Clinical characteristics of bronchopulmonary dysplasia in very preterm infants. / 极早早产儿支气管肺发育不良的临床特征.

OBJECTIVES: With the development of perinatal and neonatal intensive care medicine, the survival rate of very premature infants increases year by year. However, the incidence of bronchopulmonary dysplasia (BPD) increases year by year, which seriously affects the survival prognosis of very premature infants. How to prevent and treat BPD effectively has become the focus of neonatologists. This study aims to provide ideas for the prevention and treatment of BPD in very preterm infants via analyzing the clinical characteristics of BPD. METHODS: A total of 472 cases of very premature infants admitted to the Divison of Neonatology, Department of Pediatrics at the Second Xiangya Hospital of Central South University were retrospectively selected and assigned into a BPD group (n=147) and a non-BPD group (n=325) according to the diagnosis of BPD. Clinical data of each group were collected to find out the clinical characteristics of BPD in very preterm infants. Basic information, maternal pregnancy data, laboratory findings, nutritional support, respiratory support patterns and duration, and systemic complications were included. RESULTS: Compared with the non-BPD group, gestational age, birth weight, head circumference and body length in the BPD group were lower, the Apgar score in 1st min and 5th min and average body weight growth rate were lower (all P<0.05); the ratios of male, very low birth weight (VLBW), and extremely low birth weight (ELBW) in the BPD group were higher than those in the non-BPD group (all P<0.5); the incidence of maternal cervical insufficiency and the rate of using embryo transfer technology in the BPD group were higher than those in the non-BPD group, and the rate of using prenatal hormone in the BPD group was lower than that in the non-BPD group (all P<0.05). The positive rate of sputum culture in the BPD group was higher than that in the non-BPD group (P<0.05), and the white blood cell count, neutrophil ratio, and procalcitonin in the BPD group were higher than those in the non-BPD group (all P<0.05). The period of fasting, minimal feeding, total parenteral nutrition (TPN), and partial parenteral nutrition (PPN) in the BPD group were longer than those in the non-BPD group (all P<0.05). The duration of nasal catheter oxygen inhalation and mechanical ventilation in the BPD group was longer than that in the non-BPD group, and the rates of mechanical ventilation at Day 1, 3, 7, 14, 21 and 28 after birth were higher than those in the non-BPD group (all P<0.05). The incidence of respiratory distress syndrome, apnea of prematurity, respiratory failure, pneumonia, pulmonary hemorrhage, pleural effusion, persistent pulmonary hypertension, hemodynamic patent ductus arteriosus, cytomegalovirus infection, neonatal necrotic enterocolitis, cholestasis, anemia, abnormal blood system, hypothyroidism, retinopathy of prematurity, and internal environment disorders in the BPD group were significantly higher than those in non-BPD group (all P<0.05). CONCLUSIONS: There are significant differences between very premature infants with BPD and those without BPD in general information, maternal history, inflammatory indicators, nutritional support, respiratory support, comorbidities and complication rates. To ensure normal fetal development, reducing the inflammatory reaction of very premature infants, establishing enteral nutrition as early as possible, shortening the time of mechanical ventilation, and reducing the occurrence of complications are beneficial to decrease the incidence of BPD in very premature infants and improve the long-term prognosis of BPD.

The timing of withdrawal from caffeine citrate in very preterm infants. / æžæ—©æ—©äº§å„¿æž¸æ©¼é ¸å’–å•¡å› åœç”¨æ—¶æœºçš„ä¸´åºŠç ”ç©¶.

OBJECTIVES: To study the clinical features and outcome of very preterm infants withdrawn from caffeine citrate at different time points. METHODS: A retrospective analysis was performed on the medical data of the preterm infants with a gestational age of <32 weeks, who were hospitalized in the Division of Neonatology, the Second Xiangya Hospital of Central South University, from January 1, 2016 to November 30, 2020. According to the time of withdrawal from caffeine citrate, the infants who met the study criteria were divided into the group with withdrawal before the last week of hospitalization and the group with withdrawal within the last week of hospitalization. The two groups were compared in terms of clinical features, features of citric caffeine use, length of hospital stay and hospital costs, change in the intensity of respiratory support, and preterm complications. RESULTS: A total of 403 preterm infants were enrolled, with 285 infants in the group with withdrawal before the last week of hospitalization and 118 infants in the group with withdrawal within the last week of hospitalization. There were no significant differences in clinical features between the two groups (P>0.05). Compared with the group with withdrawal before the last week of hospitalization, the group with withdrawal within the last week of hospitalization had a significantly longer duration of the use of caffeine citrate, a significantly shorter length of hospital stay, a significantly lower rate of increased intensity of respiratory support after withdrawal, and a significantly lower incidence rate of moderate or severe bronchopulmonary dysplasia (P<0.05). CONCLUSIONS: A relatively long course of caffeine citrate treatment is more beneficial to the short-term clinical outcome of very preterm infants.

Association of vitamin D status at birth with pulmonary disease morbidity in very preterm infants.

OBJECTIVE: We aimed to assess whether serum 25-hydroxyvitamin D (25(OH)D) levels at birth are associated with pulmonary disease morbidities in very preterm infants. METHODS: This prospective cohort analysis included 93 infants born before 32 weeks of gestation in the Second Xiangya Hospital of Central South University between March 2016 and February 2017. Participants were classified into three groups according to their 25(OH)D levels at birth. The groups were compared in terms of demographic variables and pulmonary disease morbidities. RESULTS: The mean serum 25(OH)D level at birth was 35.7 ± 19.1 nmol/L, and 38 (40.9%), 31 (33.3%), and 24 (25.8%) infants had 25(OH)D levels of less than 25 nmol/L, 25-50 nmol/L, and more than or equal to 50 nmol/L, respectively. There was a statistically significant difference in neonatal respiratory distress syndrome (RDS) rates among the three groups (43.6% vs. 35.9% vs. 20.5%, p = .029). The rates of bronchopulmonary dysplasia, apnea, respiratory failure, persistent pulmonary hypertension, and pulmonary hemorrhage did not differ significantly among the groups. Logistic analysis, adjusted for gestational age and birth weight, showed that a low serum 25(OH)D level (<50 nmol/L) was a risk factor for RDS (odds ratio, 0.195; p = .017). CONCLUSION: There was a high prevalence of low 25(OH)D levels (<50 nmol/L) and an association between vitamin D status and RDS in very preterm infants. However, more research on this association is required.

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.

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.

Effect of Folic Acid Supplementation on Renal Phenotype and Epigenotype in Early Weanling Intrauterine Growth Retarded Rats.

BACKGROUND/AIMS: The objective of this study was to examine the responses of p53 promoter methylation involved in kidney structure and function of early weaning intrauterine growth retarded (IUGR) rats to dietary folic acid supplementation. METHOD: Sprague-Dawley rats were fed isocaloric diets containing either 21% protein diet (normal feed) or 10% protein diet throughout pregnancy and normal feed during lactation. After weaning, Offspring were then fed onto normal feed and normal feed supplemented with 5 mg folic acid / kg feed for a month, this produced 4 dietary groups (maternal diet/ weanling diet): Con, Folic, IUGR and IUGR+Folic. Renal function, renal structure, p53 promoter methylation and protein expression of offspring rats were measured at postnatal 2 months and 3 months. RESULTS: Glomerular volume, blood urea nitrogen, 24 hours urine protein were significantly elevated in IUGR rats compared with Con rats but were decreased by dietary folic acid supplementation. p53 protein expression in IUGR rats were significantly higher than that in Con rats, and p53 promoter methylation status in IUGR rats was reduced significantly compared with Con rats. However, the changes in p53 gene expression and DNA methylation status of IUGR rats were reversed by dietary folic acid supplementation. CONCLUSIONS: Our study showed for the first time that folic acid supplementation during early period of life could reverse the abnormality in renal p53 methylation status and protein expression, glomerular volume and renal function of IUGR rats offspring.

Dynamic p53 protein expression and phosphorylation in the kidneys of rats that experienced intrauterine growth restriction.

AIM: This study investigated the mechanisms involved in intrauterine growth restriction (IUGR). METHODS: The IUGR model was established by feeding pregnant SD rats a low-protein diet. Protein expression and phosphorylation were detected using Western blot and/or immunohistochemistry. Cell apoptosis was detected by TUNEL staining. The MDM2 mRNA expression was measured by real-time PCR. RESULTS: Pups from the IUGR group had significantly lower body (7th day, 2 months) and kidney weights (1st day, 7th day, 2 months) compared to pups from the control group (p < 0.01). The glomeruli number in IUGR pups was significantly less than that in the control pups at 2 and 3 months after birth (p < 0.01). p53 protein level and p53 phosphorylation at Ser(15) were time-dependently decreased in the kidney at 1st day, 7th day, 21st day, 2 months and 3 months, but their levels in the kidney of the IUGR pups was significantly higher than that in control pups at each time point (p < 0.05, p < 0.01, or p < 0.001). Significantly more positive p21 staining was observed in IUGR pups than in control pups at each time point. Real-time PCR of MDM2 mRNA expression showed no significant difference between IUGR and control pups (p > 0.05). Significant apoptosis was observed in the kidneys of IUGR pups compared to control pups. CONCLUSION: Malnutrition-induced IUGR may be associated with the activation of p53-p21 signaling in the kidney.

Apoptosis in the kidneys of rats that experienced intrauterine growth restriction.

AIM: Intrauterine growth retardation (IUGR) can affect kidney development, leading to reduction in glomerular number. However, the associated cellular and molecular mechanisms have not been fully elucidated. This study investigated cell apoptosis and Bcl-2 and Bax expression in the kidney of IUGR pups. METHODS: The IUGR model was established in pregnant rats with 10% low-protein diet. Renal cell apoptosis was detected using TUNEL staining. Ki67 protein expression was measured by immunohistochemistry. Bcl-2 and Bax mRNA expression was measured by real-time polymerase chain reaction (PCR). RESULTS: Significant decreases in the number of glomeruli was observed in the kidney of IUGR pups 2 and 3 months after birth (P < 0.01). Obvious apoptosis was observed in the kidney in both groups 1 d, 7 d, and 21 d after birth with a peak at 7 d. Significantly higher apoptosis index was observed in the kidney of IUGR pups compared to control pups (P < 0.01). No significant difference in proliferation was observed between the two groups. Significantly lower Bcl-2 mRNA expression, Bcl-2/Bax ratio, and higher Bax mRNA expression were observed in IUGR pups compared to control pups after birth (P < 0.01). CONCLUSION: The reduction in glomerular number in IUGR pups is associated with increase in renal cell apoptosis. The reduction in Bcl-2/Bax ratio may play a crucial role in renal cell apoptosis in IUGR pups.

[Effects of L-Arg on expression of PI3K and PKB in liver among low-birth-weight newborn rats].

OBJECTIVE: To measure the expression of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) in liver tissue among low-birth-weight newborn rats treated with L-arginine (L-Arg) in early life, and to investigate the effect of L-Arg on insulin resistance. METHODS: Eighteen pregnant rats were randomly divided into three groups: control, model and intervention (n=6 each). The control group was fed with normal protein feed (protein content=21%) during pregnancy to establish a normal-birth-weight newborn rat model, and the model and intervention groups were fed with low-protein feed (protein content=10%) during pregnancy to establish a low-birth-weight newborn rat model. Newborn rats from the three pregnant rat groups were also assigned to control, model and intervention groups. During 21 days of lactation, maternal rats in the control and model groups were fed with normal protein feed and normal drinking water, while maternal rats in the intervention group were fed with normal protein feed and drinking water rich in L-Arg (200 mg/kg·d). After ablactation, the three groups of newborn rats were fed with normal protein feed and normal drinking water. Liver tissue samples were collected from these newborn rats at 1, 3 and 8 weeks after birth. Protein expression of PI3K and PKB in liver tissue was measured by Western blot. RESULTS: At 1 week after birth, the newborn rats in the intervention group had significantly higher protein expression of PI3K than in the model group (P=0.045), but there was no significant difference when compared with the control group (P=0.503). At 8 weeks after birth, the newborn rats in the intervention group had significantly higher protein expression of PKB than the model group (P=0.039), but there was no significant difference when compared with the control group (P>0.05). CONCLUSIONS: A supplement of L-Arg in early life can boost protein synthesis, increase protein expression of PI3K and PKB in liver tissue, promote insulin signaling and reduce insulin resistance.