IL-1α Mediated Chorioamnionitis Induces Depletion of FoxP3+ Cells and Ileal Inflammation in the Ovine Fetal Gut

Endotoxin induced chorioamnionitis increases IL-1 and provokes an inflammatory response in the fetal ileum that interferes with intestinal maturation. In the present study, we tested in an ovine chorioamnionitis model whether IL-1 is a major cytokine driving the inflammatory response in the fetal ileum.Sheep bearing singleton fetuses received a single intraamniotic injection of recombinant ovine IL-1α at 7, 3 or 1 d before caesarian delivery at 125 days gestational age (term = 150 days).3 and 7 d after IL-1α administration, intestinal mRNA levels for IL-4, IL-10, IFN-γ and TNF-α were strongly elevated. Numbers of CD3+ and CD4+ T-lymphocytes and myeloidperoxidase+ cells were increased whereas FoxP3+ T-cells were detected at low frequency. This increased proinflammatory state was associated with ileal mucosal barrier loss as demonstrated by decreased levels of the intestinal fatty acid binding protein and disruption of the tight junctional protein ZO-1.Intraamniotic IL-1α causes an acute detrimental inflammatory response in the ileum, suggesting that induction of IL-1 is a critical element in the pathophysiological effects of endotoxin induced chorioamnionitis. A disturbed balance between T-effector and FoxP3+ cells may contribute to this process

Generation of Large-Scale Vorticity in a Homogeneous Turbulence with a Mean Velocity Shear

An effect of a mean velocity shear on a turbulence and on the effective force which is determined by the gradient of Reynolds stresses is studied. Generation of a mean vorticity in a homogeneous incompressible turbulent flow with an imposed mean velocity shear due to an excitation of a large-scale instability is found. The instability is caused by a combined effect of the large-scale shear motions (''skew-induced" deflection of equilibrium mean vorticity) and ''Reynolds stress-induced" generation of perturbations of mean vorticity. Spatial characteristics, such as the minimum size of the growing perturbations and the size of perturbations with the maximum growth rate, are determined. This instability and the dynamics of the mean vorticity are associated with the Prandtl's turbulent secondary flows. This instability is similar to the mean-field magnetic dynamo instability. Astrophysical applications of the obtained results are discussed.Comment: 8 pages, 3 figures, REVTEX4, submitted to Phys. Rev.

Neonatal cholestasis, hyperferritinemia, hypoglycemia and deafness:a diagnostic challenge

Neonatal conjugated hyperbilirubinemia is a diagnostic challenge. A full term, small for gestational age boy presented with cholestasis, hypoglycemia, hyperferritinemia and severe bilateral deafness. Diagnostic work-up revealed two hereditary diseases: alpha-1-antitrypsin deficiency (PI*ZZ genotype) and autosomal recessive deafness type 3 (compound heterozygous MYO15A gene mutation). In addition, we found late hypoglycemia on full enteral feeding which complicated this case. Hyperferritinemia is an uncommon finding in newborn cholestasis without liver failure

Placing <i>Ureaplasma</i> within the Context of Bronchopulmonary Dysplasia Endotypes and Phenotypes

Different pathophysiological pathways (endotypes), leading to very preterm birth may result in distinct clinical phenotypes of bronchopulmonary dysplasia (BPD). Ureaplasma is a unique player in the pathogenesis of BPD. The interaction between factors inherent to Ureaplasma (virulence, bacterial load, duration of exposure), and to the host (immune response, infection clearance, degree of prematurity, respiratory support, concomitant infections) may contribute to BPD development in a variable manner. The data reviewed herein support the hypothesis that Ureaplasma, as a representative of the infectious/inflammatory endotype, may produce pulmonary damage predominantly in parenchyma, interstitium, and small airways. In contrast, Ureaplasma may have a very limited role in the pathogenesis of the vascular phenotype of BPD. In addition, if Ureaplasma is a key factor in BPD pathogenesis, its eradication by macrolides should prevent BPD. However, various meta-analyses do not show consistent evidence that this is the case. The limitations of current definitions and classifications of BPD, based on respiratory support needs instead of pathophysiology and phenotypes, may explain this and other failures in strategies aimed to prevent BPD. The precise mechanisms through which Ureaplasma infection leads to altered lung development and how these pathways can result in different BPD phenotypes warrant further investigation

Endotypes of Prematurity and Phenotypes of Bronchopulmonary Dysplasia: Toward Personalized Neonatology

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is increasingly recognized as the consequence of a pathological reparative response of the developing lung to both antenatal and postnatal injury. According to this view, the pathogenesis of BPD is multifactorial and heterogeneous with different patterns of antenatal stress (endotypes) that combine with varying postnatal insults and might distinctively damage the development of airways, lung parenchyma, interstitium, lymphatic system, and pulmonary vasculature. This results in different clinical phenotypes of BPD. There is no clear consensus on which are the endotypes of prematurity but the combination of clinical information with placental and bacteriological data enables the identification of two main pathways leading to birth before 32 weeks of gestation: (1) infection/inflammation and (2) dysfunctional placentation. Regarding BPD phenotypes, the following have been proposed: parenchymal, peripheral airway, central airway, interstitial, congestive, vascular, and mixed phenotype. In line with the approach of personalized medicine, endotyping prematurity and phenotyping BPD will facilitate the design of more targeted therapeutic and prognostic approaches

Patent Ductus Arteriosus and Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension:A Bayesian Meta-Analysis

IMPORTANCE: Bronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH (BPD-PH) is complex and involves prenatal and postnatal factors that disrupt pulmonary vascular development, and patent ductus arteriosus (PDA) is a factor potentially associated with risk of BPD-PH that has been identified in very recent studies. OBJECTIVE: To explore the association of PDA with BPD-PH using a bayesian model-averaged (BMA) meta-analysis of studies. DATA SOURCES: PubMed and Embase were searched up to April 2023. Key search terms included BPD and PH. STUDY SELECTION: Studies examining infants with gestational age 32 weeks or less and reporting data on PDA and risk of BPD-PH. DATA EXTRACTION AND SYNTHESIS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted data, with a third reviewer checking for accuracy and completeness. Data pooling and effect size calculations were performed by BMA. MAIN OUTCOMES AND MEASURES: The primary outcome was BPD-PH. BMA was used to calculate Bayes factors (BFs). The BF10 is the ratio of the probability of the data under the alternative hypothesis (H1, association of PDA with BPD-HP) over the probability of the data under the null hypothesis (H0). RESULTS: A total of 32 studies (8513 infants) were included. BMA showed that the evidence in favor of H1 was weak for any PDA (BF10?=?2.90; 10 studies), moderate for hemodynamically significant PDA (BF10?=?3.77; 3 studies), and extreme for surgically ligated or catheter-occluded PDA (BF10?=?294.9; 16 studies). In contrast, the evidence in favor of H0 was weak for medically treated PDA (BF10?=?0.55; 6 studies). In addition, BMA found strong evidence in favor of H1 when prolonged exposure to PDA was analyzed as a dichotomous variable (BF10?=?11.80; 6 studies) and extreme evidence (BF10?=?113.60; 3 studies) when PDA exposure time was analyzed as a continuous variable. CONCLUSIONS AND RELEVANCE: In this bayesian meta-analysis, the data suggest that prolonged exposure to PDA might be associated with increased risk of pulmonary vascular disease in extremely preterm infants. This highlights the need to monitor for PH in high-risk preterm infants with prolonged exposure to PDA and to incorporate PH risk into clinical decisions regarding PDA management

Tobacco Smoking During Pregnancy Is Associated With Increased Risk of Moderate/Severe Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis

Epidemiological evidence and animal studies support that intrauterine exposure to tobacco smoke disturbs lung development and has a negative effect in the pulmonary health of the offspring. Individual studies suggest an association between fetal exposure to maternal smoking and risk of developing bronchopulmonary dysplasia (BPD). However, this association has not yet been systematically investigated. We aimed to conduct a systematic review of studies reporting on tobacco smoking during pregnancy as potential risk factor for BPD. PubMed/MEDLINE and EMBASE databases were searched. BPD was defined as requirement of supplemental oxygen on postnatal day 28 (BPD28; all BPD), at the postmenstrual age (PMA) of 36 weeks (BPD36; moderate/severe BPD), or as requirement of more than 30% oxygen and/or positive pressure at 36 weeks PMA (severe BPD). Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model. Of 2,894 potentially relevant studies, 33 met the inclusion criteria. The included studies evaluated 171,772 infants and included 30,445 cases of exposure to maternal smoking and 25,340 cases of BPD of any severity. Meta-analysis showed a significant association between tobacco smoking during pregnancy and BPD36 (17 studies, RR 1.126, 95% CI 1.008-1.259, p = 0.036), but could not demonstrate a significant association between tobacco smoking during pregnancy and BPD28 (16 studies, RR 1.021, 95% CI 0.924-1.129, p = 0.681), or severe BPD (3 studies, RR 1.143, 95% CI 0.528-2.478, p = 0.734). In conclusion, our data suggest that tobacco smoking during pregnancy increases the risk of moderate/severe BPD. Our results highlight the detrimental effects of tobacco smoking and reinforce the hypothesis of the involvement of prenatal insults in the etiopathogenesis of BPD

Tobacco Smoking During Pregnancy Is Associated With Increased Risk of Moderate/Severe Bronchopulmonary Dysplasia:A Systematic Review and Meta-Analysis

Epidemiological evidence and animal studies support that intrauterine exposure to tobacco smoke disturbs lung development and has a negative effect in the pulmonary health of the offspring. Individual studies suggest an association between fetal exposure to maternal smoking and risk of developing bronchopulmonary dysplasia (BPD). However, this association has not yet been systematically investigated. We aimed to conduct a systematic review of studies reporting on tobacco smoking during pregnancy as potential risk factor for BPD. PubMed/MEDLINE and EMBASE databases were searched. BPD was defined as requirement of supplemental oxygen on postnatal day 28 (BPD28; all BPD), at the postmenstrual age (PMA) of 36 weeks (BPD36; moderate/severe BPD), or as requirement of more than 30% oxygen and/or positive pressure at 36 weeks PMA (severe BPD). Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model. Of 2,894 potentially relevant studies, 33 met the inclusion criteria. The included studies evaluated 171,772 infants and included 30,445 cases of exposure to maternal smoking and 25,340 cases of BPD of any severity. Meta-analysis showed a significant association between tobacco smoking during pregnancy and BPD36 (17 studies, RR 1.126, 95% CI 1.008-1.259, p = 0.036), but could not demonstrate a significant association between tobacco smoking during pregnancy and BPD28 (16 studies, RR 1.021, 95% CI 0.924-1.129, p = 0.681), or severe BPD (3 studies, RR 1.143, 95% CI 0.528-2.478, p = 0.734). In conclusion, our data suggest that tobacco smoking during pregnancy increases the risk of moderate/severe BPD. Our results highlight the detrimental effects of tobacco smoking and reinforce the hypothesis of the involvement of prenatal insults in the etiopathogenesis of BPD