Uterine Artery Pulsatility Index as a Pre-eclampsia Predictor in the 3 Trimesters in Women with Singleton Pregnancies / Índice de pulsatilidade da artéria uterina como preditor de pré-eclâmpsia nos 3 trimestres em mulheres com gestações únicas

Abstract Objective To evaluate the mean uterine artery pulsatility index (UtAPI) in each trimester of pregnancy as a predictor of early or late pre-eclampsia (PE) in Colombian pregnant women. Methods The UtAPI was measured in singleton pregnancies in each trimester. Uterine artery pulsatility index as predictor of PE was evaluated by odds ratio (OR), receiver operating characteristic (ROC) curves, and Kaplan-Meier diagram. Results Analysis in the 1st and 3rd trimester showed that abnormal UtAPI was associated with early PE (OR: 5.99: 95% confidence interval [CI]: 1.64-21.13; and OR: 10.32; 95%CI: 2.75-42.49, respectively). Sensitivity and specificity were 71.4 and 79.6%, respectively, for developing PE (area under the curve [AUC]: 0.922). The Kaplan-Meier curve showed that a UtAPI of 0.76 (95%CI: 0.58-1.0) in the 1st trimester was associated with early PE, and a UtAPI of 0.73 (95%CI: 0.55-0.97) in the 3rd trimester was associated with late PE. Conclusion Uterine arteries proved to be a useful predictor tool in the 1st and 3rd trimesters for early PE and in the 3rd trimester for late PE in a pregnant population with high prevalence of PE.

Resumo Objetivo Avaliar o índice médio de pulsatilidade da artéria uterina (UtAPI) em cada trimestre da gravidez como preditor de pré-eclâmpsia (PE) precoce ou tardia em gestantes colombianas. Métodos O UtAPI foi medido em gestações únicas em cada trimestre. O UtAPI como preditor de PE foi avaliado por odds ratio (OR), curvas receiver operating characteristic (ROC) e diagrama de Kaplan-Meier. Resultados A análise no 1° e 3° trimestres mostrou que um UtAPI anormal foi associado com PE inicial (OR: 5,99; intervalo de confiança [IC] 95%: 1,64-21,13; OR: 10,32; IC95%: 2,75-42,49, respectivamente). A sensibilidade e a especificidade foram de 71,4 e 79,6%, respectivamente, para o desenvolvimento de PE (area under the curve [AUC]: 0,922). A curva de Kaplan-Meier mostrou que um UtAPI de 0,76 (IC95%: 0,58- 1,0) no 1° trimestre foi associado com PE precoce, e que um UtAPI de 0,73 (IC95%: 0,55-0,97) no 3° trimestre foi associado com PE tardia. Conclusão As artérias uterinas mostraram ser uma ferramenta preditora útil no 1° e 3° trimestres para PE inicial e no 3° trimestre para PE tardia em uma população de gestantes com alta prevalência de PE.

Association between Adverse Maternal Clinical Outcomes and Imbalance of Cytokines and Angiogenic Factors in Preterm Preeclampsia / Associação entre desfechos maternos adversos e desbalanço de citocinas e fatores angiogênicos em pré-eclâmpsia pré-termo

Abstract Objective Preeclampsia (PE) is a pregnancy-specific syndrome characterized by abnormal levels of cytokines and angiogenic factors, playing a role in the disease development. The present study evaluated whether immunological markers are associated with the gestational age and with the disease severity in preeclamptic women. Methods Ninety-five women who developed PE were stratified for gestational age as preterm PE (< 37 weeks) and term PE (≥ 37 weeks of gestation) and compared for disease severity as well as plasma concentration of angiogenic factors and cytokines. The concentrations of placental growth factor (PlGF), vascular endothelial growth factor (VEGF), Fms-like soluble tyrosine kinase (sFlt-1) and soluble endoglin (sEng), as well as the cytokines, tumor necrosis factor-α (TNF-α) and interleukin 10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA). Results The comparison between preeclamptic groups showed a higher percentage of severe cases in preterm PE (82.1%) than in term PE (35.9%). Similarly, the concentrations of TNF-α, sFlt-1, and sEng, as well as TNF-α/IL-10 and sFlt-1/PlGF ratios were significantly higher in the preterm PE group. In contrast, concentrations of PlGF, VEGF, and IL-10 were significantly lower in women with preterm PE. Negative correlations between TNF-α and IL-10 (r = 0.5232) and between PlGF and sFlt1 (r = 0.4158) were detected in the preterm PE. Conclusion In pregnant women with preterm PE, there is an imbalance between immunological markers, with the predominance of anti-angiogenic factors and TNF-α, associated with adverse maternal clinical outcomes.

Resumo Objetivo A pré-eclâmpsia (PE) é uma síndrome específica da gravidez caracterizada por níveis anormais de citocinas e fatores angiogênicos, que desempenham um papel no desenvolvimento da doença. Este estudo avaliou se os marcadores imunológicos estão associados à idade gestacional e à gravidade da doença em mulheres com pré-eclâmpsia. Métodos Noventa e cinco mulheres que desenvolveram PE foram estratificadas pela idade gestacional em PE pré-termo (< 37 semanas) e PE a termo (≥ 37 semanas de gestação) e comparadas quanto à gravidade da doença, bem como à concentração plasmática de fatores angiogênicos e citocinas. As concentrações de fator de crescimento placentário (PlGF), fator de crescimento endotelial vascular (VEGF), tirosina quinase solúvel semelhante a Fms (sFlt-1) e endoglina solúvel (sEng), bem como as citocinas, fator de necrose tumoral alfa (TNF- α) e interleucina 10 (IL-10), foram determinados porensaio de imunoabsorção enzimática (ELISA, na sigla em inglês). Resultados A comparação entre os grupos com pré-eclâmpsia mostrou maior porcentagem de casos graves em PE pré-termo (82,1%) do que em PE a termo (35,9%). Da mesma forma, as concentrações de TNF-α, sFlt-1 e sEng, bem como as razões TNF-α/IL-10 e sFlt-1/PlGF foram significativamente maiores no grupo de PE pré-termo. Em contraste, as concentrações de PlGF, VEGF e IL-10 foram significativamente menores em mulheres com PE pré-termo. Correlações negativas entre TNF-α e IL-10 (r = 0.5232) e entre PlGF e sFlt1 (r = 0.4158) foram detectadas no grupo de PE pré-termo. Conclusão Em gestantes com PE pré-termo, ocorre um desequilíbrio entre os marcadores imunológicos, com predomínio de fatores antiangiogênicos e TNF-α, associados a desfechos clínicos maternos adversos.

La aplicación de factores de crecimiento en el desarrollo de la Ingeniería de tejidos óseos / Application of growth factors in the development of bone tissue engineering

RESUMEN Introducción: los avances científico-técnicos en el campo de la Biología celular y molecular han permitido restaurar y mejorar la función de órganos y tejidos lesionados por ciertas enfermedades y traumatismos. La Ingeniería de tejido se define como el uso de los principios y métodos de la Ingeniería, la Biología y la Bioquímica, los cuales están orientados a la comprensión de la estructura y la función de los tejidos normales y patológicos, y al consecuente desarrollo de sustitutos biológicos para restaurar, mantener o mejorar su función. Objetivo: realizar un acercamiento a algunos aspectos de la Biología celular y molecular vinculada con la Ingeniería tisular ósea. Métodos: se realizó una búsqueda bibliográfica en SciELO Cuba y en Google académico durante el período de 1 de marzo al 28 de abril de 2018. Se evaluaron 134 artículos y el estudio se circunscribió a los 25 artículos que se enfocaban en estas temáticas de manera integral. Conclusiones: se ofreció una visión general de los avances que se han obtenido en la Biología celular y molecular, y en particular a: la aplicación de los factores de crecimiento en la Ingeniería del tejido óseo, así como sus futuras perspectivas. Se concluyó que es fundamental consolidar una base apropiada de conocimientos sobre la Biología celular y molecular y el desarrollo actual de la Ingeniería del tejido óseo.

ABSTRACT Introduction: scientific and technical advances in the field of cellular and molecular biology have allowed restoring and improving the function of organs and tissues injured by certain diseases and trauma. Tissue engineering is defined as the use of the principles and methods of Engineering, Biology and Biochemistry, which are aimed at understanding the structure and function of normal and pathological tissues, and the consequent development of biological substitutes to restore, maintain or improve their function. Objective: to carry out an approach to some aspects of cellular and molecular biology related to bone tissue engineering. Methods: a bibliographic review was carried out in SciELO Cuba and Google Scholar from March 1 to April 28, 2018. A number of 134 articles were evaluated and the study was limited to 25 articles that focused on these topics in an integral way. Conclusions: an overview of the advances that have been obtained in cellular and molecular biology was offered, particularly to the application of growth factors in bone tissue engineering, as well as its future perspectives. We concluded that it is essential to consolidate an appropriate knowledge base on cellular and molecular biology and the current development of bone tissue engineering.

Evaluation of angiogenic factors (PlGF and sFlt-1) in pre-eclampsia diagnosis / Avaliação dos fatores angiogênicos (PlGF e sFlt-1) no diagnóstico de pré-eclâmpsia

Abstract Objective: Recent observations support the hypothesis that an imbalance between angiogenic factors has a fundamental role in the pathogenesis of pre-eclampsia and is responsible for the clinical manifestations of the disease. The goal of the present study was to evaluate the sensitivity, specificity, and the best accuracy level of Soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in maternal serum and protein/creatinine ratio in urine sample to define the best cutoff point of these tests to discriminate between the patients with gestational hypertension and the patients with pre-eclampsia, to evaluate the possibility of using them as diagnostic methods. Methods: A prospective longitudinal study was performed, and blood samples were collected from 95 pregnant patients with hypertension to measure serum concentrations of biomarkers sFlt-1 and PlGF. Urine samples were collected for protein screening. Significance was set as p < 0.05. Results: The sFlt-1/PlGF ratio demonstrated a sensitivity of 57.5% and a specificity of 60% using 50.4 as a cutoff point. The test that showed the best accuracy in the diagnosis of pre-eclampsia was protein/creatinine ratio, with a sensitivity of 78.9% and a specificity of 70% using 0.4 as a cutoff point and showing an area under the receiver operating characteristic curve of 0.80 (p < 0.001). Conclusion: No studied laboratory test proved to be fairly accurate for the diagnosis of pre-eclampsia, except for the protein/creatinine ratio. The evidence is insufficient to recommend biomarkers sFlt-1 and PlGF to be used for the diagnosis of pre-eclampsia.

Resumo Objetivo: Pesquisas recentes sustentam a hipótese de que um desequilíbrio entre fatores angiogênicos desempenhe um papel fundamental na patogênese da pré-eclâmpsia e seja responsável pelas manifestações clínicas da doença. O objetivo do presente estudo foi avaliar a sensibilidade, a especificidade e o nível de melhor acurácia do Fator semelhante a tirosina quinase 1 (sFlt-1), Fator de crescimento placentário (PlGF), e relação sFlt-1/PlGF no soro materno e relação proteína/creatinina em amostra de urina e definir o melhor ponto de corte desses testes para distinguir pacientes com hipertensão gestacional daquelas com pré-eclâmpsia, a fim de avaliar a possibilidade de utilizá-los como métodos diagnósticos. Métodos: Foi realizado um estudo prospectivo longitudinal e foram coletadas amostras de sangue de 95 gestantes com hipertensão arterial para dosar as concentrações séricas dos biomarcadores sFlt-1 e PlGF. Amostras de urina foram coletadas para pesquisa de proteinúria. Foram consideradas significativas as diferenças com p < 0,05. Resultados: A relação sFlt-1/PlGF demonstrou sensibilidade de 57,5% e especificidade de 60% utilizando 50,4 como ponto de corte. O teste que apresentou a melhor acurácia no diagnóstico de pré-eclâmpsia foi a relação proteína/creatinina, com sensibilidade de 78,9% e especificidade de 70%, utilizando 0,4 como ponto de corte e demostrando uma área sob a curva receiver operating characteristic (ROC, na sigla em inglês) de 0,80 (p < 0,001). Conclusão: Nenhum método de rastreamento isolado se mostrou com boa acurácia para o diagnóstico de pré-eclâmpsia, exceto a relação proteína/creatinina. As evidências são insuficientes para recomendar os biomarcadores sFlt-1 e PlGF como diagnóstico de pré-eclâmpsia.

Importancia clínica y diagnóstica de la relación receptor de tirosin-quinasa tipo 1 en su forma soluble y el factor de crecimiento placentario / Clinical and diagnostic importance of the type 1 receptor tyrosine-kinase ratio in its soluble form and placental growth factor / Importância clínica e diagnóstica da relação receptor de tirosina-quinase tipo 1 em sua forma solúvel e o fator de crescimento placentário

El objetivo del trabajo fue evaluar la utilidad clínica de la relación factor de crecimiento placentario/receptor de tirosin-quinasa tipo 1 soluble (sFlt-1/ PlGF) para el diagnóstico de preeclampsia (PE) en embarazadas de alto riesgo y con diagnóstico clínico de PE en un centro de salud de Córdoba, Argentina. Se procesaron 135 muestras de embarazadas: 39 con diagnóstico clínico de PE (Grupo I), 72 con riesgo de PE (Grupo II), y 24 de grupo control (Grupo III). Se utilizó una técnica automatizada de electroquimioluminiscencia (Roche). Valores <38 se consideraron sin riesgo de PE, entre 38 y 85 (< semana 34) o 38 y 110 (> semana 34) con riesgo moderado o alto riesgo dentro de las 4 semanas posteriores a la realización de dichos marcadores y >85 en embarazadas con síntomas de aparición temprana o >110 en embarazadas con síntomas de aparición tardía, PE confirmada. En el Grupo I, 33 muestras dieron relación >38 y 6 fueron menores. De 72 muestras del Grupo II 69 dieron <38 y 3 >38. Todas las muestras del Grupo III dieron relación <38. La razón de verosimilitud positiva (LR+) fue de 20,31 y la razón negativa (LR-) fue de 0,16. La relación fue >38 en la mayoría de las embarazadas con diagnóstico de PE. La determinación es útil en aquellas mujeres embarazadas que son de alto riesgo, ya sea porque tienen hipertensión o proteinuria o algún antecedente previo, en las cuales puede ser fundamental para decidir el correcto diagnóstico.

The objective of this work was to evaluate the clinical usefulness of the relation placental growth factor/soluble tyrosine-kinase type 1 receptor (sFlt-1/PlGF) for the diagnosis of PE (preeclampsia) in pregnant women at high risk and with clinical diagnosis of PE in a health center of Córdoba, Argentina. A total of 135 samples of pregnant women were processed: 39 with clinical diagnosis of PE (Group I), 72 with risk of PE (Group II), and 24 of control group (Group III). An automated electrochemiluminescence technique (Roche) was used. Ratio sFlt-1/PlGF <38 was considered without risk of PE. Between 38 and 85 (< week 34) or 38 and 110 (> week 34), with moderate risk or high risk within 4 weeks after performing these markers. To confirm diagnosis, relationships >85 in pregnant women were considered with symptoms of early onset and >110 in pregnant women with symptoms of late onset. In Group I, 33 samples reported >38 and 6 were lower. Of 72 samples from Group II, 69 gave <38 and 3, >38. All samples from Group III gave a ratio <38. The positive likelihood ratio (LR+) was 20.31 and the negative likelihood ratio (LR-), 0.16. The ratio was >38 in the majority of women already diagnosed as PE. The test is useful in those pregnant women who are at high risk of PE, either because they have hypertension or proteinuria or a previous history. In those cases it can be fundamental to decide the correct diagnosis.

O objetivo do estudo é avaliar a utilidade clínica da relação fator de crescimento placentário/receptor de tirosina-quinase tipo 1 solúvel (sFlt-1/PIGF) para o diagnóstico de pré-eclâmpsia (PE) em grávidas de alto risco e com diagnóstico clínico de PE em um centro de saúde de Córdoba, Argentina. Foram processadas 135 amostras de gestantes, sendo 39 com diagnóstico clínico de PE (Grupo I), 72 com risco de PE (Grupo II) e 24 de grupo controle (Grupo III). Foi utilizada uma técnica automatizada de eletroquimioluminescência (Roche). Valores <38 foram considerados sem risco de PE, entre 38 e 85 (

Anti-placental growth factor antibody ameliorates hyperoxia-mediated impairment of lung development in neonatal rats

This study investigates the effect of the overexpression of the placental growth factor (PGF) and hyperoxia on lung development and determines whether anti-PGF antibody ameliorates hyperoxia-mediated impairment of lung development in newborn rats. After exposure to normoxic conditions for seven days, newborn rats subjected to normoxia were intraperitoneally or intratracheally injected with physiological saline, adenovirus-negative control (Ad-NC), or adenovirus-PGF (Ad-PGF) to create the Normoxia, Normoxia+Ad-NC, and Normoxia+Ad-PGF groups, respectively. Newborn rats subjected to hyperoxia were intraperitoneally injected with physiological saline or anti-PGF antibodies to create the Hyperoxia and Hyperoxia+anti-PGF groups, respectively. Our results revealed significant augmentation in the levels of PGF and its receptor Flt-1 in the lung tissues of newborn rats belonging to the Normoxia+Ad-PGF or Hyperoxia groups. PGF overexpression in these groups caused lung injury in newborn rats, while anti-PGF antibody treatment significantly cured the hyperoxia-induced lung injury. Moreover, PGF overexpression significantly increased TNF-α and Il-6 levels in the bronchoalveolar lavage (BAL) fluid of the Normoxia+Ad-PGF and Hyperoxia groups. However, their levels were significantly reduced in the BAL fluid of the Hyperoxia+anti-PGF group. Immunohistochemical analysis revealed that PGF overexpression and hyperoxia treatment significantly increased the expression of the angiogenesis marker, CD34. However, its expression was significantly decreased upon administration of anti-PGF antibodies (compared to the control group under hyperoxia). In conclusion, PGF overexpression impairs lung development in newborn rats while its inhibition using an anti-PGF antibody ameliorates the same. These results provided new insights for the clinical management of bronchopulmonary dysplasia in premature infants.

Negative correlation between placental growth factor and endocan-1 in women with preeclampsia / Correlação negativa entre fator de crescimento placentário e endocan-1 emmulheres com pré-eclâmpsia

Abstract Objective To analyze endocan-1, a biomarker of vascular endothelial related pathologies, and the placental growth factor (PlGF), an angiogenic factor and a placental dysfunction marker in patients with preeclampsia (PE). Methods Case-control study conducted at Hospital São Lucas, in the city of Porto Alegre, Brazil. Endocan-1 and PlGF levels were quantified in the maternal plasma using the MagPlexTH-C microsphere system (MAGPIX System, Luminex, Austin, Texas, US) and evaluated through analysis of covariance (ANCOVA) and adjusted by body mass index (BMI), gestational age and maternal age. To estimate the difference between the groups, the mean ratio (MR) and the 95% confidence interval (95%CI) were calculated. The Pearson correlation test was used to establish any association between endocan-1 and PlGF levels. The null hypothesis was rejected when p < 0.05. Results The group of patients was composed by normotensive (n = 67) patients and patients with PE (n = 50). A negative correlation between endocan-1 and the PlGF was noted in the entire normotensive group (linear correlation coefficient [r] = -0.605; p < 0.001), as well as in the PE group (r = -0.545; p < 0.001). Conclusion Endocan-1 levels are increased in patients with PE, and are inversely correlated with PlGF levels. We suggest that it is important to analyze angiogenic and proinflammatory molecules concomitantly in women with PE to better understand the pathophysiology of the disease. Both molecules are strong candidates for PE biomarkers, and future studies will examine any mechanisms connecting these factors in PE.

Resumo Objetivo Analisar o endocan-1, umbiomarcador de patologias vasculares endoteliais, e o fator de crescimento placentário (FCPl), um fator angiogênico, marcador de disfunção placentária em pacientes com pré-eclâmpsia (PE). Métodos Estudo de caso-controle realizado no Hospital São Lucas, em Porto Alegre. Os níveis de endocan-1 e FCPl foram quantificados no plasma materno usando o sistema de microesferas MagPlexTH-C (MAGPIX System, Luminex, Austin, Texas, US) e analisados por análise de covariância (ANCOVA) e ajustados por índice de massa corporal (IMC), idade gestacional e idade materna. Para calcular a diferença entre os grupos, utilizou-se a razão dasmédias (RM) e o intervalo de confiança de 95% (IC95%). O teste de correlação de Pearson foi utilizado para estabelecer a associação entre os níveis de endocan-1 e FCPl. A hipótese nula foi rejeitada quando p < 0,05. Resultados O grupo de pacientes foi composto por pacientes normotensas (n = 67) e pacientes com PE (n = 50). Uma correlação negativa entre o endocan-1 e o FCPl foi observada emtodo o grupo de pacientes normotensas (coeficiente de correlação linear [r] = -0,605; p < 0,001), bem como no grupo com PE (r = -0,545; p < 0,001). Conclusão Os níveis de endocan-1 estão aumentados em pacientes com PE e inversamente correlacionados com os níveis de FCPl. Sugerimos a importância de analisar moléculas angiogênicas e pró-inflamatórias concomitantemente em mulheres com PE para compreender melhor a fisiopatologia da doença. Ambas as moléculas são fortes candidatos a serem considerados biomarcadores de PE, e trabalhos futuros poderão avaliar quaisquer mecanismos que liguem esses fatores na PE.

Biomarcadores para el diagnóstico de los trastornos hipertensivos inducidos por el embarazo / Biomarkers for the diagnosis of hypertensive disorders induced by pregnancy

Introducción: Los trastornos hipertensivos del embarazo siguen siendo una preocupación central de la salud pública en todo el mundo debido a que son una de las principales causas de mortalidad materna. Su tratamiento adecuado depende en gran medida del diagnóstico oportuno e intervención temprana. Objetivo: Identificar los principales biomarcadores para el diagnóstico temprano de los trastornos hipertensivos inducidos por el embarazo. Método: Se revisaron artículos científicos en MedLine, Pubmed, Cochrane, Scielo, entre otras bases de datos. Resultados y discusión: Niveles elevados de kinasa de tirosina símil FMS (sFtl-1), niveles bajos de factor de crecimiento placentario (PIGF) o factor de crecimiento endotetelial vascular (VEGF) libre y niveles altos de (PlGF/sFtl-1) tienen un alto valor predictivo positivo para el diagnóstico de preeclampsia. También parace demostrar resultados efectivos la combinación de ultrasonido doppler y niveles alterados de biomarcadores como proteína placentaria 13 (PP13) y endoglina soluble (sEng). Conclusiones: El uso de biomarcadores abre una nueva era en el diagnóstico y tratamiento de trastornos hipertensivos del embarazo.

Background: Hypertensive disorders of pregnancy constitute a public health concern throughout the world, mainly because they are one of the main causes of maternal mortality. Their adequate treatment depends on a great extent on an early diagnosis and oportune intervention. Objective: To identify the most important biomarkers for the early diagnosis of hypertensive disorders induced by pregnancy. Methodology: Review of academic articles available in MedLine, Pubmed, Cochrane, Scielo, among others. Results and discusión: Elevated levels of Fms-like tyrosine kinase 1 (sFtl-1), low levels of placental growth factor (PlGF) or free vascular endotelial growth factor (VEGF), and elevated levels of (PlGF/sFtl-1) have a high positive predictive value for the diagnosis of preeclampsia. Similarly, it seems equally efective the combination of doppler ultrasound and altered levels of biomarkers including placental protein 13 (PP13) and soluble endolgin (sEng). Conclusions: The use of biobarkers opens a new era for the early diagnosis and treatment hypertensive disorders of pregnancy.

Insulinorresistencia e hipertensión gestacional: Estudio preliminar en una muestra del Municipio de La Plata / Insulin resistance and gestational hypertension: A preliminary study in a small population of La Plata Municipality / Hipertensão gestacional e resistência à insulina: Estudo preliminar numa amostra do Município de La Plata

Las mujeres embarazadas con insulino-sensibilidad disminuida están en riesgo de desarrollar trastornos hipertensivos. Utilizando el corte HOMA-IR en 2,64 la población en estudio fue dividida en dos grupos: (n=154 mujeres embarazadas), las que arrojaron un HOMA-IR basal (HOMA-0) <2,64 (no-insulinorresistentes; n=113) y aquellas con HOMA-0>2,64 (insulinorresistentes, n=41). Se analizaron: a) las concentraciones circulantes de glucosa e insulina durante una prueba de tolerancia oral a 75 g de glucosa (PTOG), y b) las relaciones entre varios parámetros de insulino-sensibilidad y la predicción del desarrollo de trastornos hipertensivos. A las mujeres embarazadas (semana 24-28) se les cuantificaron las concentraciones plasmáticas de glucosa e insulina a ambos tiempos de la PTOG. Se calcularon los valores de HOMA-IR y las relaciones glucosa a insulina (G:I) y se registraron parámetros antropométricos y resultados del embarazo. Las mujeres con HOMA-0 >2,64, aunque con glucemias en ayunas normales, mostraron mayores niveles de insulinemia y de HOMA-IR, y menores valores G:I en ambos tiempos de la PTOG. Estas mujeres embarazadas fueron las que tuvieron un mayor riesgo de desarrollar trastornos hipertensivos y mayores parámetros de morbilidad durante el período estudiado al compararlas con aquellas cuyo HOMA-0 fue <2,64.

Pregnant women with impaired insulin sensitivity are at risk for developing hypertensive disorders. By using a cut-off at 2.64 of the homeostasis model assessment (HOMA-IR) in basal condition (HOMA-0), the population under study (n=154 pregnant women) was split into two groups: 1) with basal HOMA- 0 <2.64 (non-insulin resistant; n=113) and 2) with basal HOMA-0 >2.64 (insulin resistant; n=41). Glucose and insulin circulating levels were analyzed throughout a 2-h oral 75 g glucose tolerance test (OGTT). The relationship between several parameters related to insulin resistance and the prevalence of pregnancy-induced hypertensive disorders was analyzed. Pregnant women (on week 24-28) were submitted to an OGTT, and glucose and insulin plasma concentrations were measured throughout the test. These peripheral metabolites levels and the values of the HOMA-IR and the glucose to insulin ratio (G:I) were analyzed. Anthropometric parameters and pregnancy outcome were recorded. Women with HOMA-0 >2.64 but normal fasting glycemia showed higher insulinemias, G:I values and HOMA-IR values at both times of the OGTT. The latter were at greater risk for developing late pregnancy-induced hypertension compared to women with HOMA-0 ≤2.64.

As mulheres grávidas com diminuição da sensibilidade à insulina correm o risco de desenvolver distúrbios hipertensivos. Usando o corte HOMA-IR 2,64, a população em estudo foi dividida em dois grupos: (n=154 mulheres grávidas), que deram um HOMA-IR basal (HOMA-0) ≤2,64 (não resistentes à insulina; n=113) e aquelas com HOMA-0 >2,64 (resistentes à insulina, n=41). Foram analisadas: a) as concentrações circulantes de glicose e insulina durante uma prova de tolerância oral a 75 g. de glicose (PTOG), e b) as relações entre diversos parâmetros de sensibilidade à insulina e a predição de desenvolver distúrbios de hipertensão. Foram quantificadas nas mulheres grávidas (24-28 semanas) as concentrações plasmáticas de glicose e insulina a ambos os tempos da PTOG. Valores de HOMA-IR foram calculados e as relações glicose a insulina (G:I) e se registraram parâmetros antropométricos e os resultados da gravidez. Mulheres com HOMA-0 >2,64, mas com glicemias em jejuns normais, mostraram níveis mais elevados de insulinemia e de HOMA-IR, e menores valores G:I em ambos os tempos da PTOG. Essas mulheres grávidas foram aquelas que tiveram maior risco de desenvolver distúrbios de hipertensão e maiores parâmetros de morbidade durante o período estudado em comparação com as mulheres cujo HOMA-0 foi ≤2,64.

Evaluation of nicotinamide as an anti-inflammatory and anti-angiogenic agent in uveal melanoma cell lines / Avaliação da nicotinamida como agente anti-inflamatório e anti-angiogênico em linhas celulares de melanoma uveal

ABSTRACT Purpose: To investigate the effect of nicotinamide on the secretion of pro-an giogenic and pro-inflammatory cytokines in uveal melanoma cell lines. Methods: Two human uveal melanoma cell lines (92.1 and OCM-1) were treated with nicotinamide (10 mmol/L) or control media for 48 hours in culture. The su perna tant from each culture was used in sandwich enzyme-linked immuno sorbent assay-based angiogenesis and inflammation arrays to evaluate the effects of exogenously administered nicotinamide on the secretion of a total of 20 pro-an gio genic and pro-inflammatory proteins. Results: Seven pro-angiogenic cytokines were detected under control conditions for both uveal melanoma cell lines. Treatment with nicotinamide resulted in a significant decrease in secretion of the following pro-angiogenic cytokines: angiogenin, angiopoietin-2, epidermal growth factor, and vascular epithelial growth factor-A in the 92.1 cells; basic fibroblast growth factor in the OCM-1 cells; and placenta growth factor in both cell lines. Among the pro-inflammatory proteins, monocyte chemotactic protein-1 and interleukin-8 were expressed in both untreated cell lines and both were significantly reduced when treated with nicotinamide. Conclusions: Results from this in vitro model suggest that nicotinamide may have anti-inflammatory and anti-angiogenic properties, which may open the possibility of using it as a chemopreventive agent for uveal melanoma; however, further studies including animal models are warranted.

RESUMO Objetivo: Acredita-se que a nicotinamida (NIC) seja capaz de diminuir a angiogênese induzida pelo fator de crescimento endotelial vascular (VEGF). Investigar os efeitos da nicotinamida sobre a secreção de citocinas pró-angiogênicas e pró-inflamatórias em linhagens de células de melanoma uveal humano (UM). Métodos: Duas linhagens de células humanas de UM (92,1 e OCM-1) foram tratadas com NIC (10 mmol/L) ou apenas com meio de cultura por 48 horas. O sobrenadante das culturas obtido após a administração de nicotinamida foi comparado com o sobrenadante das culturas controle quanto à expressão de 20 fatores pró-angiogênicos e pró-inflamatórios, pela técnica de enzyme-linked immunosorbent assay (ELISA). Resultados: Sete citocinas pró-angiogênicas foram detectadas nas condições de controle em ambas as linhagens de células de UM. O tratamento com nicotinamida promoveu uma redução significativa da secreção das seguintes citocinas angiogênicas: Angiogenina, ANG2, EGF e VEGF-A em células 92.1; bFGF em células OCM-1; PIGF em ambas as linhagens celulares. Quanto às proteínas pró-inflamatórias, a expressão de MCP-1 e IL-8 foi significativamente reduzida com a administração de nicotinamida em relação às culturas de células que não receberam o tratamento. Conclusões: Nicotinamida apresenta propriedades anti-inflamatórias e anti-angiogênicas em modelo experimental in vitro. Tais efeitos sugerem a possibilidade de utilizar esta substância na quimioprevenção do UM. Entretanto, estudos com modelos experimentais in vivo são necessários para melhor avaliar o benefício do tratamento do UM com nicotinamida.

Kaempferol inhibited VEGF and PGF expression and in vitro angiogenesis of HRECs under diabetic-like environment

Diabetic retinopathy (DR) is one of the common and specific microvascular complications of diabetes. This study aimed to investigate the anti-angiogenic effect of kaempferol and explore its underlying molecular mechanisms. The mRNA expression level of vascular endothelial growth factor (VEGF) and placenta growth factor (PGF) and the concentrations of secreted VEGF and PGF were measured by qTR-PCR and ELISA assay, respectively. Human retinal endothelial cells (HRECs) proliferation, migration, and sprouting were measured by CCK-8 and transwell, scratching wound, and tube formation assays, respectively. Protein levels were determined by western blot. High glucose (25 mM) increased the mRNA expression levels of VEGF and PGF as well as the concentrations of secreted VEGF and PGF in HRECs, which can be antagonized by kaempferol (25 µM). Kaempferol (5-25 µM) significantly suppressed cell proliferation, migration, migration distance and sprouting of HRECs under high glucose condition. The anti-angiogenic effect of kaempferol was mediated via downregulating the expression of PI3K and inhibiting the activation of Erk1/2, Src, and Akt1. This study indicates that kaempferol suppressed angiogenesis of HRECs via targeting VEGF and PGF to inhibit the activation of Src-Akt1-Erk1/2 signaling pathway. The results suggest that kaempferol may be a potential drug for better management of DR.

Impacts of Preeclampsia on the Brain of the Offspring / Impactos da pré-eclâmpsia no cérebro de nascituros

Abstract Preeclampsia (PE) is a significant gestational disorder that causes complications in 3- 5% of all human pregnancies. Apart from the immediate risks and complications for mother and fetus, both additionally carry elevated lifelong risks for specific complications. Offspring of PE pregnancies (PE-F1) have higher risks for hypertension, stroke and cognitive impairment compared with well-matched offspring (F1) fromuncomplicated pregnancies. Prior to the clinical onset of PE, placental angiokines secreted into the maternal plasma are deviated. In many PE patients this includes deficits in placental growth factor (PGF). Our laboratory found that mice genetically-deleted for PGF (PGF - / -) have altered cerebrovascular and brain neurological development detectable from midgestation to adulthood. We hypothesized that the PGF deficits seen in human PE, deviate fetal cerebrovascular and neurological development in a manner that impairs cognitive functions and elevates stroke risk. Here we summarize the initial analytical outcomes from a pilot study of 8-10 year old male and female PE-F1s and matched controls. Our studies were the first to report magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) and functional brain region assessment by eyemovement control and clinical psychometric testing in PE-F1s. Further studies in larger cohorts are essential to define whether there are image-based biomarkers that describe unique anatomical features in PE-F1 brains.

Resumo A pré-eclampsia (PE) é importante doença gravídica complicando 3-5% de todas as gestações humanas. Além dos riscos imediatos e complicações para a mãe e o feto, a PE associa-se a outros riscos materno-fetais elevados em longo prazo. Nascituros de gestações complicadas por PE (PE-F1) apresentam maiores riscos de desenvolver hipertensão, acidente vascular cerebral e disfunção cognitiva em comparação com prole (F1) de gestações sem complicações. Antes do aparecimento clínico da PE, angiocitocinas placentárias secretadas no plasma materno apresentam-se alteradas. Em muitos pacientes com PE, isso inclui valores plasmáticos reduzidos de Fator de Crescimento Placentário (PGF). Nosso laboratório identificou que camundongos geneticamente não produtores de PGF (PGF- / - ) apresentam alterações vasculares e de desenvolvimento cerebral detectáveis do período gestacional à idade adulta. Nossa hipótese é que os déficits de PGF identificados em mulheres que desenvolveram PE podem desviar o desenvolvimento neurológico e vascular cerebral fetal, de maneira a prejudicar funções cognitivas, elevando o risco de AVC. Aqui resumimos os resultados analíticos iniciais de um estudo piloto comcrianças do sexomasculino e feminino de 8- 10 anos de idade nascidas de mães que tiveram PE (PE-F1s) comparadas com crianças controle pareadas por idade e sexo. Nossos estudos são os primeiros a relatar a ressonância magnética (RNM), a angiorressonância e a avaliação funcional do cérebro pelo controle de movimento dos olhos e pelo teste clínico psicotécnico em PE-F1s. Estudos adicionais em coortes maiores são essenciais para definir se há biomarcadores com base em imagens que possam descrever características anatômicas únicas em cérebros de crianças PE-F1.

Circulating miR-214 level and its correlation with the extent of coronary lesion in patients with acute myocardial infarction / 中南大学学报(医学版)

OBJECTIVE@#To examine the circulating levels of miR-214 in acute myocardial infarction (AMI) patients and to explore the relationship between the circulating levels of miR-214 and the degree of coronary lesion.@*METHODS@#A total of 45 patients with AMI (AMI group) were enrolled from Xiangya Hospital of Central South University between September, 2011 and January, 2012. Twenty healthy volunteers served as a normal control group (n=20). According to the coronary artery lesion area, AMI group was also divided into a single-branch group, a double-branch group and a triple-branch group (n=20, 13, 12 respectively). Circulating levels of miR-214 and plasma levels of placental growth factor (PLGF) were measured by real time-PCR assay and enzyme-linked immunosorbent assay respectively on the day when the patients admitted to the hospital. The plasma levels of miR-214 and PLGF were compared among the various branch groups. The correlation between miR-214 and PLGF was analyzed in AMI subgroups.@*RESULTS@#The miR-214 levels in the AMI subgroups were lower than that in the control group. The more decrease in miR-214 level, the larger size of coronary lesion. There was significant difference in the different groups (all P<0.05). Compared with the control group, the levels of plasma PLGF were significantly higher in the AMI subgroups. The more increase in PLGF level, the larger size of coronary lesion. There was significant difference in the different groups (all P<0.05). The plasma levels of miR- 214 were negatively correlated with that of PLGF in the AMI group (r=-0.588, P<0.01).@*CONCLUSION@#The circulating level of miR-214 was significantly decreased in the AMI group, which might be correlated with the extent of the coronary lesion. Circulating miR-214 may be a promising biomarker for the diagnosis and prognosis of severe AMI.

Expression of soluble vascular endothelial growth factor receptor-1 and placental growth factor in fetal growth restriction cases and intervention effect of tetramethylpyrazine

OBJECTIVE@#To investigate the expression of soluble vascular endothelial growth factor receptor-1 (sFlt-1) and placental growth factor (PLGF) in the fetal growth restriction (FGR) cases and the intervention mechanism of tetramethylpyrazine.@*METHODS@#A total of 60 fetal growth restriction cases that admitted to our hospital were randomly divided into ligustrazine intervention group (group A) and nutritional support group (group B). A total of 50 healthy pregnant women were also enrolled as control group (group C). Expression level of maternal serum sFlt1, PLGF and fetal growth parameters including HC, AC, FL, BPD, EFW as well as placenta PLGF, sFlt-1 mRNA expression were recorded and compared among the three groups. A total of 15 SD rats were selected and were divided into three groups, TMP group, alcohol and tobacco group and blank control group. Three groups of rats were dissected on the twentieth day of gestation.@*RESULTS@#Expression level of sFlt-1 and PLGF in group A was not significantly different from that of group C (P>0.05); but significant difference in SFlt1 and PLGF expression level was observed between group C and group B (P0.05). There was significant difference in PLGF between FGR group with treatment and FGR group without treatment or control group (P<0.01).@*CONCLUSIONS@#PLGF level is decreased and sFlt-1 increased in patients suffered from fetal growth restriction, and FGR rats show increased sFlt-1 and decreased PLGF, thus they can be indicator of the fetal growth restriction. Ligustrazine can effectively improve sFlt-1, PLGF expression level in fetal growth restriction cases, which can be used as treatment for FGR.

Relationship between fetal growth restriction and angiogenesis factors / 南方医科大学学报

Placenta is an important organ to maintain fetal growth, metabolism, maternal and fetal physiologic balance. Angiogenesis is a critical factor in placental development involved in fetal blood circulation and vascular changes in the endometrium and placenta. Angiogenesis is closely related to angiogenesis factors such as vascular endothelial growth factor and placenta growth factor. Fetal growth restriction threats the fetal health in gestation and also increases the long-term likeliness of several diseases. In this review, the authors summarize the findings in current studies of the relationship between angiogenesis factors and fetal growth restriction.

Effects of placental growth factor on revascularization after acute myocardial infarction in rats / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effect of placental growth factor (PlGF) on revascularization after acute myocardial infarction.</p><p><b>METHODS</b>Myocardial infarction model was established by ligation of left anterior descending coronary artery in Wistar rats. Thirty AMI rats were divided into 3 groups with 10 in each group: PlGF, mouse VEGFR-1/Flt-1 antibody, or saline (control group) was injected in the infarcted border zone for each group, respectively. Two weeks later the hemodynamics parameters were measured with a left ventricular needle catheter and a biological signal analysis system; left ventricular remodeling was observed by HE staining; angiogenesis was examined by immunohistochemistry and cardiomyocyte apoptosis rate was detected by TUNEL.</p><p><b>RESULTS</b>The stroke volume, systolic pressure and left ventricular developed pressure in PlGF group were all higher than those in control group (112±7 vs 65.63±8.50 μl, P<0.01; 131.61±9.26 vs 94.84±8.53 mm Hg, P<0.01 and 175.85±11.36 vs 105.50±15.83 mm Hg, P<0.01; respectively). PlGF animals had less ventricular dilation (left ventricular diameter 8.20±0.14 vs 9.25±0.32 mm, P<0.01) and increased left ventricular wall thickness (1.81±0.10 vs 1.35±0.10 mm, P<0.01) compared to controls. The geometry parameter of anti-VEGFR1 and control animals was almost the same. PlGF animals had increased angiogenesis compared to controls (29.44±5.75 vs 15.88±2.42 endothelial cells/high-powered field, P<0.01); the alpha smooth muscle actin (α-SMA) showed that PlGF animal had a higher density of artery than others (25.14±1.83 vs 19.70±2.52 arteries/mm(2), P<0.01), and the density of artery in anti-VEFGR1 group was less than the controls. The apoptosis rate of cardiomyocytes in PlGF animals was significantly lower than that in controls (9.51%±2.75% vs 37.81%±8.74%, P<0.01).</p><p><b>CONCLUSION</b>Regional delivery of PlGF following acute myocardial infarction can improve cardiac function and left ventricular remodeling, enhance angiogenesis and reduce cardiomyocyte apoptosis rate. PlGF may be a potential agent in adjuvant therapy for acute myocardial infarction.</p>

The VEGF signaling pathway in cancer: the road ahead / 癌症

The vascular endothelial growth factor (VEGF) family of soluble protein growth factors consists of key mediators of angiogenesis and lymphangiogenesis in the context of tumor biology. The members of the family, VEGF-A (also known as VEGF), VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF), play important roles in vascular biology in both normal physiology and pathology. The generation of a humanized neutralizing antibody to VEGF-A (bevacizumab, also known as Avastin) and the demonstration of its benefit in numerous human cancers have confirmed the merit of an anti-angiogenesis approach to cancer treatment and have validated the VEGF-A signaling pathway as a therapeutic target. Other members of the VEGF family are now being targeted, and their relevance to human cancer and the development of resistance to anti-VEGF-A treatment are being evaluated in the clinic. Here, we discuss the potential of targeting VEGF family members in the diagnosis and treatment of cancer.

Relationship between serum vasoactive factors and plaque morphology in patients with non-ST-segment elevated acute coronary syndrome / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Vasoactive factors have been reported to correlate with vulnerable plaque and acute coronary syndrome (ACS). This study aimed to investigate the relationship between vasoactive factors and plaque morphology in patients suffering from non-ST-segment elevated ACS.</p><p><b>METHODS</b>From April 2007 to April 2009, 124 consecutive patients suffering from non-ST-segment elevated ACS who had received coronary angiography (CAG) and intravascular ultrasound (IVUS) in the People's Liberation Army General Hospital and Beijing Anzhen Hospital were enrolled in this study. Three serum vasoactive factors, plasma soluble vascular endothelial growth factor receptor-1 (sFlt-1), placental growth factor (PLGF) and interleukin-18 (IL-18), were measured by enzyme-linked-immunosorbent serologic assay of the patients. The levels of vasoactive factors were compared between vulnerable plaque group and stable plaque group, and between unstable angina pectoris (UAP) group and non-ST-segment elevation acute myocardial infarction (NSTE-AMI) group. The relationship between the plaque morphology and levels of vasoactive factors was analyzed.</p><p><b>RESULTS</b>The levels of vasoactive factors were similar between the UAP group (69 patients) and NSTE-AMI group (55 patients). The levels of sFlt-1 and PLGF in the vulnerable plaque group were significantly higher than those in the stable plaque group. The level of IL-18 was correlated positively with plaque morphology. Multivariate Logistic regression analysis showed that the level of PLGF was an independent risk factor for vulnerable plaque (OR=2.115, 95% CI 1.415-5.758, P=0.018). Using the ROC curve, PLGF was a significant factor for the diagnosis of vulnerable plaque (the diagnostic point was 26.3 ng/L, the proportion of square area under the ROC curve was 0.799, 95%CI 0.758-0.839, P<0.001; the sensitivity of PLGF under the ROC curve was 86%, and the specificity 63%).</p><p><b>CONCLUSION</b>Both IL-18 and PLGF are biomarkers for vulnerable plaques and helpful to predict vulnerable plaque.</p>

Preliminary research on the pathological role of cathepsin-B in subcutaneous heteroplastic pancreatic carcinoma in nude mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Cathespin-B (cath-B) is an important proteolytic enzyme involved in the disease course of invasion in many types of cancer. Cath-B expression in subcutaneous heteroplastic pancreatic carcinoma in nude mice has not been studied. We investigated the role of cath-B in a model of heteroplastic pancreatic carcinoma in BALB/c nude mice.</p><p><b>METHODS</b>Thirty-two six-week-old female BALB/c nude mice were equally divided into four groups. PANC-1 cells were inoculated subcutaneously in the left axillary region. Besides volume, weight of subcutaneous tumor, and change in body weight, cath-B expression in each group was measured by immunohistochemical staining, PCR and Western blotting. Its relationship to microvessel density (MVD), CD44v6, and placenta growth factor (PLGF) was also examined. CA-074Me, a specific inhibitor of cath-B, was injected intraperitoneally (i.p.) at different stages of tumor growth in group B and C. Gemcitabine (GEM), was also injected (i.p.) in group D to compare anti-tumor efficacy with CA-074Me.</p><p><b>RESULTS</b>Expression of cath-B at different levels was related to tumor growth, MVD, and PLGF expression. In group A (control group), cath-B expression was enhanced more than that seen in other groups. CA-074Me clearly inhibited cath-B expression and tumor growth in group B. There was no difference between group C and D with respect to anti-tumor effect.</p><p><b>CONCLUSIONS</b>Cath-B correlates with the growth and angiogenesis of tumors, but not with the adhesion induced by CD44v6. CA-074Me clearly inhibited cath-B expression and demonstrated an anti-neoplastic and anti-angiogenesis effect.</p>

Increased expression of placenta growth factor in lung tissue of paraquat-induced rat pulmonary fibrosis model / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate the dynamic expression of placenta growth factor (PLGF) in the lungs with paraquat (PQ)-induced pulmonary fibrosis.</p><p><b>METHODS</b>Forty-two adult healthy female Sprague-Dawley (SD) rats were randomly divided into two groups: the control group and the PQ group. Each group was divided into three subgroups, seven animals each. The rats in PQ group were treated intragastrically (ig) with PQ (40 mg/kg) and the rats in control group were treated with the same volume of saline at the beginning of the experiment. The animals of model and control group were sacrificed and lungs were harvested on the 7(th), 14(th) and 28th days respectively. A semiquantitative assay of histological examination and hydroxyproline in lung tissues were used to determine the severity of alveolitis and fibrosis. RT-PCR and immunohistochemistry were used to detect the mRNA and protein expression of PLGF.</p><p><b>RESULTS</b>Hydroxyproline contents in lung tissue were significantly increased after PQ administration. Inflammatory cell infiltration and fibrotic scores were more prominent in the model group compared to the control group. Further study showed that PLGF mRNA on day 7, 14 and 28 (1.28 +/- 0.29, 0.80 +/- 0.07, 0.65 +/- 0.13) and positive index of protein expression (2.27 +/- 0.34, 1.78 +/- 0.41, 1.25 +/- 0.69) in the PQ group were all upregulated as compared with those of the control group.</p><p><b>CONCLUSION</b>The PLGF expression in the lung tissue in rats with paraquat-induced pulmonary fibrosis is upregulated.</p>