26:19Z (GMT). No. of bitstreams: 1 Luiz.pdf: 5892404 bytes, checksum: 4fdceae3cd45c4ee27c8b376fbaacefb (MD5) Previous issue date: 2009 / Esse trabalho foi realizado tendo como base a pesquisa sobre as condições de abastecimento na Bacia Hidrográfica do Rio Itapicuru, Bahia, em cinqüenta e quatro municípios, dez deles localizados no trecho médio do rio, e oito dos quais banhados pelo mesmo e que apresentam grande deficiência no abastecimento d’água. Analisando o potencial produtivo de recursos hídricos subterrâneos e de superfície dessa região, foi definida uma macro região deficiente para estudo. Essa região, apesar de possuir mananciais produtivos com boas condições em quantidade e qualidade, tem o abastecimento extremamente deficiente, por não dispor de infraestrutura de adução de água para o fornecimento às populações. A região de estudo abrange o município de Quijingue e a parte norte do município de Tucano. Foram definidos aglomerados de povoados, cada qual constituindo uma Unidade de Distribuição a ser abastecida, a partir dos Pontos de Produção selecionados. A região-piloto definida para estudo, foi organizada com seis Unidades de Distribuição e oito Pontos de Produção, permitindo o exame de quarenta e oito possibilidades de adução de água, e a seleção das melhores opções para atender satisfatoriamente o abastecimento à maioria expressiva dos povoados. A decisão sobre um sistema ótimo, com tantas alternativas e variáveis envolvidas, resulta num problema complexo. Visando tratar o problema sistemicamente e, definir as melhores condições para as aduções sob um ponto de vista técnico e econômico, foi empregada a técnica de otimização. Optou-se pelo modelo de Programação Inteira Linear, considerando-se vazões máximas de produção dos pontos principais disponíveis; a demanda hídrica dos povoados; as distâncias entre os Pontos de Produção e as Unidades de Distribuição (UDs); as perdas de energia para condução das vazões; e, os custos dos sistemas de adução de água, por gravidade e por recalque, conforme as condições topográficas.Assumindo-se algumas simplificações no problema, a exemplo do traçado linear das adutoras. As curvas de custos tiveram que ser linearizadas, com isso tendo-se que introduzir variáveis inteiras binárias. O resultado do modelo de otimização apontou apenas seis adutoras, como opções ótimas,com base no objetivo de menor custo e atendendo integralmente as restrições. Concluindo-se ser promissor o emprego dessa metodologia no planejamento dos sistemas hidráulicos, visando apoiar estudos para o desenvolvimento da infraestrutura hídrica.Trata-se de abordagem sistêmica pouco usual no meio técnico, mas que pode vir a ser incorporada e, com isso, possibilitando avançar com relação às análises benefício-custos tradicionais e predominantes. / Salvador

Title: Kinematic and kinetic analysis of artistic gymnastic jumps Objectives: The aim of my master thesis is execution of kinematic - kinetic analysis of jumps in artistic gymnastics, processing data, counting force moment, which does the rotation around ventrodorsal axis, means abduction and adduction motion and recount normalized moment (moment share by body weight). Methods: The kinematic - kinetic analysis of jumps in artistic gymnastics was done by using systems Qualysis Motion Capture System and Kistler. Results: We have been researching four different gymnastic jumps in this study. Four healthy individuals underwent the measurement. They have done each jump in free valid times. There was measured abduction moment of knee joint in each jump. Adduction moments were present only in 32 % cases and lot of them hasn't significant value. There was measured abduction moment in bounces in each jump, value of standardized adduction moment wasn't signifiant. There was measured just abduction moments in dismounts of non-rotational jumps. In dismounts of rotational jumps (around longitudinal axes) was measured abduction and also adduction moment. Values of normalized abduction moments were between 0,3 - 11 m2 .s-2 . Values of normalized adduction moments were between 0 - 10 m2 .s-2 . Highest values of...

Ressource naturelle aussi précieuse qu’indispensable à nos sociétés contemporaines que pendant l’Antiquité, l’eau est le point central de ce sujet de doctorat, que nous avons décidé d’aborder sous l’angle de sa gestion par les différents échelons du pouvoir au sein de l’Empire romain mais également au niveau individuel et privé, et cela à travers l’exemple de la ville romaine de Dougga, située en Afrique Proconsulaire, l’actuelle Tunisie. Cette problématique propose ainsi de s’intéresser aux moyens mis en œuvre par les différents niveaux de responsabilités dans le but d’approvisionner et de gérer les besoins en eau d’une importante ville romaine d’Afrique, en se consacrant à l’étude des différents types d’installations hydrauliques. Cette recherche permet de distinguer les techniques de construction et d’identifier les savoir-faire locaux et les influences romaines. Enfin, la confrontation des équipements hydrauliques entre les différents types d’édifices, permet d’évaluer le mode de gestion de l’eau à l’échelle de la ville. / Natural resource as precious and indispensable to contemporary society during ancient times, water is the central topic of this thesis. We decided to address in terms of its management by different levels of power within the Roman Empire but also at individual and private, through the example of the provincial city of Thugga, in Africa Proconsularis, now Tunisia. This issue proposes to focus the resources used by the different levels of responsibilities in order to supply and manage the water needs of an important Roman city of Africa, dedicated to the study of different types of hydraulic structures.

One of the most devastating effects of tetraplegia is the inability to grasp and manipulate everyday objects necessary to living an independent life. Currently surgery is widely accepted as the solution to improve hand functionality. However, surgery becomes difficult when the user has paralysed wrists as is the case with C5 tetraplegia. The aim of this research was to develop a solution which provided controlled wrist flexion and extension which, when combined with surgery, achieves a 'key pinch' grip. This particular grip is critically important for people with C5 tetraplegia as it is used for countless grasping activities, necessary on a day-to-day basis. A systematic design process was used to evolve the solution to provide controlled wrist flexion and extension. Concept brainstorming identified four alternative solutions which were evaluated to find the preferred concept. The chosen solution was called the Self Powered Wrist Extension Orthosis, more commonly referred to as the 'orthosis'. This concept contained a shoulder harness which provided both energy and control to the wrist harness, which in turn changed the wrist position. The orthosis was developed with the use of a mathematical model which theoretically predicted the functional performance by comparing the required force needed to move the wrist harness to the achievable force supplied by the user's shoulders. Using these parameters, the orthosis was optimized using the matlab Nelder-Mead algorithm which adjusted the wrist harness geometries to maximize the functional performance. A prototype was constructed and tested with the help of two participants who when combined, achieved an average of 18.5° of wrist rotation. The theoretical model however predicted an average range of motion of 28.4°. The discrepancy found between the theoretical and experimental result can be contributed to incorrect assumptions in the theoretical model. This included unaccounted friction and inaccurate modeling of the orthosis dynamics. The feedback from potential users of the orthosis was enthusiastic and encouraging especially towards the simplicity, usability and practicality of the design.

Cette thèse a pour objectif d’étudier les aménagements hydrauliques de Termessos en Pisidie dont le site montagneux et isolé est dépourvu de sources, en rassemblant le corpus de toutes les structures explorables, et d’en définir l’intérêt technologique et socio-Historique durant l’époque hellénistique et impériale. Après le dépouillement des sources écrites et de la bibliographie moderne, nous avons effectué une exploration détaillée du terrain. Plusieurs méthodes ont été appliquées au cours des six prospections archéologiques qui ont eu lieu entre 2010 et 2013, telles qu’une étude géophysique par radar à pénétration du sol et une analyse par magnétomètre à vapeur (gradiomètre). Nous avons eu également recours à la collaboration interdisciplinaire avec des spécialistes architectes, géographes, géologues, hydrologues et archéologues. Dans le cadre d’une recherche comparative, de nombreux sites antiques ont été visités en Anatolie, en Grèce, en France et en Espagne afin de mieux appréhender l’évolution du système hydraulique dans différentes conditions géographiques. Suite à ces travaux, 162 structures hydrauliques ont été observées et inventoriées. Nous avons identifié deux nouveaux types de citernes antiques, un barrage bien conservé, un édifice de spectacle et l’unique sanctuaire dédié à Pan découvert en Anatolie jusqu’ici. Nous avons interprété les vestiges de deux constructions comme des établissements thermaux. Force est de constater que face à un milieu naturel hostile, les Termessiens ont romanisé leur ville en effectuant des travaux considérables, leur permettant de couvrir leurs besoins en eau et d’accéder au niveau de vie urbain de l’époque impériale romaine. / The aim of this PhD is not only to focus on Termessos' hydraulic settlement, which has been erected on a sourceless location, but also to examine all explorable structures in order to define their socio-Historical interest and highlight their value to the understanding of hellenistic and roman times. We have started by studying the written sources and by conducting extensive research on site. Different technics have been employed such as georadar technology (Ground Penetration Radar, GPR) and vapour magnetometer (gradiometer) in order to collect data during the six archaeological prospections which took place between 2010 and 2013. Researchers from various disciplines have brought their expertise to this work : architects, geographers, geologists, hydrologists and archaeologists. During this investigation, many ancient sites have been explored in Anatolia, Greece, France and Spain in order to understand the evolution of the hydraulic system with regard to geographical requirements. Followings this, 162 hydraulic structures have been studied and registered. The irrigation and water supply network as well as the sewerage system have been restored. We have discovered two new types of ancient tank, a well preserved water dam, an entertainment building and the only sanctuary dedicated to Pan found in Anatolia so far. The remains of two establishments have been interpreted as thermal baths. Most of all, and despite a challenging natural environment, the Termessians have romanized their city by carrying out great major construction projects allowing them to fulfill their water needs and to celebrate their power.

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Background: Knee osteoarthritis is a degenerative disease characterized by damaged joint tissues (e.g., cartilage) that leads to joint pain, and reduced mobility and quality of life. Various factors are involved in disease progression, including biomechanical, patient-reported outcome and mobility measures. This thesis provides important longitudinal data on the role of these factors in disease progression, and the trajectory of biomechanical factors in persons with knee osteoarthritis. Objectives: (1) Determine the extent to which changes over 2.5 years in knee cartilage thickness and volume in persons with knee osteoarthritis were predicted by the knee adduction and flexion moment peaks, and knee adduction moment impulse and loading frequency. (2) Determine the extent to which changes over 2 years in walking and stair-climbing mobility in women with knee osteoarthritis were predicted by quadriceps strength and power, pain and self-efficacy. (3) Estimate the relative and absolute test-retest reliabilities of biomechanical risk factors for knee osteoarthritis progression. Methods: Data were collected at 3-month intervals during a longitudinal (3-year), observational study of persons with clinical knee osteoarthritis (n=64). Magnetic resonance imaging of the study knee was acquired at the first and last assessments, and used to determine cartilage thickness and volume. Accelerometry and dynamometry data were acquired every 3 months, and used to determine knee loading frequency and knee muscle strength and power, respectively. Walking and stair-climbing mobility, as well as pain and self-efficacy data, were also collected every 3 months. Gait analyses were performed every 6 months, and used to calculate lower-extremity kinematics and kinetics. Results: (1) The knee adduction moment peak and impulse each interacted with body mass index to predict loss of medial tibial cartilage volume over 2.5 years. These interactions suggested that larger joint loads in those with a higher body mass index were associated with greater loss of cartilage volume. (2) In women, lower baseline self-efficacy predicted decreased walking and stair ascent performances over 2 years. Higher baseline pain intensity/frequency also predicted decreased walking performance. Quadriceps strength and power each interacted with self-efficacy to predict worsening stair ascent times. These interactions suggested that the impact of lesser quadriceps strength and power on worsening stair ascent performance was more important among women with lower self-efficacy. (3) Relative reliabilities were high for the knee adduction moment peak and impulse, quadriceps strength and power, and body mass index (i.e., intraclass correlation coefficients >0.80). Absolute reliabilities were high for quadriceps strength and body mass index (standard errors of measurement <15% of the mean). Data supported the use of interventions effective in reducing the knee adduction moment and body mass index, and increasing quadriceps strength, in persons with knee osteoarthritis. Conclusion: Findings from this thesis suggest that biomechanical factors play a modest independent role in the progression of knee osteoarthritis. However, in the presence of other circumstances (e.g., obesity, low self-efficacy, high pain intensity/frequency), biomechanical factors can vastly worsen the disease. Strategies aiming to curb structural progression and improve clinical outcomes in knee osteoarthritis should target biomechanical and clinical outcomes simultaneously. / Thesis / Doctor of Philosophy (PhD) / Knee osteoarthritis is a multifactorial disease whose progression involves worsening joint structure, symptoms, and mobility. Various factors are linked to the progression of this disease, including biomechanical, patient-reported outcome and mobility measures. This thesis provides important information on how these factors, separately and collectively, are involved in worsening disease over time, as well as benchmarks that are useful to clinicians and researchers in interpreting results from interventional or longitudinal research. First, we examined how different elements of knee loading were associated with changes in knee cartilage quantity over time in persons with knee osteoarthritis. Second, we examined how different elements of knee muscle capacity and patient-reported outcomes were related to changes in mobility over time in persons with knee osteoarthritis. Third, we examined the stability over time of various biomechanical risk factors for the progression of knee osteoarthritis. Novel results from this thesis showed that: (1) larger knee loads predicted cartilage loss over 2.5 years in obese individuals with knee osteoarthritis but not in persons of normal weight or overweight; (2) among women with knee osteoarthritis with lower self-efficacy (or confidence), lesser knee muscle capacity (strength, power) was an important predictor of declining stair-climbing performance over 2 years; and (3) clinical interventions that can positively alter knee biomechanics include weight loss, knee muscle strengthening, as well as specific knee surgery and alterations during walking to reduce knee loads. Interventions for knee osteoarthritis should target biomechanical and clinical outcomes simultaneously.