Myometrium infection decreases TREK1 through NHE1 and increases contraction in pregnant mice.

Intrauterine infection during pregnancy can enhance uterine contractions. A two-pore K+ channel TREK1 is crucial for maintaining uterine quiescence and reducing contractility, with its properties regulated by pH changes in cell microenvironment. Meanwhile, the sodium hydrogen exchanger 1 (NHE1) plays a pivotal role in modulating cellular pH homeostasis, and its activation increases smooth muscle tension. By establishing an infected mouse model of Escherichia coli (E. coli) and lipopolysaccharide (LPS), we used Western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence to detect changes of TREK1 and NHE1 expression in the myometrium, and isometric recording measured the uterus contraction. The NHE1 inhibitor cariporide was used to explore the effect of NHE1 on TREK1. Finally, cell contraction assay and siRNA transfection were performed to clarify the relationship between NHE1 and TREK1 in vitro. We found that the uterine contraction was notably enhanced in infected mice with E. coli and LPS administration. Meanwhile, TREK1 expression was reduced, whereas NHE1 expression was upregulated in infected mice. Cariporide alleviated the increased uterine contraction and promoted myometrium TREK1 expression in LPS-injected mice. Furthermore, suppression of NHE1 with siRNA transfection inhibited the contractility of uterine smooth muscle cells and activated the TREK1. Altogether, our findings indicate that infection increases the uterine contraction by downregulating myometrium TREK1 in mice, and the inhibition of TREK1 is attributed to the activation of NHE1.NEW & NOTEWORTHY Present work found that infection during pregnancy will increase myometrium contraction. Infection downregulated NHE1 and followed TREK1 expression and activation decrease in myometrium, resulting in increased myometrium contraction.

Light pollution during pregnancy influences the growth of offspring in rats.

OBJECTIVE: To investigate the effects of excessive light exposure during gestation on intrauterine development and early growth of neonates in rats. METHODS: Pregnant rats were randomly allocated to three groups: the constant light exposure group, non-light exposure group and control group. Blood samples were collected from the tail vein to analyze melatonin and cortisol levels. Weight, daily food and water consumption were recorded. Uterine weight, placental weight and placental diameter were measured on gestational day 19. Natural birth and neonate growth were also monitored. The expression of NR1D1(nuclear receptor subfamily 1 group D member 1) in offspring's SCN (suprachiasmatic nuclei), liver and adipose tissue was measured. Expression of NR1D1, MT1(melatonin 1 A receptor) and 11ß-HSD2 (placental 11ß-hydroxysteroid dehydrogenase type 2) in placenta was also measured. Finally, the expression of MT1 and 11ß-HSD2 in NR1D1 siRNA transfected JEG-3 cells was evaluated. RESULTS: There were no significant differences in maternal weight gain, pregnancy duration, uterine weight, placental body weight, placental diameter, fetal number among three groups. There were no significant differences in weights or lengths of offspring at birth. Compared to other two groups, constant light exposure group showed significantly more rapid growth of offspring in 21st day post-birth. The expression of NR1D1 in SCN, liver and adipose tissues of offspring was not significantly different among three groups. The maternal serum melatonin and cortisol levels of the constant light exposure group were lower and higher than other two groups, respectively. The expressions of NR1D1, MT1 and 11ß-HSD2 were all decreased in placenta of the constant light exposure group. The expression of MT1 and 11ß-HSD2 in JEG-3 cells were decreased after NR1D1 siRNA transfection. CONCLUSION: Excessive light exposure during pregnancy results in elevated cortisol and reduced melatonin exposure to fetuses in uterus, potentially contributing to an accelerated early growth of offspring in rats.

Prolonged stretching of rat uteri causes hypoxia and inhibits contractility via potassium channel TREK1.

In brief: During pregnancy, uterine kept quiescence along with uterine overdistention before labor. Prolonged stretching induced uterus myometrial hypoxia, increased TREK1 expression, and relaxed the myometrium, which may contribute to uterine quiescence and atony during pregnancy. Abstract: The mechanisms underlying pre-labor uterine quiescence and uterine atony during overdistention are unclear. TREK1 (a two-pore domain potassium channel) and hypoxia-inducible factor-1α (HIF-1α) are activated by mechanical stretch, and their expression is upregulated by decreased uterine contractility. HIF-1α is a nuclear factor which regulates numerous target proteins, but whether it regulates TREK1 during the uterine stretch to cause uterine quiescence and/or atony is unclear. We investigated uterine contractility at different gestational stages in rats, as well as in non-pregnant uteri, which were induced by prolonged stretching and hypoxia. We also assessed the effects of incubating the uteri with or without echinomycin or l-methionine. Moreover, we analyzed HIF-1α and TREK1 expression levels in each group, as well as at various gestational stages of pregnant human uteri. We found that contractility was significantly decreased in pregnant uteri when compared with non-pregnant uteri, and this decrease was associated with increases in HIF-1α and TREK1 expression levels. HIF-1α and TREK1 expression levels in human uteri increased with the gestational length. Decreased uterine contractility and increased HIF-1α and TREK1 expression levels were also observed in non-pregnant rat uteri under 8 g of stretching tension or hypoxia. Inhibition of hypoxia with echinomycin restored normal uterine contractility, while HIF-1α and TREK1 protein expression remained reduced. TREK1 inhibition with l-methionine also restored uterine contractility under tension or hypoxia. In conclusion, we demonstrated that prolonged stretching induces myometrial hypoxia, increases TREK1 expression, and relaxes the myometrium, which may contribute to uterine quiescence and atony.

Optimal delivery time for patients with diet-controlled gestational diabetes mellitus: a single-center real-world study.

BACKGROUND: To determine the optimal delivery time for women with diet-controlled gestational diabetes mellitus by comparing differences in adverse maternal-fetal outcome and cesarean section rates. METHODS: This real-world retrospective study included 1,050 patients with diet-controlled gestational diabetes mellitus who delivered at 35-42 weeks' gestation. Data on patient characteristics, maternal-fetal outcomes, and cesarean section rate based on fetal gestational age were collected and analyzed. Differences between deliveries with and without iatrogenic intervention were also analyzed. RESULTS: The cesarean section rate at ≥ 41 weeks' gestation was significantly higher than that at 39-39 + 6 weeks (56% vs. 39%, p = 0.031). There were no significant differences in multiple adverse maternal or neonatal outcomes at delivery before and after 39 weeks. Vaginal delivery rates were increased significantly at 39-39 + 6 weeks due to iatrogenic intervention (p = 0.005) and 40-40 + 6 weeks (p = 0.003) in patients without and with spontaneous uterine contractions, respectively. CONCLUSIONS: It's recommended that optimal delivery time for patients with diet-controlled gestational diabetes mellitus should be between 39- and 40 + 6 weeks' gestation. Patients who have Bishop scores higher than 4 can undergo iatrogenic intervention at 39-39 + 6 weeks. However iatrogenic interventions are not recommended for patients with low Bishop scores.

Comparative single-center study between modified laparoscopic radical hysterectomy and open radical hysterectomy for early-stage cervical cancer.

BACKGROUND: Since the release of the LACC trial results in 2018, the safety of laparoscopic radical hysterectomy (LRH) for cervical cancer has received huge attention and heated discussion. We developed modified laparoscopic radical hysterectomy (MLRH) incorporating a series of measures to prevent tumor spillage, which has been performed in our center since 2015. OBJECTIVE: Present study retrospectively analyzed relevant indicators of MLRH and evaluated disease-free survival (DFS) primarily in the treatment of early cervical cancer compared with open surgery. METHODS: Patients with 2014 International Federation of Gynecology and Obstetrics clinical stages 1B1 and 2A1 cervical cancer who underwent radical hysterectomy in the gynecological department of our hospital from October 2015 to June 2018 were enrolled retrospectively in this study. Patients were divided into two groups based on the surgical procedure: open radical hysterectomy (ORH) group (n = 336) and MLRH group (n = 302). Clinical characteristics, surgical indices, and survival prognosis were analyzed, including 2.5-year overall survival (OS) rate, 2.5-year DFS rate, recurrence rate, and recurrence pattern. RESULTS: Compared to the ORH group, the MLRH group exhibited a longer operative time, longer normal bladder function recovery time, less intraoperative blood loss volume, and more harvested pelvic lymph nodes (P < 0.05). No significant differences were observed in postoperative complications, the 2.5-year OS, 2.5-year DFS, and recurrence rate between the two groups (P > 0.05); however, the recurrence pattern was significantly different (P < 0.05). The MLRH group mainly exhibited local single metastasis (7/11), whereas the ORH group mainly exhibited distant multiple metastases (14/16). Stratified analysis revealed that overall survival rate was higher in the MLRH group than in the ORH group in patients with stage 1B1 and middle invasion (P < 0.05). CONCLUSION: MLRH does not show a survival disadvantage in the treatment of early-stage cervical cancer when compared with open surgery. In addition, MLRH shows a survival advantage in patients with stage 1B1 and middle 1/3 invasion. Considering this is a retrospective study, further prospective study is necessary for more sufficient data support. TRIAL REGISTRATION: Present research is a retrospective study. The study had retrospectively registered on Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ), and the registered number is ChiCTR1900026306.

Maternal tobacco exposure and health-related quality of life during pregnancy: a national-based study of pregnant women in China.

BACKGROUND: With the increase of the number of smokers, tobacco exposure among pregnant women is becoming more and more common. Pregnant women exposed to first-hand smoke and second-hand smoke are susceptible to physiological and psychological health issues has been proved in previous studies. Nevertheless, there are no enough studies focus on the impact of third-hand smoke during pregnancy. This study aimed to assess and compare health-related quality of life for pregnant women with exposure to first-hand smoke, second-hand smoke, third-hand smoke and non-exposure to tobacco in mainland China. METHODS: National-based cross-sectional study is based on a questionnaire survey which collects information including demographics, smoking behaviors and self-evaluation. All questionnaires were delivered and collected from August to September 2019. EuroQol group's visual analog scale and EuroQoL Five-dimension Questionnaire were used to collect data in mainland China. RESULTS: Totally, 15,682 pregnant women were included in this study, among which non-exposure to smoke were 7564 (48.2%), exposed to first-hand smoke, second-hand smoke and third-hand smoke were 89 (0.6%), 2349 (15.0%), and 5680 (36.2%) respectively. Pregnant women without tobacco exposure had the highest EuroQol group's visual analog scale score (mean value = 85.4[SD = 14.0]), while those with first-hand smoke had the lowest score (mean value = 77.4[SD = 22.2]). Among all five dimensions of EuroQoL Five-dimension Questionnaire, there were significant differences of EQ-index among groups with different tobacco exposure in usual activity and anxiety or depression dimensions (p < 0.001). CONCLUSIONS: Third-hand smoke exposure had close relationship with low health-related quality of life in pregnant women. Moreover, second-hand smoke exposure significantly led more problems on mental dimension of pregnant women.

Interleukin-1ß-Induced Senescence Promotes Osteoblastic Transition of Vascular Smooth Muscle Cells.

INTRODUCTION: Interleukin (IL)-1ß, as a key biomarker and mediator of vascular calcification in patients with end-stage renal disease (ESRD), may be involved in the process of premature senescence of vascular smooth muscle cells (VSMCs). This work sought to investigate whether IL-1ß-induced premature senescence contributes to the process of osteoblastic transition and vascular calcification in VSMCs. METHODS: Eighty-eight patients with ESRD (aged 25-81 years), 11 healthy individuals, and 15 cases of lesion-free distal radial arteries from dialysis ESRD patients with angiostomy were collected in this study. Immunohistochemical analysis was performed to detect expression of IL-1ß, p21, and bone morphogenetic protein-2 (BMP2) in the distal radial arteries. Primary human VSMCs from healthy neonatal umbilical cords were incubated with test agents for 1-3 days. Intracellular levels of reactive oxygen species (ROS) and senescence-associated-ß-galactosidase (SA-ß-gal) staining were used to detect senescent cells. Alizarin red staining and the calcium content of the cell layer were used to detect mineral deposition in VSMCs. RESULTS: Coincident with positive staining of IL-1ß, p21, and BMP2 in the lesion-free distal radial arteries, 66.67% patients showed mineral deposition. Serum IL-1ß was 0.24 ± 0.57, 1.20 ± 2.95, and 9.41 ± 40.52 pg/mL in 11 healthy individuals, 20 patients without calcification, and 53 patients with calcification, respectively. Analysis of the cross-table chi-square test showed cardiovascular calcification is not correlated with levels of serum IL-1ß in patients with ESRD (p = 0.533). In response to IL-1ß, VSMCs showed a senescence-like phenotype, such as flat and enlarged morphology, increased expression of p21, an increased activity of SA-ß-gal, and increased levels of ROS. IL-1ß-induced senescence of VSMCs was required for the activation of IL-1ß/NF-κB/p53/p21 signaling pathway. IL-1ß-induced senescent VSMCs underwent calcification due to osteoblastic transition mainly depending upon the upregulation of BMP2. Resveratrol, an activator of sirtuin-1, postponed the IL-1ß-induced senescence through blocking the NF-κB/p53/p21 pathway and attenuated the osteoblastic transition and calcification in VSMCs. CONCLUSIONS: High levels of IL-1ß in medial smooth muscles of arteries may play roles in inducing senescence-associated calcification. IL-1ß-induced senescence depending on the activation of the NF-κB/p53/p21 signaling pathway and contributing to osteoblastic transition of VSMCs.

Conservative management or cesarean hysterectomy for placenta accreta spectrum in middle-income countries: A systematic review and meta-analysis.

BACKGROUND: Cesarean hysterectomy is a dominant and effective approach during delivery in patients with placenta accreta spectrum (PAS). However, as hysterectomy results in a loss of fertility, conservative management is an alternative approach. However, management selection may be affected by a country's overall economic level. Thus the preferred treatment for PAS generates controversy in middle-income countries. OBJECTIVES: We aimed to compare conservative management and cesarean hysterectomy for managing PAS in middle-income countries. SEARCH STRATEGY: China National Knowledge Infrastructure, Wanfang Med Online Databases, Cochrane Library, Ovid MEDLINE, PubMed, Web of Science, EMBASE, clinicaltrials.gov, and Scopus were searched from inception through to October 1, 2022. SELECTION CRITERIA: We included studies that evaluated at least one complication comparing conservative management and hysterectomy. All cases were diagnosed with PAS prenatally and intraoperatively. DATA COLLECTION AND ANALYSIS: The primary outcomes were blood loss, adjacent organ damage, and the incidence of hysterectomy. Descriptive analyses were conducted for studies that did not meet the meta-analysis criteria. A fixed-effects model was used for studies without heterogeneity and a random-effects model was used for studies with statistical heterogeneity. MAIN RESULTS: In all, 11 observational studies were included, with 975 and 625 patients who underwent conservative management and cesarean hysterectomy, respectively. Conservative management was significantly associated with decreased blood loss and lower risks of adjacent organ injury and hysterectomy. Conservative management significantly reduced blood transfusions, hospitalization duration, operative time, intensive care unit admission rates, and infections. There were no significant differences in the risks of coagulopathy, thromboembolism, or reoperation. CONCLUSION: Given short-term complications and future fertility preferences for patients, conservative management appears to effectively manage PAS in middle-income countries. Owing to low levels of evidence, high heterogeneity and insufficient long-term follow-up data, further detailed studies are warranted.

MTCH2 in Metabolic Diseases, Neurodegenerative Diseases, Cancers, Embryonic Development and Reproduction.

Mitochondrial carrier homolog 2 (MTCH2) is a member of the solute carrier 25 family, located on the outer mitochondrial membrane. MTCH2 was first identified in 2000. The development in MTCH2 research is rapidly increasing. The most well-known role of MTCH2 is linking to the pro-apoptosis BID to facilitate mitochondrial apoptosis. Genetic variants in MTCH2 have been investigated for their association with metabolic and neurodegenerative diseases, however, no intervention or therapeutic suggestions were provided. Recent studies revealed the physiological and pathological function of MTCH2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction via regulating mitochondrial apoptosis, metabolic shift between glycolysis and oxidative phosphorylation, mitochondrial fusion/fission, epithelial-mesenchymal transition, etc. This review endeavors to assess a total of 131 published articles to summarise the structure and physiological/pathological role of MTCH2, which has not previously been conducted. This review concludes that MTCH2 plays a crucial role in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction, and the predominant molecular mechanism is regulation of mitochondrial function. This review gives a comprehensive state of current knowledgement on MTCH2, which will promote the therapeutic research of MTCH2.

Facile Semiconductor p-n Homojunction Nanowires with Strategic p-Type Doping Engineering Combined with Surface Reconstruction for Biosensing Applications.

Photosensors with versatile functionalities have emerged as a cornerstone for breakthroughs in the future optoelectronic systems across a wide range of applications. In particular, emerging photoelectrochemical (PEC)-type devices have recently attracted extensive interest in liquid-based biosensing applications due to their natural electrolyte-assisted operating characteristics. Herein, a PEC-type photosensor was carefully designed and constructed by employing gallium nitride (GaN) p-n homojunction semiconductor nanowires on silicon, with the p-GaN segment strategically doped and then decorated with cobalt-nickel oxide (CoNiOx). Essentially, the p-n homojunction configuration with facile p-doping engineering improves carrier separation efficiency and facilitates carrier transfer to the nanowire surface, while CoNiOx decoration further boosts PEC reaction activity and carrier dynamics at the nanowire/electrolyte interface. Consequently, the constructed photosensor achieves a high responsivity of 247.8 mA W-1 while simultaneously exhibiting excellent operating stability. Strikingly, based on the remarkable stability and high responsivity of the device, a glucose sensing system was established with a demonstration of glucose level determination in real human serum. This work offers a feasible and universal approach in the pursuit of high-performance bio-related sensing applications via a rational design of PEC devices in the form of nanostructured architecture with strategic doping engineering.

Subtype-specific estrogen receptor-mediated vasodilator activity in the cephalic, thoracic, and abdominal vasculature of female rat.

Estrogen receptors (ERs) mediate genomic and nongenomic vasodilator effects, but estrogen therapy may not provide systemic vascular protection. To test whether this is because of regional differences in ER distribution or vasodilator activity, cephalic (carotid artery), thoracic (thoracic aorta and pulmonary artery), and abdominal arteries (abdominal aorta, mesenteric artery, and renal artery) from female Sprague-Dawley rats were prepared to measure contraction to phenylephrine and relaxation to acetylcholine (ACh) and the ER activators 17ß-estradiol (E2) (all ERs), 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT) (ERα), diarylpropionitrile (DPN) (ERß), and (±)-1-[(3aR*,4S*,9bS*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone (G1) (GPR30). Phenylephrine caused contraction that was enhanced in endothelium-denuded aorta, supporting endothelial release of vasodilators. In cephalic and thoracic arteries, ACh relaxation was abolished by the nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME), suggesting a role of NO. In mesenteric vessels, ACh-induced relaxation was partly inhibited by the L-NAME + cyclooxygenase inhibitor indomethacin and blocked by the K+ channel blocker tetraethylammonium, suggesting a hyperpolarization pathway. E2 and PPT caused similar relaxation in all vessels. DPN and G1 caused smaller relaxation that was more prominent in abdominal vessels. Reverse transcription-polymerase chain reaction revealed variable ERα messenger RNA expression and increased ERß in carotid artery and GPR30 in abdominal arteries. Western blots revealed greater amounts of ERα, ERß, and GPR30 in abdominal arteries. In thoracic aorta, E2-, PPT-, and DPN-induced relaxation was blocked by L-NAME and was associated with increased nitrite/nitrate production, suggesting a role of NO. In abdominal vessels, E2-, PPT-, DPN-, and G1-induced relaxation persisted in L-NAME + indomethacin + tetraethylammonium-treated or endothelium-denuded arteries, suggesting direct effect on vascular smooth muscle. E2, PPT, DPN, and G1 caused greater relaxation of KCl-induced contraction in abdominal vessels, suggesting inhibitory effects on Ca2+ entry. Thus, E2 and ERα stimulation produces similar relaxation of the cephalic, thoracic, and abdominal arteries. In the cephalic and thoracic arteries, particularly the thoracic aorta, E2-induced and ERα- and ERß-mediated vasodilation involves NO production. ERß- and GPR30-mediated relaxation is greater in the abdominal arteries and seems to involve hyperpolarization and inhibition of vascular smooth muscle Ca2+ entry. Specific ER agonists could produce vasodilation in specific vascular beds without affecting other vessels in the systemic circulation.

The role of internal iliac artery intraoperative vascular clamp temporary occlusion in abnormally invasive placenta.

OBJECTIVE: To investigate the efficacy of internal iliac artery intraoperative vascular clamp temporary occlusion in the treatment of abnormally invasive placenta. METHOD: This retrospective study enrolled 153 patients diagnosed with abnormally invasive placenta between January 2018 and December 2021. The patients were divided into a study group (n = 88, undergoing cesarean section followed by internal iliac artery vascular clamp temporary occlusion) and a control group (n = 65, receiving routine cesarean section). The general situation, intraoperative conditions, postoperative complications, and neonatal outcomes were compared between the two groups. RESULTS: The hysterectomy rate in the study group was significantly lower than that in the control group. However, there were no significant differences in intraoperative blood loss, blood transfusion, postoperative intensive care unit transfer rate, or neonatal outcome between the groups. Further subgrouping showed that in patients with placenta increta, the hysterectomy rate and intraoperative bleeding amount were significantly lower in the occlusion group. Nevertheless, these advantages were not significantly different between the groups in patients with placenta percreta. CONCLUSION: Vascular clamp temporary occlusion of internal iliac artery is an effective method for controlling hemorrhage and decreasing the incidence of hysterectomy in patients with placenta increta. For patients with placenta percreta, the benefit is limited.

High glucose induced HIF-1α/TREK1 expression and myometrium relaxation during pregnancy.

Background: The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM patients have a significantly higher rate of cesarean section and postpartum hemorrhage, suggesting changes in uterine contractility. TWIK-1-related potassium channel (TREK1) expressed in the pregnant uterus and its role in uterine contraction. In this study, we examined the expression of HIF-1α and TREK1 proteins in GDM uterine and investigated whether high glucose levels are involved in the regulation of human uterine smooth muscle cells (HUSMCs) contraction through TREK1, and verified the role of HIF-1α in this process. Methods: Compared the uterine contractility between GDM and normal patients undergoing elective lower segment cesarean section. The HUSMCs were divided into normal glucose group, high glucose group, normal glucose with CoCl2 group, CoCl2 with echinomycin/L-Methionine group, and high glucose with echinomycin/L-Methionine group; Compare the cell contractility of each group. Compared the expression of hypoxia-inducible factor-1α (HIF-1α) and TREK1 protein in each group. Results: The contractility of human uterine strips induced by both KCl and oxytocin was significantly lower in patients with GDM compared with that in normal individuals, with increased TREK1 and HIF-1α protein expression. The contractility of cultured HUSMCs was significantly decreased under high glucose levels, which was consistent with increased expression of HIF-1α and TREK1 proteins. The contractility of HUSMCs was decreased when hypoxia was induced by CoCl2 and increased when hypoxia was inhibited by echinomycin. The TREK1 inhibitor L-methionine also recovered the decreased contractility of HUSMCs under high glucose levels or hypoxia. Discussion: The high glucose levels decreased the contractility of the myometrium, and increased expression of HIF-1a and TREK1 proteins play a role in changes in uterus contractility.

Gestational diabetes mellitus: The optimal time of delivery.

Gestational diabetes mellitus (GDM) is a common pregnancy complication strongly associated with poor maternal-fetal outcomes. Its incidence and prevalence have been increasing in recent years. Women with GDM typically give birth through either vaginal delivery or cesarean section, and the maternal-fetal outcomes are related to several factors such as cervical level, fetal lung maturity, the level of glycemic control still present, and the mode of treatment for the condition. We categorized women with GDM based on the latter two factors. GDM that is managed without medication when it is responsive to nutrition- and exercise-based therapy is considered diet- and exercise-controlled GDM, or class A1 GDM, and GDM managed with medication to achieve adequate glycemic control is considered class A2 GDM. The remaining cases in which neither medical nor nutritional treatment can control glucose levels or patients who do not control their blood sugar are categorized as class A3 GDM. We investigated the optimal time of delivery for women with GDM according to the classification of the condition. This review aimed to address the benefits and harms of giving birth at different weeks of gestation for women with different classes of GDM and attempted to provide an analytical framework and clearer advice on the optimal time for labor.

Increased MMPs expression and decreased contraction in the rat myometrium during pregnancy and in response to prolonged stretch and sex hormones.

Normal pregnancy is associated with uterine relaxation to accommodate the stretch imposed by the growing fetus; however, the mechanisms underlying the relationship between pregnancy-associated uterine stretch and uterine relaxation are unclear. We hypothesized that increased uterine stretch during pregnancy is associated with upregulation of matrix metalloproteinases (MMPs), which in turn cause inhibition of myometrium contraction and promote uterine relaxation. Uteri from virgin, midpregnant (day 12), and late-pregnant rats (day 19) were isolated, and myometrium strips were prepared for measurement of isometric contraction and MMP expression and activity using RT-PCR, Western blot analysis, and gelatin zymography. Oxytocin caused concentration-dependent contraction of myometrium strips that was reduced in mid- and late-pregnant rats compared with virgin rats. Pretreatment with the MMP inhibitors SB-3CT (MMP-2/MMP-9 Inhibitor IV), BB-94 (batimastat), or Ro-28-2653 (cipemastat) enhanced contraction in myometrium of pregnant rats. RT-PCR, Western blot analysis, and gelatin zymography demonstrated increased mRNA expression, protein amount, and activity of MMP-2 and MMP-9 in myometrium of late-pregnant>midpregnant>virgin rats. Prolonged stretch of myometrium strips of virgin rats under 8 g basal tension for 18 h was associated with reduced contraction and enhanced expression and activity of MMP-2 and MMP-9, which were reversed by MMP inhibitors. Concomitant treatment of stretched myometrium of virgin rats with 17ß-estradiol (E2), progesterone (P4), or E2+P4 was associated with further reduction in contraction and increased MMP expression and activity. MMP-2 and MMP-9 caused significant reduction of oxytocin-induced contraction of myometrium of virgin rat. Thus, normal pregnancy is associated with reduced myometrium contraction and increased MMPs expression and activity. The results are consistent with the possibility that myometrium stretch and concomitant increase in sex hormones during pregnancy are associated with increased expression/activity of specific MMPs, which in turn inhibit uterine contraction and promote uterine relaxation.

Cerclage placement in twin pregnancies with cervical dilation: a systematic review and meta-analysis.

OBJECTIVE: Existing guidelines and studies on the benefits of cerclage in twin pregnancies with a dilated cervix have low reliability and inconsistent conclusions. New randomized control trials and cohort studies focusing on twin pregnancies with cervical insufficiency were published recently. Therefore, this meta-analysis aimed to compare outcomes of cerclage placement and expectant treatment in twin pregnancies with a dilated cervix using recent data. METHODS: We screened the PubMed, Web of Science, ClinicalTrials.gov, and Cochrane Library databases to identify randomized controlled trials and cohort studies comparing maternal and perinatal outcomes of twin pregnancies with cervical dilation, with and without cerclage placement, published until December 2020. Estimates were pooled using random-effects or fixed-effect models depending on the heterogeneity. Mean difference, 95% confidence interval, and relative risk were used to compare the outcomes. The risk of bias was assessed using the Cochrane Handbook and the Newcastle-Ottawa Scale. The meta-analyses followed the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for systematic reviews of observational studies. RESULTS: Five studies, comprising 275 twin pregnancies, met the inclusion criteria; of those, 167 underwent cerclage and 108 were expectantly managed. Cerclage placement significantly prolonged the interval from the time of diagnosis to delivery and reduced the incidence of preterm delivery, perinatal death, and complications. The fetal outcomes improved significantly in cases managed with cerclage. CONCLUSION: Therefore, emergent cerclage is a potential option for managing twin pregnancies with cervical dilation of at least 1 cm.

Preserved oxytocin-induced myometrium contraction and sensitivity to progesterone inhibition following rat uterus thermal insult. Impact on fertility.

Women seeking improved fertility often undergo diagnostic hysteroscopy that could cause uterine thermal injury with unclear impact on uterine contraction, embryo implantation and fertility. We tested whether uterine thermal insult adversely affects myometrium function and contraction related receptors, channels, junctional proteins and remodeling enzymes. Female Sprague-Dawley rats were anesthetized, the left uterine horn was infused with 85 ℃ hot saline (thermal Insult) and the right horn was infused with 25℃ warm saline (control) for 3 min. After 7-days recovery, uterine strips were prepared for tissue histology and measurement of contraction, and mRNA and protein levels of oxytocin receptor, progesterone (P4) receptor A (PR-A), membrane K+ channel TREK-1, junctional protein connexin-43 (CX-43) and matrix metalloproteinases MMP-2 and MMP-9. Uterine tissue histology showed cellular swelling and inflammatory cell infiltration immediately following thermal insult, and recovery with no difference from control 7-days later. KCl (96 mM) and oxytocin (10-13-10-7 M) caused significant contraction that was not different in thermal insult vs control uterine strips. Pretreatment with P4 (10-5 M) for 1 h caused marked inhibition of KCl and oxytocin contraction that was insignificantly greater in thermal vs control uterus. RT-PCR showed decreases in oxytocin receptor, PR-A, TREK-1, CX-43, MMP-2 and MMP-9 mRNA in thermal vs control uterus. Western blots showed decreases in oxytocin receptor, no change in TREK-1 and increased PRA, CX-43, MMP-2, and MMP-9 protein levels in thermal vs control uterus. To assess the impact on fertility, female rats were housed with male rats, and on gestational day 19, the litter size, pup weight and crown-rump length, and placenta weight were not different in thermal vs control uterus. Thus, after thermal insult-induced immediate inflammation and reduced heat-sensitive mRNA expression, the uterus undergoes a recovery and adaptation process involving preserved oxytocin-induced contraction, P4 inhibition and TREK-1 channels. The uterus self-healing process appears to require improved PR-A signaling, intercellular communication via CX-43 and tissue remodeling by MMP-2 and MMP-9. The uterine thermal recovery processes could be essential for maintaining fertility and future pregnancy outcome.

Uteroplacental-Cerebral Ratio: A Doppler Parameter for Prognostic Prediction of Late-Onset Fetal Growth Restriction: Single Center Prospective Cohort Study.

Purpose: This study aimed to elucidate the accuracy of Doppler parameters in predicting the prognosis of late-onset fetal growth restriction (FGR). Methods: This was a prospective study of 114 pregnancies. Doppler parameters, including the cerebroplacental ratio and pulsatility index (PI) in the middle cerebral, umbilical, uterine artery, were recorded. The new uteroplacental−cerebro ratio (UPCR) was constructed as the ratio of (umbilical artery + mean of the left and right uterine artery) to middle cerebral artery PI. Logistic regression analyses and receiver operating characteristic curves were performed. Results: Adverse outcomes occurred in 37 (32%) neonates. The z values of the middle cerebral artery PI and cerebroplacental ratio were lower (p < 0.001), while the z values of the umbilical artery PI, mean uterine artery PI, and UPCR (p < 0.001) were higher in late-onset FGR in those with compared to those without adverse outcomes. Multivariate logistic regression revealed that only UPCR was independently associated with adverse outcomes (p < 0.001). For predicting the prognosis of late-onset FGR, UPCR showed a fair degree of accuracy (area under the curve [AUC], 0.824). Conclusion: The new UPCR, reflecting the impact of placental impedance from both fetal and maternal sides on fetal well-being, improves the accuracy of prognostic prediction for late-onset FGR.

Long-term impact of intrauterine MCMV infection on development of offspring nervous system.

This study examined the impacts of intrauterine murine cytomegalovirus (MCMV) infection on the long-term learning and memory of offspring. Sexually matured male and female BALB/C mice without MCMV infection were identified by ELISA and then mated. Seventy pregnant mice were randomly divided into the virus group (n=40) and the control group (n=30), in which the pregnant mice were subjected to placenta inoculation of MCMV suspension (1 µL, 1×106 PFU) or the same amount of cell culture medium, respectively, at gestational age of 12.5 days. Some pregnant mice [virus group (n=20), control group (n=15)] were sacrificed by cervical dislocation at gestational age of 18.5 days, and the head circumference and brain weight of the mouse fetuses were measured, and the MCMV infection in their brain tissues was detected by PCR. The other pregnant mice [virus group (n=20), control group (n=15)] delivered naturally, and the learning and memory capability of the offspring at 70-day-old was analyzed by Morris water maze test. The results showed that 28.57% mouse fetuses in the virus group developed viral infection in the brain. Their head circumference and brain weight were significantly reduced as compared with those in the control group (P<0.01). The Morris water maze test revealed that the mouse offspring in the control group found the platform with straight-line trajectories after training. In contrast, the counterparts in the virus group intended to enter the central area, but looked for the platform with a circular trajectory. And the infected mice exhibited prolonged swimming distance and swimming latency (P<0.01). It was concluded that: (1) placenta inoculation of MCMV can cause fetal brain infection and intrauterine development retardation; (2) the offspring of MCMV placenta inoculation mice showed a long-term decline in learning and memory capability.

Effect of human cytomegalovirus on invasive capability of early pregnant extravillous cytotrophoblasts.

The effect of human cytomegalovirus (HCMV) on invasive capability of early pregnant extravillous cytotrophoblasts (EVTs) was investigated in vitro. Primary EVTs were obtained by complex phosphoesterasum digestion and gradient centrifugation from villous tissue aseptically taken from healthy pregnant women. Cytokeratin7 (CK7), vimentin (Vim) and c-erbB-2 were immunocytochemically detected to identify source of cells, and HCMVpp65 antigen was assayed to determine the infection state of primary EVTs by immunocytochemical staining. The EVTs were divided into two groups: control group and HCMV group, and the expression of c-erbB-2, matrix metalloproteinase-2 (MMP-2) and MMP-9 proteins was detected in two groups by immunocytochemistry and Western blotting. Enzymic activity changes of MMP-2 and MMP-9 were tested by gelatin zymography in primary EVTs infected with HCMV. The invasion of primary EVTs was detected by cell invasion assay in vitro after they were infected by HCMV. The cell source identification showed that the cells obtained were highly-pure primary EVTs, and primary EVTs could be infected by HCMV. Primary EVTs could express c-erbB-2, MMP-2 and MMP-9 proteins, and as compared with control group, the protein expression was decreased significantly in HCMV groups (P<0.05). Primary EVTs could secrete active MMP-2 and MMP-9 in vitro, and the activity of two MMPs was decreased significantly in HCMV groups (P<0.05). The in vitro cell invasion assay showed that the number of primary EVTs permeating Matrigel in HCMV group was decreased (P<0.05). We are led to conclude that HCMV can infect primary EVTs and inhibit their invasion capability, suggesting that the impaired EVT's invasion capability might be related to the abnormal expression of c-erbB-2, MMP-2 and MMP-9 proteins.