Association of antenatal corticosteroids with mortality and morbidities in very preterm infants born to women with hypertensive disorders of pregnancy: a multicenter prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) is the most common cause of indicated preterm delivery, but the impact of prenatal steroid exposure on the outcomes of preterm infants born to HDP mothers, who may be at risk for intrauterine hypoxia-ischemia, remains uncertain. The study objective is to evaluate the mortality and morbidities in HDP for very preterm infants (VPIs) exposed to different course of ANS. METHODS: This is a prospective cohort study comprising infants with < 32 weeks gestation born to women with HDP only from 1 Jan. 2019 to 31 Dec. 2021 within 40 participating neonatal intensive care units (NICUs) in Sino-northern network. ANS courses included completed, partial, repeated, and no ANS. Univariate and multivariable analyses were performed on administration of ANS and short-term outcomes before discharge. RESULTS: Among 1917 VPIs born to women with HDP only, 987(51.4%) received a complete course of ANS within 48 h to 7 days before birth, 560(29.2%) received partial ANS within 24 h before delivery, 100(5.2%) received repeat ANS and 270 (14.1%) did not receive any ANS. Compared to infants who received complete ANS, infants unexposed to ANS was associated with higher odds of death (AOR 1.85; 95%CI 1.10, 3.14), Severe Neurological Injury (SNI) or death (AOR 1.68; 95%CI 1.29,3.80) and NEC or death (AOR 1.78; 95%CI 1.55, 2.89), the repeated ANS group exhibits a significant negative correlation with the duration of oxygen therapy days (correlation coefficient - 18.3; 95%CI-39.2, -2.1). However, there were no significant differences observed between the full course and partial course groups in terms of outcomes. We can draw similar conclusions in the non-SGA group, while the differences are not significant in the SGA group. From KM curve, it showed that the repeated group had the highest survival rate, but the statistical analysis did not indicate a significant difference. CONCLUSIONS: Even partial courses of ANS administered within 24 h before delivery proved to be protective against death and other morbidities. The differences mentioned above are more pronounced in the non-SGA group. Repeat courses demonstrate a trend toward protection, but this still needs to be confirmed by larger samples.

Sudden unexpected death from subvalvular hemorrhagic cyst complicated with coronary heart disease in an adult.

Cardiac blood cysts are rare benign tumors. It is commonly found in the heart valve and left ventricle of newborns by autopsy and is rarely seen in adults [1, 2]. The typical histopathology of cardiac blood cysts is a closed, round, blood-containing cystic mass attached to the heart valve or endocardium. This article reports a rare case of sudden death due to a giant subaortic cardiac blood cyst with coronary heart disease in an adult patient and summarizes the pathological features, aiming to provide a reference for the forensic pathological identification of cardiac blood cysts.

[Polymorphism and Mutation Rate of 20 Rapidly Mutating Y-Chromosomal Short Tandem Repeats in Chinese Han Population of Sichuan Province].

Objective: To explore the applicability of 20 rapidly mutating Y-chromosomal short tandem repeats (RM Y-STRs) in Chinese Han population of Sichuan province. Methods: Two RM Y-STR multiple amplification systems (RM1, including DYF404S1, DYF399S1, DYS547, DYS526a/b, DYS626, DYF403S1a/b, and DYS612, and RM2, including DYS1003, DYS1007, DYR88, DYS712, DYS711, DYS724, and DYF1002, with 14 RM Y-STR loci in total) and Y41SE-V1.2 (including 6 RM Y-STR loci of DYS627, DYS576, DYF387S1, DYS518, DYS570, and DYS449, 30 ordinary Y-chromosomal short tandem repeats [Y-STR] loci, and 1 Indel locus) were used for the amplification and typing of 200 unrelated males and 260 father-son pairs. The polymorphisms and mutation rates of 20 RM Y-STRs and 30 ordinary Y-STRs in Chinese Han population of Sichuan province were investigated and compared. Results: In the 200 unrelated males, the gene diversity (GD) of 20 RM Y-STR loci ranged from 0.7910 to 0.9975, and there were 200 haplotypes. Haplotype diversity (HD) was 1 and the discriminative capacity (DC) was 1. A total of 198 haplotypes were found in Y41se-v1.2 (the 30 Y-STRs), with 4 cases sharing two haplotypes, the haplotype diversity being 0.9999, and the discriminative capacity being 0.99. A total of 68 mutations were found at the 20 RM Y-STRs loci in the 260 father-son pairs, and there was slightly more increase than decrease of allele repeats (1.19∶1), with the mutation rate ranging from <3.85×10 -3 (95% C I: 0.00-1.41×10 -2) to 2.69×10 -2 (95% CI: 1.09×10 -2-5.47×10 -2), and the average mutation rate being 1.19×10 -2 (95% CI: 9.20×10 -3-1.51×10 -2). The 20 RM Y-STRs and the Y41SE-V1.2 (the 30 Y-STRs) could be used to distinguish 22.3% and 13.8% father-son pairs, respectively. Conclusion: The 20 RM Y-STRs have high gene and haplotype diversity and paternal lineage differentiation rate in Chinese Han population of Sichuan province, showing great potential for application in Chinese Han population of Sichuan province.

Association between admission hypothermia and outcomes in very low birth weight infants in China: a multicentre prospective study.

BACKGROUND: The objective of this prospective, multicentre, observational cohort study was to evaluate the association between admission hypothermia and neonatal outcomes in very low-birth weight (VLBW) infants in multiple neonatal intensive care units (NICUs) in China. METHODS: Since January 1, 2018, a neonatal homogeneous cooperative research platform-Shandong Neonatal Network (SNN) has been established. The platform collects clinical data in a prospective manner on preterm infants with birth weights (BWs) < 1500 g and gestational ages (GAs) < 34 weeks born in 28 NICUs in Shandong Province. These infants were divided into normothermia, mild or moderate/severe hypothermia groups according to the World Health Organization (WHO) classifications of hypothermia. Associations between outcomes and hypothermia were tested in a bivariate analysis, followed by a logistic regression analysis. RESULTS: A total of 1247 VLBW infants were included in this analysis, of which 1100 infants (88.2%) were included in the hypothermia group, 554 infants (44.4%) in the mild hypothermia group and 546 infants (43.8%) in the moderate/severe hypothermia group. Small for gestational age (SGA), caesarean section, a low Apgar score at 5 min and intubation in the delivery room (DR) were related to admission hypothermia (AH). Mortality was the lowest when their admission temperature was 36.5 ~ 37.5 °C, and after adjustment for maternal and infant characteristics, mortality was significantly associated with AH. Compared with infants with normothermia (36.5 ~ 37.5 °C), the adjusted ORs of all deaths increased to 4.148 (95% CI 1.505-11.437) and 1.806 (95% CI 0.651-5.009) for infants with moderate/severe hypothermia and mild hypothermia, respectively. AH was also associated with a high likelihood of respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH), and late-onset neonatal sepsis (LOS). CONCLUSIONS: AH is still very high in VLBW infants in NICUs in China. SGA, caesarean section, a low Apgar score at 5 min and intubation in the DR were associated with increased odds of hypothermia. Moderate/severe hypothermia was associated with mortality and poor outcomes, such as RDS, IVH, LOS.

Pectolinarin inhibits proliferation, induces apoptosis, and suppresses inflammation in rheumatoid arthritis fibroblast-like synoviocytes by inactivating the phosphatidylinositol 3 kinase/protein kinase B pathway.

Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs), a pathological hallmark of rheumatoid arthritis (RA), exhibit the characteristics of tumor cells. The extracts of Cirsium japonicum var. ussuriense have been shown to possess antitumor and anti-inflammatory activities. Our study aimed to investigate the effects of pectolinarin, a flavonoid compound isolated from C. japonicum var. ussuriense, on RA. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Apoptosis was determined by flow cytometry analysis and Western blot analysis of Bax and Bcl-2 levels. Inflammation was assessed by detecting the expressions and secretion of interleukin (IL)-6 and IL-8 using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The production of nitric oxide (NO) and prostaglandin E2 (PGE2) was also measured. The effects of pectolinarin on the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway were examined by Western blot. We found that pectolinarin significantly inhibited cell viability at 24 and 48 hours in a dose-dependently manner in RA-FLSs. Pectolinarin reduced the apoptotic rate, increased Bax level, and decreased Bcl-2 level in RA-FLSs. Pectolinarin inhibited the messenger RNA expression and secretion of IL-6 and IL-8, as well as the production of PGE2 and NO in RA-FLSs. Furthermore, pectolinarin inactivated the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway in RA-FLSs. Activation of the PI3K/Akt pathway by 740Y-P impaired the effects of pectolinarin on cell viability, apoptosis, and inflammation in RA-FLSs. In conclusion, pectolinarin suppressed cell proliferation and inflammatory response and induced apoptosis in RA-FLSs via inactivation of the PI3K/Akt pathway.

Neonatal mortality and morbidity among infants between 24 to 31 complete weeks: a multicenter survey in China from 2013 to 2014.

BACKGROUND: The outcome of preterm infants has been varied in different hospitals and regions in developing countries. Regular clinical monitor are needed to know the effects of health care. This study aimed to describe the survival and morbidity rates of extreme to very preterm infants in 15 neonatal-intensive care hospitals in China. METHODS: Data were collected from January 1, 2013 to December 31, 2014 for preterm neonates with gestational age (GA) between 24 and 31 complete weeks born in hospitals from our collaborative study group. The primary outcomes were survival and major morbidities prior to hospital discharge. Major morbidities included bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), patent ductus arteriosus (PDA) and sepsis. Mutivariate logistic regression was used to analyze the risk factor influencing on the outcomes. RESULTS: The preterm birth rate was 9.9 % (13 701/138 240). The proportion of extreme to very preterm infants was 1.1 % and 11.8 % respectively. The survival rate prior to discharge was increased with increasing GA (0, 24 weeks; 28 %, 25 weeks; 84.8 %, 26 weeks; 83.5 %, 27 weeks; 87.4 %, 28 weeks; 90.7 %, 29 weeks; 93.9 %, 30 weeks; 96 %, 31 weeks). Rate of survival and without severe morbidity according to GA were 0 at 24 weeks, 8 % at 25 weeks, 60.6 % at 26 weeks; 53.2 % at 27 weeks; 62.3 % at 28 weeks; 67.9 % at 29 weeks; 79.1 % at 30 weeks, 85.8 % at 31 weeks respectively. Rate of antenatal steroid use was 56 %. The antenatal steroid use was lower in GA < 28 weeks infants than that in GA between 28 and 32 weeks (28-44.3 % vs 49.7-60.1 %, P < 0.05). Infants at the lowest GAs had a highest incidence of morbidities. Overall, 58.5 % had respiratory distress syndrome, 12.5 % bronchopulmonary dysplasia, 3.9 % necrotizing enterocolitis, 15.4 % intraventricular hemorrhage, 5.4 % retinopathy of prematurity, 28.4 % patent ductus arteriosus, and 9.7 % sepsis. Mortality and morbidity were influenced by gestational age (OR = 0.891, 95 % CI: 0.796-0.999, p = 0.0047 and OR = 0.666, 95 % CI: 0.645-0.688, p = 0.000 respectively), birth weight (OR = 0.520, 95 % CI: 0.420-0.643, p = 0.000 and OR = 0.921, 95 % CI: 0.851-0.997, p = 0.041 respectively), SGA (OR = 1.861, 95 % CI: 1.148-3.017, p = 0.012 and OR = 1.511, 95 % CI: 1.300-1.755, p = 0.000 respectively), Apgar score <7 at 5 min (OR = 1.947, 95 % CI: 1.269-2.987, p = 0.002 and OR = 2.262, 95 % CI: 1.950-2.624, p = 0.000 respectively). The survival rate was increased with more prenatal steroid use (OR = 1.615, 95 % CI: 1.233-1.901, p = 0.033). CONCLUSION: Although most of the preterm infants with GAs ≥26 weeks survived, a high complication in survivors still can be observed. Rate of survival of GAs less than 26 weeks was still low, and quality improvement methods should be used to look into increasing the use of antenatal steroids in the very preterm births.

Longer duration of initial invasive mechanical ventilation is still a crucial risk factor for moderate-to-severe bronchopulmonary dysplasia in very preterm infants: a multicentrer prospective study.

OBJECTIVES: We aimed to evaluate the risk factors for moderate-to-severe bronchopulmonary dysplasia (BPD) and focus on discussing its relationship with the duration of initial invasive mechanical ventilation (IMV) in very preterm neonates less than 32 weeks of gestational age (GA). METHODS: We performed a prospective cohort study involving infants born at 23-31 weeks of GA who were admitted to 47 different neonatal intensive care unit (NICU) hospitals in China from January 2018 to December 2021. Patient data were obtained from the Sina-northern Neonatal Network (SNN) Database. RESULTS: We identified 6538 very preterm infants, of whom 49.5% (3236/6538) received initial IMV support, and 12.6% (823/6538) were diagnosed with moderate-to-severe BPD symptoms. The median duration of initial IMV in the moderate-to-severe BPD group was 26 (17-41) days, while in the no or mild BPD group, it was 6 (3-10) days. The incidence rate of moderate-to-severe BPD and the median duration of initial IMV were quite different across different GAs. Multivariable logistic regression analysis showed that the onset of moderate-to-severe BPD was significantly associated with the duration of initial IMV [adjusted odds ratio (AOR): 1.97; 95% confidence interval (CI): 1.10-2.67], late-onset neonatal sepsis (LONS), and patent ductus arteriosus (PDA). CONCLUSION: In this multicenter cohort study, the duration of initial IMV was still relatively long in very premature infants, and the longer duration of initial IMV accounts for the increased risk of moderate-to-severe BPD.

Metagenomic Next-Generation Sequencing Successfully Detects Pulmonary Infectious Pathogens in Children With Hematologic Malignancy.

Background: Pulmonary infection is a leading cause of mortality in pediatric patients with hematologic malignancy (HM). In clinical settings, pulmonary pathogens are frequently undetectable, and empiric therapies may be costly, ineffective and lead to poor outcomes in this vulnerable population. Metagenomic next-generation sequencing (mNGS) enhances pathogen detection, but data on its application in pediatric patients with HM and pulmonary infections are scarce. Methods: We retrospectively reviewed 55 pediatric patients with HM and pulmonary infection who were performed mNGS on bronchoalveolar lavage fluid from January 2020 to October 2021. The performances of mNGS methods and conventional microbiological methods in pathogenic diagnosis and subsequently antibiotic adjustment were investigated. Results: A definite or probable microbial etiology of pulmonary infection was established for 50 of the 55 patients (90.9%) when mNGS was combined with conventional microbiological tests. The positive rate was 87.3% (48 of 55 patients) for mNGS versus 34.5% (19 of 55 patients) with conventional microbiological methods (P < 0.001). Bacteria, viruses and fungi were detected in 17/55 (30.9%), 25/55 (45.5%) and 19/55 (34.5%) cases using mNGS, respectively. Furthermore, 17 patients (30.9%) were identified as pulmonary mixed infections. Among the 50 pathogen-positive cases, 38% (19/50) were not completely pathogen-covered by empirical antibiotics and all of them were accordingly made an antibiotic adjustment. In the present study, the 30-day mortality rate was 7.3%. Conclusion: mNGS is a valuable diagnostic tool to determine the etiology and appropriate treatment in pediatric patients with HM and pulmonary infection. In these vulnerable children with HM, pulmonary infections are life-threatening, so we recommend that mNGS should be considered as a front-line diagnostic test.

CircSLC7A6 promotes the progression of Wilms' tumor via microRNA-107/ ABL proto-oncogene 2 axis.

The dysregulation of circular RNAs (circRNAs) has been proved to be involved in the carcinogenesis of various cancers. Nevertheless, the biological function of circSLC7A6 remains unclear in Wilms' tumor (WT). In our study, we found that circSLC7A6 was upregulated in cancerous WT tissues and cells. Cell apoptosis was increased while cell viability, migration, and invasion were repressed by circSLC7A6 silencing. Besides, circSLC7A6 knockdown suppressed WT tumor growth in vivo. miR-107 was identified as a direct target of circSLC7A6, and circSLC7A6 could negatively regulate miR-107 expression. In addition, circSLC7A6 knockdown inhibited WT progression, while the effect was partially abolished by the downregulation of miR-107. Additionally, ABL proto-oncogene 2 axis (ABL2) was verified as a downstream gene of miR-107, and circSLC7A6 could upregulate ABL2 expression by serving as a ceRNA of miR-107. Moreover, functional assays revealed that ABL2 overexpression reversed the impact of circSLC7A6 depletion on cell proliferation, migration, invasion, and apoptosis of WT. In conclusion, the present study demonstrated that circSLC7A6 facilitated WT progression by upregulating ABL2 through inhibiting miR-107 expression. These results suggested that circSLC7A6 might serve as a potential therapeutic target for WT.

Association of necrotizing enterocolitis with antimicrobial exposure in preterm infants <32 weeks gestational age:A multicenter prospective case-control study.

Objective: To assess the risk of necrotizing enterocolitis (NEC) and explore the relationship between antibiotic overexposure and disease occurrence in a large prospective birth cohort. Methods: Based on a prospective birth cohort, the study collected hospitalization data of very preterm infants (VPIs) having gestational age of less than 32 weeks from January 1, 2018, to June 30, 2021 via the China Northern Neonatal Network. Infants diagnosed with NEC ≥ stage II were included in the case group, and each case was matched for GA and birth weight for the control group. Furthermore, the risk factors for NEC were determined by statistical analyses. Results: A total of 6425 VPIs were included in this study, and 167 (2.6%) of these subjects were diagnosed with NEC ≥ stage II. The study also included 984 extremely preterm infants (gestational age <28 weeks), including 50 (5.1%) infants diagnosed with NEC ≥ stage II. In the matched case-control study, subjects had a total of antibiotic days-of-therapy for 9015 days, of which broad-spectrum antibiotics (BSAs) accounted for 77%. The antibiotic spectrum index per antibiotic day in the case group was significantly higher and was an independent risk factor for the occurrence of NEC (p = 0.001, OR = 1.13). Conclusion: The cohort of VPIs was overexposed to antiboitics. Unreasonable combination of antibiotics and overexposure to BSAs may increase the risk of NEC in preterm infants.

Comparison of short interval and low dose (SILD) with high dose of cyclophosphamide in the susceptibility to infection in SLE: a multicentrereal-world study.

OBJECTIVE: Infection is a major cause of death in patients with SLE. This study aimed to explore the infection rate in patients with SLE receiving a low dose of intravenous cyclophosphamide (IV-CYC). METHODS: Clinical parameters of 1022 patients with SLE from 24 hospitals in China were collected. Patients were divided into the short-interval and lower-dose (SILD, 400 mg every 2 weeks) IV-CYC group and the high-dose (HD, 500 mg/m2 of body surface area every month) IV-CYC group. The clinical data and infection rate between the two groups were compared. RESULTS: Compared with HD IV-CYC, the infection rate of the SILD IV-CYC group was significantly lower (13.04% vs 22.27%, p=0.001). Respiratory tract infection (10.28% vs 15.23%, p=0.046) and skin/soft tissue infection (1.78% vs 4.3%, p=0.040) were significantly decreased in the SILD IV-CYC group. Moreover, infections occurred most likely in patients with SLE with leucopenia (OR 2.266, 95% CI 1.322 to 3.887, p=0.003), pulmonary arterial hypertension (OR 2.756, 95% CI 1.249 to 6.080, p=0.012) and >15 mg/day of glucocorticoid (OR 2.220, 95% CI 1.097 to 4.489, p=0.027). CONCLUSIONS: SILD IV-CYC showed a lower frequency of infection events than high-dose IV-CYC in patients with SLE.

Circ_0000396 inhibits rheumatoid arthritis synovial fibroblast growth and inflammatory response via miR-203/HBP1 axis.

BACKGROUND: Circ_0000396 was found to be down-regulated in the rheumatoid arthritis (RA) patients and had a high diagnostic value. However, the function and mechanisms underlying circ_0000396 in RA progression remain unclear. METHODS: The expression of circ_0000396, microRNA (miR)-203 and HMG-box transcription factor 1 (HBP1) was detected using qRT-PCR and western blot. The proliferative and apoptotic capabilities of rheumatoid arthritis synovial fibroblasts (RASFs) were measured by colony formation, CCK-8, flow cytometry and western blot assays, respectively. The levels of interleukins (IL)-6, IL-1ß, IL-8 and tumor necrosis factor-α (TNF-α) were detected using enzyme-linked immunosorbent assay (ELISA). The target correlations between miR-203 and circ_0000396 or HBP1 were validated using pull-down and dual-luciferase reporter assay. RESULTS: Circ_0000396 was decreased in RA synovial tissues and RASFs, and overexpression of circ_0000396 suppressed cell proliferation, induced cell apoptosis and reduced the release of inflammatory cytokine IL-6, IL-1ß, IL-8 and TNF-α in RASFs, while circ_0000396 deletion functioned oppositely. MiR-203 was confirmed to be a target of circ_0000396, and miR-203 reversed the protective effects of circ_0000396 on the dysfunction and inflammation of RASFs. HBP1 was a target of miR-203, and silencing miR-203 inhibited RASFs malignant changes by regulating HBP1. In addition, circ_0000396 could regulate HBP1 by sponging miR-203, and HBP1 decrease attenuated the effects of circ_0000396 on RASF growth and inflammation. CONCLUSION: Circ_0000396 inhibited the growth and inflammation in RASFs by regulating miR-203/HBP1 axis, providing a potential therapeutic target for RA.

Pathogens distribution and antimicrobial resistance in bloodstream infections in twenty-five neonatal intensive care units in China, 2017-2019.

BACKGROUND: Overcrowding, abuse of antibiotics and increasing antimicrobial resistance negatively affect neonatal survival rates in developing countries. We aimed to define pathogens and their antimicrobial resistance (AMR) of early-onset sepsis (EOS), hospital-acquired late-onset sepsis (HALOS) and community-acquired late-onset sepsis (CALOS) in 25 neonatal intensive care units (NICUs) in China. STUDY DESIGN: This retrospective descriptive study included pathogens and their AMR from all neonates with bloodstream infections (BSIs) admitted to 25 tertiary hospitals in China from January 1, 2017, and December 31, 2019. We defined EOS as the occurrence of BSI at or before 72 h of life and late-onset sepsis (LOS) if BSI occurred after 72 h of life. LOS were classified as CALOS if occurrence of BSI was ≤ 48 h after admission, and HALOS, if occurrence was > 48 h after admission. RESULTS: We identified 1092 pathogens of BSIs in 1088 infants from 25 NICUs. Thirty-two percent of all pathogens were responsible for EOS, 64.3% HALOS, and 3.7% CALOS. Gram-negative (GN) bacteria accounted for a majority of pathogens in EOS (56.7%) and HALOS (62.2%). The most frequent pathogens causing EOS were Escherichia coli (27.2%) and group B streptococcus (GBS; 14.6%) whereas in CALOS they were GBS (46.3%) and Staphylococcus aureus (41.5%). Klebsiella pneumoniae (27.9%), Escherichia coli (15.7%) and Fungi (12.8%) were the top three isolates in HALOS. Third-generation cephalosporin resistance rates in GN bacteria ranged from 9.7 to 55.6% in EOS and 26% to 63.3% in HALOS. Carbapenem resistance rates in GN bacteria ranged from 2.7 to 31.3% in HALOS and only six isolates in EOS were carbapenem resistant. High rates of multidrug resistance were observed in Klebsiella pneumoniae (60.7%) in HALOS and in Escherichia coli (44.4%) in EOS. All gram-positive bacteria were susceptible to vancomycin except for three Enterococcus faecalis in HALOS. All-cause mortality was higher among neonates with EOS than HALOS (7.4% VS 4.4%, [OR] 0.577, 95% CI 0.337-0.989; P = 0.045). CONCLUSIONS: Escherichia coli, Klebsiella pneumoniae and GBS were the leading pathogens in EOS, HALOS and CALOS, respectively. The high proportion of pathogens and high degree of antimicrobial resistance in HALOS underscore understanding of the pathogenesis and emphasise the need to devise effective interventions in developing countries.

Exosomes derived from synovial fibroblasts under hypoxia aggravate rheumatoid arthritis by regulating Treg/Th17 balance.

IMPACT STATEMENT: A comparative study of osteoarthritis (OA) and RA mice was implemented to suggest that miR-424 expression was increased in RA, and exosome-miR-424 derived from synovial fibroblasts (SFs-exo) could significantly induce T cells differentiation in which Th17 cells increased and Treg cells decreased via targeting FOXP3. And thus, miR-424 may be a potential therapeutic target for RA.

Protocatechuic acid inhibits proliferation, migration and inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a chronic joint inflammatory disease that is closely associated with dysregulation of fibroblast-like synoviocytes (FLSs). Protocatechuic acid (PCA), a phenolic compound of anthocyanins, has been proven to possess anti-inflammatory activity. However, the role of PCA in RA has not been investigated. In the present study, we aimed to explore the effects of PCA on the RA-FLSs. The results showed that PCA suppressed the proliferation, invasion, and migration of RA-FLSs in a dose-dependent manner. PCA treatment also inhibited the expressions of matrix metalloproteinase (MMP)-3 and MMP-13, as well as the secretion of inflammatory cytokines including TNF-α, IL-1ß, IL-6 in RA-FLSs. Moreover, cell apoptosis of RA-FLSs was significantly induced by PCA treatment. PCA was found to repress the activation of NF-κB signalling, which was evidenced by the decreased expression of p-p65 and increased expression of IκBα. Furthermore, PCA significantly decreased the phosphorylation levels of Akt and mTOR in RA-FLSs. In conclusion, the results indicated that PCA exhibited an inhibitory effect on RA-FLSs via inhibiting the NF-κB and Akt/mTOR signalling pathways. These findings supported the concept that PCA might be a therapeutic agent for RA treatment.

miR-188-5p Promotes Tumor Growth by Targeting CD2AP Through PI3K/AKT/mTOR Signaling in Children with Acute Promyelocytic Leukemia.

PURPOSE: Pediatric acute promyelocytic leukemia (APL) accounts for 10% of pediatric acute myelogenous leukemia (AML) case and is accompanied by a tendency to hemorrhage. miR-188-5p plays an important role in adult AML. Therefore, the purpose of this study was to explore the effects of miR-188-5p on cell proliferation and apoptosis and tumor growth, and its mechanism in pediatric APL patients. MATERIALS AND METHODS: Survival-associated miRNAs or mRNAs from TCGA database associated with AML were identified via using the "survival R" package in R language. CCK8, clone formation, flow cytometry, RT-PCR, immunohistochemistry and Western blot assays were used to detect the viability, proliferation, apoptosis, cell cycle, and related gene expression in APL cell lines. The prognostic value of miR-188-5p was evaluated using a ROC curve. The tumorigenic ability of APL cell lines was determined using a nude mouse transplantation tumor experiment. Tumor cell apoptosis was determined by TUNEL assay in vivo. The target genes of miR-188-5p were predicted using the miRDB, miRTarBase, and TargetScan databases. A PPI network was constructed using STRING database and the hub gene was identified using the MCODE plug-in of the Cytoscape software. The DAVID database was used to perform GO and KEGG pathway enrichment analyses. A luciferase reporter assay was used to demonstrate the binding of miR-188-5p to CD2AP. RESULTS: miR-188-5p overexpression or CD2 associated protein (CD2AP) inhibition was significantly associated with poor survival in pediatric APL patients. Upregulation of miR-188-5p was identified in the blood of pediatric APL patients and cell lines. Increased expression of miR-188-5p also promoted the viability, proliferation, and cell cycle progression, and reduced the apoptosis of APL cells. Additionally, upregulation of miR-188-5p regulated the expressions of cyclinD1, p53, Bax, Bcl-2 and cleaved caspase-3. The area under the ROC curve (AUC) of miR-188-5p was 0.661. miR-188-5p overexpression increased the tumorigenic ability of APL and Ki67 expression, and reduced cell apoptosis in vivo. CD2AP was identified as the only overlapping gene from the list of miR-188-5p target genes and survival-related mRNAs of the TCGA database. It was mainly enriched in the "biological process (BP)" and "cellular component (CC)" terms, and was downregulated in the blood of pediatric APL patients and cell lines. The luciferase reporter, RT-PCR, and Western blot assays demonstrated that the binding of miR-188-5p to CD2AP. CD2AP inhibition promoted the proliferation and inhibited the apoptosis of APL cells. Rescue experiments showed that inhibition of miR-188-5p inhibited cell proliferation, activated the PI3K/AKT/mTOR signaling pathway, induced G0/G1 phase arrest, regulated gene expression, and promoted cell apoptosis, which were reversed by CD2AP inhibition. CONCLUSION: miR-188-5p, an oncogene, promoted tumor growth and progression of pediatric APL in vitro and in vivo via targeting CD2AP and activating the PI3K/AKT/mTOR signaling pathway.

Dynamic Change of Thyroid Hormones With Postmenstrual Age in Very Preterm Infants Born With Gestational Age <32 Weeks: A Multicenter Prospective Cohort Study.

Background: At present, the relationship between thyrotropin (TSH) and free thyroxine (FT4) in relation to postmenstrual age (PMA) in preterm infants is still unclear, and there is no reliable standard thyroid hormone reference ranges, resulting in different diagnostic criteria for congenital hypothyroidism been used by different newborn screening programs and different countries. Objectives: To investigate the relationship between TSH/FT4 and PMA in very preterm infants (VPIs) born with gestational age (GA) <32 weeks and to derive thyroid function reference charts based on PMA. Methods: A prospective cohort study was performed on VPIs born with GA<32 weeks and born in or transferred to the 27 neonatal intensive care units from January 1, 2019 to December 31, 2019. Serial TSH and FT4 values were measured at the end of each week during the first month after birth and also at PMA36 weeks, PMA40 weeks and at discharge, respectively. The 2.5th, 5th, 50th, 95th, and 97.5th percentiles of TSH and FT4 of different PMA groups were calculated to draw the percentile charts based on PMA. Results: 1,093 preterm infants were included in this study. The percentile charts of TSH and FT4 levels based on PMA were drawn respectively, and the result indicated that the percentile charts of TSH values were gradually increased initially and then decreased with increasing PMA. The 97.5th percentile chart reached the peak at PMA30 weeks (17.38µIU/ml), and then decreased gradually, reaching the same level as full-term infants (9.07µIU/ml) at PMA38-40 weeks. The 2.5th percentile chart of FT4 was at its lowest point at PMA26-27 weeks (5.23pmol/L), then increased slowly with PMA and reached the same level as full-term infants at PMA38-40 weeks (10.87pmol/L). At PMA36 weeks, the reference intervals of the 2.5th to 97.5th percentiles of TSH and FT4 were 1.18-12.3µIU/ml and 8.59-25.98pmol/L, respectively. Conclusion: The percentile charts of TSH and FT4 in VPIs showed characteristic change with PMA. The results prompt that age-related cutoffs, instead of a single reference range, might be more useful to explain the thyroid function of VPIs. And repeated screening is necessary for preterm infants.

Pro-apoptotic and anti-inflammatory effects of araloside A on human rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis fibroblast-like synoviocytes play an essential role in the occurrence and progression of rheumatoid arthritis. As the main pharmacologically active components of Aralia taibaiensis, total saponins, particularly triterpenoid saponins, have been shown to possess multiple pharmacological activities including relieving rheumatism. However, the effect of araloside A, a triterpenoid saponin extracted from the root bark of Aralia taibaiensis, on rheumatoid arthritis remains unknown. Cell counting kit-8 assay was employed to determine cell viability. Flow cytometry analysis, caspase-3/7 activity assay and Western blot analysis of cytochrome c and B-cell lymphoma 2 were conducted to evaluate cell apoptosis. Inflammation was assessed by detecting the production of inflammatory cytokines including interleukin-6 and interleukin-8, as well as inflammatory mediators including nitric oxide and prostaglandin E2. The changes of the nuclear factor kappa B pathway were examined by Western blot. Results showed that araloside A concentration-dependently inhibited the proliferation of MH7A cells. Meanwhile, araloside A dose-dependently augmented the apoptotic rate and caspase-3/7 activity, increased cytochrome c level and decreased B-cell lymphoma 2 level in MH7A cells. Araloside A concentration-dependently curbed the production of interleukin-6, interleukin-8, prostaglandin E2 and nitric oxide in MH7A cells. In addition, we found that araloside A inhibited the nuclear factor kappa B pathway and inhibition of the nuclear factor kappa B pathway by BAY11-7082 and PDTC showed a similar role to araloside A in MH7A cells. Taken together, araloside A exerted pro-apoptotic and anti-inflammatory effects in rheumatoid arthritis fibroblast-like synoviocytes via inhibition of the nuclear factor kappa B pathway.

MicroRNA­93 inhibits chondrocyte apoptosis and inflammation in osteoarthritis by targeting the TLR4/NF­κB signaling pathway.

Osteoarthritis (OA) is a serious disease of the articular cartilage, and inflammation has been implicated in its pathogenesis. Previously, microRNAs (miRNAs) have been proposed as novel regulators of inflammation, however, the functional role of microRNAs in regulating inflammation in OA remains to be fully elucidated. The aim of the present study was to investigate the roles of miRNAs in OA inflammation and the underlying molecular mechanism. Firstly, the miRNA expression patterns were analyzed in the articular cartilage tissues from experimental OA mice using an miRNA microarray. miRNA (miR)­93 was identified with particular interest due to its reported effects on apoptosis and inflammation suppression. Subsequently, the expression of miR­93 was further validated in the articular cartilage tissues of OA mice and lipopolysaccharide (LPS)­stimulated primary chondrocytes. Using this LPS­induced chondrocyte injury model, the overexpression of miR­93 enhanced cell viability, improved cell apoptosis and attenuated the inflammatory response, as reflected by reductions in pro­inflammatory cytokines, including tumor necrosis factor (TNF)­α, interleukin (IL)­1ß and IL­6. In addition, Toll­like receptor 4 (TLR4), an important regulator of the nuclear factor­κB (NF­κB) signaling pathway, was identified as a direct target of miR­93 in chondrocytes. Furthermore, the restoration of TLR4 markedly abrogated the inhibitory effects of miR­93 on the chondrocyte apoptosis and inflammation induced by LPS. In addition, the overexpression of miR­93 by agomir­miR­93 significantly inhibited the levels of pro­inflammatory cytokines and cell apoptosis, whereas antagomir­93 exacerbated apoptosis and inflammation in vivo. Taken together, the results of the study suggested that miR­93 may be a promising therapeutic target for the treatment of human OA.

Care Practices, Morbidity and Mortality of Preterm Neonates in China, 2013-2014: a Retrospective study.

This retrospective cohort study aimed to investigate the prevalence, morbidity, mortality and the maternal/neonatal care of preterm neonates and the perinatal risk factors for mortality. We included data on 13,701 preterm neonates born in 15 hospitals for the period 2013-2014 in China. Results showed a prevalence of preterm neonates of 9.9%. Most infants at 24-27 weeks who survived more than 12 hours were mechanically ventilated (56.1%). Few infants born before 28 weeks received CPAP without first receiving mechanical ventilation (8.1%). Few preterm neonates received antenatal steroid(35.8% at 24-27 weeks, 57.9% at 28-31 weeks, 57.0% at 32-33 weeks and 32.7% at 34-36 weeks). Overall mortality was 1.9%. Most of the deaths at 24-27 weeks of gestation occurred within 12 hours after birth, accounting for 68.1%(32/47), and within 12-72 hours after birth at 28-36 weeks of gestation, accounting for 47.4%(99/209). Rates of survival to discharge increased from 68.2% at 24-27 weeks, 93.3% at 28-31 weeks, 99.2% at 32-33 weeks to 99.4% at 34-36 weeks. The smaller of the GA, there was a greater risk of morbidities due to prematurity. Preterm birth weight (OR = 0.407, 95% CI 0.346-0.478), antenatal steroid (OR = 0.680, 95% CI 0.493-0.938), and neonatal asphyxia (OR = 3.215, 95% CI 2.180-4.741) proved to significantly influence the odds of preterm neonatal death. Overall, our results support that most of the preterm neonates at 28-36 weeks of gestation survived without major morbidity. Rate of survival of GAs less than 28 weeks was still low. Maternal and infant care practices need to be improved in the very preterm births.