O principal problema desta tese é a aplicação da teoria psicoacústica sobre percepção de dissonância em novas ferramentas de computação musical em tempo real. Os objetivos e contribuições incluem: Prover uma revisão critica do Estado da Arte em teoria psicoacústica de modelos de dissonância, projetar trabalhos futuros; Explorar um potencial criativo negligenciado de modelos psicoacústicos de dissonância em Eletrônica ao Vivo; Desenvolver novas ferramentas computacionais baseadas na teoria; Investigar o potencial e limitações da teoria e técnicas. Discutir sua pertinência e impacto; Tornar a teoria e técnicas mais acessíveis a músicos por meio deste texto e as ferramentas desenvolvidas. A percepção de Dissonância é um fenômeno complexo em que a abordagem psicoacústica cobre apenas uma porção. Além disso, ainda há muito debate na área da psicoacústica sobre o desenvolvimento de modelos de dissonância. Portanto, a tese apresenta uma revisão crítica do Estado da Arte da teoria psicoacústica, apontando pontos fracos e fortes do atual conhecimento, e futuros desenvolvimentos no campo. Um teste perceptivo também foi elaborado para gerar ponderações relevantes. Os modelos foram implementados em Pure Data, e uma série de patches foi desenvolvida para testar o potencial criativo em eletrônica ao vivo. Esse processo culminou em um sistema desenvolvido em Pure Data que agrega diversas das técnicas baseadas nos modelos psicoacústicos. Suas possibilidades incluem, por exemplo, encontrar intervalos consonantes de acordo com um espectro, ou alterar componentes espectrais para que estejam de acordo com uma escala musical ou afinação particular. Essas ferramentas foram empregadas em um duo de improvisação livre com o autor e um saxofonista. O autor também compôs uma peça orquestral que utilizou o sistema desenvolvido na parte de eletrônica ao vivo. / The problem of this research is to apply the state of the art in psychoacoustic theories about dissonance perception in the development of novel creative computer music tools for composition and live electronics. Goals and contributions include: To provide a critical review of the State of the Art in Psychoacoustic theory regarding dissonance modeling, project further work; To explore neglected creative potential of psychoacoustic dissonance models in Live Electronics; To develop novel computer music tools based on the theory; To investigate the potential and limitations of the theory and techniques; To discuss its creative musical impact and pertinence; To make the theory and techniques more accessible to musicians through the text and the free developed tools. The perception of Dissonance is a complex phenomenon in which the psychoacoustical approach covers just a portion thereof. Not only that, but psychoacoustic theory is still in debate about the development of dissonance models. Therefore, the thesis provides a critical review of the state of the art in psychoacoustic theory, pointing out weaknesses and strong points of the current knowledge, and future developments in the field. A perceptual test was also designed to generate data for relevant insights. Apart from the theoretical review, the models were implemented in Pure Data, and a series of patches was developed in order to test their creative potential in Live Electronics. This culminated in a system developed as a Pure Data Patch that aggregates several techniques based on the psychoacoustic models. Their possibilities include, for example, finding consonant intervals according to a spectrum, or altering spectral components so they are in accordance to musical intervals and particular tunings. These tools were used in a Free Improvisation duo with the author and a sax player, and the author also composed an orchestral piece that applied the developed system in the Live Electronics section.

Objectifs : Développer un traitement HIFU (High-Intensity Focused Ultrasound) des anomalies placentaires au moyen d’un transducteur torique. Les essais ont été menés à partir d’un modèle ex-vivo, puis la faisabilité, l’efficacité et l’innocuité du traitement a été évaluée sur un modèle de guenons gestantes. Les premières applications thérapeutiques envisagées à l’échelle humaine, concernent le traitement du syndrome transfuseur-transfusé (STT) et les accrétions placentaires pour lesquelles un protocole d’essai clinique a été établi. Matériels et méthodes : Un transducteur torique fonctionnant à 3 MHz et muni d’une cellule d’imagerie échographique intégrée fonctionnant à 7,5 MHz ont été utilisés. Des simulations numériques de séquences de traitement HIFU ont été menées à partir d’une étude préliminaire sur la caractérisation acoustique du tissu placentaire humain. Ces séquences ont été testées au cours d’une étude ex-vivo sur des placentas humains. Deux modèles ex-vivo ont été conçus. Dans un premier temps, un modèle de traitement extracorporis. Dans un second temps, des traitements HIFU ont été réalisés à des distances variables du transducteur, par modification de la taille du ballonnet, afin de simuler un traitement per-césarienne. Le transducteur était placé au contact de la face foetale du placenta afin de simuler la séreuse utérine. A partir des résultats issus de ces essais ex-vivo, un protocole in-vivo sur des guenons gestantes a été mené afin de valider la faisabilité, l’efficacité et l’innocuité de la réalisation de lésions HIFU dans le placenta de guenons gestantes de manière totalement non-invasive. La qualité du monitoring échographique était évaluée au cours des trois études, et corrélée à l’analyse macroscopique. Une étude histologique a également été menée. Résultats : L’atténuation placentaire a été mesurée à partir de 12 échantillons placentaires humains pour un âge gestationnel compris entre 17 et 40 semaines d’aménorrhées (SA). L’atténuation augmentait en fonction de l’âge gestationnel et était compris entre 0,072 et 0,098 Np.cm-1.MHz-1. Lors d’un premier essai ex-vivo, 33 échantillons placentaires humains ont été inclus et soumis à une séquence HIFU, le temps d’insonification était de 55 secondes, la puissance acoustique utilisée était de 90 Watts. Au total, vingt-cinq lésions élémentaires étaient produites pour un diamètre et une profondeur moyens respectifs de 7,1 ± 3,2 et de 8,0 ± 3,1 millimètres. Huit lésions HIFU ont également été produites à partir de la juxtaposition de 6 tirs, pour un diamètre et une profondeur moyenne respectifs de 23,0 ± 5,0 et 11,0 ± 4,7 millimètres. Aucune lésion située en amont de la lésion produite n’a été observée pour une épaisseur de paroi abdominale similaire à celle d’une guenon gestante (10,8 ± 1,7 millimètres). Dans un second temps, 8 placentas humains pour un âge gestationnel compris entre 39 et 40 SA, ont été soumis à une séquence de traitement HIFU sans interposition de paroi abdominale. Le temps d’exposition était de 75 secondes pour une puissance acoustique de 90 Watts. Les lésions placentaires ont été produites à 2 (n=4), 6 (n=4), 7 (n=4) et 8 (n=7) millimètres de la surface du placenta. Au total, 19 lésions placentaires ont été produites, pour un diamètre et une profondeur moyenne respectifs de 14,6 ± 2,1 et de 14,1 ± 2,3 millimètres. Au cours de l’étude in-vivo, 8 guenons ont été incluses pour un âge gestationnel moyen de 72 ± 4 jours. Les puissances acoustiques utilisées étaient de 65, 80, 110 et 120 Watts pour un temps de traitement de 30, 15, 20 et 20 secondes respectivement. Au total 6 lésions placentaires ont été produites à l’issu de 13 insonifications pour des diamètres moyens de 6,4 ± 0,5 mm, 7,8 ± 0,7 mm et une profondeur moyenne de 3,8 ± 1,5 mm [etc…] / Objectives: To develop a High-intensity Focused Ultrasound (HIFU) treatment for placental abnormalities. Trials were first conducted using an ex-vivo model. Then the safety, feasibility and efficacy were demonstrated using a pregnant monkey model. The first therapeutic applications for human concern the treatment of the twin-to-twin transfusion syndrome (TTTS) and placenta accreta, for which, a clinical trial has already been established. Materials and Methods: A toroidal HIFU transducer, with an integrated ultrasound imaging probe was used. Numerical simulations have allowed identifying HIFU treatment parameters based on a preliminary experiment measuring the acoustic attenuation of human placentae. These HIFU parameters were tested during an ex-vivo study on human placentae. Two models were used. First, an extracorporis model of treatment was developed. Second, a percesarean model was developed. HIFU lesions were performed at different distances from the transducer, by adjusting the quantity of water between the transducer and tissues. The transducer was placed in contact with the fetal side of the placenta in order to simulate the uterine serosa. Using the results of these studies, an in-vivo study was conducted in a pregnant monkey model. The aim was to evaluate the feasibility, the efficacy and the harmlessness of the HIFU treatment applied to the placenta non invasively. The ultrasound monitoring was assessed during these three studies, and was correlated to the macroscopic examination. A histological study was also performed. Results: The placental attenuation was measured using 12 placental samples for a gestational age from 17 to 40 weeks of gestation (WG). The attenuation coefficient increased according to the gestational age, and was ranged from 0,072 to 0,098 Np.cm-1.MHz-1. During the first experimental ex-vivo study, 33 human placental samples were included and treated with HIFU. The treatment parameters were an exposure time of 55 seconds and an acoustic power of 90 Watts. Twenty-five HIFU singles lesions were created with an average diameter and depth of 7.1 ± 3.2 and 8.0 ± 3.1 millimeters, respectively. Eight HIFU lesions were also created by juxtaposing 6 single HIFU lesions. The average diameter and depth of these juxtaposed lesions were 23.0 ± 5.0 and 11.0 ± 4.7 millimeters, respectively. No secondary lesion was observed in overlying abdominal tissues. The thickness of these intervening tissues was similar to a pregnant monkey (10.8 ± 1.7 millimeters). In a second set of experiments, 8 human placentae for a gestational age ranging between 39 and 40 weeks were treated without intervening tissues. The time of exposure was 75 seconds and the acoustic power was 90 Watts. The placental lesions were created at 2 (n=4), 6 (n=4), 7 (n=4) and 8 (n=7) millimeters from the surface of the placenta. In total, 19 placental lesions were created with an average diameter and depth of 14.6 ± 2.1 and 14.1 ± 2.3 millimeters, respectively. Eight pregnant monkeys were included in the in-vivo experiments. The average gestational age was 72 ± 4 days. The placenta was treated non-invasively with acoustic powers of 65, 80, 110 and 120 Watts for a time of exposure of 30, 15, 20 and 20 seconds, respectively. In total, 6 placental lesions were created from 13 insonifications. The average diameters and depths of these lesions were 7.8 ± 0.7 and 3.8 ± 1.5 mm, respectively. No significant variation in maternal or fetal parameters was observed. All placental lesions appear hyperechoic in sonograms and well correlated with the macroscopic measurements. The ultrasound monitoring was better invivo when compared with ex-vivo results. The histological examination demonstrated a well delimited lesion of coagulation in all cases

Alzheimer’s disease (AD) is a neurodegenerative disorder resulting in the decline of cognitive function, memory formation and retrieval, and abrupt changes in personality. Damage to brain networks occur during prodromal stages of AD, prior to the development of clinical symptoms of dementia. Further characterising this state and identifying reliable biomarkers for early detection are priorities in AD research. I characterised neuronal changes within the dorsal CA1 and subiculum regions of the hippocampal formation (HF) in the well-characterised 3xTgAD mouse model of AD. These regions are well-established sites for early neurodegeneration in both AD patients and AD animal models. We inserted multi-electrode recording arrays into CA1 and subiculum of urethane anaesthetised 3xTgAD mice and recorded spontaneous local field potential activity. Using traditional and novel information theoretic approaches, I determined the information carrying capacity of the CA1- subiculum network during different network rhythms, and how this altered with age and AD-like pathology. A bipolar stimulating electrode was inserted into CA1, allowing the assessment of synaptic integrity between CA1 and subiculum. Results showed that synaptic and network changes occur in CA1 and subiculum during the early stages of AD-like pathology and correlates with the development of intracellular beta-amyloid. There is a progressive breakdown in synaptic facilitation as early as 3 months in the 3xTgAD mouse. These data support an advanced ageing-like phenotype in AD model mice, with an enhanced age/pathology-dependent breakdown in neuronal communication compared to age-matched controls. In agreement with other studies, 3xTgAD mice demonstrate evidence of pathology-related changes in the network rhythms of the HF. 3xTgAD mice show an increase in the power of alpha and beta rhythms, and a concurrent reduction in the power of delta oscillations. Application of novel information theoretic techniques results in a breakdown in the information carrying capacity of the hippocampal system. This deficit manifests as a reduction in information flow during delta-dominant periods of EEG rhythms, with a specific reduction during slow-wave ripple activity. This change in neuronal communication correlates with the onset of memory-retention/consolidation deficits. These network changes are complex, with alterations in the information carrying capacity of the system during theta rhythms at 6 months, and during slow-wave components by 9 months in the 3xTgAD mouse. This study provides the first evidence of an early and progressive decline in neuronal connectivity and communication that correlates with changes in cognition in the 3xTgAD mouse. Application of novel analytical techniques to multi-site EEG recording revealed early and measureable changes in information processing during the onset of AD-like pathology. These are important new biomarkers for early AD characterisation.

TEETH AND OTHER TALES is a novella and a collection of short stories that explore the blurry lines between illusion and reality. Teeth, the novella, is narrated backward in time, chronicling the life of Lucy from the age of sixty-five back to seventeen. After years of surviving an oppressive marriage, Lucy escapes her husband, but in doing so abandons her three children. In order to rationalize her decisions, Lucy uses selective memory to create her own reality to the extent that she comes to believe her own delusions. The four short stories in the collection feature protagonists who create their own personal myths and struggle to protect their distorted truths, with mixed results. These struggles between the “real,” as conventionally defined, and personal fictions are complicated by elements of magical realism and surrealism. The stories were influenced by the short fiction of Nikolai Gogol, Franz Kafka and Haruki Murakami.

Recent approaches in depression therapeutics include triple reuptake inhibitors, drugs that target three monoamine systems. Using in vivo electrophysiological and microdialysis techniques, the effects of 2- and 14-day treatments of escitalopram, nomifensine and the co-administration of these two drugs (TRI) were examined in male Sprague-Dawley rats. Short- and long-term TRI administration decreased NE firing and had no effect on DA neurons. Normal 5-HT firing rates were maintained after 2-day TRI administration compared to the robust inhibitory action of selective serotonin reuptake inhibitors (SSRIs). Escitalopram treatment enhanced the tonic activation of the 5-HT1A receptors given the increase in firing observed following WAY100635 administration. Nomifensine treatment enhanced tonic activation of the α2–adrenoceptors following idazoxan administration. TRI treatment caused a robust increase in extracellular DA levels that was in part mediated by a serotonergic contribution. Therapeutic effects of the drugs examined in this study may be due to the enhancement of 5-HT, NE and/or DA neurotransmission.

Over the past decade the concept that the hair follicle plays an important role in cutaneous wound repair has been established. Several elegant lineage tracing studies have demonstrated that hair follicle derived cells contribute to the long term maintenance of the epidermis following repair, while an absence of hair follicles is known to delay repair. The exact mechanisms surrounding hair follicle derived repair are unknown. Moreover, while multiple stem cell niches are present within the hair follicle, their relative importance during wound repair is still unclear. The hair follicle is also a regenerative mini-organ, undergoing regular cycles of growth and regression throughout life, yet surprisingly this has not been previously investigated with respect to wound repair. Data presented in this thesis reveals an unappreciated, yet fundamental link between the independent processes of hair cycle and wound repair, with a substantial acceleration in the rate of repair (~50%) observed in anagen phase. Importantly, the hair follicle appears to play a global role in repair, with differences in the contribution of multiple cell types to wound repair. In addition, this thesis addresses the early kinetics of hair follicle wound response for the first time. Anagen hair follicles are found predisposed to a more rapid and extensive response to injury, suggesting a higher overall percentage of repair derived from the hair follicle in anagen phase. Surprisingly, the bulge stem cell region, while critical for hair cycle appears to play little role in the events immediately following injury, and is not required for initiation of re-epithelialisation. Gene expression profiling reveals numerous genes associated with anagen accelerated repair, and identifies altered modulation of the immune system as a key mechanism. Further, anagen wounds are associated with an upregulation of developmental transcription factors, which may imply a more regenerative healing phenotype. These data reveal numerous targets with the potential to accelerate repair, which now require validation for their therapeutic potential. These targets could be of importance in promoting the repair of chronic wounds, an area of unmet clinical need. More generally, this thesis has established hair cycle as an important experimental variable, which must be controlled for in all future in vivo murine wounding studies.

Submitted by Fernanda Rodrigues de Lima (fernanda.rlima@ufpe.br) on 2018-09-20T20:34:18Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) TESE Victor de Almeida Nobre Pires.pdf: 1733472 bytes, checksum: fd561a8955380cd7ec58cf521d612cfe (MD5) / Approved for entry into archive by Alice Araujo (alice.caraujo@ufpe.br) on 2018-09-21T18:39:50Z (GMT) No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) TESE Victor de Almeida Nobre Pires.pdf: 1733472 bytes, checksum: fd561a8955380cd7ec58cf521d612cfe (MD5) / Made available in DSpace on 2018-09-21T18:39:50Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) TESE Victor de Almeida Nobre Pires.pdf: 1733472 bytes, checksum: fd561a8955380cd7ec58cf521d612cfe (MD5) Previous issue date: 2017-02-03 / O presente trabalho analisa a música ao vivo, a partir do estudo de concertos realizados em salas de estar de fãs com ênfase no caso da rede Sofar Sounds e de suas práticas de produção musical, sob uma perspectiva crítica da Teoria do Ator-Rede (TAR). Aqui, o objetivo é entender a música ao vivo não como uma categoria a priori, ou autoexplicativa, mas como uma rede que conforma diversas relações e associações entre actantes humanos e não-humanos para a conformação de fenômenos que compreendem muito mais que apenas a música em sentido estrito. Assim, traçarei análises a partir de controvérsias e pontos tensivos da própria rede para entender dinâmicas e práticas por vezes negligenciadas na agenda da pesquisa acadêmica na área, fornecendo bases para se pensar, dentre outras coisas, os aspectos midiáticos, produtivos, coletivos, sonoros e espaciais de uma importante rede que agencia a produção e o consumo de shows em formato intimistas em mais de 40 países. / This work analyzes live music, from the case study of living room concerts with emphasis on the Sofar Sounds network and its musical production practices from a critical perspective of the Actor-Network Theory (ANT). Here, the goal is to understand live music not as an “a priori” concept, or as a self-explanatory category, but as a network that cover diverse relationships and associations between human and non-human actants for the conformation of a phenomena that comprise much more than just music in the strict sense. Thus, I will draw analyzes from the network's controversies and tensions to understand the, sometimes neglected, dynamics and practices in the academic research agenda in the area, providing bases for thinking about, among other things, the media, the productive practices, the collective formations, and the spatiality of an important music network that organizes the production and consumption of shows in intimate formats in more than 40 countries.

A escolaridade materna tem sido amplamente reconhecida como um indicador das condições ambientais e sociais que afetam o peso ao nascer. No entanto, embora o assunto seja considerado relevante, não foram realizados estudos no Brasil que investigaram a relação da escolaridade materna sobre o peso de nascimento numa perspectiva temporal. O presente estudo avaliou as médias de peso ao nascer conforme os diferentes níveis de escolaridade materna. Trata-se de um estudo de série temporal que incluiu os nascidos vivos das 27 capitais estaduais brasileiras no período de 1996 a 2013. Os dados foram obtidos por meio do Sistema de Informação de Nascidos Vivos (SINASC) donde foram incluídos os recém-nascidos vivos únicos, com peso entre 500 e 8.000 gramas, de mães que residiam e tiveram seus partos nas capitais. As médias de peso ao nascer foram calculadas ano a ano nos três níveis de escolaridade materna – alto (≥ 12 anos), médio (8 a 11 anos) e baixo (< 8 anos). A estimativa da diferença anual de peso entre os níveis de escolaridade foi desenvolvida utilizando-se a técnica de Modelos Lineares Mistos, na qual também foram inseridas as covariáveis, idade da mãe, número de filhos nascidos vivos anteriores, número de consultas de pré-natal, duração da gestação e tipo de parto, de modo a avaliar seu impacto nas diferenças de peso ao nascer. O processamento e análise dos dados foram realizados pelo Programa “Statistical Package for Social Sciences” (SPSS) – versão 18.0. Foram analisados 12.546.282 de nascidos vivos que representaram 23,2% do total de nascimentos do país. As maiores médias anuais de peso ao nascer em relação à região geográfica foram observadas na região Norte e as menores, na região Sudeste, sendo que este padrão foi mantido durante todo o período avaliado. Em relação às médias de peso, segundo o nível de escolaridade materna, verificou-se que, no início da série, a média entre os filhos das mulheres com alta escolaridade era superior à dos filhos de mães de média e baixa, com 35 gramas e 91 gramas de diferença respectivamente. Essa diferença foi sendo reduzida e, a partir do ano de 2007, a média dos filhos das mulheres com escolaridade média foi maior do que a dos filhos das mulheres com alta escolaridade, com manutenção deste padrão até o final do período analisado, quando foi 17 gramas superior. A diferença de peso entre a alta e a baixa escolaridade também foi sendo reduzida e, em 2013, foi de 13 gramas. As análises ajustadas para o ano e região de nascimento mostraram que, no período de 1996 a 2003, as diferenças do peso ao nascer entre a média e a baixa escolaridade em relação à alta eram 7,21 gramas/ano e 11,42 gramas/ano, respectivamente; no segundo período, de 2004 a 2013, essas diferenças foram reduzidas para 1,76 gramas/ano e 1,47 gramas/ano. Quando inseridas as demais covariáveis, se evidenciou que o número de consultas de pré-natal exibiu relação positiva em reduzir a diferença de peso entre os três níveis de escolaridade materna, nos dois períodos analisados. Os ajustes efetuados para as covariáveis, idade da mãe, número de filhos nascidos vivos, duração da gestação e tipo de parto, mostraram diferente desempenho nas estimativas da diferença de peso ao nascer entre os níveis de escolaridade materna e o período avaliado, apontando as mudanças demográficas, sociais e assistencias do país, que evidenciaram aumento da faixa etária materna e da primiparidade, assim como uma elevação da prematuridade e de partos cesarianos. Os resultados revelaram as transformações observadas no país nas duas últimas décadas nos diferentes estratos sociais, fazendo diminuir as diferenças de peso ao nascimento e marcando uma transição demográfica, epidemiológica e perinatal em todas as regiões, mesmo que, em diferentes estágios. A redução na diferença de peso entre os três níveis de escolaridade materna, ocorreu principalmente devido à diminuição nos estratos mais favorecidos, pois a elevação observada nas médias de peso dos filhos das mulheres com baixa escolaridade foi pequena, mesmo com a ampliação das políticas sociais neste estrato. Devido à relação multifatorial do peso ao nascer é possível que o aumento da idade materna e a existência de comorbidades prévias ou desenvolvidas durante a gestação, a maior utilização de intervenções médicas, uso de substâncias como álcool e tabaco, a presença de sobrepeso e obesidade, assim como deficiências nutricionais, possam ter relação com as médias de peso observadas. Destacou-se a relevância na utilização do Sistema de Informações sobre Nascidos Vivos permitindo conhecer e analisar as caraterísticas dos nascimentos no Brasil, como também o desafio de aprimorar a assistência materno-infantil com vistas à obtenção de melhores resultados em todos os estratos sociais. / Maternal schooling has been widely recognized as an indicator of environmental and social conditions that affect birth weight. Although the subject is considered of significant relevance, studies that investigated the influence of maternal schooling on birth weight in a temporal perspective have not yet been conducted in Brazil. The present research evaluated the means of birth weight according to the different levels of maternal schooling. It is a time-series study that included live births throughout the 27 state capitals of Brazil in the period from 1996 to 2013. Data were obtained from the National Information System of Live Birth (SINASC), which recorded single newborns weighing between 500 and 8,000 grams of mothers who had their children in the capitals. The mean birth weight was calculated year by year against three levels of maternal education - high (≥ 12 years), medium (8-11 years) and low (< 8 years). Estimated annual weight difference between the levels of education was developed using the Linear Mixed Models technique, in which covariate maternal age, number of previous live births, number of prenatal visits, duration of gestation and type of delivery evaluate their impact on differences in birth weight. The processing and analysis of data were performed by the program "Statistical Package for Social Sciences" (SPSS) - version 18.0. A total of 12,546,282 live births were analyzed during the 18-year period, representing 23.2% of the country's total births. The highest annual average birth weight in relation to the geographical region was observed in the Northern region and the lowest in the Southeastern region, and this pattern was maintained throughout the studied period. Regarding weight averages, considered against the level of maternal schooling, results show that the average among the children of women with high schooling was higher than that of the children of mothers of medium and low, with 35 grams and 91 grams of difference, respectively. This difference was later reduced and, from the year 2007, the average of the children of women with medium education was higher than that of children of women with high education, maintaining this standard by the end of the period analyzed, when the birth weight difference was 17 grams higher. The difference in weight between high and low schooling was also reduced, and in 2013, it was 13 grams. The analyzes adjusted for year and region of birth showed that, in the period from 1996 to 2003, the differences in birth weight between the medium and the low education in relation to high were 7.21 grams/year and 11.42 grams/year, respectively. In the period from 2004 to 2013, these differences were reduced to 1.76 grams/year and 1.47 grams/year. When the other covariates were considered, it was evident that the number of prenatal visits has a positive relation in the reduction of the weight difference between the three levels of maternal education, in the two periods analyzed. However, the adjustments for covariates, mother's age, number of previous live births, duration of pregnancy and mode of delivery, showed dissimilar effects on annual differences in weight between the different levels of maternal education, in both periods evaluated. These results are related to the demographic, social and assistance changes of the country, which evidenced an increase in maternal age and primiparity, as well as prematurity increase and cesarean deliveries. The findings revealed the changes observed in the country in the last two decades in the various social strata, reducing weight differences at birth and marking a demographic, epidemiological and pe This was probably because the observed increase in the average weight of children of women with low education was modest, even with the expansion of maternal schooling and the prenatal follow-up verified in this social stratum. Thus, the changes in maternal age and parity, together with the increase in medical interventions, as demonstrated by the percentage of cesarean delivery, negatively impacted the birth weight of the three levels of education. It is possible that other factors not investigated in this study also play a role in the reduction of weight differences between the different levels of mother's education. Among these factors can be mentioned the existence of previous or developed maternal diseases during pregnancy, hypertension and diabetes, malnutrition or maternal obesity, use of licit and illicit drugs during pregnancy, as well as the quality of prenatal care received. Results also indicate the relevance of using the Information System on Live Births to know and analyze the characteristics of births in Brazil, as well as the challenge of improving maternal and childcare across in all social strata.

The overall goals of this doctoral dissertation were to 1) assess effects of nanoparticle (NP) exposure on host defense in a murine pulmonary infection model, 2) evaluate an integrated dynamic in vitro exposure system (DIVES) that overcomes limitations of submerged exposure systems for NP toxicity testing and 3) provide information on the rank of NP toxicity and assess the potential of the DIVES as a screening tool for NP toxicity. To achieve the first goal, we used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by copper (Cu) NP exposure. Cu NP exposure induced strong inflammatory responses and an impairment in host defense against bacterial lung infections in both inhalation and instillation exposure studies even though there was an upregulation of pro-inflammatory cytokines and recruitment of neutrophils to the lungs. Thus, Cu NP exposure may lead to increased risk of pulmonary infection by impairing host defense against bacteria. In the second study, we integrated the DIVES capable of generating NP aerosols and depositing NPs directly onto cells grown at the air-liquid interface (ALI) to mimic a more realistic in vivo pulmonary exposure to inhaled NPs. Furthermore, we characterized the efficiency of NP delivery, the distribution of particle deposition and the effects of exposure conditions in the DIVES on the viability of A549 cells (human alveolar type-II-like cancer cells) as a precursor to studies of NP toxicity. The DIVES was shown to provide efficient, uniform and controlled dosing of particles to epithelial cells grown at the ALI. In addition, this exposure system delivered a continuous airborne-exposure of NPs to lung cells without loss of cellular viability. Lastly, to assess the DIVES as a means to rank NP toxicity and prioritize NPs for in vivo testing, we compared in vitro measurements obtained using the DIVES and the submerged exposure system to in vivo results obtained using a murine model of lung inflammation. Exposure to Cu NPs induced a significant increase in cytotoxicity and inflammatory responses compared to Fe NPs at the ALI in the DIVES. The results of this comparison suggest that air-delivery of NPs to lung cells using the DIVES can provide evidence of toxicity at a lower concentration of NPs compared to responses in the submerged condition. More importantly, our in vitro results presented in this dissertation are in agreement with our in vivo findings showing that Cu NPs have a higher propensity for NP dissolution and this may contribute to the greater toxicity of Cu NPs than Fe NPs. Thus, the results of these comparisons suggest that the DIVES has a significant potential for screening NP toxicity and allows for a higher throughput than in vivo studies. Overall, we found that exposure of lung cells at the ALI using the DIVES is preferable to submerged exposure for in vitro NP toxicity testing and provides useful information on the rank of NP toxicity and prioritization of NPs for in vivo testing.

[ES] Esta tesis aborda la caracterización y posible utilización de la goma de alholva (Trigonella foenum-graecum) (FSG, por sus siglas en inglés) en la nutrición de gazapos durante el período posterior al destete como una alternativa al uso de antimicrobianos, centrándose en el comportamiento de la goma extraída con diferentes niveles de fibra dietaria, tanto in vitro como in vivo. En el primer experimento, a partir de una dieta basal comercial de conejo, se formularon tres dietas experimentales con niveles graduales de inclusión de FSG (0, 0.25, 0.50%) administrados a tres grupos de conejos desde el destete a los 31 días hasta el sacrificio a los 94 días. Se estudió el efecto de las dietas experimentales sobre la digestibilidad fecal en dos edades (38-41 días y 56-59 días), además de los parámetros de fermentación cecal al final del experimento. Por otro lado, a partir de la misma dieta comercial de conejo, se formularon cinco dietas experimentales que contenían 0. 0.125, 0.25, 0.50 y 100% de FSG, que se sometieron a incubación in vitro con inóculo cecal de conejo durante 72 h. Se midieron la producción de gas y las variables de fermentación. La digestibilidad fecal aparente y los parámetros de fermentación cecal no se vieron afectados significativamente por la inclusión in vivo de FSG hasta 0.5%. Sin embargo, los animales alimentados con FSG mostraron valores de pH cecal más bajos. La inclusión gradual en la dieta de FSG aumentó la concentración in vitro de ácidos grasos volátiles (VFA, por sus siglas en inglés), mientras que el FSG puro aumentó la producción asintótica de gas y la tasa máxima de degradación del sustrato y disminuyó el tiempo de incubación en el que se forma la mitad de la cantidad asintótica de gas. La incubación in vitro de FSG puro disminuyó el valor del pH, la concentración de ácido láctico y la concentración de N-NH3, y aumentó la de VFA. En el segundo experimento, el FSG se caracterizó para determinar su composición química, su contenido de galactosa y manosa y su potencial como prebiótico. Se evaluaron tanto FSG puro como niveles graduales (0, 5, 10, 15 y 20 g/kg) incluidos en dietas ricas en fibra soluble (SF, por sus siglas en inglés) de pulpa de remolacha (incluida al 10%) y dietas ricas en fibra insoluble (IF, por sus siglas en ingles) de semilla de uva desengrasada (incluida al 10%). Se sometieron a digestión enzimática con pepsina y pancreatina y luego sus fracciones indigestibles se sometieron a fermentación usando inóculo cecal. Se midieron las fracciones no digestibles después de la digestión enzimática, así como las fracciones no fermentables y las variables de fermentación después del tiempo de incubación (48 h). La FSG se compone principalmente de galactosa y manosa (630 g/kg) en una proporción de 1: 1 y un nivel moderado de proteínas (223 g/kg). El FSG puro se vio poco afectado por la digestión enzimática, ya que solo se disolvieron 145 g/kg. Sin embargo, desapareció casi por completo (984 g/kg) durante el proceso de fermentación. En consecuencia, FSG aumentó la concentración de VFA, disminuyó el valor de pH y la concentración de N-NH3. La inclusión gradual de FSG en las dietas de conejos afectó la digestión de algunos nutrientes, como las fracciones fibrosas, el almidón y las proteínas, además de aumentar la fracción fermentada en la dieta SF, pero sin ningún efecto relevante en el perfil de fermentación. En el tercer experimento, se formularon cuatro dietas de acuerdo con un diseño factorial 2 x 2: una dieta convencional de conejo (C), la misma dieta C suplementada con 10 g / kg de FSG, una dieta de bajo riesgo (LR, por sus siglas en inglés) y la misma dieta LR suplementada con 10 g/kg de FSG. Las dietas C y LR se diferenciaban en el nivel de SF y proteína bruta (CP, por sus siglas en inglés) (104 vs 205 y 156 vs 121 g/kg de SF y CP respectivamente para dietas C y LR). Doscientos dieciséis conejos de la línea LP se alojaron en jaulas individuales, se dividieron aleatoriamente entre los cuatro tratamientos y se les permitió el libre acceso al alimento y al agua. La mortalidad, la morbilidad, el índice de riesgo sanitario (HRi, por sus siglas en inglés), la ingestión diaria de pienso (DFI, por sus siglas en inglés), la ganancia media diaria (ADG, por sus siglas en inglés) y el índice de conversión alimenticia (FCR, por sus siglas en inglés) se controlaron hasta los 63 días de edad. El coeficiente de digestibilidad aparente total del tracto digestivo (CTTAD, por sus siglas en inglés) de los nutrientes se determinó en doce conejos por tratamiento, entre los 49 y 53 días de edad y finalmente se midió el ambiente cecal a los 63 días de edad. La inclusión de FSG en la dieta a 10 g/kg de alimento no afectó al rendimiento durante el cebo ni al CTTAD de los nutrientes, pero aumentó ligeramente la digestibilidad de la fibra neutrodetergente (NDF, por sus siglas en inglés) y la fibra ácido-detergente (ADF, por sus siglas en inglés) en las dietas C. Del mismo modo, los parámetros cecales no se vieron afectados por la inclusión de FSG, excepto la concentración de ácido caproico en las dietas C. Sin embargo, las dietas LR disminuyeron la mortalidad, HRi, DFI, ADG y CTTAD de materia orgánica y CP pero aumentaron FCR y CTTAD de NDF y ADF con respecto a las dietas C. Además, las dietas LR aumentaron la concentración de VFA, la proporción de ácido acético, isobutírico e isovalérico mientras que disminuyeron la materia seca del contenido cecal, NNH3 y la proporción de ácidos butírico, caproico y valérico. En resumen, la FSG responde perfectamente a las dos primeras condiciones para ser un prebiótico, ya que no es digestible por las enzimas gastrointestinales antes del ciego y es altamente fermentado una vez que alcanza el ciego. Parece afectar selectivamente a la microbiota cecal debido a su efecto sobre la concentración de VFA y N-NH3, además de su efecto sobre la proporción de caproico y valérico en dietas convencionales. FSG podría aumentar la viscosidad de la digesta limitando la solubilización de algunos nutrientes como el almidón y la proteína. FSG parece ser más efectivo en dietas comerciales convencionales que en dietas de bajo riesgo. Finalmente, se confirmó que las dietas con alto nivel de SF y bajo de CP podrían ser una buena herramienta contra la enteropatía epizoótica del conejo (ERE, por sus siglas en inglés) en un sistema de producción no medicado, a costa de peores parámetros de crecimiento. / [EN] This thesis tackles the possible characterisation and utilisation of fenugreek (Trigonella foenum-graecum) seed gum (FSG) in the nutrition of young rabbits during the post-weaning period as an alternative to antimicrobials uses. The study was focussed on the behaviour of the extracted gum with different dietary fibre levels, both in vitro and in vivo. In a first trial, starting from a basal commercial rabbit diet, three experimental diets were formulated with gradual levels of inclusion of FSG (0, 0.25, 0.50 %) given to three groups of rabbits starting from weaning at 31 days old to slaughter 94 days old. The effect of the experimental diets was studied on the faecal digestibility of the diet in two ages (38-41 days and 56-59days) and on the caecal fermentation parameters at the end of the experiment. On the other hand, starting from the same commercial rabbit diet five experimental diets were formulated containing 0, 0.125, 0.25, 0.50 and 100% of FSG that were submitted to in vitro incubation with rabbit caecal inoculum during 72h. Gas production and fermentation traits were measured. Apparent faecal digestibility and caecal fermentation parameters were not significantly affected by the in vivo inclusion of FSG up to 0.5%. However, animals fed with FSG showed lower caecal pH values. Gradual dietary inclusion of FSG increased in vitro concentration of volatile fatty acids (VFA), while pure FSG increased the asymptotic gas production and the maximum substrate degradation rate and decreased the time after incubation at which half of the asymptotic amount of gas is formed. In vitro incubation of pure FSG decreased pH value, lactic acid concentration and N-NH3 concentration and increased that of VFA. In a second trial, FSG was characterised determining its chemical composition, galactose and mannose content and prebiotic potential. Pure FSG and gradual levels of FSG (0, 5, 10, 15 and 20 g/kg), included both in diets rich in soluble fibre (SF) from beet pulp (included at 10%) or in diets rich in insoluble fibre (IF) from defatted grape seeds (included at 10 %), were evaluated. They were submitted to enzymatic digestion with pepsin and pancreatin and then their indigestible fractions were submitted to fermentation using caecal inoculum. The indigestible fractions after enzymatic digestion were measured, as well as the nonfermentable fractions and the fermentation traits after incubation time (48 h). FSG was mostly composed of galactose and mannose (630 g/kg) in 1:1 ratio and a moderate protein level (223 g/kg). Pure FSG was weakly affected by enzymatic digestion, only 145 g/kg was dissolved. However, it was almost entirely disappeared (984 g/kg) during the fermentation process. Consequently, FSG increased VFA concentration and decreased both pH value and N-NH3 concentration. Th gradual inclusion of FSG in rabbit’s diets affected some nutrients digestion such as the fibre fractions, starch and protein, besides to increase the fermentation fraction in SF diet but without any relevant effect on the fermentation profile. In a last third trial, four diets were formulated according to 2 x 2 factorial design: a conventional rabbit diet (C), the same C diet supplemented by 10 g/kg of FSG, a low-risk diet (LR), and the same LR diet supplemented by 10 g/kg of FSG. C and LR diets differed in SF and crude protein levels (CP) (104 vs 205 and 156 vs 121 g/kg of SF and CP respectively for C and LR diets). Two hundred and sixteen weaned rabbits (28 days of age) of the LP line were allocated in individual cages and divided randomly between the four treatments and allowed free access to feed and water. Mortality, morbidity, health risk index (HRi), daily feed intake (DFI), average daily gain (ADG) and feed conversion ratio (FCR) were controlled until 63 days of age. Coefficient of total tract apparent digestibility (CTTAD) of nutrients, on twelve rabbits per treatment, was determined from 49 to 53 days of age and finally, caecal environment was measured at 63 days of age. FSG dietary inclusion at 10 g/kg did not affect performance or CTTAD of nutrients but did slightly increased neutral-detergent fibre (NDF) and acid-detergent fibre (ADF) digestibility in C diets. Similarly, caecal parameters were not affected by FSG except caproic acid concentration in C diets. Nevertheless, LR diets decreased mortality, HRi, DFI, ADG and CTTAD of organic matter and CP but increased FCR and CTTAD of NDF and ADF respect to C diets. Moreover, LR diets increased VFA concentration, the proportion of acetic, isobutyric and isovaleric while decreased the dry matter of the caecal content, N-NH3 and the proportion of butyric, caproic and valeric acids. To summarise, FSG perfectly responds to the two first conditions to be prebiotic, being not digestible by gastrointestinal enzymes before the caecum and highly fermented once reached the caecum. It seems to affect selectively caecal microbiota due to its effect on VFA and N-NH3 concentration besides to its effect on caproic and valeric proportions in conventional diets. FSG could increase viscosity of digesta limiting the solubilisation of some nutrients such starch and protein. FSG seems to be more effective in conventional commercial diets than in low-risk diets. Finally, it was confirmed that diets with high SF level and low CP could be a good tool against epizootic rabbit enteropathy (ERE) in a nomedicated breeding system at the cost of impaired growth parameters. / [CA] Aquesta tesi aborda la caracterització i possible utilització de la goma de fenigrec (Trigonella foenum-graecum) (FSG, per les sigles en anglès) en la nutrició del conills durant el període posterior al deslletament com una alternativa a l'ús d'antimicrobians, centrant-se en el comportament de la goma extreta amb diferents nivells de fibra dietària, tant in vitro com in vivo. En el primer experiment, a partir d'una dieta basal comercial de conill, es van formular tres dietes experimentals amb nivells graduals d'inclusió de FSG (0, 0.25, 0.50%) administrats a tres grups de conills des del deslletament als 31 dies fins al sacrifici als 94 dies. Es va estudiar l'efecte de les dietes experimentals sobre la digestibilitat fecal en dues edats (38-41 dies i 56-59 dies), a més dels paràmetres de fermentació cecal a la fi de l'experiment. D'altra banda, a partir de la mateixa dieta comercial de conill, es van formular cinq dietes experimentals que contenien 0. 0.125, 0.25, 0,50 i 100% de FSG, que es van sotmetre a incubació in vitro amb inòcul cecal de conill durant 72 h. Es van mesurar la producció de gas i les variables de fermentació. La digestibilitat fecal aparent i els paràmetres de fermentació cecal no es van veure afectats significativament per la inclusió in vivo de FSG fins a 0.5%. No obstant això, els animals alimentats amb FSG van mostrar valors de pH cecal més baixos. La inclusió gradual en la dieta de FSG va augmentar la concentració in vitro d'àcids grassos volàtils (VFA, per les sigles en anglès), mentre que el FSG pur va augmentar la producció asimptòtica de gas i la taxa màxima de degradació del substrat i va disminuir el temps d'incubació en el qual es forma la meitat de la quantitat asimptòtica de gas. La incubació in vitro d'FSG pur va disminuir el valor del pH, la concentració d'àcid làctic i la concentració de N-NH3, i va augmentar la de VFA. En el segon experiment, el FSG es va caracteritzar per determinar la seva composició química, el seu contingut de galactosa i manosa i el seu potencial com prebiòtic. Es van avaluar tant FSG pur com nivells graduals (0, 5, 10, 15 i 20 g/kg) inclosos en dietes riques en fibra soluble (SF, per les sigles en anglès) de polpa de remolatxa (inclosa al 10%) i dietes riques en fibra insoluble (IF, per les sigles en anglès) de llavor de raïm desgreixada (inclosa al 10%). Es van sotmetre a digestió enzimàtica amb pepsina i pancreatina i després les fraccions indigeribles es van sotmetre a fermentació usant inòcul cecal. Es van mesurar les fraccions no digestibles després de la digestió enzimàtica, així com les fraccions no fermentables i les variables de fermentació després del temps d'incubació (48 h). La FSG es compon principalment de galactosa i manosa (630 g/kg) en una proporció de 1: 1 i un nivell moderat de proteïnes (223 g/kg). El FSG pur es va veure poc afectat per la digestió enzimàtica, ja que només es van dissoldre 145 g/kg. No obstant això, va desaparèixer gairebé del tot (984 g/kg) durant el procés de fermentació. En conseqüència, FSG va augmentar la concentració de VFA, va disminuir el valor de pH i la concentració de N-NH3. La inclusió gradual de FSG en les dietes de conills va afectar la digestió d'alguns nutrients, com les fraccions fibroses, el midó i les proteïnes, a més d'augmentar la fracció fermentada en la dieta SF, però sense cap efecte rellevant en el perfil de fermentació. En el tercer experiment, es van formular quatre dietes d'acord amb un disseny factorial 2 x 2: una dieta convencional de conill (C), la mateixa dieta C suplementada amb 10 g/kg de FSG, una dieta de baix risc (LR, per les sigles en anglès) i la mateixa dieta LR suplementada amb 10 g/kg de FSG. Les dietes C i LR es diferenciaven en el nivell de SF i proteïna bruta (CP, per les sigles en anglès) (104 vs 205 i 156 vs 121 g/kg de SF i CP respectivament per a dietes C i LR). Doscents setze conills de la línia LP es van allotjar en gàbies individuals, es van dividir aleatòriament entre els quatre tractaments i se'ls va permetre el lliure accés a l'aliment i a l'aigua. La mortalitat, la morbiditat, l'índex de risc sanitari (HRi, per les sigles en anglès), la ingestió diària de pinso (DFI, per les sigles en anglès), el guany mitjá diari (ADG, per les sigles en anglès) i l'índex de conversió alimentària (FCR, per les sigles en anglès) es van controlar fins als 63 dies d'edat. El coeficient de digestibilitat aparent total del tracte digestiu (CTTAD, per les sigles en anglès) dels nutrients es va determinar en dotze conills per tractament, entre els 49 i 53 dies d'edat i finalment es va mesurar l'ambient cecal als 63 dies d'edat. La inclusió de FSG en la dieta a 10 g/kg d'aliment no va afectar el rendiment durant l'engreix ni el CTTAD dels nutrients, però va augmentar lleugerament la digestibilitat de la fibra neutre-detergent (NDF, per les sigles en anglès) i la fibra àcid-detergent (ADF, per les sigles en anglès) en les dietes C. De la mateixa manera, els paràmetres cecals no es van veure afectats per la inclusió de FSG, excepte la concentració d'àcid caproic en les dietes C. No obstant això, les dietes LR van disminuir la mortalitat, HRi, DFI, ADG i CTTAD de matèria orgànica i CP però van augmentar FCR i CTTAD de NDF i ADF pel que fa a les dietes C. A més, les dietes LR van augmentar la concentració de VFA, la proporció d'àcid acètic, isobutíric i isovalèric mentre que van disminuir la matèria seca del contingut cecal, N-NH3 i la proporció d'àcids butíric, caproic i valéric. En resum, la FSG respon perfectament a les dues primeres condicions per ser un prebiòtic, ja que no és digestible pels enzims gastrointestinals abans del cec i és altament fermentat un cop que arriba al cec. Sembla afectar selectivament a la microbiota cecal pel seu efecte sobre la concentració de VFA i N-NH3, a més del seu efecte sobre la proporció de caproic i valéric en dietes convencionals. FSG podria augmentar la viscositat de la digesta limitant la solubilització d'alguns nutrients com el midó i la proteïna. FSG sembla ser més efectiu en dietes comercials convencionals que en dietes de baix risc. Finalment, es va confirmar que les dietes amb alt nivell de SF i baix de CP podrien ser una bona eina contra la enteropatia epizoòtica del conill (ERE, per les sigles en anglès) en un sistema de producció no medicat, a costa d'pitjors paràmetres de creixement. / Jihed, Z. (2020). In vitro and in vivo characterization of galactomannanes extracted from fenugreek seeds (Trigonella foenum-graecum) for young rabbit nutrition [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/153714 / TESIS