Trophoblastic mitochondrial DNA induces endothelial dysfunction and NLRP3 inflammasome activation: Implications for preeclampsia.

AIMS: Preeclampsia (PE) is characterised by systemic vascular endothelium dysfunction. Circulating trophoblastic secretions contribute to endothelial dysfunction, resulting in PE; however, the underlying mechanisms remain unclear. Herein, we aimed to determine the potential correlation between the release of trophoblastic mitochondrial deoxyribonucleic acid (DNA) (mtDNA) and endothelium damage in PE. MATERIALS AND METHODS: Umbilical cord sera and tissues from patients with PE were investigated for inflammasome activation. Following this, trophoblastic mitochondria were isolated from HTR-8/SVneo trophoblasts under 21 % oxygen (O2) or hypoxic conditions (1 % O2 for 48 h) for subsequent treatments. Primary human umbilical veinendothelial cells (HUVECs) were isolated from the human umbilical cord and then exposed to a vehicle (phosphate-buffered saline [PBS]), mtDNA, hypo-mtDNA, or hypo-mtDNA with INF39 (nucleotide oligomerisation domain-like receptor family pyrin domain containing 3 [NLRP3]-specific inhibitor) for 12 h before flow cytometry and immunoblotting. The effects of trophoblastic mtDNA on the endothelium were further analysed in vivo using enzyme-linked immunosorbent assay (ELISA) and vascular reactivity assay. The effects of mtDNA on vascular phenotypes were also tested on NLRP3 knockout mice. RESULTS: Elevated interleukin (IL)-1ß in PE sera was accompanied by NLRP3 inflammasome activation in cord tissues. In vitro and in vivo experiments revealed that the release of trophoblastic mtDNA could damage the endothelium via NLRP3 activation, resulting in the overexpression of NLRP3, caspase-1 p20, IL-1ß p17, and gasdermin D (GSDMD); reduced endothelial nitric oxide synthase (eNOS) levels; and impaired vascular relaxation. Flow cytometric analysis confirmed that extensive cell death was induced by mtDNA, and simultaneously, a more pronounced pro-apoptotic effect was caused by hypoxia-treated trophoblastic mtDNA. The NLRP3 knockout or pharmacologic NLRP3 inhibition partially reversed tumour necrosis factor-α (TNF-α) and IL-1ß levels and endothelium-dependent vasodilation in mice. CONCLUSION: These findings demonstrate that trophoblastic mtDNA induced NLRP3/caspase-1/IL-1ß signalling activation, eNOS-related endothelial injury, and vasodilation dysfunction in PE.

Quantitative analysis for grading uterine electromyography activities during labor.

BACKGROUND: The strength of uterine contraction is one of the decisive factors for labor progression and parturition. Clinicians usually encounter difficulties in early identification of inadequate contractions and in oxytocin treatment. Electromyography-an emerging technology for uterine contraction monitoring-can quantify the intensity of myoelectric activity of uterine contraction. Therefore, grading patients with different uterine contraction intensities by electromyography is of great significance to the clinical intensive management of uterine contraction and labor process. OBJECTIVE: This study aimed to quantify and grade electromyography activity during the latent phase of the first stage of labor and explore its relationship with oxytocin treatment and length of labor. STUDY DESIGN: We performed a retrospective cohort study to identify electromyography parameters as a predictor for oxytocin treatment and length of labor among a cohort of term singleton primipara (n=508) during the latent phase who delivered in Guangzhou between August 2018 and December 2021. The electromyography parameters were graded according to the quartile method, and the significance of grading and delivery outcome was explored. Univariate and multivariate logistic regression were used to determine the predictors of oxytocin treatment. RESULTS: Maternal gestational age (adjusted risk ratio, 1.2; 95% confidence interval, 1.0-1.5), root mean square (adjusted risk ratio, 0.01; 95% confidence interval, 0.004-0.03), and power (adjusted risk ratio, 0.02; 95% confidence interval, 0.01-0.05) were significant predictors of oxytocin argumentation. The low electromyography activity group had a longer first stage labor and total labor time and were more likely to use oxytocin. CONCLUSION: Electromyography parameters root mean square and power had high predictive values for later oxytocin treatment among patients with spontaneous labor. Patients with low-grade electromyography were more likely need oxytocin treatment. Electromyography grading is very important for its clinical promotion and use, and it could lead to more reliable analyses of oxytocin treatments and eventually to more effective interventions to prevent prolonged labor.

HIF-1α is essential for the augmentation of myometrial contractility during labor†.

Uterine contraction is crucial for a successful labor and the prevention of postpartum hemorrhage. It is enhanced by hypoxia; however, its underlying mechanisms are yet to be elucidated. In this study, transcriptomes revealed that hypoxia-inducible factor-1alpha was upregulated in laboring myometrial biopsies, while blockade of hypoxia-inducible factor-1alpha decreased the contractility of the myometrium and myocytes in vitro via small interfering RNA and the inhibitor, 2-methoxyestradiol. Chromatin immunoprecipitation sequencing revealed that hypoxia-inducible factor-1alpha directly binds to the genome of contraction-associated proteins: the promoter of Gja1 and Ptgs2, and the intron of Oxtr. Silencing the hypoxia-inducible factor-1alpha reduced the expression of Ptgs2, Gja1, and Oxtr. Furthermore, blockade of Gja1 or Ptgs2 led to a significant decrease in myometrial contractions in the hypoxic tissue model, whereas atosiban did not remarkably influence contractility. Our study demonstrates that hypoxia-inducible factor-1alpha is essential for promoting myometrial contractility under hypoxia by directly targeting Gja1 and Ptgs2, but not Oxtr. These findings help us to better understand the regulation of myometrial contractions under hypoxia and provide a promising strategy for labor management and postpartum hemorrhage treatment.

A study of uterine inertia on the spontaneous of labor using uterine electromyography.

OBJECTIVE: The purpose of this study is to analyze uterine electromyography burst patterns in patients with spontaneous labor and patients with uterine inertia. MATERIALS AND METHODS: Uterine electromyography was recorded using 4 silver/silver chloride electrodes placed periumbilical. Thirty women in the spontaneous labor were enrolled. Uterine electromyography was also recorded from patients with uterine inertia before and after oxytocin treatment. EMG bursts were characterized by analysis of multiple variables including burst frequency, duration, root mean squared, amplitude, and total power. RESULTS: There were significant reductions (P < .01) in all EMG burst characteristics. In addition, uterine electromyography parameters were all increased after oxytocin treatment and were comparable (P > .05) to patients in spontaneous labor. CONCLUSIONS: Uterine electromyography can be used effectively to distinguish patients progressing with spontaneous labor from patients that develop uterine inertia. Uterine inertia is characterized by reduced EMG activity and failure of cervical dilation. Uterine electromyography is a quantitative, non-invasive assessment tool that contributes to the diagnosis, evaluation and management of patients with spontaneous labor and uterine inertia.

Maternal Myometrium Metabolomic Profiles in Labor: Preliminary Results.

INTRODUCTION: Parturition involves multiple complex metabolic processes that supply essential metabolites to facilitate fetal delivery. Little is known about the dynamic metabolic responses during labor. OBJECTIVE: To profile the changes of myometrial metabolites between nonlabor and labor. METHODS: The study involved 30 women in nonlabor and 30 in labor who underwent cesarean section. The characteristics of myometrial metabolite changes during parturition were explored through untargeted metabolomic analysis. Data were analyzed by multivariate and univariate statistical analysis. RESULTS: Partial least squares-discriminant analysis plots significantly differentiated between the groups. In total, 392 metabolites were significantly distinct between the groups, among which lipid molecules were predominant. A 75% increase in fatty acids, 67% increase in fatty acid carnitines, 66% increase in glycerophospholipids, 83% increase in mono- and diacylglycerols, and 67% decrease in triacyclglycerols were observed in the patients during labor. Most glucose, amino acid, and steroid hormone metabolism also slightly increased in labor. CONCLUSIONS: An increase in lipolysis, fatty acid oxidation, amino acid catabolism, and steroid hormone metabolism was observed during parturition. The change of lipolysis and fatty acid oxidation is the most significant.

Measurement of Uterine and Abdominal Muscle Electromyography in Pregnant Women for Estimation of Expulsive Activities during the 2nd Stage of Labor.

BACKGROUND: The progression of labor and delivery of the fetus is dependent upon uterine contractions and the voluntary effort of abdominal muscle contractions. A good monitor of uterine contractions and pushing is necessary for obstetrical care. Electromyography (EMG) is the underlying basis for contractility of muscle including the myometrium. OBJECTIVES: The aim of this study was to determine the relationship between EMG activity of uterine and abdominal muscles and the duration of the 2nd stage of labor in pregnant women. METHODS: EMG of both uterine and abdominal muscles was simultaneously recorded from electrodes placed on the abdominal surface of 45 active 2nd stage-laboring nulliparous patients. EMG was recorded using filters to separate uterine and abdominal EMG signals, and various EMG signal parameters were analyzed. The duration of the 2nd stage of labor and other maternal and fetal characteristics were also recorded. RESULTS: Uterine EMG bursts precede abdominal bursts and are accompanied by feelings of "urge to push" by the patients. Abdominal root mean square (RMS) and power, but not uterine EMG parameters, are reduced (p< 0.005) in patients with longer labors and linear regression analysis demonstrated a negative correlation to the duration of 2nd stage of labor (p < 0.001). Multivariate linear regression analysis of clinical characteristics (fetal weight, body mass index, placental location, etc.) and parameters of EMG showed that only abdominal RMS is negatively correlated with the duration of labor. CONCLUSIONS: (1) Uterine and abdominal EMG activities reflect the expulsive involuntary (uterine) and voluntary (abdominal) muscular activities during the 2nd stage of labor. (2) RMS and power of abdominal EMG diminish with longer labor when uterine EMG intensities are similar. (3) Recording of uterine and abdominal muscle activity provides objective evaluation of the muscle activity during the 2nd stage of labor and may aid in the evaluation of any interventions.

The effects of ropivacaine 0.0625% and levobupivacaine 0.0625% on uterine and abdominal muscle electromyographic activity during the second stage of labor.

BACKGROUND: This study investigated the effect of ropivacaine on uterine and abdominal muscle electromyographic activity during the second stage of labor. METHODS: A total of 161 patients, including 48 patients receiving 0.0625% ropivacaine for patient-controlled epidural analgesia (PCEA), 64 patients receiving 0.0625% levobupivacaine for PCEA, and 49 patients with no PCEA completed the study. Uterine and abdominal muscle electromyographic activity was continuously recorded from the abdominal surface during the second stage of labor. Maternal demographic and clinical characteristics, maternal and neonatal outcomes, and various electromyographic parameters were recorded. RESULTS: Second stage of labor was significantly prolonged (P=0.007) for levobupivacaine compared to ropivacaine or no PCEA. The root-mean-square and duration of uterine muscle electromyographic activity was significantly lower for levobupivacaine or ropivacaine compared to no PCEA. The root-mean-square and power of abdominal muscle electromyographic activity was significantly lower for levobupivacaine compared to ropivacaine or no PCEA; the peak frequency of abdominal muscle electromyographic activity was significantly higher for ropivacaine. Visual analogue scale pain scores in patients in the levobupivacaine group or ropivacaine group decreased significantly over time compared to patients in the no PCEA group. CONCLUSIONS: In conclusion 0.0625% ropivacaine does not suppress abdominal muscle electromyographic activity during the second stage of labor. Maternal and neonatal outcomes were similar in patients receiving ropivacaine or no PCEA.

Effects of Ropivacaine in Patient-Controlled Epidural Analgesia on Uterine Electromyographic Activities during Labor.

Epidural analgesia is effective in relieving pain during labor. However, concerns as to compromised labor progress and outcomes arise. This study aimed to assess the effect of patient-controlled epidural analgesia (PCEA) with ropivacaine on uterine electromyography (EMG) activities and outcomes in labor. A total of 213 pregnant women were divided into three groups: the PCEA with ropivacaine group (n = 78), the PCEA with levobupivacaine group (n = 66), and a control group that did not receive PCEA (n = 69). Uterine EMG activities were recorded during the first stage of labor. Maternal and fetal outcomes also were assessed. The primary outcomes of this study were EMG activities. No significant differences were observed in patient demographics or neonatal weight among the three groups. Compared to the PCEA with levobupivacaine group, the control and PCEA with ropivacaine groups had lower rates of oxytocin administration (P < 0.05) and shorter durations of the first stage of labor (P < 0.05). For the EMG activities, the PCEA with ropivacaine group showed a higher power (P < 0.01) and higher peak frequency (P < 0.05) than the PCEA with levobupivacaine group. With ropivacaine, the EMG activities remained stable 30-120 min. Compared with levobupivacaine, the use of ropivacaine in PCEA has no suppressive effect on uterine EMG activities during the first stage of labor. In addition, ropivacaine leads to labor progress and delivery outcomes similar to those in the control group, as well as similar and favorable analgesic satisfaction with the use of levobupivacaine.

Uterine and Abdominal Muscle Electromyographic Activities in Control and PCEA-Treated Nulliparous Women During the Second Stage of Labor.

OBJECTIVE: Patient-controlled epidural analgesia (PCEA), used to relieve pain during delivery, delays labor but the mechanism is unknown. The aim was to investigate the effects of PCEA on uterine and abdominal muscles electromyographic (EMG) activity during the second stage of labor. METHODS: This study included 45 nulliparous pregnant women without PCEA, 42 women with standard PCEA treatment given during the first stage of labor and stopped near the end of the first stage, and 22 women with standard PCEA treatment with continued use throughout the first and second stages of labor. The EMG signals were recorded from the abdominal surface using PowerLab hardware and LabChart software (ADInstruments, New South Wales, Australia) and filtered to separate uterine and abdominal EMG. Various EMG burst parameters were obtained. RESULTS: There are no differences ( P > .05) in the age, body mass index, fetal weight, and Apgar scores between the patients from the various groups. PCEA (both stopped and continued) inhibits ( P < .05) duration, number of bursts, and root mean square of uterine EMG. PCEA also produces statistically significant ( P < .001) reductions in abdominal EMG. The decrease in EMG activity is accompanied by a significant ( P < .001) prolongation of the second stage duration (PCEA continued = 95.08 ± 8.60 minutes, PCEA stopped = 79.39 ± 6.25 minutes, no PCEA = 61.00 ± 7.23 minutes). CONCLUSION: PCEA suppresses uterine and abdominal muscle EMG during the second stage of labor but inhibition depends upon the treatment schedule. PCEA prolongs the duration of labor by inhibition of uterine and abdominal muscle and neural activity.

Simultaneous Recording and Analysis of Uterine and Abdominal Muscle Electromyographic Activity in Nulliparous Women During Labor.

OBJECTIVE: To record and characterize electromyography (EMG) from the uterus and abdominal muscles during the nonlabor to first and second stages of labor and to define relationships to contractions. METHODS: Nulliparous patients without any treatments were used (n = 12 nonlabor stage, 48 during first stage and 33 during second stage). Electromyography of both uterine and abdominal muscles was simultaneously recorded from electrodes placed on patients' abdominal surface using filters to separate uterine and abdominal EMG. Contractions of muscles were also recorded using tocodynamometry. Electromyography was characterized by analysis of various parameters. RESULTS: During the first stage of labor, when abdominal EMG is absent, uterine EMG bursts temporally correspond to contractions. In the second stage, uterine EMG bursts usually occur at same frequency as groups of abdominal bursts and precede abdominal bursts, whereas abdominal EMG bursts correspond to contractions and are accompanied by feelings of "urge to push." Uterine EMG increases progressively from nonlabor to second stage of labor. CONCLUSIONS: (1) Uterine EMG activity can be separated from abdominal EMG events by filtering. (2) Uterine EMG gradually evolves from the antepartum stage to the first and second stages of labor. (3) Uterine and abdominal EMG reflect electrical activity of the muscles during labor and are valuable to assess uterine and abdominal muscle events that control labor. (4) During the first stage of labor uterine, EMG is responsible for contractions, and during the second stage, both uterine and abdominal muscle participate in labor.

Changes in ectocervical surface area in women throughout pregnancy compared to non-pregnant and postpartum states.

OBJECTIVE: The objective of this study is to estimate changes in the surface area of the ectocervix (CA) in women during pregnancy and compare this to postpartum and non-pregnant states. METHODS: CA was evaluated in 210 normal nulliparous women divided into groups from early to late gestation, 40 postpartum women, and 25 non-pregnant women. CA in cm(2) was estimated from analysis of images taken with an endoscope of the cervical face and an mm scale. An mm scale was also used to determine fornix length and fornix area computed. RESULTS: The face, fornix, and total areas of the CA of non-pregnant and postpartum groups are significantly smaller (p < 0.001) than these areas in groups during pregnancy. Generally, the CA of the face, fornix, and total area are also less in early pregnancy compared with late gestation (p < 0.01 to <0.001). Total CA correlates with gestational age (r = 0.196, p < 0.004). CONCLUSIONS: (1) During pregnancy, CA slowly and progressively increases to >75% area compared with CA of non-pregnant patients and then reverts back to low CA postpartum. (2) Increases in CA during pregnancy occur in both the face and fornix areas. (3) Increases in CA reflect enlargement in cervical volume and remodeling during pregnancy.

TaNAC2, a NAC-type wheat transcription factor conferring enhanced multiple abiotic stress tolerances in Arabidopsis.

Environmental stresses such as drought, salinity, and cold are major factors that significantly limit agricultural productivity. NAC transcription factors play essential roles in response to various abiotic stresses. However, the paucity of wheat NAC members functionally characterized to date does not match the importance of this plant as a world staple crop. Here, the function of TaNAC2 was characterized in Arabidopsis thaliana. A fragment of TaNAC2 was obtained from suppression subtractive cDNA libraries of wheat treated with polyethylene glycol, and its full-length cDNA was obtained by searching a full-length wheat cDNA library. Gene expression profiles indicated that TaNAC2 was involved in response to drought, salt, cold, and abscisic acid treatment. To test its function, transgenic Arabidopsis lines overexpressing TaNAC2-GFP controlled by the cauliflower mosaic virus 35S promoter were generated. Overexpression of TaNAC2 resulted in enhanced tolerances to drought, salt, and freezing stresses in Arabidopsis, which were simultaneously demonstrated by enhanced expression of abiotic stress-response genes and several physiological indices. Therefore, TaNAC2 has potential for utilization in transgenic breeding to improve abiotic stress tolerances in crops.

Nuclear survivin is associated with malignant potential in epithelial ovarian carcinoma.

Survivin is a unique member of the inhibitor of apoptosis (IAP) protein family. As abnormal inhibition of apoptosis during homeostasis is considered a critical step in the initiation of cancer, we investigated prognostic value of survivin expression in epithelial ovarian carcinomas. We carried out immunohistochemical experiments using a polyclonal antisurvivin antibody to stain formalin-fixed paraffin-embedded sections from 91 patients with ovarian tumors, including 10 cystadenomas, 17 borderline tumors, and 64 epithelial ovarian carcinomas. Nuclear and cytoplasmic survivin staining was scored separately. Survivin expression was undetectable in ovarian cystadenomas and was weakly detected in 4 of 17 (23.53%) borderline tumors. In contrast, nuclear and cytoplasmic survivin staining was observed in 55 of 64 (85.94%) epithelial ovarian carcinomas. Scoring on the basis of the percentage of survivin nuclear-positive cells indicated that nuclear survivin expression was associated significantly with clinical stage, histologic grade, proliferating cell nuclear antigen (PCNA)-labeling index, and clinical outcome in ovarian epithelial carcinoma patients (P<0.01). Taken together, the results of this study provide evidence that nuclear survivin expression is a strong, independent prognostic marker for poor clinical outcomes in epithelial ovarian carcinoma.

The grading of lymphovascular space invasion in epithelial ovarian carcinoma.

INTRODUCTION: To assess the prognostic value of lymphovascular space invasion (LVSI) in epithelial ovarian carcinoma. METHODS: We reexamined single representative hematoxylin and eosin-stained sections of 66 patients with epithelial ovarian carcinoma to identify LVSI. A 4-grade system was used to classify LVSI: absent (no LVSI), mild (1-2 foci of LVSI), moderate (3-8 foci of LVSI), and severe (≥9 foci of LVSI). We investigated the possible associations between the grade of LVSI and clinicopathologic factors. RESULTS: Lymphovascular space invasion was present in 36 patients (54.5%) and absent in 30 (45.5%). Statistical analysis indicated that LVSI was significantly associated with advanced clinical stage, poor histological grade, and lymph node metastasis. Follow-up studies indicated that the disease-free survival time for patients without LVSI was significantly longer than that for patients with moderate LVSI (P = 0.01) and severe LVSI (P = 0.001). The overall survival (OS) time for patients with moderate or severe LVSI was significantly shorter than that for patients with mild or no LVSI. The grade of LVSI was found to be significantly associated with OS (P = 0.004). The grade of LVSI showed poor correlation with disease-free survival and OS. CONCLUSIONS: The grade of LVSI is an important predictive factor for disease recurrence and poor survival of patients with epithelial ovarian carcinoma.

[Genetic characteristics of wheat functional leaves at filling stage under different water regimes].

Taking one hundred and fifty doubled haploid (DH) lines of winter wheat cultivars Hanxuan 10 x Lumai 14 as well as their parents as test materials, the genetic bases of top three leaves length, breadth, and angle at mid-filling stage, and their correlations with yield traits were studied under two water regimes rainfed (drought stress, DS) and well-irrigation (WI) in 2005-2007. Under DS, the leaf length and width of DH lines and their parents were significantly lower than those under WI, whereas the leaf angle had a miscellaneous variation. Under the two water regimes, all the test traits of DH lines had a transgressive segregation, with the variation coefficients ranged from 5.1% to 45.9%. The heritability and gene numbers for the given traits showed great differences. Under WI and DS, the heritability of flag leaf angle (FLA) was the highest (91% and 97%, respectively), and that of the third leaf angle (TLA) was the lowest (23% and 31%, respectively). However, the gene number for FLA (4 and 2 under WI and DS, respectively) was the least, and that of TLA (21 and 25, respectively) in 2007 was the most. Interactive effects were observed among the genes controlling FLA, second leaf angle (SLA), and TLA under WI and DS, and controlling third leaf length (TLL) under WI. The grain number per spike and the grain weight per spike were positively correlated with the length and width of top three leaves, and the thousand-grain weight and the yield per plant were significantly correlated with TLL, FLA, and SLA, but all correlation coefficients were smaller ( < 0.481). It was suggested that the selection of top three leaves length and width should be carried out in the early generations of breeding procedure, while that of leaf angles should be carried out in advanced generations. An appropriate soil moisture regime retained in the critical growth period of the leaves would promote their growth and contribute to the grain yield.