Vital NETosis vs. suicidal NETosis during normal pregnancy and preeclampsia

Background: NETosis occurs in the context of infection or inflammation and results in the expulsion of decondensed DNA filaments called NETs (Neutrophil Extracellular Traps) into the extracellular environment. NETosis activates coagulation and contributes to the thrombotic risk of inflammatory diseases. To date, two mechanisms of NETosis have been identified: suicidal NETosis, in which neutrophils die after expelling the filaments; and vital NETosis, in which expulsion appears without altering the membrane. Human pregnancy is associated with a mild pro-inflammatory state, which is increased in the event of complications such as preeclampsia (PE). NETosis has been observed in these situations, but the mechanism of its production has not yet been studied. The aim of our study was to evaluate the balance of vital vs. suicidal NETosis in normal pregnancy and in PE.Patients/Methods: Neutrophils from healthy volunteers were stimulated with plasma from normal pregnancies (n = 13) and from women developing preeclampsia (n = 13). Immunofluorescent labelling was performed to determine the percentages and origin of NETs in both groups. Inhibition with suicidal or vital NETosis inhibitors was also performed to validate our results.Results: We found a significant increase in NETs in women with PE compared to women with normal pregnancies. We showed that vital and non-vital NETosis are present in normal and preeclamptic pregnancies. We demonstrated that the higher proportion of NETs observed in PE was due to non-vital NETosis whose main component is represented by suicidal NETosis.Discussion: These results suggest the important part of non-vital NETosis in the pathophysiology of PE

The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data

The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.Peer reviewe

Génération de thrombine et choc septique (une étude pilote)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Régulation de la génération de thrombine par l'IL-10 ; polymorphisme de l'IL-10 et risque vasculaire

REIMS-BU Santé (514542104) / SudocSudocFranceF

Early ADAMTS13 testing associates with pre-eclampsia occurrence in antiphospholipid syndrome

International audienceWomen with obstetric antiphospholipid syndrome (oAPS) still develop placental diseases, mainly pre-eclampsia (PEcl), which diagnosis is associated with reduced ADAMTS13 levels. Testing ADAMTS13 in newly pregnant oAPS may provide evidence for risk stratification.Materials and methods: We retrospectively investigated the prognostic value of ADAMTS13 activity, antigen and antibodies on stored plasma samples obtained prior to beginning low-molecular weight heparin-low dose aspirin treatment in 513 oAPS women.Results: Some women had evidences of early positive ADAMTS13 antibodies and low ADAMTS13 activity:antigen ratio, suggestive of ADAMTS13 dysfunction. Women with a subsequent PEcl had higher ADAMTS13 antibodies (p <0.0001), and lower ADAMTS13 activity and activity: antigen ratios (p <0.0001). In multivariate analysis, these markers were significant risk factors for PEcl and for the most devastating PEcl subgroups (early-onset PEcl, severe PEcl, PEcl with no living child after 28 days). ADAMTS13-related markers showed acceptable discrimination power to predict clinical events, particularly for ADAMTS13 activity:antigen ratio in predicting PEcl cases with no living child after 28 days (AUC: 0.844 (0.712-0.974), p <0.0001), with excellent negative predictive value (0.990).Conclusions: The characterization of ADAMTS13 in newly pregnant women with oAPS depicts the risk of PEcl occurrence. ADAMTS13 might help identify pregnant women with oAPS not requiring escalating treatment strategies to prevent PEcl

Analysis of the venous thromboembolic risk associated with severe postpartum haemorrhage in the NOHA First cohort.

International audienceSevere postpartum haemorrhages (PPH) are responsible for maternal morbidity/mortality. Their complex management sometimes requires haemostatic supplementation, and therapeutic trials on fibrinogen or activated factor VII, which may add to the thrombotic risk, are currently being considered. Furthermore, there is a risk of venous thromboembolism (VTE) during the postpartum period, hence we studied the relationship between severe PPH and VTE in women during their first pregnancy. Among the 32,463 women enrolled between January 1, 1999 and February 1, 2004 in the NOHA First cohort, 317 developed severe PPH, 11 postpartum VTE and 60 had postpartum superficial vein thrombosis (SVT). In the women with severe PPH, whilst there were no episodes of VTE, there were three episodes of SVT, which occurred 6 weeks postpartum. All of the women with severe PPH received packed red blood cell (RBC) units, 29 (9.1%) platelets units, 51 (16.1%) fresh frozen plasma and 29 (9.1%) fibrinogen concentrates. Three patients with both severe PPH and SVT received only packed RBC. Severe PPH or packed RBC unit transfusion were associated with postpartum SVT (adjusted relative risk: 5.3 (1.6-17) and 4.7 (1.5-15) respectively), independent of caesarean section delivery and low-molecular-weight heparin (LMWH) use in the postpartum, but were not independent indicators of one another. This the VTE and SVT risks associated with severe PPH are low (<1% and <2%, respectively). Severe PPH increases the risk of postpartum SVT, but transfusion with platelet units and plasma supplementation using fresh frozen plasma or fibrinogen concentrates do not markedly modulate the risk of venous thrombosis

Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis

International audienceOBJECTIVE:To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction.METHODS:This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10-13 6/7 weeks, 14-17 6/7 weeks, 18-21 6/7 weeks, 22-25 6/7 weeks, 26-29 6/7 weeks, 30-33 6/7 weeks, and 34-37 6/7 weeks.RESULTS:Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10-13 6/7 weeks that was most dramatic 6-8 weeks preceding delivery.CONCLUSION:Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials

Placenta‐mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes

International audiencePlacenta-mediated pregnancy complications generate short- and long-term adverse medical outcomes for both the mother and the fetus. Nucleosomes and free DNA (fDNA) have been described in patients suffering from a wide range of inflammatory conditions.Objective: The objective of our study was to compare nucleosomes and fDNA circulating levels during pregnancy and particularly in women developing a placenta-mediated complication according to the subtype (preeclampsia or intrauterine growth restriction) (NCT01736826).Patients/methods: A total of 115 women were prospectively included in the study across three groups: 30 healthy non-pregnant women, 50 with normal pregnancy, and 35 with a complicated pregnancy. Blood samples were taken up to every 4 weeks for several women with normal pregnancy and nucleosomes and fDNA were quantified using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively.Results: We show that nucleosomes and fDNA concentrations significantly increase during normal pregnancy, with concentrations at delivery differing between the two groups. Interestingly, we show that concentrations differ according to the type of placenta-mediated complications, with higher levels in preeclampsia compared to intrauterine growth restriction.Conclusions: These data suggest that nucleosomes and fDNA may be additional actors participating in placenta-mediated pregnancy complications

Obstetric antiphospholipid syndrome: early variations of angiogenic factors are associated with adverse outcomes

International audienceThe prognostic value of angiogenic factors in newly pregnant women with obstetric antiphospholipid syndrome (oAPS) has not been documented. We observed 513 oAPS who experienced three consecutive spontaneous abortions before the 10th week of gestation or one fetal loss at or beyond the 10th week. We assessed the plasma concentrations of the proangiogenic factor placenta growth factor (PIGF) and of the antiangiogenic factor soluble fms-like tyrosine kinase-1 on the eve and on the 4th day of the low-molecular weight heparin-low-dose aspirin treatment. Placenta growth factor and fms-like tyrosine kinase-1 plasma concentrations showed marked increases. Treatment-associated variations of PIGF and of soluble fms-like tyrosine kinase-1 were antagonist risk factors for placenta-mediated complications (PMC) and for severe PMC, for fetal death, stillbirth and neonatal death. The ratio between PIGF increase and soluble fms-like tyrosine kinase-1 was a summary variable whose best cut-off values (1.944.10-2) had high negative predictive values for PMC (0.918) and may be used to help rule out the development of PMC in evolutive pregnancies after 19 completed weeks. The early variations of PIGF and soluble fms-like tyrosine kinase-1 concentrations in newly pregnant oAPS may help to detect patients at low risk of PMC. (clinicaltrials.gov identifier: 02855047)