Corrigendum: Quantitative proteomics on the cerebrospinal fluid of hydrocephalus in neonatal bacterial meningitis.

[This corrects the article DOI: 10.3389/fped.2022.972032.].

The association of insufficient gestational weight gain in women with gestational diabetes mellitus with adverse infant outcomes: A case-control study.

Background: To investigate the association between insufficient maternal gestational weight gain (GWG) during dietary treatment, and neonatal complications of small-for-gestational-age (SGA) infants born to mothers with Gestational diabetes mellitus (GDM). Methods: A retrospective case-control study was conducted, involving 1,651 infants born to mothers with GDM. The prevalence of a perinatal outcome and maternal GWG were compared among SGA, adequate- (AGA), and large-for-gestational-age (LGA); association with birth weight and GWG was identified using Pearson's correlation analysis; binary logistic regression was performed to determine the odds ratio (OR) associated with SGA. Results: In total, 343 SGA, 1025 AGA, and 283 LGA infants met inclusion criteria. The frequency of SGA infants who were siblings (41.7 vs. 4.3 vs. 1.9%) and composite of complications (19.2 vs. 12.0 vs. 11.7%) were higher in SGA infants than in those in AGA or LGA infants group (both P < 0.01). GWG and pre-partum BMI were lower among the SGA mothers with GDM group (11.7 ± 4.5 kg, 25.2 ± 3.1 kg/m2) than AGA (12.3 ± 4.6 kg, 26.3 ± 3.4 kg/m2) or LGA (14.0 ± 5.1 kg, 28.7 ± 3.9 kg/m2) mothers with GDM group. Binary logistic regression showed that siblings who were SGA (AOR 18.06, 95% CI [10.83-30.13]) and preeclampsia (AOR 3.12, 95% CI [1.34-7.30]) were associated with SGA, but not GWG below guidelines (P > 0.05). The risk of SGA (25.7 vs. 19.1 vs. 14.2%) and FGR (15.3 vs. 10.9 vs. 7.8%) was higher in GWG below guidelines group than those in GWG above and within guidelines group, the risk of low Apgar score (6.4 vs. 3.0 vs. 2.8%) was higher in GWG above guidelines group than that in GWG below and within guidelines group (P < 0.05). Conclusion: Our findings demonstrated that GWG above and below guidelines, compared with GWG within guidelines, had a higher risk of adverse infant outcomes. Our findings also suggested that GWG below guidelines did not increase the risk for SGA, though SGA infants had more adverse outcomes among neonates born to mothers with GDM.

Corrigendum: The association of insufficient gestational weight gain in women with gestational diabetes mellitus with adverse infant outcomes: a case-control study.

[This corrects the article DOI: 10.3389/fpubh.2023.1054626.].

Selective targeting of MD2 attenuates intestinal inflammation and prevents neonatal necrotizing enterocolitis by suppressing TLR4 signaling.

Neonatal necrotizing enterocolitis (NEC) is an inflammatory disease that occurs in premature infants and has a high mortality rate; however, the mechanisms behind this disease remain unclear. The TLR4 signaling pathway in intestinal epithelial cells, mediated by TLR4, is important for the activation of the inflammatory storm in NEC infants. Myeloid differentiation protein 2 (MD2) is a key auxiliary component of the TLR4 signaling pathway. In this study, MD2 was found to be significantly increased in intestinal tissues of NEC patients at the acute stage. We further confirmed that MD2 was upregulated in NEC rats. MD2 inhibitor (MI) pretreatment reduced the occurrence and severity of NEC in neonatal rats, inhibited the activation of NF-κB and the release of inflammatory molecules (TNF-α and IL-6), and reduced the severity of intestinal injury. MI pretreatment significantly reduced enterocyte apoptosis while also maintaining tight junction proteins, including occludin and claudin-1, and protecting intestinal mucosal permeability in NEC rats. In addition, an NEC in vitro model was established by stimulating IEC-6 enterocytes with LPS. MD2 overexpression in IEC-6 enterocytes significantly activated NF-κB. Further, both MD2 silencing and MI pretreatment inhibited the inflammatory response. Overexpression of MD2 increased damage to the IEC-6 monolayer cell barrier, while both MD2 silencing and MI pretreatment played a protective role. In conclusion, MD2 triggers an inflammatory response through the TLR4 signaling pathway, leading to intestinal mucosal injury in NEC. In addition, MI alleviates inflammation and reduces intestinal mucosal injury caused by the inflammatory response by blocking the TLR4-MD2/NF-κB signaling axis. These results suggest that inhibiting MD2 may be an important way to prevent NEC.

Quantitative proteomics on the cerebrospinal fluid of hydrocephalus in neonatal bacterial meningitis.

Objective: Hydrocephalus in bacterial meningitis (BM) is a devastating infectious neurological disease and the proteins and pathways involved in its pathophysiology are not fully understood. Materials and methods: Label-free quantitative (LFQ) proteomics analyses was used to identify differentially expressed proteins (DEPs) in cerebrospinal fluid (CSF) samples from infants with hydrocephalus and bacterial meningitis (HBM group, N = 8), infants with bacterial meningitis (BM group, N = 9); and healthy infants (N group, N = 11). Bioinformatics analysis was subsequently performed to investigate Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enriched signaling pathways of these DEPs. Six proteins (AZU1, COX4I1, EDF1, KRT31, MMP12, and PRG2) were selected for further validation via enzyme-linked immunosorbent assay (ELISA). Results: Compared with BM group and N group, HBM group had a higher whole CSF protein level (5.6 ± 2.7 vs. 1.7 ± 1.0 vs. 1.2 ± 0.5 g/l) and lower whole CSF glucose level (0.8 ± 0.6 vs. 1.8 ± 0.7 vs. 3.3 ± 0.8 mmol/l) (both P < 0.05). Over 300 DEPs were differentially expressed in HBM group compared with BM group and BM compared with N group, of which 78% were common to both. Cluster analysis indicated that the levels of 226 proteins were increased in BM group compared with N group and were decreased in HBM group compared with BM group. Bioinformatics analysis indicated the involvement of the cell adhesion, immune response and extracellular exosome signaling were significantly enriched in HBM compared with BM group and BM compared with N group. 267 DEPs were identified between HBM group with N group, KEGG analysis indicated that DEPs mainly involved in filament cytoskeleton and immune response. The ELISA results further verified that the expression levels of AZU1 were significantly different from among three groups (both P < 0.05). Conclusion: This is the first reported characterization of quantitative proteomics from the CSF of infants with HBM. Our study also demonstrated that AZU1 could be a potential biomarker for the diagnosis of hydrocephalus in bacterial meningitis.

Insulin resistance biomarkers in small-for-gestational-age infants born to mothers with gestational diabetes mellitus.

OBJECTIVE: Early alterations in glucose homeostasis increase the risk of developing insulin resistance (IR) and obesity later in life. The study aimed to ascertain the peripheral blood levels of hormones that controlling glucose homeostasis and inflammatory factors that are correlated with IR and fetal outcomes in small-for-gestational-age (SGA) infants born to mothers with gestational diabetes mellitus (GDM). METHODS: This cohort study included a total of 90 SGA infants born to mothers with GDM (n = 37) and without GDM (n = 53). At birth, blood levels of glucose, insulin, C-peptide, growth hormone (GH), IGFBP3, lipid profiles, fibrinogen, and hypersensitive C-reactive protein (Hs-CRP) were measured; homeostatic model assessment-IR (HOMA-IR) and ponderal index were calculated. All newborns were followed up to the first year of life. RESULTS: Compared with SGA infants born to mothers without GDM, the levels of low-density lipoprotein-cholesterol (LDL-C), GH, and fibrinogen were significantly higher in the SGA infants born to mothers with GDM (p = .048, .045, and .04, respectively). However, total cholesterol, HDL-C, and apolipoprotein(a) levels were significantly lower in the SGA infants born to mothers with GDM when compared with those in with SGA infants born to mothers without GDM (all p < .05). Weight gain in the first year was higher in the SGA infants born to mothers with GDM group than SGA infants born to mothers without GDM [6644 g (5991-7572) vs. 6032 g (5529-6932)]. CONCLUSIONS: Altered biomarkers of IR were observed among SGA infants born to mothers with GDM, suggesting that these infants were more prone to develop IR after birth.

Demographic and Clinical Features of Small-for-Gestational-Age Infants Born to Mothers With Gestational Diabetes Mellitus.

We studied the demographic and clinical characteristic, risk factors, outcomes of full-term small-for-gestational-age (SGA) infants born to mothers with gestational diabetes mellitus (GDM) in China. A retrospective case-control study that included 1981 SGA infants was conducted; the demographic and clinical data between SGA infants born to mothers with and without GDM were compared. Of 383 SGA infants born to mothers with GDM, 221 (57.7%) were female, and the incidence of these infants was 1 in 155 live births. The risk of SGA siblings (RR, 1.88; 95% CI, [1.23-2.86]), low 1- and 5-min Apgar scores (RR,2.04 and 4.21; 95%CI [1.05-4.00] and [1.05-16.89], respectively), early thrombocytopenia (RR, 3.39; 95%CI, [1.33-8.64]), hypoglycemia(RR, 2.49; 95%CI, [1.55-3.98]), and hypoxic-ischemic encephalopathy (RR,5.61; 95%CI, [1.25-25.18]) were increased in SGA infants born to mothers with GDM compared to SGA infants born to mothers without GDM. SGA girls born to mothers with GDM had a significantly higher ratio of catch-up growth (CUG) (RR, 1.73; 95%CI, [1.18-2.54]) in the first year of life. These results show that genetic factors may be one of the etiologies of SGA infants born to mothers with GDM; and these infants have more adverse perinatal outcomes compared to SGA infants born to mothers without GDM. SGA girls born to mothers with GDM had accelerated CUG in the first year of life.

Bone Turnover Markers and Bone Histomorphometry in Pubertal Rats with Intrauterine Growth Restriction.

OBJECTIVE: To investigate the effect of malnutrition during pregnancy on bone development in rat pups with intrauterine growth restriction (IUGR). Methods: IUGR offspring were induced with a 10% low protein diet, while the control group was given a 21% protein diet during pregnancy. Serum biomarkers including bone glutamyl protein (BGP), amino-terminal propeptide of type 1 procollagen (P1NP), cross linked N-telopeptide of type I collagen (NTX), and insulin like growth factor 1 (IGF-1) levels were measured at 7, 21 and 56 d. Left femurs taken at 56 d were used for bone histomorphometry analysis by micro-computed tomography (micro-CT). Results: Compared with the control group, the IUGR group had lower IGF-1 and BGP levels at 7 and 21 d, and higher P1NP and NTX levels at 7 d. The IUGR group had thinner trabecular thickness (Tb.Th), lower trabecular number (Tb.N), and increased trabecular separation (Tb.Sp) at 56 d. Conclusion: The effect of IUGR on bone development may persist after birth.

MiR-199a-5p regulates sirtuin1 and PI3K in the rat hippocampus with intrauterine growth restriction.

In humans, malnutrition during pregnancy results in intrauterine growth restriction (IUGR) and an increased risk of neurological morbidities; altered miRNA characteristics have been suggested to contribute to IUGR neurological pathogenesis. A miRNA microarray was used to identify differentially expressed miRNA molecules in the hippocampi of rats with IUGR. Five of the molecules in question were selectively validated using real-time PCR in rats with IUGR. We then investigated the role of miR-199a-5p in hippocampal pathology. Bioinformatics analysis results suggested that TNF-α, caspase-3 and SIRT1 were potential targets of miR-199a-5p. Changes in PI3K, SIRT1 and caspase-3 protein expressions levels in the hippocampus were confirmed by Western blot analysis (all P < 0.05). Studies using the pheochromocytoma cell line PC12 cells and primary neurons demonstrated that miR-199a-5p modulated PI3K, caspase-3 and SIRT1 expression. Additionally, there was an inverse correlation between miR-199a-5p and caspase-3 expression, though dual-luciferase reporter assays showed that caspase-3 is not a target of miR-199a-5p. We conclude that IUGR affects hippocampal miRNAs characteristics. Our results also indicated that aberrantly high expression levels of miR-199a-5p may play an important role in the pathogenesis of IUGR by regulating SIRT1 and PI3K.

Effect of L-arginine supplementation on the hepatic phosphatidylinositol 3-kinase signaling pathway and gluconeogenic enzymes in early intrauterine growth-restricted rats.

The present study aimed to investigate the response of the phosphatidylinositol 3-kinase (PI3K) signaling pathway and gluconeogenic enzymes in intrauterine growth-restricted rats to dietary L-arginine (L-Arg) supplementation during the lactation period early in life. Pregnant Sprague-Dawley rats were randomly divided into a control group (CON), an intrauterine growth restriction group (IUGR) and an L-Arg group (LA). The pregnant rats in the CON group were fed a 21% protein diet, and those in the IUGR and LA groups were fed a 10% low protein diet, and all rats were fed a 21% protein diet after delivery. Water was available ad libitum to the pregnant rats during the 21-day lactation period, and the water provided to the LA group included 200 mg/kg/day L-Arg. Blood glucose, serum insulin, homeostasis model of assessment for insulin resistance (HOMA-IR), PI3K and protein kinase B (PKB) protein expression, and phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) mRNA expression in the offspring rats were measured postnatally at 1, 3 and 8 weeks. No significant difference in blood glucose, serum insulin and HOMA-IR were identified at any time point among the three groups. PI3K and PKB expression was lower in the IUGR group offspring compared with that in the CON group offspring, but both were increased by dietary L-Arg supplementation. PEPCK mRNA and G-6-Pase mRNA expression levels in the offspring of the IUGR group were higher compared with those in the CON group but were downregulated following L-Arg supplementation. These results suggest that dietary L-Arg supplementation during the early lactation period promoted catch-up growth and reversed abnormalities in hepatic insulin signaling and gene expression of gluconeogenic enzymes in IUGR offspring rats.

Application of spectroscopy (1HMRS) to assess liver metabolite concentrations in rats with intrauterine growth restriction.

OBJECTIVE: Proton magnetic resonance spectroscopy (1H-MRS) measurement of liver metabolism in intrauterine growth restriction rats has seldom been reported. This study investigated the application of 1H-MRS in assessing liver metabolism in newborn pups that experienced intrauterine growth restriction. METHODS: Intra-uterine growth restriction was established by feeding rats low-protein diets during pregnancy. Newborn pups received conventional magnetic resonance imaging and 1H-MRS using a 3.0T whole body MR scanner at 3, 8 and 12 weeks post birth. RESULTS: The success rate of 1H-MRS was 83.33%. Significantly lower body weight, BMI and body length at 3 weeks as well as significantly lower body weight, BMI and waist circumference at 8 and 12 weeks were observed in newborn pups of IUGR rats compared with pups of control rats. Significant differences in ACho/H2O, ACr/H2O, AGlx/H2O and ALipid/H2O at 3 and 8 weeks as well as significant differences in ACr/H2O, ALipid/H2O and AGlx/H2O at 12 weeks were observed between pups of control rats and pups of IUGR rats. CONCLUSION: 1H-MRS allows noninvasive assessment of liver metabolism in the rat and demonstrated the poor liver development of rats that experienced IUGR.

Effect of L-arginine and sildenafil citrate on intrauterine growth restriction fetuses: a meta-analysis.

BACKGROUND: Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and mortality. Several clinical trials have reported L-arginine and sildenafil citrate had effect on intrauterine growth restriction fetuses. A meta-analysis of available randomized controlled trials (RCTs) was conducted to investigate the effects of L-arginine and sildenafil citrate on major clinical outcomes of IUGR fetuses. METHODS: Systematically searched Medline, Embase, the Cochrane Library, and Clinical Trials, references of retrieved articles, and conference proceedings from 1960 to 2015. We included randomized controlled trials assessing the effects of L-arginine and sildenafil citrate on IUGR. Outcomes analyzed were the birth weight, gestational age at labor, Apgar score at 1and 5 min, the ratio of NRDS, the ratio of ICH and neonatal death, etc. RESULTS: Ten trials were included. Nine trials (576 patients) compared L-arginine with either placebo or no intervention. In the L-arginine treatment groups of the L-arginine trials, there was a significant increase in fetal birth weight (SMD 0.41, 95 % CI [0.24,0.58]), gestational age (SMD 0.30, 95 % CI [0.07,0.54]); L-arginine treatment group have a significant reduction in the ratio of neonatal respiratory distress syndrome (P = 0.009), intracranial hemorrhage of fetuses (P = 0.002), but the number of included studies and people on these outcomes are small. As only one trial (41 patients) compared sildenafil citrate with placebo, it was too small for reliable conclusions about possible differential effects could be drawn. CONCLUSIONS: The results of this meta-analysis showed that L-arginine increased birth weight and prolonged gestational age at labor of IUGR fetuses. However, further large-scale RCTs are needed to adequately assess the effect of L-arginine and Sildenafil citrate on clinical outcomes, because the number of study may be small.

Puerarin affects bone biomarkers in the serum of rats with intrauterine growth restriction.

OBJECTIVE: To investigate serum bone biomarkers in rats with intrauterine growth restriction (IUGR) in order to determine the effects of puerarin on bone metabolism. METHODS: A rat model of IUGR was induced using a low protein diet during pregnancy. The offspring were given puerarin or an identical volume of saline via subcutaneous abdominal injection. All rats were studied at 1, 3, and 8 weeks of age. Serum biomarkers of bone formation, including insulin-like growth factor-1 (IGF-1), bone-specific alkaline phosphatase (BALP), osteocalcin (OC), osteoprotegerin (OPG), receptor-activator of nuclear factor-κB Iigand (RANKL), as well as blood levels of calcium and phosphorus were measured. RESULTS: Serum BALP, OPG, IGF-1, and OC levels, as well as the OPG/RANKL ratio, were lower in the IUGR group compared with the control group at 1 week of age (P = 0.024, 0.011, 0.014, 0.004, and 0.002, respectively). At 3 weeks of age, the serum BALP and OC levels were higher in the protein-restricted group compared with the control group (P = 0.003 and 0.001, respectively). A comparison between the IUGR plus puerarin intervention group and the IUGR group revealed differences in the levels of BALP and IGF-1 at 3 weeks of age (P = 0.008 and 0.003, respectively). In addition, serum OPG and OC levels and the OPG/RANKL ratio were higher at 8 weeks of age (P = 0.044, 0.007, and 0.016, respectively). No differences in serum calcium and phosphorus levels were observed among the three groups. CONCLUSION: Our study demonstrates that the bone microenvironment of the fetus can be altered by a low protein maternal diet and that puerarin can reverse these effects. These results indicate that the nutritional environment plays an important role in early skeletal development and that the bone turnover of IUGR rats can be altered by puerarin treatment.

Cognitive and Behavioral Outcomes of Intrauterine Growth Restriction School-Age Children.

CONTEXT: Children who experienced intrauterine growth restriction (IUGR) may be at increased risk for adverse neurologic developmental outcomes during the school-age years of life. OBJECTIVE: To estimate the effect of IUGR on cognition and behavior in school-aged children. DATA SOURCES: Medline, Embase, and PsycINFO were searched for English-language articles published after 1980. DATA SELECTION: We included case-control studies reporting cognitive and/or behavioral data of children who had IUGR and were evaluated afterfifth birthday. DATA EXTRACTION: Cognitive data from 15 studies and behavioral data from 6 studies were selected with a total of 1559 cases and 1630 controls. The cognitive scores and behavioral outcomes were extracted. RESULTS: The controls had significantly higher cognitive scores than the children with IUGR (standardized mean difference [SMD] -0.38, 95% confidence interval [CI] -0.51 to -0.25, P < .00001). The IQ scores of the IUGR group were not significantly correlated with mean birth weight and gestational age (P > .05). Five trials were included in the behavioral outcomes trial, the behavior scores were significantly different between the groups with and without IUGR (SMD 0.31, 95% CI 0.13 to 0.48, P = .001). The incidence of attention-deficit/hyperactivity disorder (ADHD) was not significantly different between 2 groups (P = .11). LIMITATIONS: The number of studies that assessed behavioral and ADHD outcome is small. CONCLUSIONS: The findings demonstrate that IUGR is associated with lower cognitive scores in school-age children. However, further large-scale trials are needed to assess the effects of IUGR on the outcome of behavioral disorder and ADHD.