Novel approaches for mechanistic understanding and predicting preeclampsia.
ABSTRACT Despite intense investigation, preeclampsia (PE) remains largely enigmatic. Relatively late onset of diagnostic signs and heterogeneous nature of the disease further contribute to poor understanding of its etiology and clinical management. There exist no concrete animal models that can provide mechanistic underpinnings for evaluating targeted therapeutic intervention. Poor cross-sectional findings with potential biochemical markers reported so far have proved counterintuitive and suggest a need for novel approaches to predict the early onset of disease. Because of the co-onset of local placental anomalies and systemic manifestation of symptoms, it is highly likely that serum from PE patients can provide a "blueprint" of causative factors. Proteomic and/or functional analysis of maternal serum are expected to predict the onset of disease ahead of manifestation of clinical symptoms. A serum-based predictive assay should overcome complexities resulting from the heterogeneous etiology of PE. This review attempts to address some of these issues and discuss the signature biochemical serum factors and propose new and better ways to predict PE.
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ABSTRACT: Abstract Glycosaminoglycans are found in extracellular matrix and on the cell surface in the form of proteoglycans. There is evidence that these molecules regulate biological processes, including cell survival, migration and angiogenesis. Preeclampsia is a common pregnancy disorder associated with insufficient placental development. This study aimed to determine the concentrations of glycosaminoglycans and the proteoglycan syndecan-1 within villous trophoblast and to investigate changes associated with preeclampsia. Seventy-five placental samples collected from third trimester singleton pregnancies were divided into term placentas following labour onset, gestational age-matched placentas prior to labour onset and preterm placentas. Preterm placentas were divided into three gestational age-matched groups, spontaneous preterm labour, preterm premature rupture of membranes (PPROM) and preterm preeclampsia. Sulphated glycosaminoglycan (sGAG) concentrations in placental extracts were quantified using a modified 1,9-dimethylmethylene blue assay. Syndecan-1 expression was localised using immunohistochemistry and concentrations in placental extracts determined by immunoassay. Preterm placentas had significantly lower sGAG concentrations compared to term tissues and concentrations were significantly lower in preeclampsia compared to spontaneous preterm labour (medians 5.80 and 10.0 μg/mg protein respectively, P<0.05). Syndecan-1 expression was localised to syncytiotrophoblast and median concentrations were lower in preeclampsia compared to PPROM material (preeclampsia median = 41.7, PPROM 74.4 ng/mg tissue) but not significantly different to concentrations in spontaneous preterm labour. Multivariate analysis revealed that decreased sGAG and syndecan-1 in preeclampsia were independent of labour, gestational age and birthweight centile. These findings may provide insights into a role for these molecules in the pathophysiology of preeclampsia.Journal of Perinatal Medicine 11/2013; · 1.43 Impact Factor
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ABSTRACT: Do women with recurrent pregnancy losses (RPL) and low vitamin D have increased prevalence of auto- and cellular immune abnormalities when compared with women with RPL who have normal vitamin D, and does vitamin D have any effect on cellular immunity in vitro? A high proportion of women with RPL have vitamin D deficiency and the risk of auto- and cellular immune abnormalities is increased in women with RPL and vitamin D deficiency. Vitamin D deﬁciency in pregnant women is associated with increased risk of obstetrical complications such as pre-eclampsia, bacterial vaginosis associated preterm delivery, gestational diabetes mellitus and small-for-gestational age births. A retrospective cross-sectional study of 133 women with RPL who were enrolled in a 2-year period, together with laboratory experiments. Women with three or more consecutive spontaneous abortions prior to 20 weeks of gestation who were enrolled at the University clinic. Serum vitamin D level, cellular activity and autoimmune parameters in vivo and in vitro were measured. Sixty-three out of 133 women (47.4%) had low vitamin D (<30 ng/ml). The prevalence of antiphospholipid antibody (APA) was significantly higher in low vitamin D group (VDlow) (39.7%) than in the normal vitamin D group (VDnl) (22.9%) (P< 0.05) and the adjusted odds ratio (OR) for APA in VDlow was 2.22 with the 95% confidence interval (CI) of 1.0-4.7. The prevalence of antinuclear antigen antibody (VDlow versus VDnl; 23.8% versus 10.0%, OR 2.81, 95% CI 1.1-7.4), anti-ssDNA (19.0% versus 5.7%, OR 3.76, 95% CI 1.1-12.4) and thyroperoxidase antibody (33.3% versus 15.7%, OR 2.68, 95% CI 1.2-6.1) was significantly higher in VDlow than those of VDnl (P < 0.05 each). Peripheral blood CD19(+) B and CD56(+) NK cell levels and NK cytotoxicity at effector to target cell (E:T) ratio of 25:1 were significantly higher in VDlow when compared with those of VDnl (P < 0.05 each). Reduction (%) of NK cytotoxicity (at E:T ratio of 50:1 and 25:1) by IgG (12.5 mg/dl) was significantly lower in VDlow than those of VDnl (P < 0.05, P < 0.01, respectively). There were no differences in Th1/Th2 ratios between VDlow and VDnl. When vitamin D3 was added in NK cytotoxicity assay in vitro, NK cytotoxicity at E:T ratio of 50:1 was significantly suppressed with 10 nMol/L (nM) (11.9 ± 3.3%) and 100 nM (10.9 ± 3.7%) of vitamin D3 when compared with controls (15.3 ± 4.7%) (P < 0.01 each). TNF-α/IL-10 expressing CD3(+)/4(+) cell ratios were significantly decreased with 100 nM of vitamin D3 (31.3 ± 9.4, P < 0.05) when compared with controls (40.4 ± 11.3) in vitro. Additionally, INF-γ/IL-10 expressing CD3(+)/4(+) cell ratio was significantly decreased with 100 nM of vitamin D3 (12.1 ± 4.0, P < 0.05) when compared with controls (14.8 ± 4.6). IFN-γ and TNF-α secretion from NK cells were significantly decreased (P < 0.01 each), and IL-10, IL-1β, vascular endothelial growth factor and granulocyte colony stimulating factor levels were significantly increased (P < 0.01 each) with vitamin D3 100 nM when compared with those of controls. The prevalence of vitamin D deficiency in women with RPL in this study is open to a possible type I error since women with vitamin D supplementation were excluded from this study. Assessment of vitamin D level is recommended in women with RPL. Vitamin D supplementation should be explored further as a possible therapeutic option for RPL. This work was supported by the intramural funding from Department of Microbiology and Immunology, Chicago Medical School at Rosalind Franklin University of Medicine and Science. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.Human Reproduction 11/2013; · 4.59 Impact Factor
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ABSTRACT: Soluble fms-like tyrosine kinase (sFlt)-1-e15a, a primate-specific sFlt-1-isoform most abundant in the human placenta in preeclampsia, can induce preeclampsia in mice. This study compared the effects of full-length human (h)sFlt-1-e15a with those of truncated mouse (m)sFlt-1(1-3) used in previous preeclampsia studies on pregnancy outcome and clinical symptoms in preeclampsia.PLoS ONE 11/2014; 9(11):e110867. · 3.53 Impact Factor