TGF-α/EGFR signaling promotes lipopolysaccharide-induced abnormal elastin deposition and alveolar simplification.

Bronchopulmonary dysplasia (BPD) is characterized by shortened secondary septa and fewer, larger alveoli. Elastin deposition to the distal tips of the secondary septa is critical for elongation of the secondary septa. Alveolar myofibroblasts, which are thought to migrate to the septal tips during alveolarization, are mainly responsible for elastin production and deposition. Antenatal exposure to inflammation induces abnormal elastin deposition, thereby increasing the risk of developing BPD. Here, we found that lipopolysaccharide (LPS) significantly increased the expression of transforming growth factor-α (TGF-α) in an LPS-induced rat model of BPD and in LPS-treated human pulmonary epithelial cells (BEAS-2B). In addition, in vitro experiments suggested that LPS upregulated TGF-α expression via toll-like receptor 4 (TLR4)/tumor necrosis factor α-converting enzyme (TACE) signaling. Increased TGF-α levels via its receptor epidermal growth factor receptor (EGFR)-induced lysyl oxidase (LOX) overactivation and cell division cycle 42 (Cdc42) activity inhibition of myofibroblasts. Similarly, in vivo LOX overactivation and inhibition of Cdc42 activity were observed in the lungs of LPS-exposed pups. LOX overactivation led to abnormal elastin deposition, and inhibition of Cdc42 activity disturbed the directional migration of myofibroblasts and disrupted elastin localization. Most importantly, the EGFR inhibitor erlotinib partially rescued LOX overactivation and Cdc42 activity inhibition, and improved elastin deposition and alveolar development in antenatal LPS-treated rats. Taken together, our data suggest that TGF-α/EGFR signaling is critically involved in the regulation of elastin deposition and represents a novel therapeutic target.

Gestational age-specific hematological features in preterm infants with necrotizing enterocolitis.

BACKGROUND: This study aimed to investigate gestational age-specific hematological features in preterm infants with necrotizing enterocolitis (NEC) and identify predictive hematological biomarkers for surgical NEC. METHODS: We conducted a retrospective study comparing gestational age (GA)-specific clinical data between medical NEC (m-NEC) and surgical NEC (s-NEC) subgroups, stratified by GA as <28 weeks, 28 ≤ GA < 32 weeks, and 32 ≤ GA < 37 weeks. Multivariate logistic analysis and receiver operating characteristic curve were used to identify the independent predictors of s-NEC. RESULTS: In comparison to m-NEC at NEC onset, s-NEC infants exhibited the following findings: In GA < 28 weeks, s-NEC infants had lower platelet counts. In 28 ≤ GA < 32 weeks, lower absolute lymphocyte counts, and significant percent drop in platelets, lymphocytes, and monocytes were observed. In 32 ≤ GA < 37 weeks, lower absolute lymphocyte counts and significant percent drop in lymphocytes were found. Independent predictors were able to distinguish s-NEC from m-NEC. The area under the curve (AUC) for platelet counts in GA < 28 weeks was 0.880, while C-reactive protein in 28 ≤ GA < 32 weeks had an AUC of 0.889. The AUC for lymphocyte counts in 32 ≤ GA < 37 weeks was 0.892. CONCLUSION: This study identified hematological abnormalities in the development of NEC based on gestational age. Independent predictors may help clinicians distinguish surgical NEC from medical NEC. IMPACT: Necrotizing enterocolitis (NEC) patients with different gestational ages (GA) exhibit different hematological features and independent predictors of surgical NEC differ among different GAs. Our research made the current studies about peripheral hematological features with NEC more complete by analyzing peripheral data collected within 24 h of birth, at day 5-7, day 3-4, day 1-2 before NEC onset, at the time of NEC onset, day 1, day 2, day 3, day 4-5, day 6-7 after NEC onset. Our study is helpful to clinicians in developing a more detailed diagnostic strategy based on GA for the early identification of surgical NEC.

Mortality and extrauterine growth restriction of necrotizing enterocolitis in very preterm infants with heart disease: a multi-center cohort study.

Congenital heart disease (CHD) and patent ductus arteriosus (PDA) are risk factors of necrotizing enterocolitis (NEC) in infants. However, it is unclear whether the prognosis of NEC is different between very preterm infants (VPIs) with and without heart diseases. This was an observational cohort study that enrolled VPIs (born between 24+0 and 31+6 weeks) admitted to 79 tertiary neonatal intensive care units (NICU) in the Chinese Neonatal Network (CHNN) between 2019 and 2021. The exposure was CHD or isolated PDA, and VPIs with NEC were divided into three groups: complicated with CHD, with isolated PDA, and without heart diseases. The primary outcomes were NEC-related adverse outcomes (death or extrauterine growth restriction (EUGR)). Logistic regression models were used to adjust potential confounders and calculate the odds ratios (ORs) and 95% confidential intervals (CIs) for each outcome. A total of 1335 VPIs with NEC were enrolled in this study, including 65 VPIs with CHD and 406 VPIs with isolated PDA. The VPIs with heart diseases had smaller gestational ages and lower body weights at birth, more antenatal steroids use, and requiring inotrope prior to the onset of NEC. While suffering from NEC, there was no significant increased risks in NEC-related death in VPIs with either CHD (adjusted OR [aOR]: 1.10; 95% CI: 0.41-2.50) or isolated PDA (aOR: 1.25; 95% CI 0.82-1.87), and increased risks in EUGR were identified in either survival VPIs with CHD (aOR: 2.35; 95% CI: 1.31-4.20) or isolated PDA (aOR: 1.53; 95% CI: 1.16-2.01) in survivors. The composite outcome (death or EUGR) was also more often observed in VPIs with either CHD (aOR: 2.07; 95% confidence interval [CI]: 1.20-3.60) or isolated PDA (aOR: 1.51; 95% CI: 1.17-1.94) than that without heart diseases. VPIs with either CHD or isolated PDA were associated with significantly prolonged duration of fasting, extended time to achieve full enteral feeding, and longer ventilation duration and hospitalization duration. Similar characteristics were also seen in VPIs with isolated PDA, with the exception that VPIs with CHD are more likely to undergo surgical intervention and maintain a prolonged fast after NEC.     Conclusion: In VPIs with NEC, CHD and isolated PDA are associated with an increased risk in worse outcomes. We recommend that VPIs with cardiac NEC be managed with aggressive treatment and nutrition strategies to prevent EUGR. What is Known: • CHD and PDA are risk factors for NEC in infants, which can lead to adverse outcomes such as death and EUGR. • NEC in infants with heart disease differs clinically from that in infants without heart disease and should be recognized as a separate disease process. What is New: • CHD and isolated PDA are associated with increased risks of EUGR in VPIs with NEC. • Risk factors associated with VPIs with cardiac NEC suggested these patients should be managed with aggressive treatment and nutrition strategies to adverse outcomes.

Using a new human milk fortifier to optimize human milk feeding among very preterm and/or very low birth weight infants: a multicenter study in China.

BACKGROUND: Human milk fortifier (HMF) composition has been optimized recently. But clinical evidence of its safety and efficacy is limited in Chinese population. The aim of this study was to evaluate effects of a new HMF in growth, nutritional status, feeding intolerance, and major morbidities among very preterm (VPT) or very low birth weight (VLBW) infants in China. METHODS: VPT/VLBW infants admitted from March 2020 to April 2021 were prospectively included in the experimental (new HMF, nHMF) group, who received a new powdered HMF as a breast milk feeding supplement during hospitalization. Infants in the control group (cHMF) admitted from January 2018 to December 2019, were retrospective included, and matched with nHMF group infants for gestational age and birth weight. They received other kinds of commercially available HMFs. Weight gain velocity, concentrations of nutritional biomarkers, incidence of major morbidities, and measures of feeding intolerance were compared between the two groups. RESULTS: Demographic and clinical characteristics of infants in nHMF and cHMF groups were comparable. Weight gain velocity had no significant difference between the nHMF (14.0 ± 3.5 g/kg/d) and the cHMF group (14.2 ± 3.8 g/kg/d; P = 0.46). Incidence of morbidities, including necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity, culture-confirmed sepsis, and feeding intolerance during hospitalization between nHMF and cHMF, were similar (all P-values > 0.05). The time to achieve full enteral feeding [13.5 (10, 21) days] in the nHMF group was significantly shorter than that in the cHMF group [17 (12, 23) days, HR = 0.67, 95%CI: 0.49, 0.92; P = 0.01]. Compared with cHMF group, the decrease of blood urea nitrogen level over time in nHMF group was smaller (ß = 0.6, 95%CI:0.1, 1.0; P = 0.01). CONCLUSIONS: The new HMF can promote growth of preterm infants effectively without increasing the incidence of major morbidity and feeding intolerance. It can be used feasible in Chinese VPT/VLBW infants. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov (NCT04283799).

Association between Neonatal Outcomes and Admission Hypothermia among Very Preterm Infants in Chinese Neonatal Intensive Care Units: A Multicenter Cohort Study.

OBJECTIVE: We aimed to investigate the relationship between admission hypothermia and outcomes among very preterm infants (VPIs) in neonatal intensive care units (NICUs) in China. We also investigated the frequency of hypothermia in VPIs in China and the variation in hypothermia across Chinese Neonatal Network (CHNN) sites. STUDY DESIGN: This retrospective cohort study enrolled infants with 240/7 to 316/7 weeks of gestation with an admission body temperature ≤37.5 °C who were admitted to CHNN-participating NICUs between January 1 and December 31, 2019. RESULTS: A total of 5,913 VPIs were included in this study, of which 4,075 (68.9%) had hypothermia (<36.5 °C) at admission. The incidence of admission hypothermia varied widely across CHNN sites (9-100%). Lower gestational age (GA), lower birth weight, antenatal steroid administration, multiple births, small for GA, Apgar scores <7 at the 5th minute, and intensive resuscitation were significantly associated with admission hypothermia. Compared with infants with normothermia (36.5-37.5 °C), the adjusted odds ratios (ORs) for composite outcome among infants with admission hypothermia <35.5 °C increased to 1.47 (95% confidence interval [CI], 1.15-1.88). The adjusted ORs for mortality among infants with admission hypothermia (36.0-36.4 and <35.5 °C) increased to 1.41 (95% CI, 1.09-1.83) and 1.93 (95% CI, 1.31-2.85), respectively. Admission hypothermia was associated with a higher likelihood of bronchopulmonary dysplasia, but was not associated with necrotizing enterocolitis ≥stage II, severe intraventricular hemorrhage, cystic periventricular leukomalacia, severe retinopathy of prematurity, or sepsis. CONCLUSION: Admission hypothermia remains a common problem for VPIs in a large cohort in China and is associated with adverse outcomes. Continuous quality improvement of admission hypothermia in the future may result in a substantial improvement in the outcomes of VPIs in China. KEY POINTS: · Admission hypothermia is common in VPIs.. · The incidence of admission hypothermia in VPIs remains high in China.. · Admission hypothermia is associated with adverse outcomes in VPIs..

[Role and mechanism of epithelial-mesenchymal transition in a rat model of bronchopulmonary dysplasia induced by hyperoxia exposure]. / 上皮-间å è´¨è½¬åŒ–åœ¨é«˜æ°§è¯±å¯¼å¤§é¼ æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯æ¨¡åž‹ä¸­çš„ä½œç”¨åŠæœºåˆ¶ç ”ç©¶.

OBJECTIVES: To investigate the role and mechanism of epithelial-mesenchymal transition (EMT) in a rat model of bronchopulmonary dysplasia (BPD). METHODS: The experiment consisted of two parts. (1) Forty-eight preterm rats were randomly divided into a normoxia group and a hyperoxia group, with 24 rats in each group. The hyperoxia group was exposed to 85% oxygen to establish a BPD model, while the normoxia group was kept in room air at normal pressure. Lung tissue samples were collected on days 1, 4, 7, and 14 of the experiment. (2) Rat type II alveolar epithelial cells (RLE-6TN) were randomly divided into a normoxia group (cultured in air) and a hyperoxia group (cultured in 95% oxygen), and cell samples were collected 12, 24, and 48 hours after hyperoxia exposure. Hematoxylin-eosin staining was used to observe alveolarization in preterm rat lungs, and immunofluorescence was used to detect the co-localization of surfactant protein C (SPC) and α-smooth muscle actin (α-SMA) in preterm rat lung tissue and RLE-6TN cells. Quantitative real-time polymerase chain reaction and protein immunoblotting were used to detect the expression levels of EMT-related mRNA and proteins in preterm rat lung tissue and RLE-6TN cells. RESULTS: (1) Compared with the normoxia group, the hyperoxia group showed blocked alveolarization and simplified alveolar structure after 7 days of hyperoxia exposure. Co-localization of SPC and α-SMA was observed in lung tissue, with decreased SPC expression and increased α-SMA expression in the hyperoxia group at 7 and 14 days of hyperoxia exposure compared to the normoxia group. In the hyperoxia group, the mRNA and protein levels of TGF-ß1, α-SMA, and N-cadherin were increased, while the mRNA and protein levels of SPC and E-cadherin were decreased at 7 and 14 days of hyperoxia exposure compared to the normoxia group (P<0.05). (2) SPC and α-SMA was observed in RLE-6TN cells, with decreased SPC expression and increased α-SMA expression in the hyperoxia group at 24 and 48 hours of hyperoxia exposure compared to the normoxia group. Compared to the normoxia group, the mRNA and protein levels of SPC and E-cadherin in the hyperoxia group were decreased, while the mRNA and protein levels of TGF-ß1, α-SMA, and E-cadherin in the hyperoxia group increased at 48 hours of hyperoxia exposure (P<0.05). CONCLUSIONS: EMT disrupts the tight connections between alveolar epithelial cells in a preterm rat model of BPD, leading to simplified alveolar structure and abnormal development, and is involved in the development of BPD. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 765-773.

Zinc and selenium status in coronavirus disease 2019.

We systematically analyzed and attempted to discuss the possibility that deficiencies of zinc or selenium were associated with the incidence and severity of COVID-19. We searched for published and unpublished articles in PubMed, Embase, Web of Science and Cochrane up to 9 February 2023. And we selected healthy individuals, mild/severe, and even deceased COVID-19 patients to analyze their serum data. Data related to 2319 patients from 20 studies were analyzed. In the mild/severe group, zinc deficiency was associated with the degree of severe disease (SMD = 0.50, 95% CI 0.32-0.68, I2 = 50.5%) and we got an Egger's test of p = 0.784; but selenium deficiency was not associated with the degree of severe disease (SMD = - 0.03, 95% CI - 0.98-0.93, I2 = 96.7%). In the surviving/death group, zinc deficiency was not associated with mortality of COVID-19 (SMD = 1.66, 95%CI - 1.42-4.47), nor was selenium (SMD = - 0.16, 95%CI - 1.33-1.01). In the risk group, zinc deficiency was positively associated with the prevalence of COVID-19 (SMD = 1.21, 95% CI 0.96-1.46, I2 = 54.3%) and selenium deficiency was also positively associated with the prevalence of it (SMD = 1.16, 95% CI 0.71-1.61, I2 = 58.3%). Currently, serum zinc and selenium deficiencies increase the incidence of COVID-19 and zinc deficiency exacerbates the disease; however, neither zinc nor selenium was associated with mortality in patients with COVID-19. Nevertheless, our conclusions may change when new clinical studies are published.

Analysis of Postoperative Outcomes and Extrauterine Growth Retardation in Preterm Infants with Necrotizing Enterocolitis: A Retrospective Study.

OBJECTIVE: High mortality and extrauterine growth retardation (EUGR) remain serious problems in preterm infants after necrotizing enterocolitis (NEC) surgery. This study investigated the risk factors for mortality and EUGR in preterm infants after NEC surgery. STUDY DESIGN: The risk factors were analyzed retrospectively by univariate analysis and multivariate logistic regression analysis in 52 preterm infants, who underwent NEC surgery and were hospitalized in neonatology department of Shanghai Children's Hospital between May 2014 and December 2021. Patients were divided into survival and death groups. Survivors were divided into two groups according to whether EUGR occurred when they achieved full enteral feeding after surgery. RESULTS: The mortality of preterm infants after NEC surgery was 26.9% (14/52). About 55.3% (21/38) of survivors developed postoperative EUGR. (1) Age at surgery, proportion of shock, and intestinal perforation differed significantly between the survival and death groups (p = 0.001, 0.005, and 0.02, respectively). Shock (p = 0.02, odds ratio [OR] = 8.86, 95% confidence interval [CI]: 1.43-55.10) and intestinal perforation (p = 0.03, OR = 6.12, 95% CI: 1.16-32.41) were significant risk factors for death. (2) Compared with the non-EUGR group, proportion of preoperative EUGR, postoperative 1-week calories, and parenteral nutrition time differed significantly in EUGR group (p = 0.001, 0.01, and 0.04, respectively). Preoperative EUGR (p = 0.02, OR = 18.63, 95%CI: 1.77-196.42) was a significant risk factor for postoperative EUGR. CONCLUSION: Shock and intestinal perforation are significant risk factors for death in preterm infants after NEC surgery. Survivors are prone to EUGR, and preoperative EUGR is a significant risk factor. In addition, adequate caloric intake and achievement of full enteral feeding as soon as possible may be beneficial to improve EUGR of preterm infants after NEC surgery. KEY POINTS: · Shock and intestinal perforation are risk factors for death in preterm infants after NEC surgery.. · Preoperative EUGR is a risk factor for postoperative EUGR in preterm infants after NEC surgery.. · Active correction of shock and avoiding intestinal perforation may help improve the outcomes..

The neonatal onset diabetes mellitus of Chinese neonate with congenital generalized lipodystrophy 2: a case report.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a clinically heterogeneous disorder characterized by near total absence of adipose tissue along with metabolic complications. Diabetes mellitus developed from CGL usually present between ages 15 and 20 years, and there are few reports in neonate. CASE PRESENTATION: In this report, we described a rare clinical presentation of CGL in a 12-day-old Chinese female neonates with hyperglycemia, hyperlipidemia, and subsequently appeared diabetes, hepatomegaly and fatty liver. The two clinical-exome sequencing identified heterozygous null mutations (c.793C > T and c.565G > T) in BSCL2 gene which was inherited from father and mother respectively. To date, it was the firstly reported CGL patient with neonatal onset diabetes. The neonate was treated with antibiotic, insulin and deeply hydrolyzed formula milk to significantly decrease FBG and serum trigylcerides levels.  CONCLUSIONS: Our case report analyzes the causes of early onset diabetes may relate with the locus of BSCL2 gene mutations and infection induction. It also suggests the importance of early identification, genetic analysis, and symptomatic treatment in the CGL, which are essential for improving the prognosis of children.

The molecular basis of brain injury in preterm infants with sepsis - associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is characterized by brain dysfunction during sepsis, without central nervous system infection. Here, we explored the molecular basis of brain injury in preterm infants with SAE. From Jan 2016 to Dec 2019, a total of 20 preterm infants were hospitalized in the neonatal intensive care unit (NICU) of our hospital, including 10 preterm infants with SAE (SAE group) and 10 preterm infants without encephalopathy after sepsis (no SAE group). Among the 20 premature infants, there were 12 males and 8 females, with mean gestational age 31.0 ± 2.46 weeks, 7 cases with birth weight ≤ 1500 g and 13 cases with birth weight 1500-2500 g. Blood cultures were negative in 6 cases and positive in 14 cases, including 10 cases of Gram-negative and 4 cases of Gram-positive bacteria, respectively. Expression levels of messenger RNA (mRNA) and MicroRNA (miRNA) were analyzed in peripheral blood samples from both groups during sepsis. There were 1858 upregulated and 2226 downregulated mRNAs [fold-change (FC) > |2|, p < 0.05], and 322 upregulated and 160 downregulated miRNAs (FC > |2|, p < 0.05), respectively, in the SAE group compared with the no SAE group. Expression levels of miRNA-1197 [95% confidence intervals (CI), 0.042 to 0.166] were 6.03-fold higher in the SAE group than the no SAE group, while those of miRNA-485-5p (95% CI, 0.064 to 0.024) were lower (0.31-fold). Both high expression of miRNA-1197 and low expression of miRNA-485-5p may be associated with pathogenic alteration of the oxidative respiratory chain and energy metabolism in preterm infants with SAE.

Comparative analysis of chemical constituents by HPLC-ESI-MSn and antioxidant activities of Dendrobium huoshanense and Dendrobium officinale.

Dendrobium huoshanense is a Chinese medicinal herb that has high quality and excellent efficacy. However, the chemical basis of its activity is still unclear. Of note, Dendrobium officinale is the most widely utilized among the Dendrobium species. Therefore, the current study systematically investigated the chemical constituents of methanolic extracts and different polar fractions of aqueous extracts from the two herbs by HPLC-ESI-MSn , and then compared in vitro antioxidant activities of their five different polar extracts. Consequently, 61 and 49 compounds were identified from D. huoshanense and D. officinale, respectively, of which 43 compounds were common to both species. In addition, 17 out of 22 different compounds were identified only in D. huoshanense. Moreover, the peak areas of some shared identical compounds of D. huoshanense were significantly larger than that of D. officinale. In vitro antioxidant evaluation results showed that the n-BuOH-soluble fraction of the two herbs exhibited remarkable antioxidant activities. Furthermore, the antioxidant activities of different fractions of D. huoshanense were separately superior to that of D. officinale, which may be attributed to its variable and high contents of flavonoids, bibenzyls and phenanthrenes. These results provide the evidence for the high quality and efficacy of D. huoshanense.

Association of Thyroid Function During Pregnancy With the Risk of Pre-eclampsia and Gestational Diabetes Mellitus.

OBJECTIVE: To estimate the association of maternal thyroid dysfunction with the risk of gestational hypertension and diabetes. Whether the association was affected by gestational age at diagnosis and thyroid autoimmunity was further explored. METHODS: A cohort study of 41 647 participants was conducted. Thyroid function (ie, thyroid-stimulating hormone [TSH] and free thyroxine [FT4]) was measured by electrochemiluminescence immunoassay. Thyroid antibody positivity (eg, thyroperoxidase, thyroglobulin, and TSH receptor antibody) was indicated if the values of these antibodies exceeded the upper targets of the reference range. The relationship between maternal thyroid dysfunction and the risk of pre-eclampsia (PE) and gestational diabetes mellitus (GDM) was assessed by multivariate logistic regression. RESULTS: Isolated hypothyroxinemia (defined as 5th ≤ TSH ≤ 95th percentile, FT4 < 5th percentile) was associated with the risk of PE (odds ratio [OR], 1.32; 95% CI, 1.10-1.58). Overt hypothyroidism (TSH > 95th percentile; FT4 < 5th percentile) was related to the risk of severe PE (OR, 2.59; 95% CI, 1.05-6.37). Being positive for TSH receptor antibody was associated with a decreased risk of GDM (OR, 0.49; 95% CI, 0.35-0.70). A marginally significant association between overt hypothyroidism detected at the first trimester and the risk of GDM was found (OR, 1.60; 95% CI, 1.00-2.83). The association of thyroid dysfunction with the risk of PE and GDM was stronger among pregnant women who were negative for autoantibodies. CONCLUSION: Some types of thyroid dysfunction during pregnancy were associated with the risk of PE and GDM. The associations varied by gestational age at diagnosis and by thyroid autoantibody status.

Effects of cytomegalovirus infection on the differential diagnosis between biliary atresia and intrahepatic cholestasis in a Chinese large cohort study.

INTRODUCTION AND OBJECTIVES: Differentiating biliary atresia from other causes of neonatal cholestasis is challenging, particularly when cytomegalovirus (CMV) and biliary atresia occur simultaneously. We aimed to elucidate whether CMV infection would affect the differential diagnosis of biliary atresia and intrahepatic cholestasis. PATIENTS AND METHODS: This retrospective study was conducted among patients with neonatal cholestasis admitted to three tertiary hospitals between January 2010 and August 2019. The clinical characteristics, laboratory, and imaging findings were recorded. On the basis of the CMV serology results, the infants were classified into CMV-IgM (+) and CMV-IgM (-) groups. The clinical differences and diagnostic performances of routine predictors between biliary atresia and intrahepatic cholestasis were analyzed in each group. Finally, we compared the diagnostic performances of various tests in the two groups. RESULTS: A total of 705 patients with neonatal cholestasis were enrolled: 215 (30.5%) patients were positive for CMV-IgM, among whom 97 had biliary atresia and 118 had CMV hepatitis; 490 infants were CMV-IgM (-), among whom 240 had biliary atresia and 250 had intrahepatic cholestasis. The diagnostic performances of stool color, direct bilirubin level, γ-glutamyl transpeptidase level, abnormal gallbladder, triangular cord sign, and hepatobiliary scintigraphy between CMV hepatitis and CMV-IgM (+) biliary atresia were similar to those between CMV-IgM (-) biliary atresia and CMV-IgM (-) intrahepatic cholestasis groups. CONCLUSIONS: Our large-scale study showed a high prevalence of CMV infection in patients with neonatal cholestasis in China. The presence of CMV infection did not affect the routine predictors to discriminate biliary atresia and intrahepatic cholestasis.

The expression of miR-125b in Nrf2-silenced A549 cells exposed to hyperoxia and its relationship with apoptosis.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects the quality of life of infants. At present, premature exposure to hyperoxia for extended periods of time is believed to affect the development of lung tissue and vascularity, resulting in BPD. The oxidative stress caused by hyperoxia exposure is an important risk factor for BPD in premature infants. Nuclear factor E2-related factor 2 (Nrf2) is an important regulator of antioxidant mechanisms. As a microRNA, microRNA-125b (miR-125b) plays an important role in cell proliferation, differentiation and apoptosis. Although the Nrf2/ARE pathway has been extensively studied, little is known about the regulatory role of microRNAs in Nrf2 expression. In this study, the expression levels of Nrf2 and miR-125b in the lung tissues of premature Sprague Dawley (SD) rats and A549 cells exposed to hyperoxia were detected by quantitative real-time polymerase chain reaction (qRT-PCR), and the apoptosis of A549 cells was detected by flow cytometry. The results showed that Nrf2 and miRNA-125b in the lung tissues of premature rats increased significantly upon exposure to hyperoxia and played a protective role. Nrf2 was suppressed by small interfering RNA (siRNA) in A549 cells, miR-125b was similarly inhibited, and apoptosis was significantly increased. These results suggest that miR-125b helps protect against BPD as a downstream target of Nrf2.

Effects of hyperoxia exposure on the expression of Nrf2 and heme oxygenase-1 in lung tissues of premature rats.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease with long-term sequelae including neurodevelopmental delay. Although the precise mechanism of BPD is not well defined, oxidative stress is thought to be involved in the pathogenesis process of BPD. Nrf2 (Nuclear factor erythroid 2-related factor 2)-Keap1 (Kelch-like ECH associated protein 1)-ARE (Antioxidant Reaction Elements) signaling pathway is one of the main protective mechanisms of BPD, which can induce cytoprotective gene expression, such as heme oxygenase-1 (HO-1), nicotinamide quinone oxidoreductase 1 (NQO1) and so on. We exposed premature rats to hyperoxia and identified lung developmental retardation in preterm rats, with similar pathological changes as BPD. The expression of Nrf2 and HO-1 in premature rats was significantly higher after hyperoxia exposure. To explore the changes of Nrf2 and HO-1 in premature rats and enhance their beneficial functions may provide new treatment strategies for infants at risk of BPD.

14-3-3ß Is necessary in the regulation of polarization and directional migration of alveolar myofibroblasts by lipopolysaccharide.

Aims:Bronchopulmonary dysplasia (BPD) is characterized by alveolarization arrest. During alveolarization, alveolar myofibroblasts are thought to migrate into the septal tips and elongate secondary septa. Lipopolysaccharide (LPS) exposure has been reported to disrupt directional migration and final location of alveolar myofibroblasts in a rat model of BPD induced by intra-amniotic injection of LPS. However, molecular mechanisms that control directional migration of alveolar myofibroblasts have not so far been investigated clearly. Materials and Methods: We assessed the polarization of myofibroblast using scrape wounding assays combined with Golgi tracking. Transwell migration assay was used to detect the directional migration of myofibroblasts. Pull-down assays were performed to isolate the active GTP-bound form using the RhoA activation assay kits. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via siRNA interference. Results: Here, we showed that LPS might affect the directional migration of myofibroblasts by disturbing the polarization of myofibroblasts. In addition, as a main member of RhoGTPases family which plays a vital role in establishing and maintaining cell polarity, RhoA activity was significantly upregulated in myofibroblasts treated with LPS, while activity of epidermal growth factor receptor (EGFR) was upregulated and overexpression of its ligand, TGF-α, in myofibroblasts by LPS treatment. AG1478, an EGFR inhibitor, could abrogate the upregulated RhoA activity of myofibroblasts by LPS and rhTGF-α. Moreover, if we knock down 14-3-3ß, LPS and rhTGF-α could not activate RhoA and disturb myofibroblasts polarization. Conclusions: Taken together, our findings suggest that LPS exposure may increase RhoA activity of myofibroblasts by TGF-α/EGFR/14-3-3ß signaling pathway, and then disturb myofibroblasts polarization and directional migration.

Clinical effect and safety of continuous renal replacement therapy in the treatment of neonatal sepsis-related acute kidney injury.

BACKGROUND: Sepsis is the leading cause of acute kidney injury (AKI) in the neonatal intensive care unit (NICU). The aim of the study is to explore the efficacy and security of continuous renal replacement therapy (CRRT) in the treatment of neonatal sepsis-related AKI. METHOD: Totally12 sepsis-related AKI neonates treated with CRRT were hospitalized in the NICU of Shanghai Children's Hospital between November 2012 and November 2019, and the clinical data of these 12 cases were retrospectively analyzed. Renal function, acid-base balance, electrolytes, blood pressure and hemodynamics indexes were recorded before CRRT initiation, 12/24/48 h after CRRT initiation and at the end of CRRT respectively. The efficacy of CRRT was evaluated and the clinical outcome was observed in these 12 sepsis-related AKI neonates. Repeated measurement analysis of variance was used for statistical analysis of the data. RESULT: (1) Continuous veno-venous hemodialysis filtration (CVVHDF) was used in 12 cases of sepsis-related AKI neonates. There were 6 cases with oliguria, 3 cases with fluid overload (FO), 3 cases with septic shock. The duration of CRRT was 49 ~ 110 h, average (76.2 ± 23.5) h. (2) The blood pressure (BP) of 12 sepsis -related AKI neonates could reach the normal level (40-60 mmHg) 12 h after CRRT initiation, and the normal BP level could be maintained during the CRRT treatment. After 12 h CRRT, the blood pH value increased to the normal range (7.35 ~ 7.45). After 12 h CRRT treatment, the oxygenation index of 12sepsis-related AKI neonates could reach 200 mmHg. After 24 h CRRT treatment, it could rise to more than 300 mmHg. Serum potassium, serum urea nitrogen and serum creatinine levels decreased significantly 12 h after CRRT initiation, and reached the normal range 24 h after CRRT initiation. The urine volume significantly increased 24 h after CRRT initiation. (3) Venous catheterization was performed successfully in all sepsis-related AKI neonates. We observed 2 cases of thrombocytopenia, 1 case of obstruction and 1 case of hypotension in the course of CRRT. There were no complications such as hypothermia, hemorrhage, thrombosis and infection.11 neonates were cured and discharged. One neonate was treated with CRRT and passed through the oliguria stage of AKI, but died after the parents gave up the treatment. CONCLUSIONS: It is safe and effective to treat neonatal sepsis-related AKI with CRRT, which should be an effective measure for the treatment of sepsis-related AKI neonates.

Pharmacokinetics of three formulations of vitacoxib in horses.

The pharmacokinetic properties of three formulations of vitacoxib were investigated in horses. To describe plasma concentrations and characterize the pharmacokinetics, 6 healthy adult Chinese Mongolian horses were administered a single dose of 0.1 mg/kg bodyweight intravenous (i.v.), oral paste, or oral tablet vitacoxib in a 3-way, randomized, parallel design. Blood samples were collected prior to and at various times up to 72 hr postadministration. Plasma vitacoxib concentrations were quantified using UPLC-MS/MS, and pharmacokinetic parameters were calculated using noncompartmental analysis. No complications resulting from the vitacoxib administration were noted on subsequent administrations, and all procedures were tolerated well by the horses throughout the study. The elimination half-life (T1/2λz ) was 4.24 ± 1.98 hr (i.v.), 8.77 ± 0.91 hr (oral paste), and 8.12 ± 4.24 hr (oral tablet), respectively. Maximum plasma concentration (Cmax ) was 28.61 ± 9.29 ng/ml (oral paste) and 19.64 ± 9.26 ng/ml (oral tablet), respectively. Area under the concentration-versus-time curve (AUClast ) was 336 ± 229 ng hr/ml (i.v.), 221 ± 94 ng hr/ml (oral paste), and 203 ± 139 ng hr/ml, respectively. The results showed statistically significant differences between the 2 oral vitacoxib groups in Tmax value. T1/2λz (hr), AUClast (ng hr/ml), and MRT (hr) were significantly different between i.v. and oral groups. The longer half-life observed following oral administration was consistent with the flip-flop phenomenon.

[Expression of microRNA-495-5p in preterm infants with bronchopulmonary dysplasia: a bioinformatics analysis].

OBJECTIVE: To study the expression of microRNA-495-5p (miRNA-495-5p) in the serum of preterm infants with bronchopulmonary dysplasia (BPD) based on a bioinformatics analysis, and to provide a theoretical basis for further research on the association between miRNA-495-5p and BPD. METHODS: A total of 40 preterm infants who were admitted to the neonatal intensive care unit from January 2015 to December 2016 were enrolled. Among these infants, 20 with early clinical manifestations of BPD were enrolled as the BPD group, and 20 without such manifestations were enrolled as the control group. Peripheral blood samples were collected. The miRNA microarray technique was used to screen out differentially expressed miRNAs in serum between the two groups. RT-PCR was used for validation of results. TargetScan, miRDB, and miRWalk databases were used to predict the target genes of miRNA-495-5p. The DAVID database was used to perform gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the target genes. RESULTS: Compared with the control group, the BPD group had a significant increase in the expression of miRNA-495-5p in serum (P<0.05). A total of 117 target genes of miRNA-495-5p were predicted by the above three databases and they were involved in several molecular functions (including transcriptional regulatory activity, transcriptional activation activity, and transcription cofactor activity), biological processes (such as metabolic regulation, DNA-dependent transcriptional regulation, and vascular pattern), and cell components (including nucleoplasm, membrane components, and insoluble components) (P<0.05). As for signaling pathways, these genes were significantly enriched in the mTOR signaling pathway (P<0.05). CONCLUSIONS: MiRNA-495-5p may be involved in the development and progression of BPD by regulating angiogenesis, stem cell differentiation, apoptosis, and autophagy, which provides clues for further research on the role and functional mechanism of miRNA-495-5p in BPD.