Search

Children with Down syndrome (DS) develop more infections, have an increased mortality from sepsis and an increased incidence of chronic inflammatory conditions. Cytokine dysregulation may underpin these clinical sequelae and raised pro-inflammatory biomarkers are a feature in adults with DS. The importance of the anti-inflammatory mediators IL-1ra and IL-10, as well as cytokines Epo and VEGF, which could impact on the pathogenesis and outcomes in congenital heart disease (CHD) which is more prevalent in DS, are less well known. We examined a comprehensive array of pro-(IL-2, IL-6, IL-8, IL-18, IL-1β, TNF-α, IFN-γ), and anti-inflammatory (IL-10 and IL-1ra) mediators, cytokines involved in inflammation in response to hypoxia (EPO), propagating angiogenesis (VEGF), and myelopoiesis (GM-CSF), by enzyme linked immunosorbent assay (ELISA), as well as discussing the potential impact of significant CHD and Lipopolysaccharide endotoxin on these mediators. 114 children with DS and 60 age and sex matched controls were recruited. Children with Down syndrome exhibit significantly greater levels of pro and anti-inflammatory cytokines; IL-2, IL-6, IL-10, IL-1ra, as well as increased Epo, VEGF and GM-CSF at baseline. CHD does not seem to have an impact on circulating cytokines beyond the acute surgical phase. Both cohorts had similar responses to LPS stimulation. These differences may contribute to varied clinical outcomes, acutely like in sepsis, and over time in autoimmunity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Inflammatory mediators delay neutrophil apoptosis, which contributes to the persistence of inflammation. The mechanisms responsible for this delay and resistance to Fas antibody-induced apoptosis are unknown but are dependent on protein synthesis. These proteins have been shown to inhibit caspase activity central to the induction of apoptosis. The inhibitors of apoptosis proteins have been shown to inhibit caspase activity and prevent apoptosis in a number of cellular systems. We hypothesize that the regulation of neutrophil apoptosis is dependent on the expression of the IAPs. c-IAP-1, c-IAP-2, and XIAP are expressed in the neutrophil at both the mRNA and protein level, but their relative protein expression is low compared with other cell types. The in vitro aging of human neutrophils results in their induction of apoptosis, which is associated with the loss of c-IAP-1 expression. The pancaspase inhibitor (zVAD-FMK) and LPS, which delay spontaneous apoptosis, also prevented this loss of c-IAP-1. Gene chip microarrays have shown that LPS increases c-IAP-1 and c-IAP-2 mRNA expression in neutrophils. However, this does not correspond to an increase in protein. Neutrophils from septic patients with delayed apoptosis show an increase in XIAP, with no change in cIAP-1 or cIAP-2 mRNA, demonstrating that different mechanisms contribute to the delay in neutrophil apoptosis. This study demonstrates that the loss of IAP expression may facilitate the induction of neutrophil apoptosis, and preventing this loss of IAP expression may represent a more significant contribution to delayed apoptosis rather than an increase in their expression.

Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects. [ABSTRACT FROM AUTHOR]

Background: Efficient and accurate diagnosis of neonatal sepsis is challenging. The potential impact for a reduction in morbidity and mortality as well as antibiotic usage has stimulated the ongoing search for biomarkers of early sepsis. The objective of this pilot study was to quantify the levels of sTREM-1 and correlate with blood cultures and inflammatory markers in neonates evaluated for sepsis.Methods: Neonates with suspected sepsis were enrolled (n = 83; Preterm n = 35; Term n = 48). Routine bloods for sepsis evaluation were included and plasma sTREM-1 levels were quantified by ELISA.Results: Term and preterm neonates (n = 83; Preterm n = 35; Term n = 48) were enrolled and 16 neonates had positive blood cultures (preterm n = 15; term n = 1). sTREM-1 levels were not significantly different in infants with culture-positive or culture-negative sepsis (356 ± 218 pg/mL and 385 ± 254 pg/mL respectively). The immature-to-total granulocyte (I/T) ratio showed a significant positive correlation with sTREM-1 in the preterm group with positive blood cultures. Additionally, sTREM-1 showed a positive correlation with CRP in the preterm group with negative blood cultures.Conclusions: sTREM-1 was associated with traditional markers of inflammation (I/T ratio and CRP). However, in this cohort sTREM-1 did not improve the early detection of neonatal culture-positive sepsis. [ABSTRACT FROM AUTHOR]

Unusually for a viral infection, the immunological phenotype of severe COVID-19 is characterised by a depleted lymphocyte and elevated neutrophil count, with the neutrophil-to-lymphocyte ratio correlating with disease severity. Neutrophils are the most abundant immune cell in the bloodstream and comprise different subpopulations with pleiotropic actions that are vital for host immunity. Unique neutrophil subpopulations vary in their capacity to mount antimicrobial responses, including NETosis (the generation of neutrophil extracellular traps), degranulation and de novo production of cytokines and chemokines. These processes play a role in antiviral immunity, but may also contribute to the local and systemic tissue damage seen in acute SARS-CoV-2 infection. Neutrophils also contribute to complications of COVID-19 such as thrombosis, acute respiratory distress syndrome and multisystem inflammatory disease in children. In this Progress review, we discuss the anti-viral and pathological roles of neutrophils in SARS-CoV-2 infection, and potential therapeutic strategies for COVID-19 that target neutrophil-mediated inflammatory responses. [ABSTRACT FROM AUTHOR]

Infection and persistent inflammation have a prominent role in the pathogenesis of brain injury and cerebral palsy, as well as other conditions associated with prematurity such as bronchopulmonary dysplasia. The NLRP3 inflammasome-interleukin (IL)-1β pathway has been extensively studied in adults and pre-clinical models, improving our understanding of innate immunity and offering an attractive therapeutic target that is already contributing to clinical management in many auto-inflammatory disorders. IL-1 blockade has transformed the course and outcome of conditions such as chronic infantile neurological, cutaneous, articular (CINCA/NOMID) syndrome. Inflammasome activation and upregulation has recently been implicated in neonatal brain and lung inflammatory disease and may be a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Background: To determine the association of maternal and fetal inflammatory factors with gender-specific infant adiposity, independent of leptin.Methods: Analysis of anthropometry from 265 mother-infant pairs at birth and 280 pairs at 6 months from the randomised control trial of low glycaemic index diet in pregnancy (ROLO) study (Randomised control trial of low glycaemic index diet) and their association with Maternal TNF-alpha, interleukin 6 and leptin as measured in early and late pregnancy and fetal levels in cord blood.Results: No associations were noted in the male cohort. On multiple regression amongst the female neonatal cohort late pregnancy IL-6 was inversely associated with sum of skinfolds (p ≤ .001); at 6 months infant sum of skinfolds were positively associated with early pregnancy IL-6 (p = .046) and central adiposity positively associated with early pregnancy TNF alpha (p = .018) independent of leptin.Conclusion: Although maternal inflammatory cytokines were not associated with neonatal adiposity independent of leptin (as this association is known), both IL-6 and TNF-α were associated with female infant anthropometry at 6 months of age independent of leptin. These results suggest inflammatory cytokines may exert an in-utero influence on later infant adiposity with a tendency to influence female adiposity more than male. Further research is required to ascertain whether these cytokines may be used as reliable early predictors of infant adiposity. [ABSTRACT FROM AUTHOR]

Introduction: In neonatology, males exhibit a more severe disease course and poorer prognosis in many pathological states when compared to females. Perinatal brain injury, respiratory morbidity, and sepsis, among other complications, preferentially affect males. Preterm neonates (born <37 weeks gestation) display a particularly marked sexual disparity in pathology, especially at the borders of viability. The sex biases in preterm neonatal outcomes and underlying multifactorial mechanisms have been incompletely explored. Sex-specific clinical phenomena may be partially explained by intrinsic differences in immune function. The distinct immune system of preterm neonates renders this patient population vulnerable, and it is increasingly important to consider biological sex in disease processes and to strive for improved outcomes for both sexes. Areas covered: We discuss the cellular responses and molecular intermediates in immune function which are strongly dependent on sex-specific factors such as the genetic and hormonal milieu of premature birth and consider novel findings in a clinical context. Expert commentary: The role of immune function in the manifestation of sex-specific disease manifestations and outcomes in preterm neonates is a critical prognostic variable. Further mechanistic elucidation will yield valuable translational and clinical information of disease processes in preterm neonates which may be harnessed for modulation. [ABSTRACT FROM PUBLISHER]

Aim: Inflammatory cytokines may play a role in the final common pathway in the pathogenesis of hypoxic-ischaemic injury in experimental models. We aimed to profile the systemic pro-and anti-inflammatory response over the first week of life in term infants at risk of neonatal encephalopathy.Method: In a tertiary referral university neonatal intensive care unit, serial blood samples were analysed from 41 term infants (requiring resuscitation at birth) in this prospective observational pilot study. Serum levels of 10 pro-and anti-inflammatory cytokines were evaluated including interleukin(IL)-1α, IL-1β, IL-6, IL-8, IL-10, tumour necrosis factor(TNF)-α, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), granulocyte/colony-stimulating factor (G-CSF) and granulocyte macrophage/colony-stimulating factor (GM-CSF).Results: Infants with neonatal encephalopathy and abnormal neuroimaging (n = 15) had significantly elevated granulocyte macrophage/colony-stimulating factor at 0-24 h and interleukin-8, interleukin-6 and interleukin-10 at 24-48 hour. Tumour necrosis factor-α and vascular endothelial growth factor levels were lower at 72-96 hour (p < 0.05). Significantly elevated levels of interleukin-10 were associated with mortality.Conclusion: Serum cytokine changes and innate immune dysregulation in the first week of life may be indicators of outcome in neonatal encephalopathy but require validation in larger studies. [ABSTRACT FROM AUTHOR]

Objective: We studied the effect of labor on maternal neutrophil phenotype. Study design: Neutrophil apoptosis with inflammatory cytokines and the expression of CD11b, CD34 and toll-like receptor 4 (TLR4) were assessed with flow cytometry in women at uncomplicated vaginal delivery (VD), and elective cesarean section (ElCS) without labor, emergency cesarean section with (EmCSL+) or without (EmCSL-) labor. Results: Spontaneous neutrophil apoptosis is delayed in maternal neutrophils after VD, EmCSL+ or EmCSL- versus ElCS. In all groups lipopolysaccharide delayed apoptosis and increased CD11b expression. Elevated TLR4 expression in ElCS was associated with lipopolysaccharide responsiveness. CD34 was diminished in VD, indicating increased cell maturity. Conclusion: Normal labor primes the neutrophil and may enhance antibacterial function by inducing a mild maternal inflammatory response syndrome. Delayed neutrophil apoptosis may promote the neutrophilia seen in women after VD. We suggest that labor of any duration may be immunologically beneficial to the parturient. [ABSTRACT FROM AUTHOR]