Hydrogen sulphide rescues preeclampsia-like phenotype aggravated by high sFlt-1 in Placenta Growth Factor (PlGF) deficiency

INTRODUCTION: Low circulating levels of placenta growth factor (PlGF) is strongly associated with the onset of preeclampsia, a maternal hypertensive disorder characterized by high blood pressure and proteinuria after 20 weeks of gestation. Although, PlGF-deficient mice are born healthy and fertile at a Mendelian ratio, the physiological importance of PlGF in the pathogenesis of preeclampsia is unclear. We hypothesised that decreased levels of PlGF in pregnancy exacerbates the fetal growth restriction associated with preeclampsia in the presence of high sFlt-1. METHODS: Pregnant PlGF-/- mice were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) at high (i) 1.5x109 pfu/ml and low (ii) 0.5x109 pfu/ml doses. Mean arterial blood pressure (MBP), biochemical and histological assessments of maternal kidney, placenta and embryos were performed. RESULTS: Ad-sFlt-1 significantly increased MBP and induced severe glomerular endotheliosis in PlGF-/- mice at E10.5 gestation compared to wild-type animals. High sFlt-1 also significantly elevated albumincreatinine ratio and increased levels of urinary kidney injury molecule-1, a marker for proximal tubule injury.At a high dose of sFlt-1, there was complete fetal resorption in the pregnant PlGF-/- mice, and even the lower dose of sFlt-1 induced severe fetal resorption and abnormal placental vascularization. Hydrogen sulphide-releasing agent, GYY4137, significantly reduced resorption, hypertension and proteinuria in Ad-sFlt-1 treated pregnant PlGF-/- mice. To determine if placental PlGF is critical for preventing fetal growth restriction associated with preeclampsia, we generated haploinsufficient PlGF+/- placentas and embryos were generated in wild-time dams and exposed to high sFlt-1 environment. This resulted in reduced fetal resorption, gestational hypertension and proteinuria when compared to pregnant PlGF-/- mice. CONCLUSIONS: Placental PlGF is a critical protective factor against the damaging effects of high sFlt-1 in preeclampsia and the hydrogen sulphide pathway may rescue preeclampsia phenotypes.

The Effects of Brominated Flame Retardants on Thyroid Hormone Homeostasis in Human Placenta Tissues and Cell Culture

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) that have been heavily used in consumer products such as furniture foams, plastics, and textiles since the mid-1970’s. BFRs are added to products in order to meet state flammability standards intended to increase indoor safety in the event of a fire. The three commercial PBDE mixtures, Penta-, Octa-, and DecaBDE, have all been banned in the United States, however, limited use of DecaBDE is still permitted. PBDEs were phased out of production and added to the Stockholm Convention due to concerns over their environmental persistence and toxicity. Human exposure to PBDEs occurs primarily through the inadvertent ingestion of contaminated house dust, as well as though dietary sources. Despite the phase-out and discontinued use of PBDEs, human exposure to this class of chemicals is likely to continue for decades due to the continued use of treated products and existing environmental reservoirs of PBDEs. Extensive research over the years has shown that PBDEs disrupt thyroid hormone (TH) levels and neurodevelopmental endpoints in rodent and fish models. Additionally, there is growing epidemiological evidence linking PBDE exposure in humans to altered TH homeostasis and neurodevelopmental impairments in children. Due to the importance of THs throughout gestation, there is a great need to understand the effects of BFRs on the developing fetus. Specifically, the placenta plays a critical role in the transport, metabolism, and delivery of THs to the fetal compartment during pregnancy and is a likely target for BFR bioaccumulation and endocrine disruption. The central hypothesis of this dissertation research is that BFRs disrupt the activity of TH sulfotransferase (SULT) enzymes, thereby altering TH concentrations in the placenta.

In the first aim of this dissertation research, the concentrations of PBDEs and 2,4,6-TBP were measured in a cohort of 102 placenta tissue samples from an ongoing pregnancy cohort in Durham, NC. Methods were developed for the extraction and analysis of the BFR analytes. It was found that 2,4,6-TBP was significantly correlated with all PBDE analytes, indicating that 2,4,6-TBP may share common product applications with PBDEs or that 2,4,6-TBP is a metabolite of PBDE compounds. Additionally, this was the first study to measure 2,4,6-TBP in human placenta tissues.

In the second aim of this dissertation research, the placenta tissue concentrations of THs, as well as the endogenous activity of deiodinase (DI) and TH SULT enzymes were quantified using the same cohort of 102 placenta tissue samples. Enzyme activity was detected in all samples and this was the first study to measure TH DI and SULT activity in human placenta tissues. Enzyme activities and TH concentrations were compared with BFR concentrations measured in Aim 1. There were few statistically significant associations observed for the combined data, however, upon stratifying the data set based on infant sex, additional significant associations were observed. For example, among males, those with the highest concentrations of BDE-99 in placenta had T3 levels 0.80 times those with the lowest concentration of BDE-99 (95% confidence interval (CI): 0.59, 1.07). Whereas females with the highest concentrations of BDE-99 in placenta had T3 levels 1.50 times those with the lowest concentration of BDE-99 (95% CI: 1.10, 2.04). Additionally, all BFR analyte concentrations were higher in the placenta of males versus females and they were significantly higher for 2,4,6-TBP and BDE-209. 3,3’-T2 SULT activity was significantly higher in female placenta tissues, while type 3 DI activity was significantly higher in male placenta tissues. This research is the first to show sex-specific differences in the bioaccumulation of BFRs in human placenta tissue, as well as differences in TH concentrations and endogenous DI and SULT activity. The underlying mechanisms of these observed sex differences warrant further investigation.

In the third aim of this dissertation research, the effects of BFRs were examined in a human choriocarcinoma placenta cell line, BeWo. Michaelis-Menten parameters and inhibition curves were calculated for 2,4,6-TBP, 3-OH BDE-47, and 6-OH BDE-47. 2,4,6-TBP was shown to be the most potent inhibitor of 3,3’-T2 SULT activity with a calculated IC50 value of 11.6 nM. It was also shown that 2,4,6-TBP and 3-OH BDE-47 exhibit mixed inhibition of 3,3’-T2 sulfation in BeWo cell homogenates. Next, a series of cell culture exposure experiments were performed using 1, 6, 12, and 24 hour exposure durations. Once again, 2,4,6-TBP was shown to be the most potent inhibitor of basal 3,3’-T2 SULT activity by significantly decreasing activity at the high and medium dose (1 M and 0.5 M, respectively) at all measured time points. Interestingly, BDE-99 was also shown to inhibit basal 3,3’-T2 SULT activity in BeWo cells following the 24 hour exposure, despite exhibiting no inhibitory effects in the BeWo cell homogenate experiments. This indicates that BDE-99 must act through a pathway other than direct enzyme inhibition. Following exposures, the TH concentrations in the cell culture growth media and mRNA expression of TH-related genes were also examined. There was no observed effect of BFR treatment on these endpoints. Future work should focus on determining the downstream biological effects of TH SULT disruption in placental cells, as well as the underlying mechanisms of action responsible for reductions in basal TH SULT activity following BFR exposure.

This was one of the first studies to measure BFRs in a cohort of placenta tissue samples from the United States and the first study to measure THs, DI activity, and SULT activity in human placenta tissues. This research provides a novel contribution to our growing understanding of the effects of BFRs on TH homeostasis within the human placenta, and provides further evidence for sex-specific differences within this important organ. Future research should continue to investigate the effects of environmental contaminants on TH homeostasis within the placenta, as this represents the most critical and vulnerable stage of human development.

Ocean acidification and its potential effects on the early life-history of non-calcifying and calcifying echinoderm (Odontaster validus, Patiriella regularis and Arachnoides placenta) larvae, 2011

Ocean acidification, as a result of increased atmospheric CO2, has the potential to adversely affect the larval stages of many marine organisms and hence have profound effects on marine ecosystems. This is the first study of its kind to investigate the effects of ocean acidification on the early life-history stages of three echinoderms species, two asteroids and one irregular echinoid. Potential latitudinal variations on the effects of ocean acidification were also investigated by selecting a polar species (Odontaster validus), a temperate species (Patiriella regularis), and a tropical species (Arachnoides placenta). The effects of reduced seawater pH levels on the fertilization of gametes, larval survival and morphometrics on the aforementioned species were evaluated under experimental conditions. The pH levels considered for this research include ambient seawater (pH 8.1 or pH 8.2), levels predicted for 2100 (pH 7.7 and pH 7.6) and the extreme pH of 7.0, adjusted by bubbling CO2 gas into filtered seawater. Fertilization for Odontaster validus and Patiriella regularis for the predicted scenarios for 2100 was robust, whereas fertilization was significantly reduced in Arachnoides placenta. Larval survival was robust for the three species at pH 7.8, but numbers declined when pH dropped below 7.6. Normal A. placenta larvae developed in pH 7.8, whereas smaller larvae were observed for O. validus and P. regularis under the same pH treatment. Seawater pH levels below 7.6 resulted in smaller and underdeveloped larvae for all three species. The greatest effects were expected for the Antarctic asteroid O. validus but overall the tropical sand dollar A. placenta was the most affected by the reduction in seawater pH. The effects of ocean acidification on the asteroids O. validus and P. regulars, and the sand dollar A. placenta are species-specific. Several parameters, such as taxonomic differences, physiology, genetic makeup and the population's evolutionary history may have contributed to this variability. This study highlights the vulnerability of the early developmental stages and the complexity of ocean acidification. However, future research is needed to understand the effects at individual, community and ecosystem levels.

La homocisteína como factor de riesgo y de pronóstico a medio y largo plazo en el infarto de miocardio prematuro

Programa de doctorado: Avances en Medicina Interna. La fecha de publicación es la fecha de lectura

PROJETOS PROBLEMÁTICOS: Proposta de Framework para diagnóstico prematuro e direcionamento de ações preventivas

Ao longo dos últimos anos vários estudos de benchmarking em gerenciamento de projetos têm demonstrado a baixa evolução nos indicadores de desempenho de gerenciamento de projetos, sinalizando que as empresas pouco têm aprendido com as experiências negativas.Projetos com algum nível de deterioração em seus indicadores, caracterizados pela literatura e pelo mercado como complexos, problemáticos, em crise ou fracassados são frequentes e não tem sido percebido iniciativas preventivas a fim de impedir antecipadamente a deterioração dos indicadores destes projetos. A partir do estudo da bibliografia técnica e científica disponível, este trabalho buscou responder ao seguinte questionamento: É possível desenvolver um Framework, voltado para o diagnóstico prematuro e direcionamento de ações preventivas de projetos problemáticos, a partir da experiência de pessoas que vêm atuando nestes projetos e da literatura e pesquisas disponíveis? A partir da definição de um recorte que defina a expressão “projetos problemáticos” e da análise de referenciais bibliográficos, buscou-se reconhecer, via questionário de pesquisa quantitativa, com amostra não probabilística por conveniência, os sintomas que são percebidos com maior frequência nesses projetos. O questionário foi aplicado no segundo semestre de 2015, com foco nos respondentes da região Sudeste do Brasil, tendo sido obtidas 265 respostas válidas. A partir da análise dos dados obtidos, concluiu-se que os sintomas mais frequentes reconhecidos nos projetos problemáticos vivenciados por profissionais atuantes em projetos na região Sudeste do Brasil estão relacionados às hipóteses de que “O planejamento do projeto e o gerenciamento de riscos não ocorreram conforme as boas práticas de gerenciamento de projetos”, e de que “Não havia uma iniciativa efetiva de gestão do conhecimento em todo o ciclo de vida do projeto”. Utilizando como norte os resultados de maior expressividade obtidos via questionário de pesquisa, propôs-se um Framework genérico voltado para o diagnóstico prematuro de projetos problemáticos, e eventual direcionamento de ações preventivas e corretivas, nos casos em que já haja deterioração efetiva do desempenho desses projetos.

Prevalencia de acortamiento y embudización del cérvix, y factores asociados a parto prematuro en mujeres atendidas en el Hospital Vicente Corral Moscoso 2012. Cuenca

Objetivo: Determinar la prevalencia del acortamiento del cérvix más embudización y otros factores asociados al parto prematuro, en mujeres de 20 a 34 semanas de gestación que acuden al hospital Vicente Corral Moscoso 2012. Materiales y Métodos: Se realizó un estudio transversal en mujeres embarazadas entre 20 y 34 semanas de gestación, durante el año 2012. Las pacientes fueron asignadas en forma secuencial cumpliendo los criterios de inclusión y exclusión. La longitud cervical y la presencia o no de embudización fueron medidas con Ecografía Transvaginal y los demás datos se obtuvieron de la ficha clínica y por entrevista directa siendo trascritas a un cuestionario; mismos que fueron procesados con software Microsoft Exel y SPSS. Resultados obtenidos: La prevalencia de partos prematuros fue del 12,06%. La prevalencia de acortamiento cervical fue del 14%, la de embudización del 4,5%. Dentro de los factores de riesgo asociados al parto prematuro con significancia estadística se muestran: acortamiento del cérvix, embudización del cérvix, la escolaridad y el antecedente de parto prematuro. Conclusiones: Seestudió un grupo de 506 mujeres cuya edad gestacional mínima fue de 20 semanas la máxima de 34,6 con una media de 30,14. La edad inferior fue de 16 años y la superior de 42, con una media de 24,18. La prevalencia de partos prematuros fue del 12,06%. La prevalencia de acortamiento cervical fue del 14% y la de embudización del 4,5%. Dentro de los factores de riesgo asociados al parto prematuro con significancia estadística se muestran: acortamiento del cérvix, embudización del cérvix, la escolaridad y el antecedente de parto prematuro.

Influencia de las ametropías en el desarrollo general del niño prematuro

Tesis (Maestria en Ciencias de la Visión).-- Universidad de La Salle. Maestria en Ciencias de la Visión, 2014

Parto prematuro: enfoques presentes en la producción científica nacional e internacional

Objetivo del estudio fue conocer la producción científica sobre el parto prematuro. Se trata de un estudio bibliográfico, realizado con 24 trabajos completos que abordan la prematuridad, derivado de la Biblioteca Virtual en Salud, publicados entre los años 2008 y 2013. El análisis de la literatura se llevó a cabo temáticamente, emergiendo cuatro categorías: factores de riesgo asociados al parto prematuro, nacimiento prematuro: Aspectos positivos y negativos; conducta profesional relacionada con el parto prematuro y el papel de la atención de enfermería en el trabajo de parto prematuro. Este estudio indica que muchos investigadores están preocupados por los factores de riesgo asociados con la prematuridad, lo que contribuye a la identificación temprana y a la reducción de las tasas de esta complicación. Aún así, son pocos los estudios que brindan contribuciones a la enfermería, dejando de contribuir al conocimiento y proceso de trabajo de estos profesionales, también responsables de producir salud en este momento de la vida de mujeres y familias que viven la prematuridad.

Estudo do estresse oxidativo e expressão da aromatase e receptor relacionado ao estrógeno gama na placenta humana

 Introdução: Durante a gravidez, devido ao aumento da exigência metabólica placentária há um aumento na produção das espécies reativas de oxigénio (ROS) que podem causar, por exemplo, oxidação de ácidos graxos poli-insaturados na placenta, além disso, nesta fase ocorre um aumento na expressão da aromatase e do receptor relacionado ao estrógeno gama (ERRgama) na placenta humana. Objetivo: O objetivo do estudo foi avaliar os parâmetros de estresse oxidativo e imunomarcação da aromatase e do ERRgama na placenta humana. Métodologia: A capacidade antioxidante total (ACAP), atividade da glutamato cisteína ligase (GCL), concentração glutationa (GSH), peroxidação lipídica e imunomarcação da aromatase e do ERRgama foram analisados em tecido placentário de 58 parturientes. Estas análises foram relacionadas com os dados socio-demográficos das participantes. Resultados: Os recém-nascidos de mães fumantes nasceram com menor peso (p=0,001). A concentração de GSH diminuiu a produção da peroxidação lipídica (p<0,05), por outro lado, a atividade de GCL teve efeito oposto (p<0,001). Encontramos uma diminuição na capacidade antioxidante total e aumento da peroxidação lipídica (p<0,05) na placenta. A placenta de mães fumantes tinham menos marcação da aromatase (p=0,037) já, as mães mais velhas tiveram menos marcação do ERRgama (p=0,009) na placenta. A GSH teve efeito positivo na imunomarcação de ERRgama (p=0,001). Conclusões: A expressão da aromatase e do ERRgamma na placenta são alterados tanto por fatores exógenos, tais como o fumo do cigarro, como por fatores endógenos, tais como a concentração de GSH e a idade da mãe. Os marcadores de estresse oxidativo na placenta são mais elevados em mães mais velhas e em placenta com menor capacidade antioxidante total. 

Factores de riesgo asociados a retinopatía del prematuro en menor o igual a 1750 gramos al nacer, que requirió tratamiento con láser en Hospital de Niños Benjamín Bloom de Enero 2012 a Diciembre 2013

Las retinas inmaduras de los recién nacidos prematuros son susceptibles a insultos que interrumpen el crecimiento neurovascular, que conduce a la retinopatía de la prematuridad. Por eso es de gran importancia conocer los factores de riesgo que se ven involucrados en la génesis de dicha enfermedad. Objetivos: conocer los factores de riesgos asociados a retinopatía del prematuro menor o igual a 1750 gramos al nacer que requirió tratamiento con láser en el Hospital de Niños Benjamín Bloom de Enero de 2012 a Diciembre 2013. Material y método: se realizó un estudio de tipo descriptivo, de corte retrospectivo en el cual se hará revisión sistemática de los expedientes de los pacientes sin dar a conocer la identidad de los mismos, seleccionando a pacientes menor o igual a 1750 gramos independientemente del sexo, evaluado en Hospital Nacional de Niños Benjamín Bloom y al que se le ha realizado intervención con láser; de los cuales se verificará los factores de riesgo asociados al desarrollo de retinopatía del prematuro en estadios severos, se realizó una hoja de datos en Excel y se utilizó el programa SPSS para la agrupación de los datos, posterior se realizó el análisis de los datos. Resultado: se encontraron 56 casos de prematuros con grado severo de retinopatía que utilizó laser, de los cuales fueron 30 masculinos y 26 femeninos; se excluyeron veinte casos por no cumplir criterios de inclusión. Los dos factores de riesgo principalmente involucrados en la ROP son edad gestacional igual o inferior a 30 semanas de gestación y peso al nacimiento igual o inferior a 1300 gr. Otros factores de riesgo encontrados son: la no ganancia de peso para la edad gestacional con un 92.7%, anemia y transfusión sanguínea con un 76.9%, sepsis temprana y nososcomial, en menor proporción apneas, aplicación de surfactante, administración de esteroides prenatales, el estadio con mayor frecuencia encontrado es el III, el déficit visual y ceguera son las secuelas encontradas en los pacientes con retinopatía severa. Conclusiones: la retinopatía de la prematuridad es una entidad multifactorial en la que cada uno de los factores juega un papel importante en la evolución de dicha patología.

Descolamento da retina

Esta imagem integra o curso Oftalmologia na Atenção Básica à Saúde (2016) que tem o objetivo de ampliar a capacidade de resolução clínico-oftalmológica na Atenção Básica à saúde. Apresenta uma demonstração por imagem do Descolamento Retiniano.

Trabalho de parto prematuro: fatores de risco e estratégias para a sua predição e prevenção

A prematuridade continua sendo o principal problema da saúde pública em obstetrícia. As intervenções para reduzir a morbidade e a mortalidade do nascimento prematuro podem ser primárias (dirigidas a todas as mulheres), secundárias (destinadas a eliminar ou reduzir os riscos existentes) ou terciárias (visa melhorar resultados para bebês prematuros). Diante dessas considerações, o objetivo primeiro deste trabalho foi identificar os fatores biológicos maternos relacionados às intercorrências na gravidez que podem desencadear o trabalho de parto prematuro. A pesquisa integrativa da literatura foi feita em artigos indexados e disponíveis no Medline,Pubmed, SciELO e Bireme. As publicações selecionadas, no período de 1996 a 2010, foram as que apresentaram a metodologia bem descrita e rigorosa, ou seja, permitindo a reprodução da pesquisa, resultados apresentados de forma clara e cujas conclusões estivessem de acordo com os objetivos e resultados obtidos. O critério de exclusão, para a elaboração deste estudo, foi de artigos de opinião de autores e/ou que se encontravam repetidos no mesmo banco de dados. Conclui-se que a maioria dos esforços até agora têm sido intervenções, tais como os cuidados no pré-natal e o tratamento com corticosteróide, tocolíticos e antibióticos. Essas medidas têm reduzido a morbidade e mortalidade perinatal, mas a incidência de parto prematuro é maior. Avanços em cuidados primários e secundários, seguindo as estratégias utilizadas para outros problemas de saúde mais complexos, são necessários para prevenir doenças relacionadas com a prematuridade.

Icam-1 Expression On Immune Cells In Chronic Villitis.

ICAM-1 expression on the villous syncytiotrophoblast (ST) is believed to participate in migration of maternal cells into the inflamed villi regardless of villitis etiology. However, its expression on immune cells in chronic villitis (CV) has yet to be analyzed. ICAM-1 induces cell-cell adhesion allowing intercellular communication, T cell-mediated defense mechanism, and inflammatory response. 21 cases of CV (all without an identifiable etiologic agent) and 3 control placentas were analyzed using ICAM-1, and for immune cells CD45, CD3 and CD68. These cells were subdivided according to their location in inflamed villi: a) within the inflamed villi and b) outside forming perivillous aggregates. Large amounts of CD45, CD3 and CD68 were found within the inflamed villi and forming perivillous aggregates attached to areas of trophoblastic loss. Inflamed villi usually showed ICAM-1+ ST. The majority of immune cells surrounding areas of trophoblastic rupture presented marked expression of ICAM-1. In contrast, a small number of immune cells within the inflamed villi exhibited ICAM-1 expression. Only some (<5%) inflamed villi without trophoblastic rupture and with ICAM-1+ ST presented adherence of immune cells. In inflamed villi of chronic villitis, the level of ICAM-1 expression on immune cells depends on their location: high in number of cells in the perivillous region and low within the villi. The strongest expression of ICAM-1 on immune cells attached to areas of trophoblastic rupture suggests that the loss of trophoblast can lead to an amplification of the inflammatory response.

Pregnancy In Women Undergoing Hemodialysis: Case Series In A Southeast Brazilian Reference Center.

To describe maternal and neonatal outcomes in pregnant women undergoing hemodialysis in a referral center in Brazilian Southeast side. Retrospective and descriptive study, with chart review of all pregnancies undergoing hemodialysis that were followed-up at an outpatient clinic of high- risk prenatal care in Southeast Brazil. Among the 16 women identified, 2 were excluded due to follow-up loss. In 14 women described, hypertension was the most frequent cause of chronic renal failure (half of cases). The majority (71.4%) had performed hemodialysis treatment for more than one year and all of them underwent 5 to 6 hemodialysis sessions per week. Eleven participants had chronic hypertension, 1 of which was also diabetic, and 6 of them were smokers. Regarding pregnancy complications, 1 of the hypertensive women developed malignant hypertension (with fetal growth restriction and preterm delivery at 29 weeks), 2 had acute pulmonary edema and 2 had abruption placenta. The mode of delivery was cesarean section in 9 women (64.3%). All neonates had Apgar score at five minutes above 7. To improve perinatal and maternal outcomes of women undergoing hemodialysis, it is important to ensure multidisciplinary approach in referral center, strict control of serum urea, hemoglobin and maternal blood pressure, as well as close monitoring of fetal well-being and maternal morbidities. Another important strategy is suitable guidance for contraception in these women.