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In utero undernutrition is associated with increased risk for insulin resistance, obesity, and cardiovascular disease during adult life. A common phenotype associated with low birth weight is reduced skeletal muscle mass. Given the central role of skeletal muscle in whole body metabolism, we hypothesized that predisposition to metabolic disease is, in part, due to low oxidative capacity and dysfunctional mitochondrial energetics in muscle. We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine female offspring from undernourished dams (U) and control offspring from ad libitum fed dams (C). U have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 4 week 40% calorie restricted diet they lose half as much weight as calorie restricted controls. Skeletal muscle mitochondria from U have decreased coupled and uncoupled respiration and increased maximal respiration compared to C. In permeabilized fiber preparations from mixed fiber type muscle, U have decreased mitochondrial content and decreased adenylate free leak respiration, fatty acid oxidative capacity, and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity does not differ between U and C. We next aimed to determine if the impaired skeletal muscle energetics observed in U also exist in primary muscle cells derived from these mice. We measured oxidative and glycolytic capacities in primary myotubes from U and C using cellular bioenergetics. Myotubes from U have decreased resting respiration and increased glycolysis compared to myotubes from C. There was no difference in myotube mitochondrial content. Findings suggest that undernutrition in utero causes a primary muscle defect. Energetics in cardiac muscle were also examined. U have impaired cardiac muscle homogenate energetics, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate, and decreased proton leak respiration. Additionally, we measured plasma acylcarnitine levels and found that short-chain acylcarnitines are increased in U. Overall, results reveal that in utero undernutrition alters metabolic physiology through a profound effect on skeletal muscle and cardiac muscle energetics. These effects may be mediated by epigenetic mechanisms which could be explored in future research.

Healthy maternal–infant attachment is the foundation on which a child’s physical, cognitive, psychological, and emotional development rests. This relationship between the dyad does not begin at birth but rather prior to conception or any time throughout pregnancy. Our understanding of how this relationship develops between a mother and her fetus remains largely intangible for researchers and clinicians alike as it is a highly complex process with many variables influencing the evolving bond. Situated within a poststructural critical feminist framework, the purpose of this qualitative study using a grounded theory approach was to gain a better understanding of how women who use substances during pregnancy experience the process of a developing relationship with their fetuses, and to identify intersecting variables that may influence their health behaviours. Five main categories emerged including choosing the mothering path, balancing the risks, needing safe passage, breaking the cycle, and mothering against all odds. All of the women in the study described feeling an increase in maternal–fetal attachment as the pregnancy progressed and demonstrated efforts to reduce substance use, engage with the health care system, and improve dietary choices to limit negative consequences for their developing fetuses. Barriers to changing health behaviours were identified by the participants as well as by health care providers working with this population. In gaining a deeper understanding of the variables that influence maternal–fetal attachment in women who use substances and development of a substantive theory, nursing practice may be informed by providing direction around how best to support harm reduction approaches in this population.

We established that acute adrenergic receptor stimulation in β-cells suppresses oxidative metabolism. This effect provides the basis for understanding how CAs reduce cell proliferation. Furthermore, the effects of acute CA on Min6 cells were distinguished from chronic CA culture using proteomics. Together, the RNAseq, qPCR and proteomic studies support a role for adrenergic receptor signaling in the regulation of proliferaton in β-cells. This work describes the genetic and proteomic profile underlying chronic adrenergic signaling and identifies CA independent suppression of β-cell growth and metabolism. Through the use of multiple models and comparative bioinformatics, we refined the list of molecular dysfunctions associated with the IUGR pathology to a set of specific and testable adrenergic targets.

Corticosterone in foetal tissues after injection of the mother with ¹⁴C-corticosterone was determined by acetylation. with ³H-acetic anhydride and crystallization to constant specific activity. The corticosterone content of whole foetal tissue varied between gestational days 13 and 17 from 641 to 300 ng/g respectively. The specific activity of foetal hormone recovered remained essentially constant; after a 15-minute pulse this was as much as one-fourth that of maternal hormone. However, placenta, head and liver showed distinctly different patterns of metabolism, which changed greatly during this time in head and liver, with a decrease in the conversion of corticosterone to 11-dehydrocorticosterone and a rise in foetal liver 113-hydroxysteroid:NADP oxidoreductase activity. This mitochondrial enzyme, Km=33yM, pH optimum 6, which reduces the 11-dehydro metabolite to the biologically active 116-OH compound, increased sharply, raising the relative amount of the latter in foetal tissues from 15 to 91% during this period. One day after removal of maternal adrenals, foetal corticosterone was normal and maternal levels close to normal, indicating ability of foetal adrenals to function. Maternal hormone, however, crossed to the foetus readily and it was considered most likely that, normally, the maternal source predominates. Regardless of origin, foetal or maternal, however, the hormone is maintained in different foetal tissues in a distinct and different manner. / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

De nombreuses données indiquent qu’un petit poids à la naissance, résultant en partie d’une sous-nutrition materno-fœtale, est associé à une augmentation de la morbidité et de la mortalité durant la période néonatale, et conduit également à un risque accru de développer à l'âge adulte un syndrome métabolique (diabète de type 2, obésité, hypertension artérielle et dyslipidémie). Les mécanismes de cette programmation prénatale sont encore mal connus et impliqueraient plusieurs molécules et systèmes physiologiques distincts. De nombreuses études suggèrent que le placenta serait impliqué dans la programmations de ces pathologies métaboliques. En effet, celui-ci constitue un organe de communication entre la mère et son fœtus et participe à la régulation de l'homéostasie fœtale. En raison de la proportion croissante de femmes présentant des troubles de la nutrition durant la grossesse et en lien avec leurs répercussions potentielles chez la descendance, il est nécessaire de mieux comprendre les interactions entre l’alimentation maternelle et l’unité fœto-placentaire et d’identifier les mécanismes impliqués dans les altérations de la croissance fœtale. En conséquent, le placenta constitue un organe de choix pour étudier les interactions entre l’alimentation maternelle et le fœtus au cours de la grossesse. Durant cette thèse, nous avons tenté d’identifier de nouvelles voies moléculaires placentaires impliquées dans le contrôle de la croissance fœtale chez le rat, puis d'étudié l'expression de ces facteurs dans des placentas humains provenant de grossesses impliquant des anomalies de la croissance fœtale. Comme la malnutrition maternelle constitue une part importante dans l'étiologie de la restriction de croissance intra-utérine (RCIU), nous avons utilisé un modèle expérimental effectué chez le rat, qui consiste en une réduction (de 50% à 70%) de la ration alimentaire quotidienne maternelle durant la gestation. Ces régimes conduisent à des troubles de la croissance de l'unité fœto-placentaire révélés par des réductions drastiques du poids du placenta et des poids de naissance à terme. Afin d'identifier de nouvelles voies placentaires impliquées dans RCIU, nous avons utilisé deux méthodologies différentes: une approche protéomique et une évaluation de deux protéines récemment caractérisées.Premièrement, nous avons étudié le protéome placentaire chez le rat RCIU provenant de mères dénutris par une analyse protéomique (2D-PAGE et spectrométrie de masse). Cette stratégie nous a permis de découvrir de nouvelles voies modulées par le RCIU et, étonnamment, des modulations importantes ont été observées pour plusieurs protéines mitochondriales, suggérant un effet ciblé de la dénutrition sur ces organites. Par la suite, en utilisant diverses techniques d'analyses moléculaires, protéomiques et fonctionnelles, nous avons montré que ces organites élaborent une réponse adaptative à la restriction alimentaire maternelle qui pourrait avoir des conséquences sur la régulation de la croissance fœtale. Deuxièmement, nous avons étudié deux autres protéines atypiques: le brain-derived neurotrophic factor et l'hormone apéline. Nos résultats suggèrent que ces deux facteurs pourraient être impliqués, au niveau placentaire, dans le contrôle de la croissance fœtale à la fois chez le rat et chez l'homme. En conclusion, comme les techniques cliniques actuelles ne permettent pas de diagnostiquer avec précision un RCIU, nos résultats pourraient permettre une meilleure compréhension de la physiopathologie placentaire et permettre de développer de nouveaux marqueurs de diagnostique et/ou de traitement dans le but d'améliorer la croissance placentaire et fœtale en conditions pathologiques. / Growing evidences indicate that a small birthweight, resulting from maternal malnutrition or others prenatal alterations, is associated with an increased neonatal morbidity and mortality and may lead to higher propensity to develop a metabolic syndrome (including type 2 diabetes, obesity, hypertension and dyslipidemia) in adulthood. However, the physiopathological mechanisms acting in utero on the programming of the offspring's metabolic profile remain confused and may implicate numerous molecules and physiological systems. Several data suggest that the placental alterations may have long-lasting consequences and could thus contribute to the programming of adult metabolic diseases. The placenta is the primary means of communication and nutrient delivery to the fetus and is also involved in fetal homeostasis. Thus, the placenta may constitute an appropriate organ for investigating how differences in maternal food consumption are sensed by the fetus along the pregnancy. Because of the increasing proportion of women eating inadequately during pregnancy and because such nutritional disturbances may have huge repercussions on adult health of the offspring, we urgently have to better understand how the placenta elaborates adaptive responses to maternal food intake modulations. My PhD aimed at identifying new placental pathways implicated in fetal growth restriction in rat, and investigated in human placental samples, the expression of these factors in pregnancies with fetal growth disturbances.As maternal malnutrition constitutes an important part in the etiology of intrauterine growth restriction (IUGR), we used an experimental model performed in rats which consists of a reduction (from 50% to 70%) of the daily maternal food intake during the gestation. These regimens lead to profound growth disturbances of the feto-placental unit revealed by drastic reductions of both placental and birth weights at term. To identify new placental pathways implicated in IUGR, we have used two different strategies: a proteomic approach and the evaluation of two proteins recently characterized in the placenta.First, we investigated the placental proteome in IUGR rats from undernourished mothers using 2D-PAGE electrophoresis and mass spectrometry identification. This strategy allowed the discovery of new pathways modulated by IUGR. Surprisingly, major modulations were observed for several proteins localized in mitochondria, suggesting specific effects of maternal undernutrition on these organelles. Thereafter, using multiple molecular, proteomic and functional analyses, we have shown that these organelles develop adaptive responses to maternal nutrient restriction that may have functional consequences on the regulation of the fetal growth. Secondly, we studied two others atypical proteins: the brain-derived neurotrophic factor and the hormone apelin. Our findings suggest that both of these factors may be implicated in the control of fetal growth at the placental level in rat and putatively in human. As actual clinical methods do not permit to diagnose precisely fetal growth disturbances, our results may permit to better understand the placental physiological pathways implicated during these pathologies and could lead to the development of markers and/or treatments in order to improve both placental functions and fetal growth.

Orientador: Jose Guilherme Cecatti / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-07-23T19:32:25Z (GMT). No. of bitstreams: 1 Perrotti_MariaReginaMachado_M.pdf: 4664028 bytes, checksum: 2a5d7e1a157402585d9888c93184e7a5 (MD5) Previous issue date: 1998 / Resumo: O objetivo deste estudo foi elaborar uma curva de valores do índice de líquido amniótico em gestantes normais, da cidade de Campinas, de 20 a 42 semanas de gestação, e avaliar a associação destes valores com variáveis sociodemográficas e obstétricas. Para tanto, realizou-se um estudo descritivo. Estudaram-se 2.868 gestantes normais, através da realização de um exame ultra-sonográfico obstétrico de rotina, incluindo a biometria fetal e também a medida do índice de líquido amniótico, pela técnica de Phelan (1987), modificada por Jeng (1990). Os dados foram analisados através de análise uni e multivariada da variação do índice de líquido amniótico e demais variáveis, com avaliação das diferenças pelos teste t de Student, teste de Kruskal-Wallis, teste Qui-Quadrado, análise de variância para medidas independentes, análise de regressão linear múltipla e construção dê uma curva dos percentis 2,5; 10, 50; 90 e 97,S dos valores do índice de líquido amniótico em relação à idade gestacional, posteriormente submetida a procedimento de alisamento, por ajustes polinomiais de segundo grau. Houve variação significativa do índice de líquido amniótico nas diferentes idades gestacionais, permanecendo sua mediana praticamente constante, em torno de 150 milímetros, das 20 às 33 semanas, quando iniciou-se um declínio, especialmente acentuado após a 38a semana. Não houve variação estatisticamente significativa quando avaliou-se isoladamente a associação do índice de líquido amniótico à idade materna, cor, escolaridade, hábito de fumar, paridade e presença de cicatriz de cesárea, nem quando a avaliação foi conjunta por análise multivariada. Conclui-se que a curva dos percentis 2,5; 10; 50; 90 e 97,5 dos valores do índice de líquido amniótico mostra um decréscimo significativo com a idade gestacional, especialmente após a 30a - 32a semana / Abstract: The purpose of this study was to elaborate an amniotic fluid index values curve in normal pregnant women of Campinas City, from the 20th to the 42nd week of gestation. It also aimed to evaluate the association between these values and the sociodemographic and obstetric variables. A descriptive study was perfomed for this purpose, and 2868 normal pregnant women were studied through routine obstetric ultrasound examinations, including fetal biometry and also the measurement of the amniotic flúid index, using the Phelan technique (1987), modified by Jeng (1990). The data was analyzed through the univariate and multivariate analysis of the amniotic fluid index variation and the other variables. The differences were evaluated by t-Student test, Kruskal-Wallis test, Chi-square test, analysis of variance for independent measurements, and linear and multiple regression analysis. The differences were also evaluated by fitting a curve of the percentiles 2,5; 10; 50; 90, and 97,5 of the amniotic fluid index values in relation to the gestational age, submitted afterwards to a smoothing procedure by quadratic polynomial adjustments. There was a significant variation of the amniotic fluid index in the differEmt gestational ages. However, the median remained practically constant around 150 millimetres, from the 20th to the 38th week. There wasn't a statistically significant variation when evaluating separately the association of the amniotic fluid index with mother' s age, color, education, smoking habit, parity, and the presence of cesarean section scars, not even when the evaluation was concurrent through multivariated analysis. It is concluded that the curve of the percentiles 2,5; 10; 50; 90 and 97,5 of the amniotic fluid index values show a significant decrease with the gestational age, especially afier the 30th - 32nd weeks / Mestrado / Tocoginecologia / Mestre em Tocoginecologia

Made available in DSpace on 2014-06-12T23:02:06Z (GMT). No. of bitstreams: 2 arquivo9039_1.pdf: 2295894 bytes, checksum: 5b874a171afea93832753cb0a467211a (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2012 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo desta dissertação foi avaliar em ratos adultos, os efeitos da desnutrição protéica perinatal no metabolismo energético do músculo esquelético isolado submetido à estimulação adrenérgica. Ratas Wistar foram divididas em dois grupos de acordo com a manipulação nutricional durante toda gestação e lactação: o grupo controle recebeu uma dieta com 17% caseína (C, n=6) e o grupo desnutrido recebeu uma dieta com 8% de caseína (LP, n=6). O peso corporal e o consumo alimentar foram avaliados semanalmente. No primeiro dia após o nascimento foi verificado o tamanho e o peso das ninhadas. Após o desmame os filhotes receberam dieta padrão de biotério e foram avaliados quanto ao peso corporal, comprimento corporal e o ganho de peso corporal até a idade adulta. Aos 100 dias de idade os animais foram submetidos a um jejum de 12 horas e foram sacrificados para retirada dos tecidos. Foi retirado o sangue do animal para avaliar, através de espectrofotometria e ELISA, as concentrações séricas de proteínas totais, glicose, colesterol, triglicerídeos, leptina e insulina. Ambos, os músculos sóleo e EDL foram removidos e incubados em equipamento de banho isolado de tecidos por duas horas com fenilefrina 10-5 M, um agonísta seletivo do receptor α1- adrenérgico, ou com isoprenalina 10-5 M, um agonista dos receptores β1- e β2- adrenérgico. Após a estimulação adrenérgica dos músculos, foram avaliadas a atividade das enzimas citrato sintase, PFK e β-HAD. Nossos resultados demonstram que animais submetidos à desnutrição protéica perinatal apresentam menor peso no nascimento e maior ganho de peso pós-natal. Com relação às avaliações do soro observamos apenas uma redução na concentração de proteínas totais em animais desnutridos. No músculo sóleo, foi observado que animais desnutridos apresentaram menor atividade da enzima β-HAD e que mesmo quando estimulados com α ou β agonistas a atividade desta enzima permaneceu reduzida. No músculo EDL, a atividade das enzimas PFK e CS foi maior em animais desnutridos em relação ao controle. Quando tratados com isoprenalina animais desnutridos apresentaram redução da atividade da enzima PFK e um aumento da atividade da enzima β-HAD em relação aos animais desnutridos que foram tratados com fenilefrina e os que não foram tratados. O presente estudo mostrou que a desnutrição protéica perinatal programa o metabolismo energético de forma diferente em dois tipos de músculos esqueléticos. No músculo predominantemente oxidativo, diminui a atividade da enzima chave da beta oxidação de ácidos graxos, sendo este efeito persistente mesmo quando estimulados com agonistas adrenérgicos. Enquanto que, no músculo predominantemente glicolítico, aumenta a atividade de enzimas chaves do metabolismo dos carboidratos e quando estimulados com β-agonista adrenérgico induz o metabolismo dos ácidos graxos e inibe o metabolismo glicolítico

Orientador : Anibal Faundes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-07-18T12:28:56Z (GMT). No. of bitstreams: 1 Parpinelli_MaryAngela_M.pdf: 1922860 bytes, checksum: 69fde2df040b0f15dc4bc9d024c7dc25 (MD5) Previous issue date: 1993 / Resumo: A hipertensão arterial na gravidez é uma das mais importantes causas de morbimortalidade materna e perinatal em todo mundo. O prognóstico gestacional diverge, segundo diferentes aspectos e formas de hipertensão e, clinicamente, nem sempre se consegue identificar o correto fator etiológico da doença. A maior duração e a precocidade de sua instalação, entre outros, têm sido considerados como fatores de mau prognóstico materno e perinatal. Avaliou-se a influência destas duas variáveis sobre os resultados maternos e perinatais de 267 gestações de mulheres hipertensas e de 274 produtos conceptuais correspondentes. As gestantes foram divididas em três grupos, segundo a época de instalação Da hipertensão (até 28, de 28,1 a 36 e após 36 semanas) e em dois grupos segundo a duração da mesma (até 30 e superior a 30 dias). Utilizou-se os testes estatísticos t de Student ou F de Senedecor para as variáveis quantitativas, Qui-quadrado para as variáveis qualitativas e, análise multivariada (por regressão logística ou regressão linear múltipla). A precocidade da instalação da hipertensão arterial relacionou-se aos maiores níveis de pressão arterial durante a gravidez e parto, à maior freqüência de parto prematuro terapêutico, maior tempo de internação materna, prematuridade, retardo de crescimento intrauterino, baixo peso, sofrimento fetal crônico, depressão neonatal e mortalidade perinatal. A duração da hipertensão na gravidez não se relacionou ao prognóstico materno e perinatal. / Abstract: Hypertension during pregnancy is one of the most important causes of maternal and child morbidity and mortality alI over the world. The evolution and outcome of pregnancy varies, according to the characteristics and types of hypertension, which etiology is not always clinically identified. Its longer duration and early occurrence, among other factors, have been proposed as indicating poor maternal and perinatal prognosis. The influence of both variables on maternal and perinatal outcomes of 267 gestations of hypertensive mothers and their 274 babies were evaluated. The pregnant women were divided in three groups, according to the time when hypertension was detected (up to 28 weeks, from 28.1 to 36 weeks and after 36 weeks), and in two groups, according to the duration of hypertension (up to 30 and over 30 days). The statistic tests "t" of student and "F" of Senedecor were used for quantitative variables and multivariate analysis (through logistic regression or multiple linear regression). The early installation of hypertension was related to a higher blood pressure during pregnancy and delivery, a higher frequency of medically induced premature births, longer maternal hospitalization, prematurity, intrauterine growth retardation, low birth-weight, chronic fetal distress, neonatal depression and perinatal mortality. The duration of hypertension in pregnancy was not related to the maternal and perinatal outcome. / Mestrado / Tocoginecologia / Mestre em Medicina

Orientador : João Luiz Pinto e Silva / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-07-18T18:53:19Z (GMT). No. of bitstreams: 1 Franzin_CleideMaraMazzottideOliveira_M.pdf: 2132815 bytes, checksum: 0151bdd6b01d58c96dd9c8751b401fdd (MD5) Previous issue date: 1993 / Resumo: Com a finalidade de construir curvas de crescimento para avaliação da idade gestacional e diagnosticar distúrbios de crescimento fetal, foram realizados 674 exames ultra-sonográficos em 106 gestantes atendidas no Serviço de Ultra-Sonografia do Centro de Atenção Integral à Saúde da Mulher, entre a sétima e 41a semana. As variáveis analisadas foram: diâmetro biparietal, diâmetro occipitofrontal, circunferência cefálica, diâmetro abdominal anteroposterior, diâmetro abdominal transversal, circunferência abdominal, comprimento do fêmur, distância interorbital externa, distância interorbital interna e índice cefálico. As medidas fetais estudadas mostraram alta correlação com a idade gestacional, com exceção do índice cefálico, que se manteve constante durante a gestação. Pela primeira vez na literatura as medidas do diâmetro abdominal anteroposterior, diâmetro abdominal transversal e diâmetro occipitoposterior correlacionaram-se com a idade gestacional. As que apresentaram maior correlação foram: o comprimento do fêmur, seguido pelo diâmetro biparietal, circunferência abdominal, distância interorbital externa c circunferência cefálica. Os coeficientes de correlação obtidos igualaram-se ou superaram os relatados na literatura, sendo de 0,99 para DBP, 0,99 para CC, 0,95 para DOF, 0,97 e 0,99 para DAT, 0,99 para DAAP, 0,99 para CA, 0,99 para CF, 0,95 e 0,98 para DIOE, 0,49, 0,88 e 0,92 para DIOI. Foram construídas curvas de crescimento e tabelas com valores estimados para idade gestacional com os respectivos limites, inferior e superior, da banda de confiança de 95 %, para viabilizar sua utilização prática. / Abstract: The aim of this presentation is to build a growth curve to evaluate the pregnancy age and to diagnose fetal disturbance of growth. 674 scannings were made on 106 pregnant women at CAISM (Centro de Atenção Integral à Saúde da Mulher). These exams were performed from the 7th to 41th week of pregnancy. The variables taken into account were: biparietal diameter, occiptofrontal diameter, cephalic circunference, abdominal anteroposterior diameter, abdominal transverse, abdominal circunference, femur lenght, interorbital external distance, interorbital internal distance and cephalic index. The measures presented high correlation with the length of pregnancy, with exception of the cephalic index, which was constant durinkpregnancy. The measurements that presented higher correlation were: femur length, biparietal diameter, abdominal circunference, interobital external distance and cephalic circunference. The obtained correlation coefficients were equal to or higher than those shown in the literature. They were 0.99 for biparietal diameter, 0.99 for cephalic circunference, 0.95 for occiptofrontal diameter, 0.97 and 0.99 for transversal abdominal diameter, 0.99 anteroposterior abdominal diameter, 0.99 for abdominal circunference, 0.99 for femur length, 0.95 and 0.98 for external interorbital distance 0.49, 0.88 and 0.92 for internal interorbital distance. Growth curves and tables with expected values for gestacional age, with lower and upper bounds of the 95 % interval range were constructed for practical use. / Mestrado / Mestre em Ciências Médicas