Copies of author's previously published articles inserted. / Bibliography: leaves 160-173. / xi,173 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / A prospective, descriptive study of every case of eclampsia which occurred in the United Kingdom during 1992. Multiple logistic regression analyses were carried out to help assess which factors of the eclamptic episode were associated with poorer maternal and fetal outcomes. / Thesis (M.D.)--University of Adelaide, Dept. of Obstetrics and Gynaecology, 1996?

Thesis (Ph.D.)--Virginia Commonwealth University, 2010. / Prepared for: Dept. of Physiology. Title from title-page of electronic thesis. Bibliography: leaves 118-146.

Resumo: O novo conceito de pré-eclâmpsia precoce e tardia estabeleceu a hipótese de que essas duas entidades possam estar associadas a diferentes modelos de adaptação vascular. A tonometria de aplanação é capaz de avaliar, de forma não invasiva, diversas características vasculares e pode ser utilizada para estudar a fisiopatologia das diferentes formas de pré-eclâmpsia. Comparar as características vasculares de gestantes portadoras de pré-eclâmpsia precoce e tardia, determinadas por meio da tonometria de aplanação. Estudo transversal e analítico realizado em 85 gestantes portadoras de pré-eclâmpsia (PE) que, no momento do diagnóstico, foram estratificadas em PE precoce e tardia, de acordo com a idade gestacional da manifestação clínica da doença. O cálculo do tamanho amostral foi baseado no estudo de Khalil et al. (2009) e estimado em 33 pacientes por grupo. Considerou-se o nível de significância de 5% (α = 0,05) e o poder de 80% (β = 0,20). Foram avaliadas a pressão arterial periférica e central, a pressão de pulso periférica e central, o índice de amplificação, a pressão de aumento, o índice de viabilidade subendocárdica e a duração de ejeção. Todos os índices foram determinados por meio da tonometria de aplanação (SphygmoCor®). A análise estatística foi feita no programa SPSS 10.5. As variáveis foram representadas por média e desvio padrão, mediana e porcentagem. A média foi utilizada para variáveis com distribuição normal e a mediana para variáveis que não apresentaram distribuição normal. Para a comparação das médias dos grupos pré-eclâmpsia precoce e tardia foi utilizado o teste t de Student e, quando necessário, o teste de Mann-Whitney. Para comparação das proporções foi utilizado o teste de qui-quadrado. Foi considerado nível de significância de 5%. Considerando-se as características da população estudada verificou-se... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The new concept of early and late preeclampsia established the hypothesis that these two entities may be associated with different models of vascular adaptation. The applanation tonometry is able to evaluate, noninvasively, several vascular features and can be used to study the pathophyology of different forms of preeclampsia. To compare vascular characteristics of pregnant women with early and late preeclampsia, determined by applanation tonometry. Cross sectional and analytical study conducted in 85 pregnant women with preeclampsia (PE) that, at the time of diagnosis, were stratified into early and late PE, according to the gestational age of the clinical manifestation of the disease. The calculation of the sample size was based on the study of Khalil et al. (2009) and estimated at 33 patients per group. It was considered the significance level of 5% (α = 0.05) and 80% power (β = 0.20). It was also evaluated the peripheral and central blood pressure, peripheral and central pulse pressure, augmentation index, the augmentation pressure, subendocardial viability ratio and the ejection duration. All indexes were determined by applanation tonometry (SphygmoCor ®). Statistical analysis were done using SPSS 10.5. Variables were presented as mean and standard deviation, median and percentage. The mean was used for variables with normal distribution and median for variables that did not show normal distribution. For the comparison of the mean in the group with early and late preeclampsia it was used a student t test and, when necessary, the Mann-Whitney test. To compare proportions it was used the qui-quadrado test. It was considered a significance level of 5%. Considering the characteristics of the population studied it was verified that body mass index, proteinuria and gestational age were significantly different between the groups. As for the vascular features determined by applanation... (Complete abstract click electronic access below) / Orientador: José Carlos Peraçoli / Coorientador: Vera Theresinha Medeiros Borges / Banca: Maria Letícia Sperandéo de Macedo Luminoso / Banca: Ricardo de Carvalho Cavalli / Mestre

There is currently no clinically useful screening test available to identify nulliparous women at high risk of developing pre-eclampsia. This study aimed to identify novel biomarkers using hypothesis generating proteomic methods applied to plasma samples obtained prior to clinical diagnosis of pre-eclampsia. Plasma samples taken at 15 weeks gestation from women who subsequently developed late pre-eclampsia (> 34 weeks), early pre-eclampsia (< 34 weeks) and two distinct groups of women with uncomplicated pregnancies (each n=12) were pooled. Pooled plasma was immunodepleted, labelled using iTRAQ-8 plex reagent and separated into fractions using high pH reverse phase chromatography. Fractions were analysed by LC-MS/MS and data interrogated using ProteinPilot 3.0. The merits of two immunodepletion systems were compared; the Seppro® IgY 14 -SuperMix LC column system removes up to 100 highly abundant plasma proteins and the Multiple Affinity Removal LC column depletes 14 highly abundant plasma proteins. Removal of more high abundance proteins allowed identification of more, potentially interesting, low abundance proteins, but was less reproducible than removing fewer proteins. Two methods of LC-MS/MS analysis were assessed; the QStar XL qTOF and 5800 MALDI-TOF-TOF. The protein identifications and the quantification data acquired by each method was comparable and complementary and increased the total number of proteins identified. A total of 502 proteins were identified. A stringent two stage analysis was developed to identify candidate proteins which changed in abundance in plasma from women who later developed pre-eclampsia compared to women with uncomplicated pregnancies. Analysis identified a total of 113 proteins which were both reproducibly quantified and changed by more than the expected range of biological variation. Six candidate proteins changed in abundance in the plasma taken from women who subsequently developed early pre-eclampsia were selected for further validation. A high throughput, low cost, method of multiple reaction monitoring which allows relative quantitation without the use of costly isotopically labelled peptides was developed to validate candidate proteins. Candidate proteins were also assessed by western blot and ELISA. Only one candidate protein; platelet basic protein, was validated by all three methods and demonstrated similar increases in the abundance. This investigation suggests that measurement of platelet basic protein at 15 weeks gestation is a novel candidate predictive marker for pre-eclampsia. Validation of platelet basic protein in a large, independent, sample set is required to confirm changes in protein expression and to evaluate potential, alongside other factors, to identify nulliparous women at high risk of developing pre-eclampsia later in pregnancy.

Made available in DSpace on 2014-06-11T19:27:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-22Bitstream added on 2014-06-13T19:35:50Z : No. of bitstreams: 1 silva_eg_me_botfm.pdf: 504986 bytes, checksum: 7886cf3f829ed694ababaaa6122a9a77 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Gestantes com pré-eclâmpsia apresentam alterações nas vias aéreas superiores e no sistema cardiovascular quando comparadas com gestantes normais. O objetivo do presente estudo foi avaliar as pressões respiratórias máximas, a espirometria e a capacidade funcional de exercício em gestantes com pré-eclâmpsia, através de manovacuometria, espirometria e teste de caminhada de seis minutos. Foram avaliadas 74 gestantes, sendo 37 normais (controle) e 37 com pré-eclâmpisa, entre estas 16 com préeclâmpsia leve e 21 com pré-eclâmpsia grave. As pressões respiratórias máximas e a maioria das variáveis espirométricas foram semelhantes entre os grupos pré-eclâmpsia e controle, exceto o maior volume minuto [14 (12; 16) x 12 (10; 14)] e menor capacidade vital forçada [100 (97; 106) x 106 (98; 111)] verificados no grupo pré-eclâmpsia, quando comparado com o grupo controle, respectivamente. A capacidade funcional de exercício representada pela distância percorrida no teste de caminhada de seis minutos foi menor no grupo pré-eclâmpsia (421±59 m) quando comparado com o grupo controle (497± 39 m). A análise de regressão múltipla identificou a presença de pré-eclâmpsia e a capacidade vital forçada como preditores da distância percorrida no teste de caminhada de seis minutos (R2= 98,5%). Conclui-se que, a pré-eclâmpsia está associada com menor tolerância ao exercício, quando avaliada pelo teste de caminhada de seis minutos. Apenas dois parâmetros espirométricos, volume minuto e capacidade vital forçada, apresentaram alterações significativas no grupo com pré-eclâmpsia, sendo que a capacidade vital forçada influenciou no desempenho durante o exercício. A pré-eclâmpsia não interfere nas funções musculares respiratórias representadas pelas pressões inspiratória e expiratória máximas. / Pregnants with pre-eclampsia present upper airway and cardiovascular dysfunctions when compared with healthy pregnants. The aim of the current study was to assess maximal respiratory pressures, spirometry and functional exercise capacity in pregnants womem with pre-eclampsia, by evaluation of manovacuometer, spirometry and six-minute walk test. Seventy-four pregnants were evaluated, 37 healthy (control) and 37 with preeclampsia: 16 with mild and 21 with severe pre-eclampsia. Maximal respiratory pressures and most of spirometrics variables were similar between pre-eclampsia and control groups, exception the higher minute ventilation [14 (12;16) x 12 (10;14)] and the minimal forced vital capacity [100 (97;106) x 106 (98;111)] observed in pre-eclampsia compared with control group, respectively. Functional exercise capacity represented by the distance performed for the six-minute walk test, was lower in pre-eclampsia group (421±59 m) compared with control group (497± 39 m). Multiple regression analysis identified pre-eclampsia and forced vital capacity as predictors of distance performed on the six-minute walk test (R2= 98,5%). Therefore it was concluded that pre-eclampsia is associated with lower exercise tolerance when assessed by the six-minute walk test. Only two spirometrics variables presented significative alteration in pre-eclampsia group, minute ventilation and forced vital capacity which influenced the exercise performance. Pre-eclampsia does not interfere in respiratory muscle function, represented by the maximal inspiratory and expiratory pressures.

Made available in DSpace on 2014-06-11T19:29:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-27Bitstream added on 2014-06-13T21:00:23Z : No. of bitstreams: 1 volpi_scp_me_botfm.pdf: 576023 bytes, checksum: 7dd3829998229954fc827b11bf062fd2 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / É grande a preocupação com o desenvolvimento motor de prematuros de muito baixo peso, mas as idades de seus marcos motores não estão bem estabelecidas. Determinar as idades cronológica e corrigida dos marcos motores até a marcha, em prematuros de muito baixo peso. Estudo de coorte, em 143 prematuros com menos de 1500g e idade gestacional menor ou igual a 34 semanas, sem alterações neurossensoriais, selecionados no ambulatório de seguimento de recém-nascidos de Unidade de Terapia Intensiva Neonatal do Hospital das Clinicas da Faculdade de Medicina de Botucatu- Universidade Estadual Paulista, no período de 1998 a 2003 e avaliados a cada dois meses de seguimento até a marcha. Dos 155 prematuros incluídos houve perda de 9% da coorte, restando no estudo143 lactentes. A média de idade gestacional foi 30±2 semanas.O peso ao nascimento de 1130±222g, sendo 59% do sexo feminino e 43% pequenos para Idade gestacional. Houve atraso superior a um mês nas idades cronológicas do controle de cabeça, rastejar e engatinhar, mas na idade corrigida todos os marcos foram alcançados no prazo previsto. Não houve diferença entre meninos e meninas. Os pequenos para idade gestacional diferiram dos adequados, mas obtiveram seus marcos dentro da normalidade. Houve correlação significativa entre os marcos motores. Prematuros de muito baixo peso, sem alterações neurossensoriais, apresentam marcos motores no prazo normal: controlam a cabeça no 2o mês, sentam aos sete meses e andam com 12,8 meses de idade corrigida, correspondendo respectivamente ao 4o, 9o e 15o mês de idade cronológica. Os marcos motores são mais tardios nos prematuros pequenos para idade gestacional. / There is great concern regarding to the neurodevelopment of very low birthweight infants, but the ages of gross motor milestone attainement are not well established. To determine the chronological and corrected ages of gross motor milestones until walking attainment in very low birthweight infants. Methods: Prospective cohort study, including 143 preterm infants < 1500g and ≤ 34 weeks of gestation, without neurological and sensorial sequelae, recruited from 1998 to 2003 in the Neonatal High Risk Follow-up Clinic of HC- Botucatu Medical School-UNESP, and bimonthly evaluated up to walking attainment. Of the 155 preterm included, there was loss of 9% of the cohort, and 143 were studied. Mean gestational age was 30±2 weeks, birth weight 1130±222g, 59% were female and 43% small for gestational age. Chronologic ages were delayed more than one month for the head control, creeping, and crawling, however all motor milestones attainment were normal for the correct age. Males did not differ from females. Small for gestational age infants attained their milestones later than those of appropriate size for gestational age, although in the normal range of the expected time. There was a significant correlation between the gross motor milestones. Very low birthweight infants, without neurosensorial sequelae, have a normal profile of the gross motor milestones: head control at 2nd month, siting at 7 months and walking at 12,8 months of corrected age, corresponding to 4th, 9th, and 15th months of chronologic age respectively. Motor milestones are later in the small for getational age infants.

Pre-eclampsia is a pregnancy-related disorder characterised by high blood pressure, proteinuria and oedema. The aetiology of the disease is unclear but evidence suggests that endothelial dysfunction is central to the development of the maternal syndrome. Kinins are endogenous peptides released by the endothelium that contribute to the regulation of cardiovascular homeostasis by inducing vasodilation, fibrinolysis and angiogenesis. Given that pre-eclampsia is associated with reduced endotheliumdependent relaxation, coagulation abnormalities and an angiogenic imbalance, it was hypothesised that alterations of kinin receptor-mediated responses may be involved in the pathogenesis of the condition. To investigate whether changes in kinin receptor activity are involved in the impairment of endothelium-dependent relaxation observed in pre-eclampsia, the effects of specific B2 and B1 receptor agonists and antagonists on myometrial vascular tone were tested on arteries from healthy pregnancy and pre-eclampsia. The results demonstrated that in addition to classical bradykinin B2 receptor-mediated relaxation, a subset of healthy patients exhibited nitric oxide-dependent relaxation to the B1 receptor agonist Lys-des- Arg9-BK (LDABK) which could not be inhibited by either B1 or B2 receptor antagonists. Also, vessels that exhibited this novel response to LDABK were more sensitive to bradykinin. Furthermore, this study revealed that patients with pre-eclampsia had an attenuated response to both bradykinin and LDABK. Immunolocalisation and mRNA expression of the kinin receptors in the myometrium revealed no differences between healthy pregnancy and pre-eclampsia suggesting that disturbances of kinin receptor signalling rather than changes in receptor distribution or expression levels may be involved in the reduction of kinin-mediated responses in these patients. The role of kinins in mediating placental angiogenesis in healthy pregnancy and preeclampsia was determined using the endothelial tube formation assay in primary human umbilical vein endothelial cells (HUVECs) isolated from healthy women and women with pre-eclampsia. B2 and B1 receptor agonists induced endothelial tube formation via a VEGF-dependent, nitric oxide-independent mechanism in healthy HUVECs cultured in normoxic conditions. HUVECs isolated from women with pre-eclampsia cultured under normoxia and HUVECs from healthy pregnancies cultured under hypoxia exhibited greater levels of angiogenic branching compared with healthy normoxic cells, but were unresponsive to bradykinin and LDABK. Incubation of these cells with a VEGF receptor inhibitor reduced the elevated levels of tube formation indicating that this effect may be due to hypoxic upregulation of VEGF or an intrinsic difference in their angiogenic capacity. Further studies are required to determine the cause for the differences in angiogenic potential between healthy and pre-eclamptic cells and the impact this could have on placental vascular development and the pathogenesis of preeclampsia.

Eclampsia is defined as de novo seizure in a woman with the hypertensive complication of pregnancy known as preeclampsia (PE), and is a leading cause of maternal and fetal morbidity and mortality worldwide. The pathogenesis of eclamptic seizure remains unknown, but is considered a form of hypertensive encephalopathy where an acute rise in blood pressure causes loss of cerebral blood flow (CBF) autoregulation and hyperperfusion of the brain that results in vasogenic edema formation and subsequent seizure. However, eclamptic seizure can occur during seemingly uncomplicated pregnancies, in the absence of hypertension and PE, suggesting that normal pregnancy may predispose the brain to hypertensive encephalopathy or seizure, independently of PE. The overall goal of this dissertation was to investigate the effect of pregnancy and PE on the cerebrovasculature and neurophysiological properties that may promote brain injury and eclamptic seizure. For this dissertation project, a rat model of PE was established that combined placental ischemia, induced by restricting blood flow to the uteroplacental unit, and maternal endothelial dysfunction that was induced by a prolonged high cholesterol diet. Rats with PE developed several PE-like symptoms, including elevated blood pressure, fetal growth restriction, placental dysfunction, and were in a state of oxidative stress and endothelial dysfunction. We found that pregnancy had an overall protective effect on the maintenance of CBF that was potentially due to a nitric-oxide dependent enhancement of the vasodilation of cerebral arteries to decreased intravascular pressure. Further, maintenance of CBF during acute hypertension was similar in pregnancy and PE. Thus, it does not appear that pregnancy and PE are states during which CBF autoregulation is compromised in a manner that would promote the development of hypertensive encephalopathy. However, the brain was found to be in a hyperexcitable state during normal pregnancy that was augmented in PE, and could contribute to onset of eclamptic seizure. Under chloral hydrate anesthesia, generalized seizure was induced by timed infusion of the convulsant pentylenetetrazole (PTZ), with simultaneous electroencephalography that was stopped at the first onset of spikewave discharge indicative of electrical seizure. Seizure threshold was determined as the amount of PTZ required to elicit seizure. Compared to the nonpregnant state, seizure threshold was ~44% lower in pregnant rats and ~80% lower in rats with PE. Further, pregnant rats were more susceptible to seizure-induced vasogenic edema formation than the nonpregnant state. Mechanisms by which pregnancy and PE lowered seizure threshold appeared to be through pregnancy-associated decreases in cortical gamma-aminobutyric acid type A receptor (GABAAR) subunits and PE-induced disruption of the blood-brain barrier (BBB) and microglial activation, indicative of neuroinflammation. Magnesium sulfate (MgSO4), the leading treatment for seizure prophylaxis in women with PE, restored seizure threshold to control levels by reversing neuroinflammation in PE rats, without affecting BBB permeability. Overall, this dissertation provides evidence that pregnancy increases susceptibility of the brain to seizure and vasogenic edema formation that likely contribute to the onset of eclampsia during seemingly uncomplicated pregnancies. Further, the pathogenesis of eclampsia during PE likely involves breakdown of the BBB and subsequent neuroinflammation, resulting in a state of greater seizure susceptibility that is ameliorated by MgSO4 treatment.

La hipertensión es el desorden más común que complica el embarazo (1), y del cual el 70% corresponden a hipertensión gestacional y pre-eclampsia. (2) La pre-eclampsia es un desorden multisistémico de causa desconocida que es única en el embarazo humano, siendo caracterizado por una respuesta vascular anormal a la placentación y que se asocia con resistencia vascular, incremento de la agregación placentaria, activación de la coagulación sistémica y disfunción de las células endoteliales. (3) La preeclampsia a llegado a constituir la mayor causa de mortalidad materna (15 a 20% en países desarrollados), morbilidad materna, muerte perinatal, parto pretérmino y restricción de crecimiento. (4) Siendo su diagnóstico confirmado con la presencia de hipertensión arterial asociado a proteinuria con o sin otra alteración multisistémica. (1,2,5) Sin embargo la hipertensión gestacional es considerada benigna, manifestándose solo por hipertensión, no ocasionando daño renal ni repercusiones sistémicas, además de presentar resultados perinatales similares a los de la población en general (6,7)

El presente trabajo de investigación tiene como objetivo principal describir la morbimortalidad perinatal existente en gestantes con parto pretérmino asociado a preeclampsia y eclampsia, obteniendo datos que permitan aportar información actual y basada en evidencias. Es un estudio retrospectivo, transversal y descriptivo. Siendo el lugar de ejecución el servicio de obstetricia de Hospital Nacional Edgardo Rebagliati Martins en donde se investigó una población de 292 pacientes tuvieron con parto pretérmino asociado a preeclampsia y eclampsia en el año 2005. Los resultados fueron 87 gestantes (29.79%) presentaron preeclampsia leve y parto pretérmino, 203 (69.52%) presentaron preeclampsia severa y parto pretérmino y solamente 2 (0.69%) pacientes presentaron eclampsia y parto pretérmino. De los 87 casos de preeclampsia leve 74 no presentaron patologías y 13 presentaron patologías, las más frecuente fueron otras (20.41%) taquípnea transitoria (18.37%), ictericia (16.33%). Se presentaron 11 muertes perinatales: de gestantes con preeclampsia leve se presentaron 03 casos de muerte perinatal debidas: 01 caso anomalía congénita, 02 casos debidas a otras causas, mientras que en preeclampsia severa se presentaron 03 casos debido a infecciones intrahospitalaria ,02 hemorragias del sistema nerviosos central 01 por anomalías congénitas y 02 por otras causas. Se concluye que la morbilidad perinatal en gestantes con parto pretérmino asociado a Preeclampsia y eclampsia es mayor en preeclampsia severa y que la mortalidad perinatal en gestantes con parto pretérmino asociado a Preeclampsia y eclampsia es mayor en preeclampsia severa.