Project description:Gene expression in blood of children with autism spectrum disorder (ASD) was studied. Transcriptional profiles were compared with age and gender matched, typically developing children from the general population (GP) or IQ matched children with mental retardation or developmental delay (MR/DD). Keywords: autism analysis
Project description:Preschool children with recurrent wheezing are heterogeneous, with differing responses to respiratory viral infections. Although neutrophils are crucial for host defense, their function has not been studied in this population. We performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n=16; no sensitization, n=36). Blood neutrophils were purified and cultured overnight with polyinosinic:polycytidylic acid (poly(I:C)) as a viral analog stimulus. Neutrophils underwent next-generation sequencing with Reactome pathway analysis and were analyzed for cytokine secretion, apoptosis, myeloperoxidase and extracellular DNA release. CD14+ monocytes were also exposed to neutrophil culture supernatant and analyzed for markers of M1 and M2 activation. 495 genes, related largely to the innate immune system and neutrophil degranulation, were differently expressed in children with versus without aeroallergen sensitization. Functional experiments identified more neutrophil degranulation and extracellular trap formation (i.e., more myeloperoxidase and extracellular DNA) and less neutrophil pro-inflammatory cytokine secretion in children with aeroallergen sensitization. Neutrophils also shifted CD14+ monocytes to a more anti-inflammatory (i.e., M2) phenotype in sensitized children and a more pro-inflammatory (i.e., M1) phenotype in non-sensitized children. Although both groups experienced viral exacerbations, annualized exacerbation rates prompting unscheduled healthcare were also higher in children without aeroallergen sensitization after enrollment. Systemic neutrophil responses to viral infection differ by allergic phenotype and may be less effective in preschool children without allergic inflammation. Further studies of neutrophil function are needed in this population, which often has less favorable therapeutic responses to inhaled corticosteroids and other therapies directed at T2-high inflammation.
Project description:Around 42,000 children suffer from severe sepsis each year in the US alone, resulting in significant morbidity, mortality and billion dollar expenditures in the US healthcare system. Sepsis recognition is a clinical challenge in children. Biomarkers are needed to tailor appropriate antimicrobial therapies and improve risk stratification. The goal of this study was to determine if gene expression profiles from peripheral blood were associated with pathogen type and sepsis severity in children treated for suspected sepsis.
Project description:Gene expression in blood of children with autism spectrum disorder (ASD) was studied. Transcriptional profiles were compared with age and gender matched, typically developing children from the general population (GP) or IQ matched children with mental retardation or developmental delay (MR/DD). Experiment Overall Design: Transcriptional profiles were compared with age and gender matched, typically developing children from the general population (GP) or IQ matched children with mental retardation or developmental delay (MR/DD)
Project description:Asthma is an inflammatory disease of the airways characterised by episodic airway obstruction resulting in cough, episodic shortness of breath. It is, and is clinically and physiologically heterogeneous. It is estimated that around 300 million people worldwide have the diseaseare diagnosed with asthma, including up to 20% of children (Asher et al, 2006), with 5–10% of these children believed to have severe or difficult-to-treat asthma. Asthma has often been classified in terms of severity and based on clinical diagnostic criteria, but it is now apparent that the heterogeneity that exists at the physiological level is also a feature of the underlying pathological mechanisms (Lotvall et al, 2011). The aim of this study was to identify blood transcriptomics profiles for children diagnosed with asthma or wheeze, and establish whether these profiles suggested endotypes or mechanisms that could underlie disease, or be related to disease severity, in these children. Importantly, given that children are currently treated with the same medicines as adults, we also aimed to compare profiles of children to those of adults with asthma to help determine whether efforts should be directed to the development of medicines targeting pathways and mechanisms that may be unique to children. To this end, we used gene transcriptome data generated from blood samples from adults and children from the U-BIOPRED consortium to ask how similar or different the differential gene expression profiles were between groups of adults and pre-school or school-aged children with severe or mild-moderate asthma (or wheeze for the pre-school aged children) using current definitions. The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project was set up as a public-private partnership within the framework of the Innovative Medicines Initiative (IMI), engaging academia, the pharmaceutical industry and patient groups. The goal of this investigation was to identify transcript fingerprints in whole blood that characterize patients with severe asthma and to determine whether subgroups of severe asthmatics can be identified.
Project description:Preventive zinc supplementation provided as a stand-alone dispersible tablet, or via home fortification as multiple micronutrient powders (MNPs), has been considered a potential strategy to prevent zinc deficiency and improve health (including immune) outcomes among children in low- and middle-income countries. However, the impact of zinc supplementation on immune profiles has not been well characterised. We sought to define the effect of zinc supplementation on peripheral blood gene expression among young children in Dhaka, Bangladesh. In a sub study of a large randomized, controlled, community-based efficacy trial where children 9-11 months of age received one of the following interventions on a daily basis for 24 weeks 1) MNPs containing 10 mg of zinc; 2) dispersible tablet containing 10 mg zinc; or 3) placebo powder, we used RNA-sequencing to profile the peripheral blood gene expression, as well as highly sensitive multiplex assays to detect cytokine profiles. We profiled samples from 100 children enrolled in the parent trial. We did not detect an effect from either zinc intervention on differential peripheral blood gene expression at the end of intervention, or an effect from intervention on change in gene expression from baseline. We also did not detect an effect from either intervention on cytokine concentrations. Exploratory analysis did not identify an association between undernutrition (defined as stunting, underweight or wasting) on peripheral blood gene expression.
Project description:Human bocavirus (HBoV) is a newly discovered parvovirus identified from pooled nasopharyngeal aspirate specimens. Human bocavirus 1 (HBoV1) is a respiratory virus observed in respiratory samples from small children presenting bronchiolitis, wheezing, cough, fever, and rhinorrhea. It is the fourth most common virus detected in respiratory infections. DNA of HBoV1 was detected in up to 18% of nasal or nasopharyngeal samples and another study has been shown that over than 85% of children in the United States have antibodies to this virus. HBoV1 is a small DNA virus with a nonenveloped icosahedral capsid. This virus previously has been associated with wheezing, acute otitis media, severe pneumonia and respiratory failure. HBoV 1 has been also detected in the blood of acute respiratory patients and the selected group of immunocompromised children and also determined in healthy blood donors. The role of HBoV1 in the inflammatory process is poorly known. The aim of this project is to clarify the role of HBOV1 in the immunoregulatory mechanisms.
Project description:Background Impaired interferon response and allergic sensitisation may contribute to virus induced wheeze and asthma development in young children. Plasmacytoid dendritic cells (pDC) play a key role in antiviral immunity as critical producers of type I interferons (IFN-I). pDC also express the high affinity IgE receptor (FcRI) through which IFN-I production may be negatively regulated. If antiviral function of pDC is associated with recurrent episodes of wheeze in young children is not well understood. This study aimed to evaluate the phenotype and function of circulating pDC in children with a longitudinally defined wheezing phenotype. Methods We performed multiparameter flow cytometry on peripheral blood mononuclear cells from 38 children presenting to the emergency department with an acute episode of respiratory wheeze and 19 controls. RNA sequencing on isolated pDC from the same individuals was also performed. For each subject, their longitudinal exacerbation phenotype was determined using the Western Australia public hospital database. Results We observed a significant depletion of circulating pDC in young children with a persistent phenotype of wheeze. The same individuals also displayed upregulation of the IgE receptor (FcRI) on their pDC. Based on transcriptomic analysis, pDC from these individuals did not mount a robust systemic antiviral response as observed in children who displayed a non-recurrent wheezing phenotype. Conclusion Our data suggests that circulating pDC phenotype and function are altered in young children with a persistent longitudinal exacerbation phenotype. Expression of FcRI is increased and their function as major IFN producers is impaired during acute exacerbations of wheeze.