Background
Kidney disease of children markedly affects their health and development. Limited clinical data of early‐stage kidney disease render a tremendous challenge for the accurate diagnosis. Trio ...whole‐exome sequencing (Trio‐WES) is emerging as a first‐line diagnostic strategy in pediatric kidney disease, and shows important implications for the precision medicine strategies of children with kidney disease.
Methods
Trio‐WES was performed in 133 Chinese children with kidney disease and their parents. The results for casual variants in genes known to cause kidney disease were analyzed. We further assessed the genetic diagnostic yield and the clinical implications of genetic testing.
Results
An overall diagnostic yield of 52.63% (70/133) was found, and the diagnostic rates ranged from 44.74% to 59.62% in different clinical phenotypes. The diagnostic yield of the three groups of simple proteinuria, renal insufficiency, and “other” was 50%, 50%, and 54.55%, respectively. Eight‐seven diagnostic variants were identified in 70 probands with variants spanning 30 genes. The top 7 genes with diagnostic variants were COL4A5 (23, 26.44%), COL4A4 (13, 14.94%), ADCK4 (7, 8.05%), CLCN5 (3, 3.45%), ACE (3, 3.45%), PKD1 (3, 3.45%), and SLC12A3 (3, 3.45%), accounting for 63.22% of all variations in the cohort.
Conclusions
The retrospective cohort study summarized the clinical utility of genetic testing in 133 probands, and expanded the phenotypic and genetic profiles of kidney disease in children. Trio‐WES is an efficient diagnostic tool for children with kidney disease, which facilitates the clinical diagnosis and treatment. Our findings have important implications for the precise diagnosis of childhood nephropathy and may provide clinical guideline for disease management.
Our findings have important implications for the precise diagnosis of childhood nephropathy and may provide clinical guideline for disease management.
Background:
A fetal bronchogenic cyst (BC) is a rare congenital anomaly with an incidence of 0.147–0.238‰. The coronavirus disease 2019 (COVID-19) pandemic, as a particular situation, hindered ...pregnant women from receiving periodic prenatal checkups.
Case Description:
Until 34
+6
weeks of gestation, a fetal case of the intrathoracic cyst was found by ultrasound examination. Further, MRI examination confirmed the diagnosis of the congenital mediastinal cystic lesion, probably a BC. Genetic testing was not conducted due to the COVID-19 pandemic. At 38
+5
weeks of gestation with maternal COVID-19 testing negative, a live girl was delivered by cesarean section. Five months later, the child underwent bronchocystectomy, and the postoperative pathological lesions confirmed a (right upper mediastinum) BC.
Conclusion:
Herein, we reported the prenatal and postnatal management for a rare case of the congenital BC by multidisciplinary approaches during the COVID-19 pandemic. Fetal MRI and screening for fetal chromosomal abnormalities are especially recommended. This case contributes to the awareness that the COVID-19 pandemic interferes with regular follow-up schedules during pregnancy and may interfere with timely performed additional tests; which leads to more accurate genetic counseling. A combination of multidisciplinary approaches, including radiology, infection control, genetic counseling, obstetrics, and pediatric surgery, is pivotal for managing fetal BC during the COVID-19 pandemic.
Our previous studies demonstrated that prenatal caffeine exposure causes intrauterine growth retardation (IUGR), fetuses are over-exposed to high levels of maternal glucocorticoids (GC), and ...intrauterine metabolic programming and associated metabonome alteration that may be GC-mediated. However, whether maternal metabonomes would be altered and relevant metabolite variations might mediate the development of IUGR remained unknown. In the present studies, we examined the dose- and time-effects of caffeine on maternal metabonome, and tried to clarify the potential roles of maternal GCs and metabonome changes in the metabolic programming of caffeine-induced IUGR. Pregnant rats were treated with caffeine (0, 20, 60 or 180mg/kg·d) from gestational days (GD) 11 to 20, or 180mg/kg·d caffeine from GD9. Metabonomes of maternal plasma on GD20 in the dose–effect study and on GD11, 14 and 17 in the time–course study were analyzed by 1H nuclear magnetic resonance spectroscopy, respectively. Caffeine administration reduced maternal weight gains and elevated both maternal and fetal corticosterone (CORT) levels. A negative correlation between maternal/fetal CORT levels and fetal bodyweight was observed. The maternal metabonome alterations included attenuated metabolism of carbohydrates, enhanced lipolysis and protein breakdown, and amino acid accumulation, suggesting GC-associated metabolic effects. GC-associated metabolite variations (α/β-glucoses, high density lipoprotein-cholesterol, β-hydroxybutyrate) were observed early following caffeine administration. In conclusion, prenatal caffeine exposure induced maternal GC elevation and metabonome alteration, and maternal GC and relevant discriminatory metabolites might be involved in the metabolic programming of caffeine-induced IUGR.
•Prenatal caffeine exposure elevated maternal blood glucocorticoid levels.•Prenatal caffeine exposure altered maternal blood metabonomes.•Maternal metabonome alterations were associated with glucocorticoid elevation.•Maternal metabonomes were altered at early stage after caffeine exposure.•Maternal glucocorticoid and associated metabolites may be involved in fetal programming.
Background
Birthweight have profound impacts on health status throughout lifetime, however, the relationship between maternal ferritin level in pregnancy and birthweight of the newborn remains ...controversial.
Objective
This retrospective cohort research was to analyze the association between maternal ferritin levels during pregnancy with birthweight outcomes, primarily for low birthweight (LBW) and small for gestational age (SGA).
Methods
Newborns weighing lower than 2,500 grams were defined as LBW. SGA is defined as birthweight lower than the 10
th
percentile of the distribution of newborns' birthweight of the same gestational age. Multivariable logistic regressions have been used to explore the association of maternal ferritin levels and birthweight related outcomes, in which the ferritin concentration was logarithm transformed in the model. We further used restricted cubic spline models to explore linear/non-linear dose–response manners of ferritin level and birthweight outcomes.
Results
A total of 3,566 pregnant women were included in the study. In the results of the present study, we observed that maternal ferritin levels were linearly associated with the risk of LBW (
p-
trend = 0.005) and SGA (
p-
trend = 0.04), with the adjusted odds ratios (ORs) of 1.78 (95% CI 1.37–2.32) for LBW and 1.87 (95% CI 1.38–2.54) for SGA with an increase in Ln-ferritin concentrations per unit. The adjusted ORs across quartiles of ferritin levels were 2.14 (95% CI 1.03–4.47) for Quartile 2, 3.13 (95% CI 1.47–6.69) for Quartile 3, and 3.63 (95% CI 1.52–8.68) for Quartile 4 for LBW. The adjusted ORs of LBW and SGA among women using supplemental iron were 0.56 (95% CI 0.38, 0.85) and 0.65 (95% CI 0.40, 1.05) compared with non-users, respectively.
Conclusions
Our findings found a linear dose–response relationship between ferritin levels and an increased risk of poor birthweight outcomes, suggesting that maternal ferritin level during pregnancy may provide an additional predictor for differentiating poor birthweight related outcomes. Further exploration should be conducted to ensure maternal ferritin thresholds and iron supplement doses.
Compared with other types of hydrogels, natural derived hydrogels possess intrinsic advantages of degradability and biocompatibility. However, due to the low mechanical strength, their potential ...applications in biomedical areas are limited. In this study, Hofmeister effect-enhanced gelatin/oxidized dextran (Gel/O-Dex) hydrogels were designed with improved mechanical properties and biocompatibility to accelerate wound healing. Gel and O-Dex were chemically crosslinked through Schiff base reaction of aldehyde and amino groups. After soaking in kosmotrope solutions physical crosslinking domains were induced by Hofmeister effect including α-helix structures, hydrophobic interaction regions and helical junction zones among Gel molecular chains. The type of anions played different influence on the properties of hydrogels, which was consistent with the order of Hofmeister series. Particularly, H2PO4− treated hydrogels showed enhanced mechanical strength and fatigue resistance superior to that of Gel/O-Dex hydrogels. The underlying mechanism was that the physical crosslinking domains sustained additional mechanical stress and dissipated energy through cyclic association and dissociation process. Furthermore, Hofmeister effect only induced polymer chain entanglements without triggering any chemical reaction. Due to Hofmeister effect of H2PO4− ions, aldehyde groups were embedded in the center of entangled polymer chains that resulted in better biocompatibility. In the full-thickness skin defects of SD rats, Hofmeister effect-enhanced Gel/O-Dex hydrogels by H2PO4− ions accelerated wound healing and exhibited better histological morphology than ordinary hydrogels. Therefore, Hofmeister effect by essential inorganic anions is a promising method of improving mechanical properties and biocompatibility of natural hydrogels to promote medical translation in the field of wound healing from bench to clinic.
Hofmeister effect enhanced hydrogel mechanical properties in accordance with the order of Hofmeister series through physical crosslinking that induced α-helix structures, hydrophobic interaction regions and helical junction zones among Gel molecular chains. Due to the Hofmeister effect of H2PO4− ions, aldehyde groups were embedded in the center of entangled polymer chains that resulted in better biocompatibility. Hofmeister effect-enhanced Gel/O-Dex hydrogels through H2PO4− ions accelerated wound healing and exhibited better histological morphology than ordinary hydrogels. Therefore, Hofmeister effect by essential inorganic anions is a promising method to improve mechanical properties and biocompatibility of natural hydrogels for their medical applications..
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Background
Placental mosaicism is one of the major reasons for noninvasive prenatal testing (NIPT) discrepancy. Herein, we discovered a rare case of placenta with complex karyotypes that caused ...false‐positive and false‐negative results in noninvasive prenatal testing.
Methods
Next‐generation sequencing (NGS) and Quantitative fluorescent polymerase chain reaction (QF‐PCR) were performed on the cord blood sample, fetal tissues, and eight placental biopsies. Fluorescent In Situ Hybridization (FISH) and karyotyping were also carried to confirm the fetal genome status.
Results
The results suggested that the fetal chromosome was 47,XXX and the placenta had three karyotypes of 48,XXX,+21, 47,XX,+21, and 47,XXX. QF‐PCR indicated that the extra chromosome 21 and chromosome X were all from the father. It is speculated that the zygote may have 48,XXX,+21 karyotype and trisomy rescue could be the main mechanism for the development of the homogeneous fetus and complex mosaic placenta.
Conclusion
Overall, the complicated nature of our case underlines the importance of discussing with parents the possibility of both atypical and discordant results during preconfirmatory amniocentesis counseling and consent.
The composition of the unusual placental mosaicsim that caused NIPT discrepancy was complex. The karyotype for the paternal sperm may be an unusual diploid gamete (25,XX,+21) and zygote is likely to be a double trisomy (48,XXX,+21). After the fifth cleavage, the zygote grows into a morula and then into a blastocyst. The blastocyst contains two major part of compositions. One is the inner cell mass (yellow), which develops into the embryo (the homogeneous 47,XXX). The other is trophoblast cells (blue), which develops with some inner cell mass into the placenta (the mosaic 47,XXX, 47,XX,+21 or 48,XXX,+21).
The facts that LPA is present at high concentration in ovarian cancer patients' ascites and it may serve as a stimulator to cell migration, implicate the role of LPA in the ovarian cancer metastasis. ...Since LPA mediates various biological functions through its interaction with LPA receptors, we aim to investigate the correlation between the expression of LPA receptors and the metastasis of ovarian cancer.
To test whether the LPA responsiveness correlated with the metastatic capability of ovarian cancer cells, we performed LPA induced invasion assay and peritoneal metastatic colonization assay with a panel of established human ovarian cancer cell lines. The expression of LPAR1-3 in different ovarian cancer lines was examined by qRT-PCR. We also tested the effects of LPAR1 inhibition or overexpression on ovarian cancer cell's invasiveness. To confirm our laboratory results, we detected LPARs expression in specimens from 52 ovarian cancer patients by qRT-PCR and immunohistochemistry.
Thirteen ovarian cancer cells were enrolled in the invasion assay. Ovarian cancer cell lines which responded well to LPA-induced invasion, also displayed good capability for metastatic colonization. On the contrary, cell lines with poor LPA responsiveness showed inferior metastatic potential in peritoneal colonization assay. High expression level of LPAR1 was detected in all of the metastatic ovarian cancer cell lines. T-test showed that LPAR1, not LPAR2 or LPAR3, expression was significantly higher in the metastatic cell lines than in the non-metastatic cell lines (P = 0.003). Furthermore, silencing LPAR1 alone could significantly reduce LPA-induced invasion (P < 0.001). Finally, we analyzed the correlation between the LPARs expression and clinicopathological features of the clinical cases. It indicated that LPAR1 expression rate increased significantly along with the more advanced stages (stage I: 16.67 %; II 50.00 %; III: 75.00 %; and IV: 100.00 %; P = 0.003). Besides that, LPAR1 expression was detected in all the 13 cases with abdominal metastasis more than 2 cm, 10 cases with retroperitoneal lymph node metastasis and 6 cases with hepatic metastasis. Moreover, the expression rate of LPAR2 significantly increased in ovarian cancer than in normal specimens (P = 0.039). LPAR3 expression showed the same trend as LPAR2, though the difference is not statistically significant (P = 0.275). Besides that LPAR2 and LPAR3 expression increased along with poorer differentiation (P = 0.002, P = 0.034, respectively).
Metastatic capability of ovarian cancer cells correlated well with their responsiveness to LPA for cell invasion. LPAR1 acts as the main mediator responsible for LPA-stimulated ovarian cancer cell invasion. LPAR2 and LPAR3 might play an role in carcinogenesis of ovarian cancer.
To investigate the mechanisms of lysophosphatidic acid (LPA) in stimulating invasion and metastatic colonization of ovarian cancer cells.
The metastatic ability in vivo of ovarian cancer SK-OV3, HEY, ...OVCAR3, and IGROV1 cells was determined in tumor-bearing nude mouse models. Matrigel assay was used to detect the changes of response in vitro of ovarian cancer cells to LPA after Rac(-) or Rac(+) adenovirus treatment. LPA-induced Rho GTPase activation was detected by GST-fusion protein binding assay.
The peritoneal metastatic colonization assay showed overt metastatic colonization in mice receiving SK-OV3 and HEY cell inoculation, indicating that they are invasive cells. Metastatic colonization was not detected in animals receiving OVCAR3 and IGROV1 cells, indicating that these cells are non-invasive cells. In the matrigel invasion assay, exposure to LPA led to a notably greater migratory response in metastatic SK-OV3 and HEY cells (Optical density: SK-OV3 cells: 0.594±0.023 vs. 1.697±0.049, P<0.01; HEY cells: 0
•Epigenetic markers undergo changes during endometrial stromal cell decidualisation.•Environmentally relevant Bisphenol A (BPA) level affects MLL1 and EZH2 expression.•Environmentally relevant BPA ...level influences decidual marker gene expression.
Bisphenol A(BPA) is one of the most widespread endocrine disruptors in the environment and is associated with reproductive diseases. In this study, we focused on the correlation between environmentally relevant levels of BPA exposure and histone modification during endometrial stromal cells decidualization. BPA exposure changed the morphology of decidualized endometrial stromal cells, with inhibition of mixed-lineage leukemia 1(MLL1) and induction of enhancer of zeste homolog2 (EZH2) during in vitro decidualization. The expression of HOXA10, PRL and IGFBP-1 was down-regulated upon BPA treatment. Furthermore, chromatin immunoprecipitation quantitative PCR(ChIP-qPCR) was performed to evaluate the recruitment of histone-3, lysine-4 trimethylation (H3K4me3) and histone-3, lysine-27 trimethylation (H3K27me3) at the gene promoters. The decreased H3K4me3 and the increased H3K27me3 at HOXA10, PRL and IGFBP-1 promoter regions were consistent with the expression of MLL1 and EZH2 respectively. The effect of BPA on MLL1 and EZH2 could be abrogated by ICI 182,780. Our study provides the first indication that environmentally relevant levels of BPA exposure can regulate the expression of decidualization-related genes by affecting histone modification, impairing endometrial decidualization.
Preeclampsia is one of the most important complications during pregnancy and the leading cause of maternal morbidity and mortality; however, the pathogenesis of preeclampsia remains partially ...misunderstood. The aim of this study was to identify placenta-derived exosomal microRNAs (miRNAs) involved in the preeclampsia process.
Peripheral blood was collected from normal and preeclampsia pregnant women, and placenta-derived exosomes were extracted. Small RNA sequencing was performed to identify the exosomal miRNAs involved in preeclampsia. The function of a differentially expressed exosomal miRNA was verified.
The extracted exosomes presented round or ovallike structures with diameters of approximately 80 nm and could be recognized by antibodies against CD9, CD81, and placental alkaline phosphatase. A total of 1013 exosomal miRNAs were identified by small RNA sequencing, of which 946 were known miRNAs and 67 were novel miRNAs. Twenty-six miRNAs were identified as differentially expressed when comparing the data of the preeclampsia and normal groups. One of the differentially expressed miRNAs, hsa-miR-370-3p, which was upregulated in the preeclampsia group, was shown to bind to the 3' untranslated region of C-X-C motif chemokine 12, a chemokine that plays important role during preeclampsia process. Moreover, functional analysis revealed that hsamiR-370-3p could inhibit proliferation, migration, and invasion while promoting apoptosis of HTR-8/SVneo cells.
A total of 1013 placenta-derived exosomal miRNAs were identified by small RNA sequencing, of which 26 were differentially expressed. The function of one differentially expressed miRNA (hsa-miR-370-3p) was verified. Our results provide new perspectives on the pathogenesis of preeclampsia and potential biomarkers for preeclampsia diagnosis.
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