Effect of Anti-D titers in RhD-negative pregnant women on fetuses and newborns: A retrospective study.

BACKGROUND: Transplacental-derived anti-D IgG in RhD-negative pregnant women can trigger an immune response to Rh D-positive red cells in fetuses and newborns. We assessed the effect of anti-D titers in RhD-negative pregnant women on fetuses and newborns. METHODS: The clinical data of 142 singleton RhD-sensitized pregnancies were retrospectively collected. The pregnant women received routine prenatal care and the newborns had standard care. Based on the tertile categories of the pregnancies, the maximum titers of anti-D IgG in the pregnant women were divided into three groups ranging from low to high as follows: low-titer group (anti-D titer: 1:4-1:128, n = 57); medium-titer group (anti-D titer: 1:256-1:512, n = 50); and high-titer group (anti-D titer: 1:1024-1:4096, n = 35). RESULTS: The frequencies of major neonatal complications did not significantly differ among the three groups. The high-titer group had the highest frequency of pregnancies requiring intrauterine transfusion (IUT) and number of IUTs among the three groups. The high-titer group had a significantly higher frequency of newborns treated with top-up transfusion, number of top-up transfusions, frequency of newborns treated with exchange transfusion (ET), and number of ETs when compared to the low-titer group. CONCLUSION: Higher anti-D titers in RhD-negative pregnant women predict more severe fetal and neonatal hemolytic anemia. Increasing maternal anti-D titers results in an increased need for IUTs, and neonatal top-up transfusions and ETs. Methods for reducing titers of anti-D IgG in RhD-sensitized pregnant women warrants further investigation.

Impact of using peer role-playing on the clinical skills performance of pediatric trainees.

OBJECTIVE: The aim of this study was to evaluate the impact of peer role-playing on the clinical skills performance of pediatric trainees. METHODS: Seventy-eight clinical medicine trainees were randomly divided into a role-playing group and a traditional teaching group, with 39 students in each group. The role-playing group alternated between the roles of clinicians and patients, while the traditional teaching group received the bedside teaching mode of verbal instruction. After two weeks traineeship, mini-Clinical Evaluation Exercise(Mini-CEX) was used to evaluate the trainees' competence in physician-patient communication and clinical practice. A questionnaire was given to the role-playing group to assess their satisfaction with the method. RESULTS: The Mini-CEX scores showed that the role-playing group had superior clinical skills (p < 0.05), including communication, history taking, professionalism, organization, clinical skills, and physical examination, compared to the traditional teaching group. Furthermore, trainee satisfaction was high with the role-playing method,and the satisfaction were more than 95%. CONCLUSION: The role-playing method effectively improved the clinical skills of pediatric trainees, developed clinical communication skills, and enhanced the application of medical knowledge in a simulated medical environment.

Dopamine inhibits group 2 innate lymphoid cell-driven allergic lung inflammation by dampening mitochondrial activity.

Neuronal signals have emerged as pivotal regulators of group 2 innate lymphoid cells (ILC2s) that regulate tissue homeostasis and allergic inflammation. The molecular pathways underlying the neuronal regulation of ILC2 responses in lungs remain to be fully elucidated. Here, we found that the abundance of neurotransmitter dopamine was negatively correlated with circulating ILC2 numbers and positively associated with pulmonary function in humans. Dopamine potently suppressed lung ILC2 responses in a DRD1-receptor-dependent manner. Genetic deletion of Drd1 or local ablation of dopaminergic neurons augmented ILC2 responses and allergic lung inflammation. Transcriptome and metabolic analyses revealed that dopamine impaired the mitochondrial oxidative phosphorylation (OXPHOS) pathway in ILC2s. Augmentation of OXPHOS activity with oltipraz antagonized the inhibitory effect of dopamine. Local administration of dopamine alleviated allergen-induced ILC2 responses and airway inflammation. These findings demonstrate that dopamine represents an inhibitory regulator of ILC2 responses in allergic airway inflammation.

Decreased Polymorphonuclear Myeloid-Derived Suppressor Cells and ROS Production Correlated Closely with Bronchopulmonary Dysplasia in Preterm Infants.

Background: Bronchopulmonary dysplasia (BPD) is one of the most serious complications in premature infants. Myeloid-derived suppressor cells (MDSCs) have been indicated to promote immune tolerance and induce anti-inflammatory responses during the neonatal stage. However, the role of MDSCs in BPD has not been completely expounded. Methods: 130 cases of newborns were collected from six tertiary hospitals in Guangzhou from August 2019 to June 2022. They were divided into BPD group, non-BPD preterm infants group, and term infants group according to gestational age and presence of BPD. The peripheral blood was collected and used to analyze the proportion, phenotypic, and function of MDSCs at 3 to 7 days and 8 to 14 days after birth, respectively. Results: We indicated that the number of both MDSCs in premature infants is reduced, and the number of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in peripheral blood of BPD infants was significantly lower than that of non-BPD infants under 34 weeks of gestational age (P < 0.05). Furthermore, PMN-MDSCs from peripheral blood of patients presented inhibitory effect on proliferation of CD4+T and CD8+T cells in each group. However, PMN-MDSCs from BPD group had obviously weaker inhibitory effect on proliferation of CD4+T and CD8+T cells than that from non-BPD preterm infants group. In addition, we demonstrated that the expression of NADPH oxidase (Nox2) and reactive oxygen species (ROS) in PMN-MDSCs of BPD children was significantly lower than that in non-BPD preterm infants, suggesting that ROS pathway was affected in BPD in premature infants. Conclusion: This study preliminarily revealed the role of PMN-MDSCs in the pathogenesis of BPD in premature infants. The specific immune regulation mechanism of PMN-MDSCs in BPD will provide new ideas and strategies for clinical prevention and treatment of BPD in premature infants.

Mechanisms regulating transitory suppressive activity of neutrophils in newborns: PMNs-MDSCs in newborns.

Transitory appearance of immune suppressive polymorphonuclear neutrophils (PMNs) defined as myeloid-derived suppressor cells (PMNs-MDSCs) in newborns is important for their protection from inflammation associated with newly established gut microbiota. Here, we report that inhibition of the type I IFN (IFN1) pathway played a major role in regulation of PMNs-MDSCs-suppressive activity during first weeks of life. Expression of the IFN1 receptor IFNAR1 was markedly lower in PMNs-MDSCs. However, in newborn mice, down-regulation of IFNAR1 was not sufficient to render PMNs immune suppressive. That also required the presence of a positive signal from lactoferrin via its receptor low-density lipoprotein receptor-related protein 2. The latter effect was mediated via NF-κB activation, which was tempered by IFN1 in a manner that involved suppressor of cytokine signaling 3. Thus, we discovered a mechanism of tight regulation of immune suppressive PMNs-MDSCs in newborns, which may be used in the development of therapies of neonatal pathologies.

Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.

Congenital heart defects (CHDs) represent the most common human birth defects. Our previous study indicates that the malfunction of microRNAs (miRNAs) in cardiac neural crest cells (NCCs), which contribute to the development of the heart and the connected great vessels, is likely linked to the pathogenesis of human CHDs. In this study, we attempt to further search for causative single-nucleotide variants (SNVs) from CHD patients that mediate the mis-regulating of miRNAs on their downstream target genes in the pathogenesis of CHDs. As a result, a total of 2,925 3'UTR SNVs were detected from a CHD cohort. In parallel, we profiled the expression of miRNAs in cardiac NCCs and found 201 expressed miRNAs. A combined analysis with these data further identified three 3'UTR SNVs, including NFATC1 c.*654C>T, FGFRL1 c.*414C>T, and CTNNB1 c.*729_*730insT, which result in the malfunction of miRNA-mediated gene regulation. The dysregulations were further validated experimentally. Therefore, our study indicates that miRNA-mediated gene dysregulation in cardiac NCCs could be an important etiology of congenital heart disease, which could lead to a new direction of diagnostic and therapeutic investigation on congenital heart disease.

Long-Term Outcome of Secondary Steroid-Resistant Nephrotic Syndrome in Chinese Children.

INTRODUCTION: Secondary steroid-resistant nephrotic syndrome (SRNS) refers to the condition when patients with initial steroid-sensitive nephrotic syndrome develop steroid resistance in subsequent relapses. Long-term outcomes of secondary SRNS in children are uncertain. METHODS: This was a single-center retrospective study of 56 children with secondary SRNS between 2006 and 2016. The survival curve was estimated using the Kaplan-Meier method. Independent risk factors for end-stage renal disease (ESRD) were determined using Cox proportional hazards model. RESULTS: The median time from nephrotic syndrome onset to secondary SRNS was 7.8 months. Biopsy results at diagnosis secondary SRNS showed that 64.3% of cases were minimal change disease (MCD). No remission was observed in seven (12.5%) patients within the first year. The mean follow-up time was 7.8 ± 3.2 years. Eight patients were clinically cured, one died before ESRD, 10 reached ESRD, and 75.0% (3 of 4) of patients recurred post-transplantation. The 10-year ESRD-free survival rate was 85.8%. No response to intensified immunosuppression (IIS) in the first year was the independent predictor for ESRD. Repeat biopsies were performed in 20 cases, revealing that the reclassification from MCD to mesangial hypercellularity and focal segmental glomerulosclerosis (FSGS) in two when secondary steroid resistance appeared, from MCD and mesangial hypercellularity to FSGS in seven who developed multidrug resistance, and from FSGS to MCD and mesangial hypercellularity in two with favorable outcomes. CONCLUSIONS: The long-term outcome in children with secondary SRNS was heterogeneous, and no response to IIS in the first year was the independent predictor for ESRD. In patients with repeat biopsy, changes in histological appearance to FSGS were associated with multidrug resistance.

Melatonin-induced lncRNA LINC01512 prevents Treg/Th17 imbalance by promoting SIRT1 expression in necrotizing enterocolitis.

Despite the fact that melatonin regulates the expression of long noncoding RNAs (lncRNAs) under different physiological and pathological conditions, it has not been confirmed whether melatonin-induced lncRNAs regulate the differentiation of Treg and Th17 cells. Herein, we show that the expression of LINC01512 is significantly down-regulated and correlates with imbalanced Treg/Th17 ratios in necrotising enterocolitis (NEC) tissues. Through gain- and loss-of-function approaches, we found that LINC01512 promotes the differentiation of Treg cells but interferes with that of Th17 cells. Mechanistically, LINC01512 promotes SIRT1 in Treg and Th17 cells, and subsequently enhances the differentiation of Treg cells and inhibits that of Th17 cells. Furthermore, we demonstrate that melatonin up-regulates the transcription of LINC01512 via the AMPK signalling pathway and that the blockade of AMPK represses LINC01512 expression in Treg and Th17 cells. Overall, our results confirm that SIRT1-regulated differentiation of Treg/Th17 cells is actually modulated by melatonin-induced LINC0512. Moreover, manipulation of the AMPK/LINC01512/SIRT1 axis via melatonin may be a novel therapeutic approach to reduce inflammation.

Weighted gene coexpression network reveals downregulation of genes in bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a serious lung disease observed in premature infants, known to cause considerable morbidity and mortality. Its prognosis is influenced by a complex network of genetic interactions. In this study, we determined the potential key factors in the pathogenesis of this condition. METHODS: We constructed scale-free gene coexpression network using weighted gene coexpression network analysis. The analysis was carried out on the GSE8586 dataset, which contains the expression profiles of umbilical cord tissue homogenates from 20 neonates with BPD and 34 unaffected controls. RESULTS: Our analysis identified one significantly downregulated coexpression module related to the BPD phenotype. It was significantly enriched in genes related to human T-cell leukemia virus infection and the mitogen-activated protein kinase pathway. In this module, the expression of the following four hub genes in infants with BPD was significantly decreased: Fos proto-oncogene (FOS), BTG antiproliferation factor 2 (BTG2), Jun proto-oncogene (JUN), and early growth response protein 1 (EGR1). The downregulation of these hub genes was verified in clinical samples derived from blood and umbilical cord tissue. CONCLUSION: The decreased expression of FOS, BTG2, JUN, and EGR1 is associated with BPD and, therefore, could be used as biomarkers to diagnose early BPD.

Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice.

Inflammation plays a critical role in the development of severe neonatal morbidities. Myeloid-derived suppressor cells (MDSCs) were recently implicated in the regulation of immune responses in newborns. Here, we report that the presence of MDSCs and their functional activity in infants are closely associated with the maturity of newborns and the presence of lactoferrin (LF) in serum. Low amounts of MDSCs at birth predicted the development of severe pathology in preterm infants - necrotizing enterocolitis (NEC). In vitro treatment of newborn neutrophils and monocytes with LF converted these cells to MDSCs via the LRP2 receptor and activation of the NF-κB transcription factor. Decrease in the expression of LRP2 was responsible for the loss of sensitivity of adult myeloid cells to LF. LF-induced MDSCs (LF-MDSCs) were effective in the treatment of newborn mice with NEC, acting by blocking inflammation, resulting in increased survival. LF-MDSCs were more effective than treatment with LF protein alone. In addition to affecting NEC, LF-MDSCs demonstrated potent ability to control ovalbumin-induced (OVA-induced) lung inflammation, dextran sulfate sodium-induced (DSS-induced) colitis, and concanavalin A-induced (ConA-induced) hepatitis. These results suggest that cell therapy with LF-MDSCs may provide potent therapeutic benefits in infants with various pathological conditions associated with dysregulated inflammation.

125I seed brachytherapy versus external beam radiation therapy for the palliation of painful bone metastases of lung cancer after one cycle of chemotherapy progression.

PURPOSE: This study aimed to compare the outcomes of 125I seed brachytherapy versus external beam radiation therapy (EBRT) for the palliation of painful bone metastases of lung cancer after one cycle of chemotherapy progression. MATERIALS AND METHODS: We analyzed retrospectively 158 patients with painful bone metastases secondary to lung cancer after one cycle of chemotherapy progression treated between June 2013 and May 2016. Seventy-six patients with 96 lesions received 125I brachytherapy (Group A), whereas 82 patients with 98 metastases received EBRT (Group B). Pain intensity on Brief Pain Inventory, percentage of patients with pain severity, and quality of life were recorded prior to treatment (T0), 2, 4, 6, 8, 12, 16, 20, and 24 weeks (T2, T4, T6, T8, T12, T16, T20, and T24) after treatment during a 24-hour period. Cost-effectiveness and number of treatment appointments were also compared between groups. RESULTS: One hundred and fifty-eight patients had been treated. Visual analog scale for worst pain in Group A was significantly lower than in Group B at T2, T4, T6, T16, T20, and T24. Group A was superior to group B concerning quality of life scores (T2, T4, T20, and T24), cost-effectiveness, and number of treatment appointments. No significant differences were observed for complications. CONCLUSION: Compared with EBRT, 125I seed brachytherapy can be an alternative method for painful bone metastases from lung cancer after one cycle of chemotherapy progression.

Risk of Coronary Heart Disease in Different Criterion of Impaired Fasting Glucose: A Meta-Analysis.

The cut-point for diagnosing impaired fasting glucose (IFG) had been dispute, as reports about the associated clinical events are inconsistent. This meta-analysis evaluated the risk of coronary heart disease (CHD) in association with different criterion of IFG according to the American Diabetes Association (ADA) or the World Health Organization (WHO) Expert Group. We included prospective cohort studies with multivariate-adjusted data on IFG and CHD for analysis. The relative risks (RRs) of CHD were calculated and reported with 95% confidence intervals (95% CIs). Seventeen prospective cohort studies, comprising 527,021 individuals were included. The risks of CHD were increased in both participants with IFG defined as the ADA or WHO criterion (RR 1.11, 95% CI 1.02-1.21; and RR 1.18, 95% CI 1.10-1.28, respectively). Subgroup analyses showed that in both definition of IFG, the risk of CHD was only increased in studies with possibility of enrolling patients with increased 2 hours plasma glucose (2-h PG), or in studies with inadequate adjustment, but not in studies excluded participants with increased 2-h PG or in those with adequate adjustment of other risk factors. Our meta-analysis demonstrates that the presence of IFG was significantly associated with future risk of CHD. The risk of CHD was increased when fasting plasma glucose was as low as 100 mg/dL according to the lower cut-point of IFG by the ADA criterion. However, the risk maybe confounded by the undetected increased 2-h PG or other cardiovascular risk factors.

Different patterns of NF-κB and Notch1 signaling contribute to tumor-induced lymphangiogenesis of esophageal squamous cell carcinoma.

BACKGROUND: Lymph node involvement and tumor-induced lymphangiogenesis appear as the earliest features of esophageal squamous cell carcinoma (ESCC), although the molecular regulatory mechanisms involved have remained unclear. Our aim was to investigate the contribution of NF-κB and Notch1 signaling to lymph node involvement and tumor-induced lymphangiogenesis in ESCC. MATERIAL AND METHODS: NF-κB and Notch1 expression in 60 tissue samples of ESCC were assessed by immunohistochemical staining. The correlations of NF-κB and Notch1 with lymph node involvement, lymphatic vessel density (LVD), podoplanin, and vascular endothelial growth factor-C (VEGF-C) were further evaluated to determine the association of NF-κB and Notch1 expression with tumor-induced lymphangiogenesis. RESULTS: Chi-square tests revealed that NF-κB and Notch1 expression in ESCC tissues were significant associated with lymph node metastasis, LVD, podoplanin, and VEGF-C expression. Strong expression of NF-κB, but weak expression of Notch1, was observed in tumor tissues with lymph nodes involvement (P < 0.05 for both). The mean histoscores of LVD, podoplanin, and VEGF-C staining were higher in high-NF-κB-expressing tissue than in low-expressing tissue (P < 0.05 for each). In contrast, the mean histoscores of LVD and VEGF-C staining were lower in high-Notch1-expressing tissue than in low-expressing tissue (P < 0.05 for both). A multiple factors analysis of LVD and VEGF-C further demonstrated that LVD and VEGF-C status were significantly correlated with NF-κB and Notch1 expression in tumors. NF-κB and Notch1 expression were also significantly inversely correlated (P < 0.05). CONCLUSION: These results suggest that different patterns of NF-κB and Notch1 signaling contribute to lymph nodes metastasis and tumor-induced lymphangiogenesis of ESCC, and reveal that up-regulation of NF-κB is associated with down-regulation of Notch1 in tumor tissue.