Genetic examination for fetuses with increased nuchal translucency by exome sequencing.

AIM: This retrospective study aimed to investigate the value of exome sequencing (ES) in fetuses with isolated first-trimester increased nuchal translucency (NT) and normal chromosomes. METHODS: ES was performed on 103 fetuses with isolated first trimester increased NT and normal chromosomes. The detection rate of monogenic conditions was analyzed. RESULTS: Diagnostic variants were detected in nine cases in which phenotypes and genotypes correlated well, two positive cases were Thanatophoric dysplasia type I, and one case was Kabuki syndrome, which had been detected in previous studies. Eight of the nine cases with diagnostic variants developed additional structural malformations later in pregnancy. Among the nine positive cases, six had a NT thickness between 95th percentile (95th-3.4 mm), and three cases with an increased NT of 3.5 mm or greater. Also, there was no statistical difference in the diagnosis of diagnostic variants in cases with or without a thickened nuchal fold (NF). CONCLUSIONS: The diagnostic yield of prenatal ES is low for fetuses with an isolated increased NT. In addition to Noonan syndrome, there are additional genetic syndromes such as Kabuki syndrome and Thanatophoric dysplasia type I that are potentially associated with an increased NT. A cut-off of greater than the 95th percentile may be useful in case selection for ES. Whether it is clinically meaningful to monitor NF values for fetuses with isolated increased NT and normal chromosomes worth considering.

Pathogenic/likely pathogenic copy number variations and regions of homozygosity in fetal central nervous system malformations.

OBJECTIVE: To explore pathogenic/likely pathogenic copy number variations (P/LP CNVs) and regions of homozygosity (ROHs) in fetal central nervous system (CNS) malformations. METHODS: A cohort of 539 fetuses with CNS malformations diagnosed by ultrasound/MRI was retrospectively analyzed between January 2016 and December 2019. All fetuses were analyzed by chromosomal microarray analysis (CMA). Three cases with ROHs detected by CMA were subjected to whole-exome sequencing (WES). The fetuses were divided into two groups according to whether they had other structural abnormalities. The CNS phenotypes of the two groups were further classified as simple (one type) or complicated (≥ 2 types). RESULTS: (1) A total of 35 cases with P/LP CNVs were found. The incidence of P/LP CNVs was higher in the extra-CNS group [18.00% (9/50)] than in the isolated group [5.32% (26/489)] (P < 0.01), while there was no significant difference between the simpletype and complicated-type groups. (2) In the simple-type group, the three most common P/LP CNV phenotypes were holoprosencephaly, Dandy-Walker syndrome, and exencephaly. There were no P/LP CNVs associated with anencephaly, microcephaly, arachnoid cysts, ependymal cysts, or intracranial hemorrhage. (3) Only four cases with ROHs were found, and there were no cases of uniparental disomy or autosomal diseases. CONCLUSION: The P/LP CNV detection rates varied significantly among the different phenotypes of CNS malformations, although simple CNS abnormalities may also be associated with genetic abnormalities.

A randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in women at high risk in China.

BACKGROUND: Low-dose aspirin has been the most widely studied preventive drug for preeclampsia. However, guidelines differ considerably from country to country regarding the prophylactic use of aspirin for preeclampsia. There is limited evidence from large trials to determine the effect of 100 mg of aspirin for preeclampsia screening in women with high-risk pregnancies, based on maternal risk factors, and to guide the use of low-dose aspirin in preeclampsia prevention in China. OBJECTIVE: The Low-Dose Aspirin in the Prevention of Preeclampsia in China study was designed to evaluate the effect of 100 mg of aspirin in preventing preeclampsia among high-risk pregnant women screened with maternal risk factors in China, where preeclampsia is highly prevalent, and the status of low-dose aspirin supply is commonly suboptimal. STUDY DESIGN: We conducted a multicenter randomized controlled trial at 13 tertiary hospitals from 11 provinces in China between 2016 and 2019. We assumed that the relative reduction in the incidence of preeclampsia was at least 20%, from 20% in the control group to 16% in the aspirin group. Therefore, the targeted recruitment number was 1000 participants. Women were randomly assigned to the aspirin or control group in a 1:1 allocation ratio. Statistical analyses were performed according to an intention-to-treat basis. The primary outcome was the incidence of preeclampsia, diagnosed along with a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg after 20 weeks of gestation, with a previously normal blood pressure (systolic blood pressure of <140 mm Hg and diastolic blood pressure of <90 mm Hg), and complicated by proteinuria. The secondary outcomes included maternal and neonatal outcomes. Logistic regression analysis was used to determine the significance of difference of preeclampsia incidence between the groups for both the primary and secondary outcomes. Interaction analysis was also performed. RESULTS: A total of 1000 eligible women were recruited between December 2016 and March 2019, of which the final 898 patients were analyzed (464 participants in the aspirin group, 434 participants in the control group) on an intention-to-treat basis. No significant difference was found in preeclampsia incidence between the aspirin group (16.8% [78/464]) and the control group (17.1% [74/434]; relative risk, 0.986; 95% confidence interval, 0.738-1.317; P=.924). Likewise, adverse maternal and neonatal outcomes did not differ significantly between the 2 groups. Meanwhile, the incidence of postpartum hemorrhage between the 2 groups was similar (6.5% [30/464] in the aspirin group and 5.3% [23/434] in the control group; relative risk, 1.220; 95% confidence interval, 0.720-2.066; P=.459). We did not find any significant differences in preeclampsia incidence between the 2 groups in the subgroup analysis of the different risk factors. CONCLUSION: A dosage of 100 mg of aspirin per day, initiated from 12 to 20 gestational weeks until 34 weeks of gestation, did not reduce the incidence of preeclampsia in pregnant women with high-risk factors in China.

Genetic diagnosis of common fetal renal abnormalities detected on prenatal ultrasound.

OBJECTIVES: This retrospective study aimed to investigate the correlations between phenotypes of fetal renal abnormalities on prenatal ultrasound and genetic aetiologies detected using chromosomal microarray analysis (CMA) and whole-exome sequencing (WES). METHODS: Fetuses with renal abnormalities were subjected to CMA and were further analysed by WES when CMA-negative. The detection rates for chromosomal abnormalities and monogenic variants among different types of isolated renal abnormalities and those with extrarenal abnormalities (non-isolated cases) were determined and compared. RESULTS: CMA detected chromosomal abnormalities in 78 of 577 fetuses (13.52%). WES detected monogenic variants in 31 of 160 fetuses (19.38%) that had non-diagnostic CMA results. In cases of isolated hyperechogenic kidney, polycystic kidney disease, and multicystic dysplastic kidney, the detection rates of copy number variants (CNVs) by CMA and monogenic variants by WES were not significantly different (p > 0.05). However, monogenic variants were more frequently detected than CNVs when kidney abnormalities were accompanied by reduced amniotic fluid (p < 0.05). Other renal abnormalities identified on prenatal ultrasound had different detection rates. CONCLUSIONS: Our findings contribute to the overall knowledge of genetic variants associated with prenatally identified renal anomalies and may aid in decision making regarding prenatal genetic testing options for affected pregnancies.

Changes in the live birth profile in Henan, China: A hospital registry-based study.

BACKGROUND: Preterm complications and neonatal asphyxia are the leading causes of death in those under 5 years of age. However, little information exists for the province of Henan, China. The purpose of this study was to explore changes in the live birth profile in a provincial hospital over the past 32 years in Henan, China. METHODS: A retrospective analysis was conducted to reveal the characteristics of live neonates from 1987 to 2018. RESULTS: There were 118 253 live births during the period, including 19 798 (16.74%) preterm births. The neonatal death rate was 6.45‰, and the top risk factor was preterm birth complications and birth asphyxia. Before 1998, neonatal death occurred primarily among term infants. Between 1999 and 2018, preterm infants, especially extreme and very preterm infants with very low birthweight, constituted more than half of all mortalities, and the preterm birth rate increased from 5.94% in 1999 to 16.69% in 2018. The risk factors associated with preterm birth were being male (aOR = 1.18, P < 0.001), advanced maternal age (>35 years old; aOR = 1.08, P = 0.008), gravidity ≥2 (aOR = 1.15, P < 0.001), parity ≥2 (aOR = 1.50, P < 0.001), placenta previa (aOR = 7.41, P < 0.001), twin or multiple births (aOR = 10.63, P < 0.001), hypertension (aOR = 2.08, P < 0.001), and rupture of membrane (aOR = 5.03, P < 0.001). CONCLUSIONS: The preterm birth rate has increased over the past 32 years from 4.98% to 16.69% in a provincial hospital in China. Preterm birth was the leading reason for neonatal death, and birth asphyxia was the major risk factor for death in term infants.

Methylation Mediated Silencing of miR-155 Suppresses the Development of Preeclampsia In Vitro and In Vivo by Targeting FOXO3.

Preeclampsia (PE) is a common pregnancy-related syndrome characterized by chronic immune activation. This study is aimed at exploring the role of miR-155 in the inflammatory pathogenesis of PE. Placental tissues and peripheral blood were collected from all subjects. BSP detection analysis was performed to evaluate miR-155 methylation levels. ELISA was performed to measure the levels of inflammatory cytokines and MMP2 in serum samples and cellular supernatants. HTR-8/SVneo and JEG-3 cells were transfected with miR-155 mimic and the inhibitor to establish the overexpressed miR-155 and silenced miR-155 cell models, respectively. Treatment with 5-Aza was performed to alter the DNA methylation level of miR-155. The PE rat model was established after subcutaneous injection of NG-nitro-L-arginine methyl ester. The CCK-8 assay, TUNEL staining, and Transwell assay were performed. Reverse transcription-quantitative PCR, Western blot analysis, and immunohistochemical assay were used to analyze related gene expression levels. The luciferase reporter assay was used to investigate the direct interaction between FOXO3 and miR-155. Results showed that miR-155 was remarkably upregulated and inversely correlated with the promoter methylation level in the placental tissue from PE patients. The in vitro experiments indicated that miR-155 decreased viability, migration, and invasion, but increased apoptosis in trophoblast cells. FOXO3 was confirmed as the target of miR-155. Transfection of the miR-155 inhibitor suppressed inflammation and oxidative stress, but elevated proliferation, migration, and invasion of trophoblast cells, which were abolished by 5-Aza treatment or cotransfection with si-FOXO3. In summary, our data suggested that methylation-mediated silencing of miR-155 can inhibit the apoptosis, inflammation, and oxidative stress of trophoblast cells by upregulating FOXO3.

Expression and role of miR-146a and SMAD4 in placental tissue of pregnant women with preeclampsia.

INTRODUCTION: To investigate the expression of miR-146a in severe preeclampsia (PE) and its effect on trophoblast cell proliferation, invasion and apoptosis, as well as its relationship with SMAD4. MATERIAL AND METHODS: Participants were divided into the severe PE group (n = 30) and the normal group (n = 30). The expression of miR-146a and SMAD4 in placenta tissue was detected by immunohistochemistry, qRT-PCR, and western blot. Trophoblast cell lines HTR-8/SVneo were cultured to detect the expression of miR-146a under the Cobalt chloride (CoCl2 )-simulated hypoxia. The effects of miR-146a transfection on cell proliferation, invasion, apoptosis, and SMAD4 expression were analyzed. RESULTS: Compared with the normal group, miR-146a expression was decreased and the protein and mRNA levels of SMAD4 were increased in placenta tissues of the severe PE group. Our in vitro experiments showed that the expression of miR-146a decreased after CoCl2 treatment. Silencing miR-146a caused increased expression of SMAD4 and decreased expression of VEGF. After transfection with miR-146a inhibitor, compared with the NC group, the invasion and proliferation of HTR-8/Svneo cells were decreased, while the apoptosis was enhanced. CONCLUSION: The expression of miR-146a decreased in severe PE and was negatively correlated with SMAD4 expression. The expression of miR-146a was inhibited under hypoxia, and the low expression of miR-146a affected the proliferation, invasion, and apoptosis of trophoblast cells.

Downregulation of LINC00221 promotes angiopoiesis in HUVEC and inhibits recruitment of macrophages by augmenting miR-542-3p in trophoblast cells.

PURPOSE: To investigate the effects of long intergenic non-protein coding RNA 221 (LINC00221) on preeclampsia (PE) and its mechanism. METHODS: The expression of LINC00221 was detected in placental tissues from PE patients and normal pregnant women (non-PE). Next, the effects of LINC00221 silencing on trophoblast cells (HTR-8/SVneo and JEG-3) and co-cultured HUVECs or macrophages were evaluated. Afterwards, miR-542-3p was confirmed to bind to LINC00221 directly, and miR-542-3p mimics and inhibitors were transfected into trophoblast cells. Next, a rescue experiment was performed to examine the effect of LINC00221/miR-542-3p axis. Finally, the effect of LINC00221 was also verified in vivo in rat PE models. RESULTS: The expression of LINC00221 was higher in placental tissues of PE patients than those of non-PE. LINC00221 silencing significantly reduced MCP1 level and increased the VEGF level in trophoblast cells. LINC00221 knockdown in trophoblast cells remarkably enhanced VEGFR expression and the angiopoiesis of HUVECs, and decreased the migration and invasion of macrophages and reduced TNF-α level. Besides, LINC00221 knockdown decreased CHOP, p-IREα, p-PERK, and iNOS expression and increased Trx expression. Notably, LINC00221 negatively regulated miR-542-3p expression. MiR-542-3p overexpression had an effect to that of LINC00221 knockdown, while miR-542-3p inhibition had the opposite effect. Treatment with miR-542-3p inhibitors partially reversed the protective effect of LINC00221 silencing. PE rat model results were consistent with those of in vitro experiments. CONCLUSIONS: Downregulation of LINC00221 might reduce dysfunction, inflammatory responses, endoplasmic reticulum stress, and oxidative stress, and thereby protect against PE by augmenting miR-542-3p.

Pathogenic variants identified by whole-exome sequencing in 43 patients with epilepsy.

BACKGROUND: Epilepsy is a group of neurological disorders characterized by recurrent epileptic seizures. Epilepsy is affected by many factors, approximately 20-30% of cases are caused by acquired conditions, but in the remaining cases, genetic factors play an important role. Early establishment of a specific diagnosis is important to treat and manage this disease. METHODS: In this study, we have recruited 43 epileptic encephalopathy patients and the molecular genetic analysis of those children was performed by whole-exome sequencing (WES). RESULTS: Fourteen patients (32.6%, 14/43) had positive genetic diagnoses, including fifteen mutations in fourteen genes. The overall diagnostic yield was 32.6%. A total of 9 patients were diagnosed as pathogenic mutations, including 4 variants had been reported as pathogenic previously and 6 novel variants that had not been reported previously. Therefore, WES heralds promise as a tool for clinical diagnosis of patients with genetic disease. CONCLUSION: Early establishment of a specific diagnosis, on the one hand, is necessary for providing an accurate prognosis and recurrence risk as well as optimizing management and treatment options. On the other hand, to unveil the genetic architecture of epilepsy, it is of vital importance to investigate the phenotypic and genetic complexity of epilepsy.

Expression and significance of microRNA-126 and VCAM-1 in placental tissues of women with early-onset preeclampsia.

OBJECTIVE: To investigate the expression of microRNA-126 (miR-126) and vascular endothelial cell adhesion molecule-1 (VCAM-1) in the placental tissues of women with early-onset preeclampsia (EOPE) and their effects on trophoblast invasion. MATERIALS AND METHODS: The placental tissues of 30 pregnant women with EOPE who delivered in the Third Affiliated Hospital of Zhengzhou University from November 2019 to May 2020 were selected as the preeclampsia (PE) group, and the placental tissues of 30 healthy pregnant women with normal prenatal examination were selected as the normal group. Immunohistochemistry was used to localize VCAM-1 in placental tissues，the expression of miR-126 and VCAM-1 in placenta tissues of two groups and HTR-8/SVneo cells transfected with miR-126 were detected by real-time polymerase chain reaction (RT-PCR) and Western blot, and the correlation between them was analyzed. The invasion ability of cells transfected with miR-126 was observed by Transwell invasion test. RESULTS: Compared with the normal group, the expression of miR-126 was higher and VCAM-1 was lower in the placental tissues of the PE group, and the difference were statistically significant (p < 0.01). Moreover, VCAM-1 was negatively correlated with the expression of miR-126 (r = -0.391, p < 0.05). In vitro experiment, the expression level of VCAM-1 in miR-126 mimics transfection group was decreased, and the expression level of VCAM-1 in miR-126 inhibitor transfection group was increased; the invasion ability of HTR-8/SVneo cells transfected with miR-126 mimics was decreased, and the invasion ability of HTR-8/SVneo cells transfected with miR-126 inhibitor was enhanced. CONCLUSION: There was a negative correlation between the expression of miR-126 and VCAM-1 in EOPE.MiR-126 and VCAM-1 may participate in the occurrence and development of EOPE by affecting the invasion ability of trophoblast cells.

A Slug-dependent mechanism is responsible for tumor suppression of p53-stabilizing compound CP-31398 in p53-mutated endometrial carcinoma.

Mutation in the tumor suppressor gene p53 is the most frequent molecular defect in endometrial carcinoma (EC). Recently, CP-31398, a p53-stabilizing compound, has been indicated to possess the ability to alter the expression of non-p53 target genes in addition to p53 downstream genes in tumor cells. Herein, we explore the alternative mechanisms underlying the restoration of EC tumor suppressor function in mutant p53 by CP-31398. A p53-mutated EC cell was constructed in AN3CA cells with restored or partial loss of Slug using lentiviral vectors, followed by treatment with 25 µM CP-31398. A p53-independent mechanism of CP-31398 was confirmed by the interaction between mouse double minute 2 homolog (MDM2) and Slug AN3CA cells treated with IWR-1 (inhibitor of Wnt response 1). Furthermore, the AN3CA cells were treated with short hairpin RNA against Slug, Wnt-specific activators (LiCl) or inhibitors (XAV-939) followed by CP-31398 treatment. Moreover, AN3CA cell proliferation and apoptosis were examined. A tumorigenicity assay was conducted in nude mice. CP-31398 could promote the apoptosis of p53-mutated EC cells, while Slug reversed this effect. Slug ubiquitination was found to occur via binding of Slug to MDM2 in AN3CA cells. We found that CP-31398 increased the GSK-3ß, p-Slug, Puma, Wtp53, and Bax expressions whereas Wnt, Mtp-53, Slug, Bcl-2, and Ki-67 expressions were decreased. However, these findings were reversed following the activation of the Wnt pathway and overexpression of Slug. Finally, the in vivo experimental evidence confirmed that CP-31398 with depleted Slug suppressed tumor growth by downregulating the Slug. Collectively, CP-31398-regulated Slug downregulation represses the p53-mutated EC via the p53/Wnt/Puma pathway.

Does the sex ratio of singleton births after frozen single blastocyst transfer differ in relation to blastocyst development?

PURPOSE: To investigate the associations between blastocyst development and the sex ratio (male:female) among singleton live births resulting from single-blastocyst frozen embryo transfer (FET) cycles. METHODS: Patients with singleton live births following the first autologous single FET of non- preimplantation genetic testing (PGT) blastocysts in a single reproductive medicine department between January 2015 and February 2019 were included in this retrospective study. The primary outcome measure was the singleton sex ratio. Multivariable logistic regression models were used to estimate the associations between blastocyst quality and singleton sex ratio after adjustment for some potential confounders. RESULTS: There were 638 high-quality and 572 poor-quality single blastocyst FETs, and the blastocysts were conceived via 855 IVF and 355 ICSI treatments. A total of 1210 singleton live births were assessed. High-quality single blastocyst FET resulted in a significantly higher sex ratio than did poor-quality single blastocyst FET (60% vs. 49.7%, P < 0.001). The infertility cause was not associated with sex ratio among singleton live births (P = 0.537). The results of a multivariate analysis revealed that a high-quality blastocyst has a 150% higher probability of being male than a poor-quality blastocyst (adjusted odds ratio (aOR) 1.57; 95% CI 1.24-2, P < 0.001). Among the three blastocyst morphological parameters, Grade B trophectoderm was significantly associated with a higher sex ratio than Grade C (aOR 1.71; 95% CI 1.33-2.21. P < 0.001). Neither expansion degree nor inner cell mass degree were significantly associated with the singleton sex ratio. CONCLUSIONS: A single high-quality blastocyst FET has a higher chance of resulting in a male infant than a female infant. The results demonstrate that grade B trophectoderm confers benefits in improving the implantation potential of male blastocysts.

Gene Signatures and Prognostic Values of m6A RNA Methylation Regulators in Ovarian Cancer.

BACKGROUND: N6-methyladenosine (m6A) is the most common form of mRNA modification under the field of "RNA epigenetics." However, its role in ovarian cancer (OC) development is poorly understood. In the current study, we aimed to identify gene signatures and prognostic values of m6A RNA methylation regulators. METHOD: Specifically, we downloaded Mutations and Copy number variant (CNV) data from the TCGA database for 579 OC patients, then analyzed gene expression and prognosis value using integrative bioinformatics. Thereafter, we verified the related biological processes of Wilms' tumor 1-associating protein (WTAP) gene using Gene set enrichment analysis (GSEA). RESULTS: Results showed that almost all ovarian cancer patients (99.31%) have CNVs with at least 1 m6A regulatory gene, whereas 83.76% of cases exhibited concurrence of CNVs in more than 4 m6A regulatory genes. Additionally, alteration of m6A regulators was associated with historical grade, whereas integrative bioinformatics and Cox multivariate model analysis revealed a significant correlation between high WTAP expression and worse ovarian cancer outcomes. Moreover, GSEA revealed that high WTAP expression was associated with cell cycle regulation and MYC targets. CONCLUSION: Overall, our findings demonstrate the significance of high-frequency genetic alterations of m6A RNA methylation regulators and WTAP's poor prognosis value in OC. These findings provide valuable insights into the role of m6A methylation in OC, and will be vital in guiding development of novel treatment therapies.

CP-31398 inhibits the progression of cervical cancer through reversing the epithelial mesenchymal transition via the downregulation of PAX2s.

CP-31398, a styrylquinazoline, emerges from a screen for therapeutic agents that restore the wild-type DNA-binding conformation of mutant p53 to suppress tumors in vivo, but its effects on cervical cancer (CC) remain unknown. Hence, this study aimed to explore the effects CP-31398 has on the CC cells and to investigate whether it is associated with paired box 2 (PAX2) expression. CC cells were treated with different concentrations of CP-31398 (1, 2, 4, 6, 8, and 10 µg/ml) to determine the optimum concentration using fluorometric microculture cytotoxicity assay. After constructing the sh-PAX2 vector, CC cells were transfected with sh-PAX2 or treated with CP-31398. The effects of CP-31398 or PAX2 silencing on CC cell proliferation, apoptosis, invasion, and migration were evaluated. Epithelial mesenchymal transition (EMT)-related genes such as E-cadherin, vimentin, N-cadherin, snail, and twist in CC cells were detected. Tumor formation experiment in nude mice was performed to observe tumor growth. The optimum concentration of CP-31398 was 2 µg/ml. PAX2 was overexpressed in CC cells. CC cells treated with CP-31398 or treated with sh-PAX2 inhibited proliferation, invasion, and migration but promoted apoptosis with decreased PAX2 expression. The EMT process in CC cells was also reversed after treatment with CP-31398 or sh-PAX2. Moreover, the tumor formation experiment in nude mice revealed the inhibitory activity of CP-31398 in CC tumor in nude mice by suppressing PAX2. Our results provide evidence that CP-31398 could inhibit EMT and promote apoptosis of CC cells to curb CC tumor growth by downregulating PAX2.

Identification of a novel splicing mutation in the SLC25A13 gene from a patient with NICCD: a case report.

BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder and one of the most common inherent causes of cholestatic jaundice in Asian infants. Mutations in the SLC25A13 gene, which encodes citrin protein expressed in the liver, have been identified as the genetic cause for NICCD. CASE PRESENTATION: Here, we report a 4-month-old female with clinical features including jaundice, hyperbilirubinemia, hyperlactacidemia, and abnormal liver function. The patient was diagnosed with NICCD by differential diagnosis using genetic analysis. Mutations in 60 jaundice-related genes were tested by using amplicon sequencing, which was performed on an Ion S5XL genetic analyzer. A compound heterozygous mutation in the SLC25A13 gene was identified, consisting of a known deletion SLC25A13:c.852_855delTATG and a novel splicing mutation SLC25A13:c.1841 + 3_1841 + 4delAA. Sanger sequencing for the proband and her parents was performed to validate the result and reveal the source of mutations. CONCLUSION: A compound heterozygous mutation in the SLC25A13 gene was identified in a 4-month-old female patient with NICCD. Our data suggest that amplicon sequencing is a helpful tool for the differential diagnosis of inherited diseases with similar symptoms. Further studies of the mutation spectrum of neonatal jaundice in China are warranted.

Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs.

PURPOSE: To compare the effects of metformin with insulin on maternal and neonatal outcomes in gestational diabetes mellitus (GDM). METHODS: A literature search in PUBMED, EMBASE, Science Direct, Springer link, and Cochrane library was conducted using the following search terms: "Gestational Diabetes" or "GDM", and "insulin" and "metformin". Quality assessment of included studies was determined with Quality Assessment of Diagnostic Accuracy Studies. Review Manger 5.2 was used to analyze mean difference (MD)/risk ratio (RR) and 95 % confidence interval (CI) in random-effects model or fixed-effects model depending on the level of heterogeneity. RESULTS: A total of 11 studies were identified. There was no significant difference of the effect on maternal outcomes between the two treatments in glycohemoglobin A1c levels (P = 0.37), fasting blood glucose (P = 0.66), and the incidence of preeclampsia (P = 0.26); whereas, significantly reduced results were found in the metformin group in pregnancy-induced hypertension (PIH) rate (RR = 0.53, 95 % CI 0.31-0.90, P = 0.02), average weight gains after enrollment (MD = -1.28, 95 % CI -1.54 to -1.01, P < 0.0001), and average gestational ages at delivery (MD = 0.94, 95 % CI -0.21 to -0.01, P = 0.03). Regarding neonatal outcomes, when compared with insulin group, metformin presented significantly lower average birth weights (MD = -44.35, 95 % CI -85.79 to -2.90, P = 0.04), incidence of hypoglycemia (RR = 0.69, 95 % CI 0.55-0.87, P = 0.001) and neonatal intensive care unit (NICU) (RR = 0.82, 95 % CI 0.67-0.99, P = 0.04). CONCLUSION: Metformin can significantly reduce several adverse maternal and neonatal outcomes including PIH rate, incidence of hypoglycemia and NICU, thus it may be an effective and safe alternative or additional treatment to insulin for GDM women.

[Relationship between disintegrin and metalloproteinase gene polymorphism of bronchial asthma and its severity in Uygur population].

OBJECTIVE: To explore the relationship between disintegrin and metalloproteinase (ADAM33) gene polymorphism of bronchial asthma and its severity in Xinjiang Uygur population. METHODS: From January to December 2009, a total of 126 consecutive Uighur asthmatics with a definite diagnosis at First Affiliated Hospital of Xinjiang Medical University were assigned into intermittent mild (n = 62), moderate (n = 39) and severe (n = 25) groups according to the severity of illness. The control group was a 1: 1 paired population from healthy subjects matched similarly with regards to gender, race, residence and age (with a difference <5 years). The ADAM33 gene polymorphisms of F+1, S+1, T1, T2 and V4 locus allele in each group were tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: In ADAM33, the distribution of T1, T2 and V4 locus allele in asthmatics and controls had a significant difference (χ² = 8.064, P = 0.018; χ² = 8.013, P = 0.018 and χ² = 11.737, P = 0.003). The distribution of allelic frequency showed that all T1 (C), T2 (A) and V4 (G) locus allele increased the relative risk degree of asthmatics (OR = 2.080, 2.139 and 1.912). The distribution frequency of T1 (TC and TT), T2 (AG and GG), V4 (GG and CC) genotypes in mild, moderate and severe groups had significant differences (all P < 0.05).Linkage disequilibrium analysis showed that in asthmatics, the presence of Hap2 (CATGC) was much lower than controls (20.4% vs 30.4%; χ² = 6.597, P = 0.010) while Hap4 (CACAC) and Hap5 (TACAG) were much higher than those in controls (9.6% vs 4.8% and 6.8% vs 2.8%; χ² = 4.545, P = 0.033 and χ² = 4.377, P = 0.036). CONCLUSIONS: The ADAM33 gene polymorphism of T1, T2 and V4 locus allele may be associated with asthma and its severity in Xinjiang. And Uighur population may have both susceptible and protective haplotypes of asthmatics.

[Relationship between letrozole administration during the luteal phase after oocyte retrieval and the early-stage ovarian hyperstimulation syndrome oocurrence].

OBJECTIVE: To investigate the effect of letrozole in decreasing the early-stage ovarian hyperstimulation syndrome (OHSS) occurrence during the luteal phase for patients of OHSS high-risk after oocyte retrieval. METHODS: A total of 176 high-risk OHSS patients were randomly divided into two groups after oocyte retrieval. Patients in experiment group (n = 86) received 5 mg letrozole per day from the retrieval day and last for 5 days. Others in control group (n = 90) received placebo. The serum concentration of FSH, LH, estradiol (E2), progesterone (P) and vascular endothelial growth factor (VEGF) from the day of hCG injection to days after injection (5 days, 8 days, 10 days) were measured. And the incidence of moderate and severe OHSS was observed. RESULTS: The concentration of E2 on the indicated days (5 days, 8 days, 10 days after hCG injection) in experiment group and control group were (5 727±2 089) versus (11 826±4 281) pmol/L, (1 613±879) versus (7 925±3 507) pmol/L, (193± 90) versus (1 628±888) pmol/L; the concentration of VEGF on the indicated days in the two groups were (80±14) versus (108±19) ng/L, (66±11) versus (126±14) ng/L, (48±7) versus (148±14) ng/L; the concentration of E2 and VEGF were lower than those in control group (all P < 0.01). The FSH concentration in experiment group were (2.1±1.1) and (3.5±1.3) U/L on the day of fifth and eighth day after hCG injection, which were significantly higher than (0.7±0.3) and (0.7±0.4) U/L in control group (P < 0.05); the LH concentration in experiment group were (0.26±0.19) and (0.72±0.60) U/L on the day of fifth and eighth day after hCG injection, which were significantly higher than (0.11±0.03) and (0.14±0.08) U/L in control group (P < 0.05). The incidence of moderate and severe OHSS was signicantly decreased after letrozole treatment compared with control group [2% (2/86) versus 12% (11/90), P < 0.05]. CONCLUSION: Administration of 5 mg/d letrozole for 5 days during the luteal phase can reduce the E2 and VEGF levels for the high-risk OHSS patients who needed cryopreserve all embryos, and also reduce the occurrence of early OHSS.

Application of Uterine Artery Embolization in Patients With Placenta Accreta Spectrum After Abdominal Aortic Balloon Occlusion.

OBJECTIVE: To evaluate the application of different uterine artery embolization procedures under balloon occlusion of the abdominal aorta in patients with Placenta Accreta Spectrum (PAS) undergoing cesarean section. MATERIALS AND METHODS: A retrospective analysis was performed on clinical data from 72 patients who underwent uterine artery embolization for hemostasis during cesarean section with PAS. The patients were divided into two groups according to the embolization method used during surgery: group A (n = 43) underwent uterine artery embolization by withdrawing the balloon and inserting a Cobra catheter into the uterine artery for embolization, while group B (n = 29) underwent uterine artery embolization with a Cobra catheter inserted via contralateral puncture of the femoral artery and balloon occlusion. General information, surgical data, and postoperative recovery were compared between the 2 groups. RESULTS: The bleeding and transfusion volumes were lower in group B than in group A and the differences between the 2 groups were statistically significant. There were no significant differences in surgical duration, number of embolized vessels, length of hospital stay, postoperative complications, or menstrual recovery between the 2 groups. CONCLUSION: For patients with PAS undergoing cesarean section, uterine artery embolization for hemostasis is preferably performed by inserting a Cobra catheter via contralateral puncture of the femoral artery under abdominal aortic balloon occlusion.

AP-2α suppresses invasion in BeWo cells by repression of matrix metalloproteinase-2 and -9 and up-regulation of E-cadherin.

Preeclampsia complicates 5-10% of pregnancies and is a leading cause of maternal/fetal morbidity and mortality. Although the cause is unknown, the reduced migration/invasion of extravillous trophoblasts is generally regarded as a key feature of preeclampsia genesis. The present study examined the expression of activator protein-2α (AP-2α), tissue inhibitor of metalloproteinase 2 (TIMP-2), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and E-cadherin in severe preeclamptic placentas and normal placentas using real-time PCR and immunohistochemistry. The expression levels of AP-2α, TIMP-2, and E-cadherin were elevated, while MMP-2 and MMP-9 levels were decreased in severe preeclamptic placentas when compared with normal placentas. To explore the underlying molecular mechanisms, BeWo cells were transfected with an AP-2α-expression construct as well as a siRNA against AP-2α. The over-expression of AP-2α decreased the invasive abilities of BeWo cells. AP-2α induction was followed by the induction of TIMP-2 and E-cadherin and a significant reduction of MMP-2 and MMP-9. Whereas in AP-2α-silencing BeWo cells, we observed the decreased expression of TIMP-2 and E-cadherin and the increased expression of MMP-2 and MMP-9. We presume that AP-2α may suppress trophoblast invasion by repression of MMP-2 and MMP-9 and up-regulation of E-cadherin, thus leading to shallow placentation in severe preeclampsia.