Celastrol ameliorates hypoxic-ischemic brain injury in neonatal rats by reducing oxidative stress and inflammation.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear. METHODS: Here, we established both in vitro and in vivo models of HI brain damage using CoCl2-treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models. RESULTS: Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA. CONCLUSIONS: We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE. IMPACT: We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries. Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.

Proteomic analysis reveals potential therapeutic targets for childhood asthma through Mendelian randomization.

BACKGROUND: Asthma is the most common chronic disease among children and poses a significant threat to their health. This study aims to assess the relationship between various plasma proteins and childhood asthma, thereby identifying potential therapeutic targets. METHODS: Based on publicly available genome-wide association study summary statistics, we employed a two-sample Mendelian randomization (MR) approach to elucidate the causal relationship between plasma proteins and asthma. Mediation analysis was then conducted to evaluate the indirect influence of plasma proteins on childhood asthma mediated through risk factors. Comprehensive analysis was also conducted to explore the association between plasma proteins and various phenotypes using the UK Biobank dataset. RESULTS: MR analysis uncovered a causal relationship between 10 plasma proteins and childhood asthma. Elevated levels of seven proteins (TLR4, UBP25, CBR1, Rac GTPase-activating protein 1 [RGAP1], IL-21, MICB, and PDE4D) and decreased levels of three proteins (GSTO1, LIRB4 and PIGF) were associated with an increased risk of childhood asthma. Our findings further validated the connections between reported risk factors (body mass index, mood swings, hay fever or allergic rhinitis, and eczema or dermatitis) and childhood asthma. Mediation analysis revealed the influence of proteins on childhood asthma outcomes through risk factors. Furthermore, the MR analysis identified 73 plasma proteins that exhibited causal associations with at least one risk factor for childhood asthma. Among them, RGAP1 mediates a significant proportion (25.10%) of the risk of childhood asthma through eczema or dermatitis. Finally, a phenotype-wide association study based on these 10 proteins and 1403 diseases provided novel associations between these biomarkers and multiple phenotypes. CONCLUSION: Our study comprehensively investigated the causal relationship between plasma proteins and childhood asthma, providing novel insights into potential therapeutic targets.

Per- and polyfluoroalkyl substances inhibit human and rat 17ß-hydroxysteroid dehydrogenase 1: Quantitative structure-activity relationship and molecular docking analysis.

Per- and polyfluoroalkyl (PFAS) substances are enduring industrial materials. 17ß-Hydroxysteroid dehydrogenase isoform 1 (17ß-HSD1) is an estrogen metabolizing enzyme, which transforms estrone into estradiol in human placenta and rat ovary. Whether PFAS inhibit 17ß-HSD1 and what the structure-activity relationship (SAR) remains unexplored. We screened 18 PFAS for inhibiting human and rat 17ß-HSD1 in microsomes and studied their SAR and mode of action(MOA). Of the 11 perfluorocarboxylic acids (PFCAs), C8-C14 PFCAs at a concentration of 100 µM substantially inhibited human 17ß-HSD1, with order of C11 (half-maximal inhibition concentration, IC50, 8.94 µM) > C10 (10.52 µM) > C12 (14.90 µM) > C13 (30.97 µM) > C9 (43.20 µM) > C14 (44.83 µM) > C8 (73.38 µM) > others. Of the 7 per- and poly-fluorosulfonic acids (PFSAs), the potency was C8S (IC50, 14.93 µM) > C7S (80.70 µM) > C6S (177.80 µM) > others. Of the PFCAs, C8-C14 PFCAs at 100 µM markedly reduced rat 17ß-HSD1 activity, with order of C11 (IC50, 9.11 µM) > C12 (14.30 µM) > C10 (18.24 µM) > C13 (25.61 µM) > C9 (67.96 µM) > C8 (204.39 µM) > others. Of the PFSAs, the potency was C8S (IC50, 37.19 µM) > C7S (49.38 µM) > others. In contrast to PFOS (C6S), the partially fluorinated compound 6:2 FTS with an equivalent number of carbon atoms demonstrated no inhibition of human and rat 17ß-HSD1 activity at a concentration of 100 µM. The inhibition of human and rat enzymes by PFAS followed a V-shaped trend from C4 to C14, with a nadir at C11. Moreover, human 17ß-HSD1 was more sensitive than rat enzyme. PFAS inhibited human and rat 17ß-HSD1 in a mixed mode. Docking analysis revealed that they bind to the NADPH and steroid binding site of both 17ß-HSD1 enzymes. The 3D quantitative SAR (3D-QSAR) showed that hydrophobic region, hydrogen bond acceptor and donor are key factors in binding to 17ß-HSD1 active sites. In conclusion, PFAS exhibit inhibitory effects on human and rat 17ß-HSD1 depending on factors such as carbon chain length, degree of fluorination, and the presence of carboxylic acid or sulfonic acid groups, with a notable V-shaped shift observed at C11.

Mechanisms underlying palmitic acid-induced disruption of locomotor activity and sleep behavior in Drosophila.

The globally prevalent of sleep disorders is partly attributed to unhealthy dietary habits. This study investigated the underlying mechanisms of elevated palmitic acid (PA) intake on locomotor activity and sleep behavior in Drosophila. Our results indicate that exposure to PA significantly elevated Drosophila's daytime and nighttime locomotor activity while concurrently reducing overall sleep duration. Utilizing 16S rRNA sequencing, we observed substantial alterations in the composition of the gut microbiota induced by PA, notably, characterized by a significant reduction in Lactobacillus plantarum. Furthermore, PA significantly increased the levels of inflammatory factors Upd3 and Eiger in Drosophila intestines, and downregulated the expression of Gad and Tph, as well as 5-HT1A. Conversely, Gdh and Hdc were significantly upregulated in the PA group. Supplementation with L. plantarum or lactic acid significantly ameliorated PA-induced disruptions in both locomotor activity and sleep behavior. This supplementation also suppressed the expression of intestinal inflammatory factors, thus restoring impaired neurotransmitter-mediated sleep-wake regulation. Moreover, specific knockdown of intestinal epithelial Upd3 or Eiger similarly restored disrupted neurotransmitter expression, ultimately improving PA-induced disturbances in Drosophila locomotor activity and sleep behavior. These findings provide important insights into the intricate interplay between dietary components and essential behaviors, highlighting potential avenues for addressing health challenges associated with modern dietary habits.

Case report: One case of umbilical vein thrombosis in the second trimester with associated portal vein thrombosis after childbirth.

Background: Umbilical vein thrombosis is a rare pregnancy complication, that is difficult to detect prenatally but can lead to poor fetal outcomes. Case presentation: We described a 33-year-old primiparae who was identified as having umbilical vein thrombosis by ultrasound at 21 weeks gestation, and the neonate was found to have a portal vein thrombus after delivery. Following enoxaparin anticoagulant therapy, the thrombus disappeared within 4 weeks. No thrombus formation occured during the 10-month follow-up, and the baby was in excellent clinical condition. Conclusion: Owing to the poor fetal outcomes related to umbilical thrombosis, pay attention to abnormal clinical signs during prenatal ultrasound, fetal heart monitoring and counting fetal movements can help in the early identification of umbilical cord thrombosis.The findings highlight the importance of regular prenatal ultrasound evaluation, enabling early detection and monitoring of any anomalies or vascular abnormalities related to the fetal umbilical vein. Further research is warranted to explore the clinical implications and long-term outcomes associated with these findings.

Myricetin attenuates hypoxic-ischemic brain damage in neonatal rats via NRF2 signaling pathway.

Introduction: Hypoxic-ischemic encephalopathy (HIE) is a crucial cause of neonatal death and neurological sequelae, but currently there is no effective therapy drug for HIE. Both oxidative stress and apoptosis play critical roles in the pathological development of HIE. Myricetin, a naturally extracted flavonol compound, exerts remarkable effects against oxidative stress, apoptosis, and inflammation. However, the role and underlying molecular mechanism of myricetin on HIE remain unclear. Methods: In this study, we established the neonatal rats hypoxic-ischemic (HI) brain damage model in vivo and CoCl2 induced PC12 cell model in vitro to explore the neuroprotective effects of myricetin on HI injury, and illuminate the potential mechanism. Results: Our results showed that myricetin intervention could significantly reduce brain infarction volume, glia activation, apoptosis, and oxidative stress marker levels through activating NRF2 (Nuclear factor-E2-related factor 2) and increase the expressions of NRF2 downstream proteins NQO-1 and HO-1. In addition, the NRF2 inhibitor ML385 could significantly reverse the effects of myricetin. Conclusion: This study found that myricetin might alleviate oxidative stress and apoptosis through NRF2 signaling pathway to exert the protective role for HI injury, which suggested that myricetin might be a promising therapeutic agent for HIE.

[Clinical phenotype and genetic analysis of a child with 3p26.3p25.3 deletion].

OBJECTIVE: To explore the genetic basis for a child with facial dysmorphism and multiple malformations. METHODS: The child, born at 34+6 weeks' gestation due to premature rupture of amniotic membrane, dichorionic diamniotic twinning and gestational diabetes, was subjected to chromosomal karyotyping analysis and copy number variations sequencing (CNV-seq). RESULTS: The child was found to have facial dysmorphism, hypospadia, cryptorchidism and hypotonia. He was found to have a 46,XY,del(3)(p26) karyotype in addition with a 9.80 Mb deletion (chr3: 60 000-9 860 000) encompassing 33 protein coding genes. CONCLUSION: The 3p26.3p25.3 deletion probably underlay the multiple malformations in this child. Continuous follow-up is required to improve his quality of life.

Multiple brain abscesses in an extremely preterm infant and a 12-year follow up: a case report.

BACKGROUND: Brain abscesses are uncommon but life-threatening in extremely preterm (EP, Gestational Age < 28 weeks) infants. The information of long-time follow-up is rare, but very few cases presented almost intact neural function after injury. CASE PRESENTATION: We report the clinical course and the outcome of a 27-week preterm infant with multiple brain abscesses. The brain abscesses were detected by cranial magnetic resonance imaging (MRI) and were treated with surgical aspiration twice and a 7-week course of intravenous antibiotics. The patient had two episodes of seizure like activities at 8 and 11 years old respectively, whereas she had normal results of electroencephalogram (EEG). MRI showed encephalomalacia and periventricular leukomalacia. Otherwise, she had no obvious neurological deficits based on multiple physical examination and her intellectual quotient (IQ) was in normal range in the long-time follow-up. CONCLUSIONS: Early diagnosis of brain abscesses and appropriate therapy can improve the prognosis. Furthermore, this case report provides an example of the possible neuroplasticity of brain in EP infants.

Simvastatin Inhibits NLRP3 Inflammasome Activation and Ameliorates Lung Injury in Hyperoxia-Induced Bronchopulmonary Dysplasia via the KLF2-Mediated Mechanism.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly found in premature infants. Excessive inflammation and oxidative stress contribute to BPD occurrence and development. Simvastatin, as an inhibitor of HMG-CoA reductase, has been reported to have antioxidative and anti-inflammatory effects. However, its effect and possible mechanisms in hyperoxia-induced lung injury are rarely reported. In this study, in vivo and in vitro experiments were conducted to investigate whether simvastatin could ameliorate hyperoxia-induced lung injury and explore its potential mechanism. For the in vivo study, simvastatin could improve alveolar development after hyperoxic lung injury and reduce hyperoxic stress and inflammation. The in vitro study revealed that simvastatin can reduce inflammation in A549 cells after high-oxygen exposure. Simvastatin suppressed NLRP3 inflammasome activation and played anti-inflammatory and antioxidant roles by increasing KLF2 (Krüppel-like factor 2) expression. In vitro experiments also revealed that these effects of simvastatin were partially reversed by KLF2 shRNA, indicating that KLF2 was involved in simvastatin effects. In summary, our findings indicate that simvastatin could downregulate NLRP3 inflammasome activation and attenuate lung injury in hyperoxia-induced bronchopulmonary dysplasia via KLF2-mediated mechanism.

Early aEEG can predict neurodevelopmental outcomes at 12 to 18 month of age in VLBWI with necrotizing enterocolitis: a cohort study.

BACKGROUND: Studies have shown that neurological damage is common in necrotizing enterocolitis (NEC) survivors. The purpose of the study was to investigate the predictive value of amplitude-integrated electroencephalogram (aEEG) for neurodevelopmental outcomes in preterm infants with NEC. METHODS: Infants with NEC were selected, and the control group was selected based on 1:1-2 pairing by gestational age. We performed single-channel (P3-P4) aEEG in the two groups. The Burdjalov scores were compared between the two groups. Cranial magnetic resonance imaging (MRI) was performed several months after birth. The neurological outcomes at 12 to 18 months of age were compared with the Gesell Developmental Schedules (GDS). The predictive value of aEEG scores for neurodevelopmental delay was calculated. RESULTS: There was good consistency between the two groups regarding general conditions. In the 1st aEEG examination, the patients in NEC group had lower Co (1.0 (0.0, 2.0) vs. 2.0 (2.0, 2.0), P = 0.001), Cy (1.0 (0.0, 2.0) vs. 3.0 (3.0, 4.0), P < 0.001), LB (1.0 (0.0, 2.0) vs. 2.0 (2.0, 2.0), P < 0.001), B (1.0 (1.0, 2.0) vs. 3.0 (3.0, 3.5), P < 0.001) and T (3.0 (2.0, 8.0) vs. 10.0 (10.0, 11.5), P < 0.001), than the control group. Cranial MRI in NEC group revealed a widened interparenchymal space with decreased myelination. The abnormality rate of cranial MRI in the NEC group was higher than that in the control group (P = 0.001). The GDS assessment indicated that NEC children had inferior performance and lower mean scores than the control group in the subdomains of gross motor (71 (SD = 6.41) vs. 92 (SD = 11.37), P < 0.001), fine motor (67 (SD = 9.34) vs. 96 (SD = 13.69), adaptive behavior (76 (SD = 9.85) vs. 95 (SD = 14.38), P = 0.001), language (68 (SD = 12.65) vs. 95 (SD = 11.41), P < 0.001), personal-social responses (80 (SD = 15.15) vs. 93(SD = 14.75), P = 0.037) and in overall DQ (72 (SD = 8.66) vs. 95 (SD = 11.07), P < 0.001). The logistic binary regression analysis revealed that the NEC patients had a significantly greater risk of neurodevelopmental delay than the control group (aOR = 27.00, 95% CI = 2.561-284.696, P = 0.006). Confirmed by Spearman's rank correlation analysis, neurodevelopmental outcomes were significantly predicted by the 1st aEEG Burdjalov score (r = 0.603, P = 0.001). An abnormal 1st Burdjalov score has predictive value for neurodevelopmental delay with high specificity (84.62%) and positive predictive value (80.00%). CONCLUSIONS: Children with NEC are more likely to develop neurodevelopmental delay. There is high specificity and PPV of early aEEG in predicting neurodevelopmental delay.

Soluble Triggering Receptors Expressed on Myeloid Cells-1 as a Neonatal Ventilator-Associated Pneumonia Biomarker.

BACKGROUND: Neonatal ventilator-associated pneumonia (NVAP) is one of the main infections acquired in hospitals, and soluble triggering receptors expressed on myeloid cells-1 (sTREM-1) are a TREM-1 subtype that can be released into the blood or bodily fluids during an infection. METHODS: The patients included in the present study were divided into three groups: the NVAP group, the first control group, and the second control group (n = 20, each). Children requiring respiratory treatment were assigned to the NVAP group, newborns who received mechanical ventilation and had neonatal respiratory distress syndrome were assigned to the first control group, and newborns with normal X-ray and electrocardiogram results but no non-pulmonary infection was assigned to the second control group. The blood and bronchoalveolar lavage fluid (BALF) sTREM-1 levels in all newborns were analyzed. RESULTS: The acute-phase blood and BALF sTREM-1 levels were significantly higher in the NVAP group than in the first control group, and the blood sTREM-1 expression level was lower in the second control group than in the NVAP group. CONCLUSION: The present results suggest that sTREM-1 might be a useful biomarker for NVAP prediction in the Department of Pediatrics.

Two Novel HSD17B4 Heterozygous Mutations in Association With D-Bifunctional Protein Deficiency: A Case Report and Literature Review.

Background: D-Bifunctional protein deficiency (D-BPD) is an autosomal recessive disorder caused by peroxisomal ß-oxidation defects. According to the different activities of 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase protein units, D-bifunctional protein defects can be divided into four types. The typical symptoms include hypotonia and seizures. The gene that encodes D-BP was HSD17B4, which is located in chromosome 5q23.1. Case Presentation: We report the first case of D-BPD in a Chinese patient with neonatal onset. Cosmetic malformations, severe hypotonia and seizures are prominent. The blood bile acid profile showed increased taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid. Very-long-chain fatty acids (VLCFAs) revealed significant increases in hexacosanoic acid (C26:0), tetracosanoic acid/docosanoic acid (C24:0/C22:0), and hexacosanoic acid/docosanoic acid (C26:0/C22:0). Cranial MRI revealed bilateral hemispheric and callosal dysplasia, with schizencephaly in the right hemisphere. EEG showed loss of sleep-wake cycle and epileptiform discharge. Other examinations include abnormal brainstem auditory evoked potentials (BAEPs) and temporal pigmented spots on the optic disc in the right eye. After analysis by whole-exome sequencing, heterozygous c.972+1G>T in the paternal allele and c.727T>A (p.W243R) in the maternal allele were discovered. He was treated with respiratory support, formula nasogastric feeding, and antiepileptic therapy during hospitalization and died at home due to food refusal and respiratory failure at the age of 5 months. Conclusions: Whole-exome sequencing should be performed in time to confirm the diagnosis when the newborn presents hypotonia, seizures, and associated cosmetic malformations. There is still a lack of effective radical treatment. Supportive care is the main treatment, aiming at controlling symptoms of central nervous system like seizures and improving nutrition and growth. The disease has a poor outcome, and infants often die of respiratory failure within 2 years of age. In addition, heterozygous deletion variant c.972+1G>T and missense mutations c.727T>A (p.W243R) are newly discovered pathogenic variants that deserve further study.

Escherichia coli Causing Neonatal Meningitis During 2001-2020: A Study in Eastern China.

BACKGROUND AND OBJECTIVE: Neonatal meningitis (NM) caused by Escherichia coli remains a major health problem in industrialized countries. Currently, information on the epidemiology and antimicrobial susceptibility patterns of NM in developing countries such as China is relatively scarce. Therefore, the present study investigated changes in the antimicrobial susceptibility of E. coli causing NM in a perinatal center in eastern China over the past 20 years. METHODS: This survey was conducted during three periods: 2001-2006, 2007-2012, and 2013-2020. NM was diagnosed according to the number of white blood cells in the cerebrospinal fluid (CSF) and the presence of a single potential pathogenic bacterium in the culture prepared from the blood or CSF of a newborn baby. Changes in the antimicrobial susceptibility of E. coli were analyzed. RESULTS: In total, 182 NM cases were identified. E. coli was identified in 69 of these cases, and in 21 of these cases, extended-spectrum beta-lactamase (ESBL) production was detected. E. coli was the main cause of NM identified in this study. The overall susceptibility of E. coli to third-generation cephalosporins such as cefotaxime decreased from 100% during 2001-2006 to 50% during 2007-2012 and, subsequently, increased to 71.0% during 2013-2020. This pattern of change is correlated with bacterial ESBL production. Only 8.3% of E. coli found in samples collected from infants with early onset meningitis (EOM) produced ESBL, while 37.3% of E. coli isolated from children with late-onset meningitis (LOM) produced ESBL. CONCLUSION: E. coli remains the primary pathogen of NM. Compared with that isolated from infants with LOM, the percentage of ESBL-producing multidrug-resistant E. coli isolated from infants with EOM is significantly lower. Clinicians should consider this trend when determining appropriate and effective antibiotics as empirical treatment for NM.

Neferine Protects against Hypoxic-Ischemic Brain Damage in Neonatal Rats by Suppressing NLRP3-Mediated Inflammasome Activation.

Hypoxic-ischemic encephalopathy (HIE) is recognized as the main cause of neonatal death, and efficient treatment strategies remain limited. Given the prevalence of HIE and the associated fatality, further studies on its pathogenesis are warranted. Oxidative stress and neuroinflammatory injury are two important factors leading to brain tissue injury and nerve cell loss in HIE. Neferine, an alkaloid extracted from lotus seed embryo, exerts considerable effects against several diseases such as cancers and myocardial injury. In this study, we demonstrated the neuroprotective effect of neferine on HIE and hypothesized that it involves the inhibition of neuronal pyroptosis, thereby ameliorating neurological inflammation and oxidative stress. We demonstrated that the mRNA levels of proteins associated with pyroptosis including caspase-1, the caspase adaptor ASC, gasdermin D, interleukin- (IL-) 18, IL-1ß, and some inflammatory factors were significantly increased in neonatal HIBD model rats compared to those in the control group. The increase in these factors was significantly suppressed by treatment with neferine. We stimulated PC12 cells with CoCl2 to induce neuronal HIBD in vitro and investigated the relationship between neferine and pyroptosis by altering the expression of the NLRP3 inflammasome. The overexpression of NLRP3 partially reversed the neuroprotective effect of neferine on HIBD, whereas NLRP3 knockdown further inhibited caspase-1 activation and IL-1ß and IL18 expression. In addition, simultaneous alteration of NLRP3 expression induced changes in intracellular oxidative stress levels after HIBD. These findings indicate that neferine ameliorates neuroinflammation and oxidative stress injury by inhibiting pyroptosis after HIBD. Our study provides valuable information for future studies on neferine with respect to neuroinflammation and pyroptosis.

Mortality and Morbidity of Infants Born Extremely Preterm at Tertiary Medical Centers in China From 2010 to 2019.

Importance: Extreme prematurity is associated with a substantial burden on health care systems worldwide. However, little is known about the prognosis of infants born extremely preterm in developing countries, such as China. Objective: To describe survival and major morbidity among infants born extremely preterm in China over the past decade. Design, Setting, and Participants: This retrospective cohort study was conducted from January 1, 2010, through December 31, 2019. Included individuals were infants with gestational age less than 28 weeks discharged from 1 of 68 neonatal intensive care units located in 31 provinces in China. Data were analyzed from August through October 2020. Exposure: Extremely preterm birth. Main Outcomes and Measures: Survival to discharge and major morbidity (ie, bronchopulmonary dysplasia, grades III-IV intraventricular hemorrhage, white matter injury, stage II-III necrotizing enterocolitis, sepsis, or severe retinopathy of prematurity) were measured. Results: Among 8514 eligible infants, 5295 (62.2%) were male and 116 infants (2.0%) were small for gestational age (SGA). Overall, 5302 infants (62.3%) survived to discharge. The survival rate was 1 of 21 infants (4.8%) at 22 weeks, 13 of 71 infants (18.3%) at 23 weeks, 144 of 408 infants (35.3%) at 24 weeks, 480 of 987 infants (48.6%) at 25 weeks, 1423 of 2331 infants (61.0%) at 26 weeks, and 3241 of 4692 infants (69.1%) at 27 weeks. Survival increased from 136 of 241 infants (56.4%; 95% CI, 50.1%-62.7%) in 2010 to 1110 of 1633 infants (68.0%; 95% CI, 65.7%-70.2%) in 2019 for infants born at 24 to 27 weeks (mean difference, 11.5%; 95% CI, 4.9%-18.2%; P < .001), without a significant change for infants born at less than 24 weeks. Major morbidity was found in 5999 of 8281 infants overall, for a rate of 72.4%, which increased from 116 of 223 infants (52.0%; 95% CI, 45.4%-58.6%) to 1363 of 1656 infants (82.3%; 95% CI, 80.5%-84.1%) from 2010 to 2019 (mean difference, 30.3%; 95% CI, 23.5%-37.1%, P < .001). Regional variations in survival were identified, with an almost 2-fold increase (1.94-fold; 95% CI, 1.66-2.27; P < .001) from 188 of 474 infants (39.7%) in northwest China to 887 of 1153 infants (76.9%) in north China. Gestational age (adjusted risk ratio [aRR], 1.084; 95% CI, 1.063-1.105; P < .001), birth weight (aRR, 1.028; 95% CI, 1.020-1.036; P < .001), premature rupture of membranes (aRR, 1.025; 95% CI, 1.002-1.048; P = .03), and antenatal steroids (aRR, 1.029; 95% CI, 1.004-1.055; P = .02) were associated with improved survival, while being born SGA (aRR, 0.801; 95% CI, 0.679-0.945; P = .01), being male (aRR, 0.975; 95% CI, 0.954-0.997; P = .02), multiple birth (aRR, 0.955; 95% CI, 0.929-0.982; P = .001), having a mother with gestational diabetes (aRR, 0.946; 95% CI, 0.913-0.981; P = .002), and low Apgar score (aRR, 0.951; 95% CI, 0.925-0.977; P < .001) were found to be risk factors associated with decreased chances of survival. Conclusions and Relevance: This study found that infants born extremely preterm were at increased risk of mortality and morbidity in China, with a survival rate that improved over time and a major morbidity rate that increased. These findings suggest that more active and effective treatment strategies are needed, especially for infants born at gestational age 25 to 27 weeks.

A neonate with molybdenum cofactor deficiency type B.

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive disease which leads to a combined deficiency of molybdenum cofactor dependent enzymes. There are four different genes in molybdenum cofactor biosynthesis, MOCS1, MOCS2, MOCS3, GEPH. The patients with MOCS2 homozygous mutation who onset in the neonatal period always have severe seizures, feeding difficulties, progressive neurological deterioration. The incidence of the disease is low, and certain types have never been reported in China. Here, we present a Chinese term infant with MOCS2 who presented seizure, intolerance to feed and hypotonia on the third day after birth. Treatment included intravenous nutrition, antibiotic, and anticonvulsant therapy. The seizure can't be controlled and her encephalopathy progressed. A homozygous mutation in exon 4 in MOSC2 gene was found and the mutation of the patient has not been reported before. In conclusion, the patients with MOCS2 who onset in neonatal period often shows uncontrolled seizure, feeding difficulties, hypotonia and early death. And the MRI of them shows severe encephalomalacia. There is no treatment for the disease by now, but early diagnosis and genetic detection can give the family genetic counseling.

LXA4 protects against hypoxic-ischemic damage in neonatal rats by reducing the inflammatory response via the IκB/NF-κB pathway.

Hypoxia and the resultant decreases in cerebral blood flow in the perinatal period can lead to neonatal hypoxic-ischemic (HI) brain injury, which can, in turn, cause severe disability or even death. However, the efficacy of current treatment strategies remains limited. Several studies have demonstrated that lipoxin A4 (LXA4), as one of the earliest types of endogenous lipid mediators, can inhibit the accumulation of neutrophils, arrest inflammation, and promote the resolution of inflammation. However, research on LXA4 in the nervous system has rarely been carried out. In the present study, we sought to investigate the protective effect of LXA4 on HI brain damage in neonatal rats, as well as the underlying mechanisms. Through experiments conducted using an HI animal model, we found that the LXA4 intervention promoted the recovery of neuronal function and tissue structure following brain injury while maintaining the integrity of the blood-brain barrier in addition to reducing cerebral edema, infarct volume, and inflammatory responses. Our results suggest that LXA4 interfered with neuronal oxygen-glucose deprivation insults, reduced the expression of inflammatory factors, inhibited apoptosis, and promoted neuronal survival in vitro. Finally, the LXA4 intervention attenuated HI-induced activation of inhibitor kappa B (IκB) and degradation of nuclear factor-κB (NF-κB). In conclusion, our data suggest that LXA4 exerts a neuroprotective effect against neonatal HI brain damage through the IκB/NF-κB pathway. Our findings will help inform future studies regarding the effects of LXA4 on neuroinflammation, blood-brain barrier integrity, and neuronal apoptosis.

Caffeine prevents hyperoxia-induced lung injury in neonatal mice through NLRP3 inflammasome and NF-κB pathway.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and hyperoxia exposure is a major cause. In hyperoxic lung injury animal model, alveolar simplification and pro-inflammatory cells infiltration are the main pathophysiologic changes. Caffeine is a drug used to treat apnea in premature infants. Early use of caffeine can decrease the rate and the severity of BPD while the mechanisms are still unclear. The purpose of this study was to evaluate the effects of caffeine on inflammation and lung development in neonatal mice with hyperoxic lung injury and to explore the possible mechanism. METHODS: Following 14 d of 75% oxygen exposure in newborn mouse, the BPD model was established. Caffeine at a dose of 1 g/L was added in drinking water to nursing mouse. We measured the concentration of caffeine in serum and oxidative stress in lung by commercially available kits. Adenosine 2A receptor (A2AR) expression and lung inflammation were measured by Immunohistochemistry and western blotting. Apoptosis and surfactant protein-C (SFTPC) levels were measured by immunofluorescence. The inflammasome and NF-κB pathway proteins were assessed by western blotting. RESULTS: We found that the caffeine concentration in plasma at present dose significantly decreased the expression of A2AR protein in mice lung. Caffeine treatment significantly reduced oxidative stress, improved weight gain, promoted alveolar development, attenuated inflammatory infiltration and lung injury in hyperoxia-induced lung injury mice. Moreover, caffeine decreased the cell apoptosis in lung tissues, especially the Type II alveolar epithelial cell. The expression of NLRP3 inflammasome protein and NF-κB pathway were significantly inhibited by caffeine treatment. CONCLUSION: Caffeine treatment can protect hyperoxia-induced mice lung from oxidative injury by inhibiting NLRP3 inflammasome and NF-κB pathway.

Association between fetal growth restriction and maternal exposure to polybrominated diphenyl ethers.

Humans are exposed to polybrominated diphenyl ethers (PBDEs) via ingestion of food, dust inhalation, and dermal absorption. Exposure to PBDEs via the placenta and breast milk is a special and important pathway in infants. This nested case-control study aimed to investigate the levels of PBDEs in maternal serum and colostrum, and to assess the association between the occurrence of fetal growth restriction (FGR) and prenatal exposure to PBDEs. We recruited 293 mother-newborn pairs, including 98 FGR cases and 195 healthy controls in Wenzhou, China. Maternal serum and colostrum samples were collected during pregnancy and after delivery, respectively, and the levels of PBDEs were measured by gas chromatography-tandem mass spectrometry. The total levels of PBDEs in maternal serum and colostrum were found to be in equilibrium, but congener profiles of PBDEs in these matrices were different. Increased BDE-207, BDE-209, ∑BDE196-209 and ∑PBDEs levels in maternal serum and BDE-99, ∑BDE17-154 and ∑PBDEs levels in colostrum were correlated with decreased birth weight Z score. Increased concentrations of higher brominated BDEs in maternal serum (odds ratio (OR) = 1.010, 95%CI = 1.003-1.018) and low-to moderately brominated BDEs in colostrum (OR = 1.004, 95%CI = 1.000-1.009) were associated with increased risk of FGR, which showed an exposure-response relationship. In addition, infants with FGR were more exposed to PBDEs in colostrum after birth than healthy infants. Longitudinal birth cohort studies are needed to determine the prolonged effect of PBDEs exposure on the growth of FGR infants in the future.

3'UTRs Regulate Mouse Ntrk2 mRNA Distribution in Cortical Neurons.

There are two major isoforms of NTRK2 (neurotrophic receptor tyrosine kinase 2, or TrkB), full-length isoform with tyrosine kinase (TK) domain intact (+) and spliced isoform without tyrosine kinase domain (TK(-)). Within each isoform, there exist subtypes with minor modifications of the protein sequences. In human, the NTRK2 mRNA transcripts encoding TK(+) have same 3'UTRs, while the transcripts encoding subtypes of NTRK2 TK(-) have two completely different 3'UTRs. In mouse, the mRNA transcripts encoding same NTRK2 protein sequence for either TK(+) or TK(-) have long or short 3'UTRs, respectively. The physiological functions of these different 3'UTRs are still unknown. Pilocarpine stimulation increased Ntrk2 mRNA levels in soma, while the increase in synaptosome was smaller. FISH results further showed that mouse Ntrk2 transcripts with different 3'UTRs were distributed differently in cultured cortical neurons. The transcripts with long 3'UTR were distributed more in apical dendrites compared with transcripts with short 3'UTR. Our results provide evidence of non-coding 3'UTR function in regulating mRNA distribution in neurons.