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Premature rupture of membranes (PROM) before 37 weeks of gestation is a common obstetrical event, whose pathophysiology is still poorly understood. Our objective was to study the mechanical strength of fetal membranes in women with a clinical risk factor for preterm premature rupture of membranes (PPROM). We included, in a prospective, descriptive, single-center study, patients scheduled for cesarean section at term (≥ 37 weeks of gestation). For each patient, we performed uniaxial tensile tests on fetal membranes with a universal testing machine equipped with a force sensor (EZ20®, Lloyds), allowing the recording of an applied force/time curve. We collected maximum force (Fmax), maximum stress (σMax), and Young's modulus of elasticity. The thickness of each membrane sample was also measured. We compared the values obtained according to certain clinical risk factors for PPROM such as age, body mass index, gravidity, parity, a history of PPROM or preterm birth, smoking, gestational diabetes, geographic origin, and socioeconomic level. We analyzed 31 patients and found no association between the studied risk factors and σMax. Fmax was lower in primiparous patients (p = 0.02) but increased with patient parity (p = 0.005). Gestational diabetes was associated with a higher Fmax (p = 0.033) and sub-Saharan geographical origin with a greater thickness (p = 0.0043). As membrane thickness increased, σMax (p = 0.009) and Young's modulus decreased (p = 0.037). Primiparous patients have lower membrane mechanical strength than patients who have had one or more deliveries. Mechanically, the thicker membranes are less rigid and less resistant.

An increasing number of experimental chemotherapeutic agents induce apoptosis by directly triggering mitochondrial membrane permeabilization (MMP). Here we examined MMP induced by lonidamine, arsenite, and the retinoid derivative CD437. Cells overexpressing the cytomegalovirus-encoded protein vMIA, a protein which interacts with the adenine nucleotide translocator, were strongly protected against the MMP-inducing and apoptogenic effects of lonidamine, arsenite, and CD437. In a cell-free system, lonidamine, arsenite, and CD437 induced the permeabilization of ANT proteoliposomes, yet had no effect on protein-free liposomes. The ANT-dependent membrane permeabilization was inhibited by the two ANT ligands ATP and ADP, as well as by recombinant Bcl-2 protein. Lonidamine, arsenite, and CD437, added to synthetic planar lipid bilayers containing ANT, elicited ANT channel activities with clearly distinct conductance levels of 20+/-7, 100+/-30, and 47+/-7 pS, respectively. Altering the ATP/ADP gradient built up on the inner mitochondrial membrane by inhibition of glycolysis and/or oxidative phosphorylation differentially modulated the cytocidal potential of lonidamine, arsenite, and CD437. Inhibition of F(0)F(1)ATPase without glycolysis inhibition sensitized to lonidamine-induced cell death. In contrast, only the combined inhibition of glycolysis plus F(0)F(1)ATPase sensitized to arsenite-induced cell death. No sensitization to cell death induction by CD437 was achieved by glucose depletion and/or oligomycin addition. These results indicate that ANT is a target of lonidamine, arsenite, and CD437 and unravel an unexpected heterogeneity in the mode of action of these three compounds.

Similar to most if not all pro-apoptotic members of the Bcl-2 family, Bid (and its truncated product t-Bid) triggers cell death via mitochondrial membrane permeabilization (MMP). This effect can be monitored in intact cells, upon microinjection of recombinant Bid protein into the cytoplasm, as well as in purified mitochondria, upon addition of Bid protein. Here we show that Bid-induced MMP can be inhibited, both in cells and in the cell-free system, by three pharmacological inhibitors of the permeability transition pore complex (PTPC), namely cyclosporin A, N-methyl-4-Val-cyclosporin A, and bongkrekic acid (a ligand of the adenine nucleotide translocase, ANT, one of the PTPC components). Bid effects on synthetic membranes were studied either in proteoliposomes or in synthetic bilayers subjected to electrophysiological measurements. Full length Bid preferentially permeabilizes membranes and induces the formation of large conductance channels at neutral pH, when added to liposomes or bilayers containing both purified ANT and Bax, yet has no or little effect combined with ANT or Bax alone. t-Bid acts on membranes containing ANT alone with the same efficiency as on those containing both ANT and Bax. These results suggest that the proapoptotic effects of Bid are mediated, at least in part, by its functional interaction with ANT, one of the major components of PTPC.

Nitric oxide (NO), peroxynitrite, and 4-hydroxynonenal (HNE) may be involved in the pathological demise of cells via apoptosis. Apoptosis induced by these agents is inhibited by Bcl-2, suggesting the involvement of mitochondria in the death pathway. In vitro, NO, peroxynitrite and HNE can cause direct permeabilization of mitochondrial membranes, and this effect is inhibited by cyclosporin A, indicating involvement of the permeability transition pore complex (PTPC) in the permeabilization event. NO, peroxynitrite and HNE also permeabilize proteoliposomes containing the adenine nucleotide translocator (ANT), one of the key components of the PTPC, yet have no or little effects on protein-free control liposomes. ANT-dependent, NO-, peroxynitrite- or HNE-induced permeabilization is at least partially inhibited by recombinant Bcl-2 protein, as well as the antioxidants trolox and butylated hydroxytoluene. In vitro, none of the tested agents (NO, peroxynitrite, HNE, and tert-butylhydroperoxide) causes preferential carbonylation HNE adduction, or nitrotyrosylation of ANT. However, all these agents induced ANT to undergo thiol oxidation/derivatization. Peroxynitrite and HNE also caused significant lipid peroxidation, which was antagonized by butylated hydroxytoluene but not by recombinant Bcl-2. Transfection-enforced expression of vMIA, a viral apoptosis inhibitor specifically targeted to ANT, largely reduces the mitochondrial and nuclear signs of apoptosis induced by NO, peroxynitrite and HNE in intact cells. Taken together these data suggest that NO, peroxynitrite, and HNE may directly act on ANT to induce mitochondrial membrane permeabilization and apoptosis.

Background Maternal agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AAs) have been implicated in the pathophysiology of preeclampsia, but their presence in their offsprings and their possible neonatal effects have not been specifically explored. This prospective study aimed to evaluate the presence of AT1-AAs and their potential clinical effects in neonates of AT1-AAs positive mothers. Methods Women with preeclampsia and their neonates were included. Blood samples were collected in order to search for AT1-AAs. Results AT1-AA determination was positive in 35 out of 64 of the studied women (54.7%). Thirty one newborns from the group of AT1-AA positive women were included and 22 (71%) were AT1-AA positive. The mothers’ and children’s AT1-AAs titers were significantly correlated. The 33 newborns from the group of AT1-AA negative women were all negative for AT1-AAs. Regarding the clinical data of newborns (birth weight, percentile of weight, gestational age, Apgar score at five minutes, mechanical or noninvasive ventilation), no significant difference was observed between the children with or without detected AT1-AAs. Conclusion Even though AT1-AAs are detected in newborns of positive mothers during the first days of life, no specific clinical signs seem to be associated with the presence of these antibodies.

BackgroundUrine protein assessment is important when glomerular disease or injury is suspected. Normal values of proteinuria already published for preterm newborns suffer from limitation, with small cohorts of patients. This prospective study was conducted to update the urine total protein- and albumin-to-creatinine ratio values.MethodsUrine samples were collected from 231 preterm newborns within the first 48 h (D0–1) and/or between 72–120 h of life (D3–4). Total protein, albumin, and creatinine were measured, their distribution and upper-limit values determined.ResultsAt D0–1 and D3–4, respectively, the median for the total protein-to-creatinine ratio were 80 and 107 mg/mmol (upper-limit values 223 and 289 mg/mmol) in the whole studied population, 149 and 214 mg/mmol in children born before 29 weeks of gestational age, 108 and 130 mg/mmol in those born between 29 and 33 weeks, and 61 and 93 mg/mmol in those born after 33 weeks. For the albumin-to-creatinine ratio, the median were 12 and 17 mg/mmol (upper-limit values 65 and 62 mg/mmol) in the whole studied population, 22 and 50 mg/mmol in children born before 29 weeks, 21 mg/mmol in those born between 29 and 33 weeks, and 8 and 12 mg/mmol in those born after 33 weeks. The use of nephrotoxic drugs and mechanical ventilation seems to influence proteinuria and albuminuria values.ConclusionsWe report distribution of proteinuria- and albuminuria-to-creatinine in preterm newborns, including the upper-limit values. These values should be taken into account in the detection and diagnosis of glomerular disease and/or injury in daily clinical practice.

Peptides corresponding to the BH3 domains of Bax (BaxBH3) or Bcl-2 (Bcl2BH3) are potent inducers of apoptosis when fused to the Atennapedia plasma membrane translocation domain (Ant). BaxBH3Ant and Bcl2BH3Ant caused a mitochondrial membrane permeabilization (MMP) and apoptosis, via a mechanism that was not inhibited by overexpressed Bcl-2 or Bcl-X(L), yet partially inhibited by cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition pore. When added to isolated mitochondria, BaxBH3 and Bcl2BH3 induced MMP, which was inhibited by CsA. However, Bcl-2 or Bcl-X(L) failed to inhibit MMP induced by BaxBH3 and Bc2BH3 in vitro, while they efficiently suppressed the induction of MMP by the Vpr protein (from human immunodeficiency virus-1), a ligand of the adenine nucleotide translocator (ANT). BaxBH3 but not Bcl2BH3 was found to interact with ANT, and only BaxBH3 (not Bcl2BH3) permeabilized ANT proteoliposomes and induced ANT to form non-specific channels in electrophysiological experiments. In contrast, both BaxBH3 and Bcl2BH3 were able to stimulate channel formation by recombinant Bax protein. Thus, BaxBH3 might induce MMP via an action on at least two targets, ANT and Bax-like proteins. In contrast, Bcl2BH3 would elicit MMP in an ANT-independent fashion. In purified mitochondria, two ligands of ANT, bongkrekic acid and the protein vMIA from cytomegalovirus, failed to prevent MMP induced by BaxBH3 or Bcl2BH3. In conclusion, BaxBH3 and Bcl2BH3 induce MMP and apoptosis through a mechanism which overcomes cytoprotection by Bcl-2 and Bcl-X(L).

Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, leading to a variety of symptoms in the unborn child that range from asymptomatic to death in utero. Our objective was to better understand the mechanisms of placental infection by HCMV clinical strains, particularly during the first trimester of pregnancy. We thus characterized and compared the replication kinetics of various HCMV clinical strains and laboratory strains by measuring viral loads in an ex vivo model of first trimester villi and decidua, and used NGS and PCA analysis to analyze the genes involved in cell tropism and virulence factors. We observed that first trimester villi and decidua are similarly permissive to laboratory and symptomatic strains, and that asymptomatic strains poorly replicate in decidua tissue. PCA analysis allowed us to segregate our clinical strains based on their clinical characteristics, suggesting a link between gene mutations and symptoms. All these results bring forth elements that can help better understand the mechanisms that induce the appearance of symptoms or in the congenitally infected newborn.

Background: Congenital CMV infection is the leading cause of neonatal neurological deficit. We herein studied in vitro and ex vivo the potential of the hyperimmune globulin Cytotect CP® (Biotest, Germany) for congenital infection prevention and treatment. Methods: In vitro neutralization assays were conducted in fibroblasts and retinal epithelial cells on the CMV strains TB40/E and VHL/E to determine the 50% and 90% neutralizing doses (ND50 and ND90). The toxicity was assessed by measuring LDH release. Ex vivo assays were conducted in first-trimester villi explants with the TB40/E strain, namely, neutralization assays, the prevention of villi infection, and the inhibition of viral replication in infected villi. Viability was assessed by β-HCG quantification in supernatants. Results: The in vitro neutralization tests showed that Cytotect CP®® inhibits the development of infection foci (DN50: 0.011–0.014 U/mL for VHL/E and 0.032–0.033 U/mL for TB40E) without any toxicity. In the ex vivo neutralization assays, the DN50 were 0.011 U/mL on day 7 and 0.093 U/mL on day 14. For the prevention of villi infection, the EC50 was 0.024 U/mL on day 7. Cytotect-CP® did not inhibit viral growth in infected villi. No impact on villi viability was observed. Conclusions: These results sustained that Cytotect CP® has the potential to prevent CMV congenital infection.

Premature rupture of membranes (PROM) before 37 weeks of gestation is a common obstetrical event, whose pathophysiology is still poorly understood. Our objective was to study the mechanical strength of fetal membranes in women with a clinical risk factor for preterm premature rupture of membranes (PPROM). We included, in a prospective, descriptive, single-center study, patients scheduled for cesarean section at term ([greater than or equal to] 37 weeks of gestation). For each patient, we performed uniaxial tensile tests on fetal membranes with a universal testing machine equipped with a force sensor (EZ20.sup.®, Lloyds), allowing the recording of an applied force/time curve. We collected maximum force (Fmax), maximum stress ([sigma]Max), and Young's modulus of elasticity. The thickness of each membrane sample was also measured. We compared the values obtained according to certain clinical risk factors for PPROM such as age, body mass index, gravidity, parity, a history of PPROM or preterm birth, smoking, gestational diabetes, geographic origin, and socioeconomic level. We analyzed 31 patients and found no association between the studied risk factors and [sigma]Max. Fmax was lower in primiparous patients (p = 0.02) but increased with patient parity (p = 0.005). Gestational diabetes was associated with a higher Fmax (p = 0.033) and sub-Saharan geographical origin with a greater thickness (p = 0.0043). As membrane thickness increased, [sigma]Max (p = 0.009) and Young's modulus decreased (p = 0.037). Primiparous patients have lower membrane mechanical strength than patients who have had one or more deliveries. Mechanically, the thicker membranes are less rigid and less resistant.