In very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood–brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain. Postpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity. On P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS-sensitized HI induction, and white matter injury (decreased myelination and increased astrogliosis) was observed on P12 compared with controls. Immunohistochemical analyses revealed increased CXCL5 expression in the white matter 6 and 24 h after insult. Immunofluorescence experiments revealed upregulated CXCL5 expression in the activated microglia and endothelial cells 24 h after insult. CXCL5 inhibition by SB225002, a selective nonpeptide inhibitor of CXCR2, significantly attenuated microglial activation and BBB damage, increased myelination, and reduced astrogliosis in the white matter after LPS-sensitized HI. In addition, CXCL5-sensitized HI or CXCL5 alone significantly induced BBB damage and white matter injury in association with different neuroinflammation mechanisms. CXCL5-sensitized HI-induced microglial activation and neutrophil infiltration, whereas CXCL5 alone predominately caused neutrophil infiltration. CXCL5 is a potential biomarker for white matter injury in preterm infants. Pharmacological blockade of CXCL5 signaling that attenuates dysregulated neuroinflammation can be used a therapeutic strategy against white matter injury in the immature brain.

Neonatal hypoglycemia is a common metabolic occurrence among small for gestational age (SGA) neonates. This study aims to determine the incidence of early neonatal hypoglycemia and confirms the potential risk factors among term and late preterm SGA neonates in a well-baby newborn nursery of a tertiary medical center in Southern Taiwan. We performed a retrospective medical record review of term and late preterm SGA (birth weight <10 percentile) neonates, born between January 1, 2012 and December 31, 2020, in the well-baby newborn nursery, of a tertiary medical center in Southern Taiwan. Blood glucose monitoring was routinely performed at 0.5, 1, 2, and 4 h of life. Antenatal and postnatal risk factors were recorded. Mean blood glucose level, age of occurrence, symptomatic hypoglycemia, and need for intravenous glucose treatment of early hypoglycemia in SGA neonates were documented. 690 SGA neonates in the nursery met the criteria and were retrospectively enrolled in the study, 358 of whom (51.80%) were male and 332 (48.10%) female. Of 690 enrolled SGA neonates, 134(19.42%) SGA neonates developed hypoglycemia during a well-baby nursery stay. Among these neonates, 97% of early hypoglycemic episodes occur during the first 2 h of life. The lowest blood glucose level was 46.78 ± 11.13 mg/dL, recorded in the first hour of life. Among the hypoglycemic 134 neonates, 26 (19.40%) neonates had to be transferred from the nursery to the neonatal ward and they required intravenous glucose treatment to achieve euglycemia. 14 (10.40%) neonates had symptomatic hypoglycemia. A multivariate logistic regression analysis revealed that cesarean delivery, small head circumference, small chest circumference, and low 1-min Apgar score were significant risk factors for early hypoglycemia in these neonates. Periodic routine blood glucose level monitoring within the first 4 h of life in term and late preterm SGA neonates is required, especially those with cesarean delivery and low Apgar score.

Imperatorin, a dietary furocoumarin, is found not only in medicinal plants, but also in popular culinary herbs, such as parsley and fennel. Recently, imperatorin has been shown to activate GPR119 in cells. Another GPR, GPR131, also called TGR5 or G-protein-coupled bile acid receptor 1 (GPBAR1), is known to regulate glucose metabolism. Additionally, TGR5 activation increases glucagon-like peptide (GLP-1) secretion to lower blood sugar levels in animals. Therefore, the present study aims to determine whether the effects of imperatorin on GLP-1 secretion are mediated by TGR5. First, we transfected cultured Chinese hamster ovary cells (CHO-K1 cells) with the TGR5 gene. Glucose uptake was confirmed in the transfected cells using a fluorescent indicator. Moreover, NCI-H716 cells, which secrete GLP-1, were used to investigate the changes in calcium concentrations and GLP-1 levels. In addition, streptozotocin (STZ)-induced type 1-like diabetic rats were used to identify the effects of imperatorin in vivo. Imperatorin dose-dependently increased glucose uptake in CHO-K1 cells expressing TGR5. In STZ diabetic rats, similar to the results in NCI-H716 cells, imperatorin induced a marked increase of GLP-1 secretion that was reduced, but not totally abolished, by a dose of triamterene that inhibited TGR5. Moreover, increases in GLP-1 secretion induced by imperatorin and GPR119 activation were shown in NCI-H716 cells. We demonstrated that imperatorin induced GLP-1 secretion via activating TGR5 and GPR119. Therefore, imperatorin shall be considered as a TGR5 and GPR119 agonist.

Background: Thrombomodulin (TM) exerts anticoagulant and anti-inflammatory effects to improve the survival of patients with septic shock. Heat stroke resembles septic shock in many aspects. We tested whether TM would improve cognitive deficits and related causative factors in heat-stressed (HS) mice. Methods: Adult male mice were exposed to HS (33°C for 2 hours daily for 7 consecutive days) to induce cognitive deficits. Recombinant human soluble TM (1 mg/kg, i.p.) was administered immediately after the first HS trial and then once daily for 7 consecutive days. We performed the Y-maze, novel objective recognition, and passive avoidance tests to evaluate cognitive function. Plasma levels of lipopolysaccharide (LPS), high-mobility group box 1 (HMGB1), coagulation parameters, and both plasma and tissue levels of inflammatory and oxidative stress markers were biochemically measured. The duodenum and hippocampus sections were immunohistochemically stained. The intestinal and blood-brain barrier permeability were determined. Results: Compared with controls, HS mice treated with TM had lesser extents of cognitive deficits, exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and inflammatory, oxidative, and coagulatory injury to heart, duodenum, and hippocampal tissues, and increased plasma HMGB1. In addition to reducing cognitive deficits, TM therapy alleviated all the abovementioned complications in heat-stressed mice. Conclusions: The findings suggest that HS can lead to exacerbated stress reactions, endotoxemia, gut barrier disruption, blood-brain barrier disruption, hippocampal inflammation, coagulopathy, and oxidative stress, which may act as causative factors for cognitive deficits. TM, an anti-inflammatory, antioxidant, and anti-coagulatory agent, inhibited heat stress-induced cognitive deficits in mice.

Hypoglycemia is a common metabolic disorder that occurs in the neonatal period. Early identification of neonates at risk of developing hypoglycemia can optimize therapeutic strategies in neonatal care. This study aims to develop a machine learning model and implement a predictive application to assist clinicians in accurately predicting the risk of neonatal hypoglycemia within four hours after birth. Our retrospective study analyzed data from neonates born ≥35 weeks gestational age and admitted to the well-baby nursery between 1 January 2011 and 31 August 2021. We collected electronic medical records of 2687 neonates from a tertiary medical center in Southern Taiwan. Using 12 clinically relevant features, we evaluated nine machine learning approaches to build the predictive models. We selected the models with the highest area under the receiver operating characteristic curve (AUC) for integration into our hospital information system (HIS). The top three AUC values for the early neonatal hypoglycemia prediction models were 0.739 for Stacking, 0.732 for Random Forest and 0.732 for Voting. Random Forest is considered the best model because it has a relatively high AUC and shows no significant overfitting (accuracy of 0.658, sensitivity of 0.682, specificity of 0.649, F1 score of 0.517 and precision of 0.417). The best model was incorporated in the web-based application integrated into the hospital information system. Shapley Additive Explanation (SHAP) values indicated mode of delivery, gestational age, multiparity, respiratory distress, and birth weight < 2500 gm as the top five predictors of neonatal hypoglycemia. The implementation of our machine learning model provides an effective tool that assists clinicians in accurately identifying at-risk neonates for early neonatal hypoglycemia, thereby allowing timely interventions and treatments.

This study aimed to compare the prevalence rate of atypical sensory processing in late preterm (LP) and term children at two years of age and to further investigate the co-occurrence of atypical sensory processing and behavioral problems (internalizing/externalizing) in both groups of children. A total of 104 children (52 LP and 52 sex- and birth order-matched term children) were included. The primary caregivers were asked to complete the Infant/Toddler Sensory Profile—Chinese version and the Child Behavior Checklist 1.5-5Y—Chinese version (CBCL-C/1.5-5). We found that the LP group had a similar prevalence rate of atypical sensory processing to the term group. However, neonatal intensive care unit experience (r = −0.356, p = 0.013, with visual processing) and days of ventilation and supplementary oxygen (r = −0.392, p = 0.004, with low registration) after birth were significantly correlated with the atypical sensory processing of LP children. Both LP and term children with behavioral problems seemed to have a higher prevalence rate of atypical sensory processing than their peers without behavioral problems. However, when Bonferroni correction was used to control for the statistical errors of multiple comparisons, only in the LP group did the co-occurrence of atypical sensory processing (auditory and oral sensory processing and sensation avoiding) and behavioral problems reach significance. In conclusion, the influence of late preterm birth on sensory processing may become subtle at age two, with the exception of those LP children experiencing complicated medical management after birth. A high level of co-occurrence of atypical sensory processing and behavioral problems suggests that the administration of a sensory processing assessment may be helpful to clarify the cause of problematic behavior and to recommend an appropriate intervention for LP children with behavioral problems.