Showing papers by "Juan Pedro Kusanovic published in 2009"
TL;DR: A novel signaling pathway impact analysis (SPIA) that combines the evidence obtained from the classical enrichment analysis with a novel type of evidence, which measures the actual perturbation on a given pathway under a given condition.
Abstract: Motivation: Gene expression class comparison studies may identify hundreds or thousands of genes as differentially expressed (DE) between sample groups. Gaining biological insight from the result of such experiments can be approached, for instance, by identifying the signaling pathways impacted by the observed changes. Most of the existing pathway analysis methods focus on either the number of DE genes observed in a given pathway (enrichment analysis methods), or on the correlation between the pathway genes and the class of the samples (functional class scoring methods). Both approaches treat the pathways as simple sets of genes, disregarding the complex gene interactions that these pathways are built to describe.
Results: We describe a novel signaling pathway impact analysis (SPIA) that combines the evidence obtained from the classical enrichment analysis with a novel type of evidence, which measures the actual perturbation on a given pathway under a given condition. A bootstrap procedure is used to assess the significance of the observed total pathway perturbation. Using simulations we show that the evidence derived from perturbations is independent of the pathway enrichment evidence. This allows us to calculate a global pathway significance P-value, which combines the enrichment and perturbation P-values. We illustrate the capabilities of the novel method on four real datasets. The results obtained on these data show that SPIA has better specificity and more sensitivity than several widely used pathway analysis methods.
Availability: SPIA was implemented as an R package available at http://vortex.cs.wayne.edu/ontoexpress/
Contact: [email protected]
Supplementary information:Supplementary data are available at Bioinformatics online.
952 citations
TL;DR: The PlGF/sEng ratio and its delta and slope had an excellent predictive performance for the prediction of early-onset preeclampsia, with very high likelihood ratio for a positive test result and very low likelihood ratios for a negative test result.
Abstract: Objective. Changes in the maternal plasma concentrations of angiogenic (placental growth factor (PlGF) and vascular endothelial growth factor (VEGF)) and anti-angiogenic factors (sEng and vascular endothelial growth factor receptor-1 (sVEGFR-1)) precede the clinical presentation of preeclampsia. This study was conducted to examine the role of maternal plasma PlGF, sEng, and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.Methods. This longitudinal cohort study included 1622 consecutive singleton pregnant women. Plasma samples were obtained in early pregnancy (6–15 weeks) and midtrimester (20–25 weeks). Maternal plasma PlGF, sEng, and sVEGFR-1 concentrations were determined using sensitive and specific immunoassays. The primary outcome was the development of preeclampsia. Secondary outcomes included term, preterm, and early-onset preeclampsia. Receiving operating characteristic curves, sensitivity, specificity, positive and nega...
280 citations
TL;DR: It is proposed that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms and systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis.
Abstract: The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p < 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p < 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (p < 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p < 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms.
174 citations
TL;DR: It is indicated that MIAC does not follow widespread infection of CAMs, but precedes it, and the importance of assessing the intra-amniotic compartment for diagnosis and treatment of preterm birth is emphasized.
142 citations
TL;DR: The syndromic nature of spontaneous labour was a concept first proposed in 1994 and this article outlines the potential flaws in this concept, which it is believed has halted progress in the prevention of pre term birth and in the treatment of preterm labour.
Abstract: The syndromic nature of spontaneous labour was a concept first proposed in 1994 [1] It has important implications for understanding the biology of preterm parturition, and also, setting realistic
135 citations
TL;DR: The fetal inflammatory response syndrome (FIRS) is considered the counterpart of the systemic inflammatory response disorder (SIRS) but similarities in their regulatory mechanisms are unclear as discussed by the authors, and the fetal mRNA transcriptome of peripheral leukocytes is characterized to identify key biological processes and pathways involved in FIRS.
Abstract: Problem The fetal inflammatory response syndrome (FIRS) is considered the counterpart of the systemic inflammatory response syndrome (SIRS), but similarities in their regulatory mechanisms are unclear. This study characterizes the fetal mRNA transcriptome of peripheral leukocytes to identify key biological processes and pathways involved in FIRS.
Method of study Umbilical cord blood from preterm neonates with FIRS (funisitis, plasma IL-6 >11 pg/mL; n = 10) and neonates with no evidence of inflammation (n = 10) was collected at birth.
Results Microarray analysis of leukocyte RNA revealed differential expression of 541 unique genes, changes confirmed by qRT-PCR for 41 or 44 genes tested. Similar to SIRS and sepsis, ontological and pathway analyses yielded significant enrichment of biological processes including antigen processing and presentation, immune response, and processes critical to cellular metabolism. Results are comparable with microarray studies of endotoxin challenge models and pediatric sepsis, identifying 25 genes across all studies.
Conclusion This study is the first to profile genome-wide expression in FIRS, which demonstrates a substantial degree of similarity with SIRS despite differences in fetal and adult immune systems.
115 citations
TL;DR: An SNP involved in controlling fetal inflammation (interleukin-6 receptor 1) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix metabolism approximately doubled the risk of PTB.
95 citations
TL;DR: The novel findings reported herein strongly suggest that post‐transcriptional regulation of genes by miRNAs, coupled with the changes of miRNA processing machinery in the chorioamniotic membranes, plays a role in pregnancy and parturition.
Abstract: MicroRNAs (miRNAs) are involved in the post-transcriptional regulation of gene expression during development. This study was performed to determine gestational age-dependent changes in miRNA expression in the chorioamniotic membranes and to assess the significance of miRNAs in human pregnancy and parturition. The expression profile of 455 miRNAs was compared between patients at term without labor (TNL: n=10), in labor (TL: n=10), and preterm labor (PTL: n=10) using microarrays. A total of 39 miRNAs were differentially expressed between term and preterm cases, of which 31 (79.5%) were down-regulated at term. Expression of 10 miRNAs, including miR-338, differentially expressed between PTL and TL groups was decreased at term. Computational analyses using miRBase Targets have identified PLA2G4B, a phospholipase implicated in parturition, as a putative target of miR-338. Inhibition of endogenous miR-338 with anti-miR-338 increased the mRNA and protein expression of PLA2G4B in decidual cells. Luciferase assay with reporter constructs confirmed that the suppression of PLA2G4B occurs through binding of miR-338 to the 3’UTR of PLA2G4B. Interestingly, the expression of Dicer, a key miRNA-processing enzyme, was markedly decreased at term, particularly with labor in the chorioamniotic membranes. Collectively, the novel findings reported herein strongly suggest that post-transcriptional regulation of genes by miRNAs, coupled with the changes of miRNA processing machinery in the chorioamniotic membranes, plays a role in pregnancy and parturition. Furthermore, the expression level of Dicer in the chorioamniotic membranes dichotomizes pathological preterm labor and physiological spontaneous labor at term.
90 citations
TL;DR: The main goal of this study was to determine the accuracy and precision of new fetal weight estimation models, based on fractional limb volume and conventional two‐dimensional sonographic measurements during the second and third trimesters of pregnancy.
Abstract: Objectives
The main goal was to determine the accuracy and precision of new fetal weight estimation models, based on fractional limb volume and conventional 2D sonographic measurements during the second and third trimesters of pregnancy.
85 citations
TL;DR: Homogeneity of male and female growth responses to maternal height and weight is investigated and sex differences in response to maternal size are under‐appreciated sources of variation in fetal growth studies and may reflect differential growth strategies.
Abstract: Sex differences in fetal growth have been reported, but how this happens remains to be described. It is unknown if fetal growth rates, a reflection of genetic and environmental factors, express sexually dimorphic sensitivity to the mother herself. This analysis investigated homogeneity of male and female growth responses to maternal height and weight. The study sample included 3,495 uncomplicated singleton pregnancies followed longitudinally. Analytic models regressed fetal and neonatal weight on tertiles of maternal height and weight, and modification by sex was investigated (n = 1,814 males, n = 1,681 females) with birth gestational age, maternal parity, and smoking as covariates. Sex modified the effects of maternal height and weight on fetal growth rates and birth weight. Among boys, tallest maternal height influenced fetal weight growth before 18 gestational weeks of age (P = 0.006), and prepregnancy maternal weight and body mass index subsequently had influence (P < 0.001); this was not found among girls. Additionally, interaction terms between sex, maternal height, and maternal weight identified that males were more sensitive to maternal weight among shorter mothers (P = 0.003) and more responsive to maternal height among lighter mothers (P ≤ 0.03), compared to females. Likewise, neonatal birth weight dimorphism varied by maternal phenotype. A male advantage of 60 g occurred among neonates of the shortest and lightest mothers (P = 0.08), compared to 150 and 191 g among short and heavy mothers, and tall and light-weight mothers, respectively (P = 0.01). Sex differences in response to maternal size are under-appreciated sources of variation in fetal growth studies and may reflect differential growth strategies. Am. J. Hum. Biol., 2010. © 2009 Wiley-Liss, Inc.
84 citations
TL;DR: Differential expression of proteins in AF of patients who delivered preterm in the absence of IAI is observed in comparison with those with PTL who delivered at term including Mimecan precursor, latent-transforming growth factor β-binding protein isoform 1L precursor, and Resistin.
Abstract: Objective. Examination of the amniotic fluid (AF) proteome has been previously attempted to identify useful biomarkers in predicting the outcome of preterm labor (PTL). Isobaric Tag for Relative and Absolute Quantitation (iTRAQ TM ) labeling allows direct ratiometric comparison of relative abundance of identified protein species among multiplexed samples. The purpose of this study was to apply, for the first time, the combination of iTRAQ and tandem mass spectrometry to identify proteins differentially regulated in AF samples of women with spontaneous PTL and intact membranes with and without intra-amniotic infection/inflammation (IAI). Methods. A cross-sectional study was designed and included AF samples from patients with spontaneous PTL and intact membranes in the following groups: (1) patients without IAI who delivered at term (n ¼26); (2) patients who delivered preterm without IAI (n ¼25); and (3) patients with IAI (n ¼24). Proteomic profiling of AF samples was performed using a workflow involving tryptic digestion, iTRAQ labeling and multiplexing, strong cation exchange fractionation, and liquid chromatography tandem mass spectrometry. Twenty-five separate 4-plex samples were prepared and analyzed. Results. Collectively, 123,011 MS 2 spectra were analyzed, and over 25,000 peptides were analyzed by database search (X!Tandem and Mascot), resulting in the identification of 309 unique high-confidence proteins. Analysis of differentially present iTRAQ reporter peaks revealed many proteins that have been previously reported to be associated with preterm delivery with IAI. Importantly, many novel proteins were found to be up-regulated in the AF of patients with PTL and IAI including leukocyte elastase precursor, Thymosin-like 3, and 14-3-3 protein isoforms. Moreover, we observed differential expression of proteins in AF of patients who delivered preterm in the absence of IAI in comparison with those with PTL who delivered at term including Mimecan precursor, latent-transforming growth factor b-binding protein isoform 1L precursor, and Resistin. These findings have been confirmed for Resistin in an independent cohort of samples using ELISA. Gene ontology enrichment The iFirst version of this article published online ahead of print (DOI10.3109/14767050903067386) on 6 August 2009 and contained several errors in text citations and reference numbers. The corrected version is currently displayed online.
TL;DR: The main goal was to investigate the relationship between prenatal sonographic parameters and birth weight in predicting neonatal body composition.
Abstract: Objectives
The main goal was to investigate the relationship between prenatal sonographic parameters and birth weight in predicting neonatal body composition.
Methods
Standard fetal biometry and soft tissue parameters were assessed prospectively in third-trimester pregnancies using three-dimensional ultrasonography. Growth parameters included biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), mid-thigh circumference and femoral diaphysis length (FDL). Soft tissue parameters included fractional arm volume (AVol) and fractional thigh volume (TVol) that were derived from 50% of the humeral or femoral diaphysis lengths, respectively. Percentage of neonatal body fat (%BF) was determined within 48 h of delivery using a pediatric air displacement plethysmography system based on principles of whole-body densitometry. Correlation and stepwise multiple linear regression analyses were performed with potential prenatal predictors and %BF as the outcome variable.
Results
Eighty-seven neonates were studied with a mean ± SD %BF of 10.6 ± 4.6%. TVol had the greatest correlation with newborn %BF of all single-parameter models. This parameter alone explained 46.1% of the variability in %BF and the best stepwise multiple linear regression model was: %BF = 0.129 (TVol) − 1.03933 (P < 0.001). Birth weight similarly explained 44.7% of the variation in %BF. AC and estimated fetal weight (EFW) accounted for only 24.8% and 30.4% of the variance in %BF, respectively. Skeletal growth parameters, such as FDL (14.2%), HC (7.9%) and BPD (4.0%), contributed the least towards explaining the variance in %BF.
Conclusions
During the late third trimester of pregnancy %BF is most highly correlated with TVol. Similar to actual birth weight, this soft tissue parameter accounts for a significant improvement in explaining the variation in neonatal %BF compared with fetal AC or EFW alone. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.
TL;DR: The main goals were to provide normal reference ranges for fractional limb volume as a new index of generalized fetal nutritional status, to evaluate the reproducibility of fractional fetal limb volume measurements during the second and third trimester of pregnancy, and to demonstrate technical considerations for this technique.
Abstract: Objectives
The main goals were to provide normal reference ranges for fractional limb volume as a new index of generalized fetal nutritional status, to evaluate the reproducibility of fractional fetal limb volume measurements during the second and third trimesters of pregnancy, and to demonstrate technical considerations for this technique.
TL;DR: This is the first description of the changes in the human cervical transcriptome with ripening before the onset of labor, and biological processes, pathways and molecular functions were identified with the use of this unbiased approach.
Abstract: Objective. The aim of this study was to identify changes in the cervical transcriptome in the human uterine cervix as a function of ripening before the onset of labor.Study Design. Human cervical tissue was obtained from women at term not in labor with ripe (n = 11) and unripe (n = 11) cervices and profiled using Affymetrix GeneChip® HGU133Plus2.0 arrays. Gene expression was analyzed using a moderated t-test (False Discovery Rate 5%). Gene ontology and pathway analysis were performed. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for confirmation of selected differentially expressed genes.Results. (1) Ninety-one genes were differentially expressed between ripe and unripe groups. (2) Cervical ripening was associated with enrichment of specific biological processes (e.g. cell adhesion, regulation of anatomical structure), pathways and 11 molecular functions (e.g. extracelluar matrix (ECM)-structural constituent, protein binding, glycosaminoglycan binding). (3) qRT-PCR confi...
TL;DR: The view that an imbalance of angiogenic factors participates in the pathophysiology of spontaneous preterm parturition is supported.
Abstract: Objective. An imbalance between angiogenic and anti-angiogenic factors in maternal blood has been observed in several obstetrical syndromes including preeclampsia, pregnancies with fetal growth restriction and fetal death. Vascular lesions have been identified in a subset of patients with spontaneous preterm labor (PTL). It is possible that PTL may be one of the manifestations of an anti-angiogenic state. The aim of this study was to determine if patients prior to the clinical diagnosis of PTL leading to preterm delivery had plasma concentrations of angiogenic and anti-angiogenic factors different from normal pregnant women.Study Design. This longitudinal nested case–control study included normal pregnant women (n = 208) and patients with PTL leading to preterm delivery (n = 52). Maternal blood samples were collected at 6 gestational age intervals from 6 to36.9 weeks of gestation. The end point (time of diagnosis) of the study, ‘True PTL’, was defined as patients presenting with PTL and delivered within 1...
TL;DR: Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/total adip onectin ratio, a specific marker of adiponECTin biologic activity.
Abstract: Objective: Obesity, insulin resistance, and dyslipidemia are associated with preeclampsia Recently, "adipose tissue failure", characterized by dysregulation of adipokine production, has been implicated in the pathophysiology of these metabolic complications Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine, circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms These multimers exert differential biological effects, and HMW to total adiponectin ratio (S A ) has been reported to be a specific marker of adiponectin activity The aim of this study was to determine whether preeclampsia is associated with changes in circulating adiponectin multimers Study design: This cross-sectional study included women with: 1) normal pregnancy (n= 2 25); and 2) patients with mild preeclampsia (n=111) The study population was further stratified by first trimester BMI (normal weight <25 kg/m 2 vs overweight/obese ≥25 kg/m 2 ) Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA Non-parametric statistics were used for analysis Results: 1) The median maternal HMW and LMW adiponectin concentrations were lower in patients with preeclampsia than in those with normal pregnancies (P < 0001 and P =001, respectively); 2) patients with preeclampsia had a lower HMW/total adiponectin ratio (P<0001) and higher MMW/total adiponectin and LMW/ total adiponectin ratios than those with a normal pregnancy (P < 0001 and P = 0009, respectively); 3) the presence of preeclampsia was independently associated with lower maternal serum HMW adiponectin concentrations (P= 0 001) and with a low HMW/total adiponectin ratio (P<0001) after correction for maternal age, maternal BMI, the difference in BMI between the third and the first trimester, and gestational age at sampling; and 4) overweight/obese pregnant women had a lower median total and HMW adiponectin concentration than normal weight pregnant women among women with normal pregnancies, but not among those with preeclampsia Conclusion: 1) Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/ total adiponectin ratio, a specific marker of adiponectin biologic activity; 2) in contrast to normal pregnancy, preeclampsia is not associated with decreased circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in preeclampsia ; 3) collectively, these findings suggest that preeclampsia is characterized by alterations in adiponectin multimers and their relative distribution implying a role for adiponectin multimers in the mechanism of disease in preeclampsia
TL;DR: GDM is characterized by a distinctive pattern of concentrations and relative distribution of adiponectin multimers akin to Type 2 diabetes mellitus, and dysregulation of adip onectin multimeres can provide a mechanistic basis for the association between adiposity and GDM.
Abstract: Objective: Adiponectin, an adipokine with profound insulin-sensitizing effect, consists of heterogeneous species of multimers. These oligomeric complexes circulate as low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms and can exert differential biological effects. The aims of this study were to determine whether there is a change in circulating adiponectin multimers in the presence of gestational diabetes mellitus (GDM), overweight/obesity or with a treatment with sulfonylurea or insulin in patients with GDM. Study design: This cross-sectional study included women with: 1) normal pregnancy (n=149); and 2) patients with GDM (n=72). Thirty-three patients with GDM were managed with diet alone. Among the others 39 diabetic patients, 17 were treated with Glyburide and 22 with insulin. The study population was further stratified by first trimester body mass index (BMI) (normal weight <25 kg/m 2 vs. overweight/obese ≥25 kg/m 2 ). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Results: 1) The median maternal serum of total, HMW, MMW and LMW were lower in patients with GDM than in those with normal pregnancies (P < 0.001 for all comparisons) ; 2) patients with GDM had a lower HMW/total adiponectin ratio and a higher MMW/total and LMW/total adiponectin ratio than those with a normal pregnancy (P<0.001 for all comparisons); and 3) among GDM patients, there were no differences in the concentrations and relative distribution of adiponectin multimers between those who were managed with diet, and those who were treated with pharmacological agents. Conclusion: 1) GDM is characterized by a distinctive pattern of concentrations and relative distribution of adiponectin multimers akin to Type 2 diabetes mellitus; 2) dysregulation of adiponectin multimeres can provide a mechanistic basis for the association between adiposity and GDM.
TL;DR: The median maternal plasma concentration of visfatin peaks between 19–26 and has a nadir between 27–34 weeks of gestation, and normal and overweight/obese pregnant women differed in the pattern of changes in circulating visFatin concentrations as a function of gestational age.
Abstract: Objective: Adipose tissue has now emerged as a powerful endocrine organ via the production of adipokines. Visfatin, a novel adipokine with diabetogenic and immunomodulatory properties has been implicated in the pathophysiology of insulin resistance in patients with obesity and Type-2 diabetes mellitus. The aim of this study was to determine whether there are changes in the maternal plasma concentration of visfatin with advancing gestation and as a function of maternal weight. Study design: In this cross-sectional study, maternal plasma concentrations of visfatin were determined in normal weight and overweight/obese pregnant women in the following gestational age groups: 1) 11–14 weeks (ns52); 2) 19–26 weeks (ns68); 3) 27–34 weeks (ns93); and 4) )37 weeks (ns60). Visfatin concentrations were determined by ELISA. Non parametric statistics were used for analysis. Results: 1) The median maternal plasma visfatin concentration was higher in pregnant women between 19–26 weeks of gestation than that of those between 11–14 weeks of gestation (P-0.01) and those between 27–34 weeks of gestation (P-0.01); 2) among normal
TL;DR: It is indicated that mothers with a FD have evidence of increased in vivo thrombin generation and platelet activation than women with normal pregnancies.
Abstract: Objective. Fetal death can lead to disseminated intravascular coagulation or fetal death syndrome. However, currently it is not clear what are the changes in the coagulation system in patients with a fetal death without the fetal death syndrome. This study was undertaken to determine: (1) whether fetal death in the absence of fetal death syndrome is associated with changes in hemostatic markers in maternal plasma and amniotic fluid; and (2) whether maternal hypertension or placental abruption are associated with further changes in the hemostatic profile of these patients.Methods. A cross-sectional study included the following: (1) determination of changes in markers of coagulation and platelet activation in patients with a normal pregnancy (n = 71) and patients with fetal demise (FD) without disseminated intravascular coagulation (n = 65); (2) determination of the amniotic fluid (AF)–tissue factor concentration and activity, as well as the concentrations of thrombin–antithrombin III (TAT) complexes in pat...
TL;DR: Patients with spontaneous preterm labor and intact membranes with microbial invasion of the amniotic cavity had higher medianAmniotic fluid concentration of complement split products C3a, C4a, and C5a than patients without intra-amniotic infection.
Abstract: Objective. The complement system plays an important role in host defense against infection. Concentrations of complement split products or anaphylatoxins (C3a, C4a, and C5a) in biological fluids are considered to reflect complement activation. The purpose of this study was to determine if term and preterm parturition are associated with evidence of complement activation in the amniotic fluid.Study design. Amniotic fluid (AF) samples were collected from 270 women in the following groups: (1) normal pregnant women in midtrimester (n = 70), (2) term not in labor (n = 23), (3) term in labor (n = 48), and (4) preterm labor (PTL) (n = 129). PTL was categorized into: (a) PTL without microbial invasion of the amniotic cavity (MIAC) who delivered at term (n = 42), (b) PTL who delivered preterm without MIAC (n = 57), and (c) PTL with MIAC (n = 30). C5a, C4a, and C3a concentrations in amniotic fluid were determined by ELISA. Nonparametric tests were used for statistical analysis.Results. (1) The median AF C5a concen...
TL;DR: Placental mesenchymal dysplasia should be considered in the differential diagnosis of every placental mass, especially in cases of multicystic placental lesion with lack of high‐velocity signals inside the lesion, and a normal karyotype.
Abstract: Objective—Placental mesenchymal dysplasia (PMD) is an uncommon vascular anomaly of the placenta characterized by mesenchymal stem villous hyperplasia. Its main sonographic features is a thickened placenta with hypoechoic areas, and an accurate sonographic diagnosis is challenging. The aim of this study was to report two cases of PMD, and discuss the differential diagnosis of its sonographic features. Methods—Cases of placental masses studied by two-dimensional (2D), three-dimensional (3D) and Color Doppler imaging. Results—Case 1 - a thick placenta with multiple hypoechoic areas was noted at 13 weeks of gestation. At 19 weeks, the multi-cystic area, clearly demarcated from a normal looking placenta, measured 6.5×8.5cm and enlarged gradually. The patient delivered a 625 gram female after a spontaneous labor at almost 26 weeks’ gestation. Case 2 - a first sonographic examination at 25 weeks’ gestation revealed a thickened placenta with hypoechoic areas and a fetus with a single umbilical artery and a ventricular septal defect. At 27 weeks, the abnormal area of the placenta measured 14.5×7.5cm. At 32 weeks’ gestation, a caesarean section was performed due to nonreassuring fetal heart tracing and a 1415 gram female infant was delivered. Both cases were evaluated by 2D, 3D and Color Doppler imaging and the pathologic features of both placentas were consistent with PMD. Conclusions—Placental mesenchymal dysplasia should be considered in the differential diagnosis of every placental mass, especially in cases of multi-cystic placental lesion with lack of high velocity signals inside the lesion, and a normal karyotype.
TL;DR: The linkage between increased maternal circulating visfatin and the presence of GDM or delivery of an LGA neonate supports the hypothesis that perturbation of adipokines homeostasis may play a role in the pathophysiology of G DM or excess fetal growth.
Abstract: Objective: Adipose tissue dysfunction, characterized by dysregulation of adipokines production and/or secretion, has been implicated in the pathophysiology of type-2 diabetes mellitus, a metabolic complication closely related to gestational diabetes mellitus (GDM). Recently, an association between circulating maternal visfatin, a novel adipokine with metabolic and immunoregulatory properties, and impaired glucose metabolism as well as with altered fetal growth, has been proposed. The aims of this study were to determine whether there is an association between maternal plasma visfatin concentration, GDM, and a large-for-gestational-age (LGA) newborn. Study design: This cross-sectional study, included pregnant women at term in the following groups: 1) normal pregnancy and an appropriate-for-gestational-age (AGA) neonate (ns54); 2) normal pregnancy and an LGA newborn (ns47); 3) GDM and an AGA newborn (ns56); 4) GDM and an LGA newborn (ns45). The study population was further stratified by first trimester BMI (-25 vs. G25 kg/m 2 ). Maternal plasma visfatin concentration was
TL;DR: Fetal systemic inflammation is associated with phenotypic and metabolic changes consistent with activation in fetal immune cells but not in maternal blood.
Abstract: OBJECTIVE
The fetal inflammatory response syndrome (FIRS) is present in a fraction of fetuses exposed to intra-amniotic infection and is associated with the impending onset of labor and multisystem organ involvement. Neonates born with funisitis, the histologic counterpart of fetal systemic inflammation, are at increased risk for cerebral palsy and bronchopulmonary dysplasia. The aim of this study was to determine whether fetal and maternal granulocytes and monocytes have the phenotypic and metabolic characteristics of activation in cases with FIRS.
TL;DR: It is proposed that sTREM-1 play a role in the innate immune response against intra-amniotic infection and increases with advancing gestation, and does not change in the presence of spontaneous labor at term.
Abstract: Objective. Intra-amniotic infection/inflammation (IAI) is one of the most important mechanisms of disease in preterm birth. Triggering receptor expressed on myeloid cells (TREM)- 1 is a transmembrane glycoprotein expressed by neutrophils, macrophages and mature monocytes. TREM-1 is upregulated in biological fluids and tissues infected by Gram (+) and Gram (−) bacteria and fungi, amplifies the production of pro-inflammatory cytokines and chemokines, and its soluble form (sTREM-1) is released in the presence of infection. The aim of this study was to determine the effect of gestational age, parturition (term and preterm) and IAI in the amniotic fluid (AF) concentrations of sTREM-1.Study design. This cross-sectional study included 434 patients in the following groups: (1) mid-trimester of pregnancy (14–18 weeks, n = 38); (2) normal pregnant women at term with (n = 39) and without (n = 39) labor; (3) patients with spontaneous preterm labor (PTL) and intact membranes classified into: (a) PTL who delivered at t...
TL;DR: PTL with IAI is characterized by high maternal circulating visfatin concentrations, and these findings suggest that visFatin plays a role in the regulation of the metabolic adaptations to insults resulting in PTL in the context of IAI.
Abstract: Objective. Visfatin, a novel adipokine with diabetogenic and immunoregulatory properties, has been implicated in the pathophysiology of insulin resistance, as well as in various acute and chronic inflammatory disorders. We have previously reported that amniotic fluid concentrations of visfatin are higher in patients with preterm labor (PTL) and intra-amniotic infection than in patients with PTL without infection. The aim of this study was to determine whether spontaneous PTL with intact membranes and intra-amniotic infection/inflammation (IAI) is associated with changes in maternal plasma circulating visfatin concentrations.Study design. This cross-sectional study included patients in the following groups: (1) normal pregnant women (n = 123); (2) patients with an episode of PTL and intact membranes without IAI who delivered at term (n = 57); (3) PTL without IAI who delivered preterm (n = 47); and (4) PTL with IAI who delivered preterm (n = 57). Plasma visfatin concentrations were determined by ELISA. Non-...
TL;DR: It is suggested that adiponectin plays a dynamic role in normal gestation and in the presence of IAI, which is a physiologic constituent of AF.
Abstract: Objective. Adiponectin, an anti-inflammatory and anti-diabetogenic adipokine, has an important regulatory effect on both the innate and adaptive limbs of the immune response. The objective of this study was to determine whether adiponectin is present in amniotic fluid (AF) and if its concentration changes with gestational age, in the presence of labor, and in the presence of intra-amniotic infection (IAI) in patients with spontaneous preterm labor (PTL) and intact membranes.Study design. This cross-sectional study included 468 patients in the following groups: (1) women in the mid-trimester of pregnancy (14–18 weeks) who underwent amniocentesis for genetic indications and delivered a normal neonate at term (n = 52); (2) normal pregnant women at term with (n = 49) and without (n = 41) spontaneous labor; (3) patients with an episode of PTL and intact membranes who were classified into: (a) PTL who delivered at term (n = 149); (b) PTL who delivered preterm (<37 weeks gestation) without IAI (n = 108); and (c)...
TL;DR: Findings suggest a role for fragment Bb in the host immune response against IAI, a physiologic constituent of the AF, and its concentration increases with advancing gestational age and in pregnancies complicated with IAI.
Abstract: Objective. Fragment Bb is an activator of the alternative pathway of the complement system. Recently, increased first trimester maternal plasma concentrations of this fragment were reported in patients destined to have a spontaneous preterm delivery before 34 weeks of gestation. The aim of this study was to determine whether the amniotic fluid (AF) concentrations of fragment Bb change with gestational age, spontaneous labor (term and preterm) and in the presence of intra-amniotic infection/inflammation (IAI).Study design. This cross-sectional study included patients in the following groups: (1) mid-trimester (n = 64); (2) term in spontaneous labor (n = 70); (3) term not in labor (n = 43); (4) spontaneous preterm labor (PTL) who delivered at term (n = 76); (5) PTL without IAI who delivered preterm (n = 73); (6) PTL with IAI (n = 76); (7) preterm prelabor rupture of membranes (PROM) without IAI (n = 71); and (8) preterm PROM with IAI (n = 71). Fragment Bb concentration in AF was determined by an enzyme-link...
TL;DR: It is proposed that adiponectins and adipokines in general provide a mechanism to organise the metabolic demands generated by the process of preterm parturition regardless of the nature of the insult.
Abstract: Objective. Intra-amniotic and systemic infection/inflammation have been causally linked to preterm parturition and fetal injury. An emerging theme is that adipose tissue can orchestrate a metabolic response to insults, but also an inflammatory response via the production of adipocytokines, and that these two phenomenons are interrelated. Adiponectin, an insulin-sensitising, anti-inflammatory adipocytokine, circulates in multimeric complexes including low-molecular weight (LMW) trimers, medium-molecular weight (MMW) hexamers and high-molecular weight (HMW) isoforms. Each of these complexes can exert differential biological effects. The aim of this study was to determine whether spontaneous preterm labor (PTL) with intact membranes and intra-amniotic infection/inflammation (IAI) is associated with changes in maternal serum circulating adiponectin multimers.Study design. This cross-sectional study included patients in the following groups: (1) normal pregnant women (n = 158); (2) patients with an episode of ...
TL;DR: Pregnancies complicated by an SGA neonate are characterized by a alterations in the maternal serum adiponectin multimers concentrations and their relative abundance, and the findings suggest that maternal adipose tissue may play a role, in the pathogenesis of SGA.
Abstract: Objective: Several mechanisms of disease have been implicated in the pathophysiology of small-for-gestational-age (SGA) including an anti-angiogenic state, and an exaggerated intravascular pro-inflammatory response. Adiponectin plays a role in a wide range of biological activities including those that have been implicated in the pathophysiology SGA. Thus, the aim of this study was to determine if third trimester adiponectin concentrations differed between women with normal weight infants and those with an SGA neonate. Study design: This cross-sectional study included women with: 1) a normal pregnancy (n =234); and 2) an SGA neonate (n = 78). SGA was defined as a birth weight below the 10 th percentile for gestational age at birth. The study population was further stratified by first trimester body mass index (BMI) (normal weight <25 kg/m 2 vs. overweight/obese ≥25 kg/m 2 ). Maternal serum adiponectin multimers [total, high-molecular-weight (HMW), medium-molecular-weight (MMW) and low-molecular-weight (LMW)] concentrations were determined by ELISA. Non-parametric statistics were used for analyses. Results: 1) The median maternal serum concentrations of total, HMW and MMW adiponectin were significantly lower in patients with an SGA neonate than in those with normal pregnancies; 2) patients with an SGA neonate had a significantly lower median HMW/total adiponectin ratio and higher median MMW/total adiponectin and LMW/total adiponectin ratios than those with a normal pregnancy; 3) among patients with an SGA neonate, neither maternal serum concentrations of adiponectin multimers, nor their relative distribution differ between normal weight and overweight/obese patients. Conclusion: 1) Pregnancies complicated by an SGA neonate are characterized by a alterations in the maternal serum adiponectin multimers concentrations and their relative abundance; 2) the findings reported herein suggest that maternal adipose tissue may play a role, in the pathogenesis of SGA.
TL;DR: A stereotypic pattern of gene expression in the myometrium of women with an arrest of descent is identified using a genome-wide approach and indicated enrichment of biological processes and molecular functions related to inflammation and muscle function.