The Genetic Landscape of Familial Pulmonary Fibrosis.

Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction.

The Association Between Expanded ACEs and Behavioral Health Outcomes Among Youth at First Time Legal System Contact.

A growing body of literature has documented high rates of adverse childhood experiences (ACEs) and their effects on behavioral health among adolescents impacted by the juvenile legal system. Most research with justice-impacted youth assesses the ten standard ACEs, encompassing abuse, neglect, and household dysfunction. This body of work has largely ignored the five expanded ACEs which assess social and community level adversity.

Development and Progression of Radiologic Abnormalities in Individuals at Risk for Familial Interstitial Lung Disease.

The preclinical natural history of progressive lung fibrosis is poorly understood. Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia. Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA.

Kinetics of lung tissue factor expression and procoagulant activity in bleomycin induced acute lung injury.

Background: Activation of coagulation by expression of tissue factor (TF) in the airspace is a hallmark of acute lung injury (ALI) but the timing of TF activation in relationship to increases in lung permeability and inflammation are unknown.

Methods: To test the hypothesis that TF is upregulated early in the course of acute bleomycin lung injury and precedes increased permeability and inflammation we studied the early course of bleomycin-induced ALI in mice. Mice were treated with 0.

Fibrosing mediastinitis complicating prior histoplasmosis is associated with human leukocyte antigen DQB1*04:02 - a case control study.

Background: Fibrosing mediastinitis (FM) is an idiosyncratic reaction to infection with Histoplasma capsulatum with a prevalence of 3:100,000 people infected. The rarity of post-histoplasmosis fibrosing mediastinitis (PHFM) in areas where H. capsulatum is endemic suggests that an abnormal immunological host response may be responsible for the development of fibrosis.

Rare variants in RTEL1 are associated with familial interstitial pneumonia.

Rationale: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.

Objectives: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.

Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA.

Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.

Rationale: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease.

Objectives: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset.

Methods: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.

A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia.

Short telomeres are frequently identified in patients with idiopathic pulmonary fibrosis (IPF) and its inherited form, familial interstitial pneumonia (FIP). We identified a kindred with FIP with short telomeres who did not carry a mutation in known FIP genes TERT or hTR . We performed targeted sequencing of other telomere-related genes to identify the genetic basis of FIP in this kindred.

Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation.

Glycosylphophatidylinositol (GPI)-anchored proteins play important roles in many biological processes, and mutations affecting proteins involved in the synthesis of the GPI anchor are reported to cause a wide spectrum of intellectual disabilities (IDs) with characteristic additional phenotypic features. Here, we describe a total of five individuals (from three unrelated families) in whom we identified mutations in PGAP3, encoding a protein that is involved in GPI-anchor maturation. Three siblings in a consanguineous Pakistani family presented with profound developmental delay, severe ID, no speech, psychomotor delay, and postnatal microcephaly.

Medication adherence among Latino and non-Latino white children with asthma.

Objective: Latino children of Caribbean descent remain at high risk for poorly controlled asthma. Controller medications improve asthma control; however, medication adherence remains suboptimal, particularly among minorities. This study assessed socioeconomic, family-based, and parent factors in medication adherence among children with asthma from Rhode Island (RI; Latino and non-Latino white [NLW]) and Puerto Rico.

Telomerase deficiency does not alter bleomycin-induced fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is characterized by interstitial lung infiltrates, dyspnea, and progressive respiratory failure. Reports linking telomerase mutations to familial interstitial pneumonia (FIP) suggest that telomerase activity and telomere length maintenance are important in disease pathogenesis. To investigate the role of telomerase in lung fibrotic remodeling, intratracheal bleomycin was administered to mice deficient in telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) and to wild-type controls.

Accuracy and reproducibility of a multiplex immunoassay platform: a validation study.

Background: Multiplex immunoassays offer many advantages over singleplex assays for the analysis of multiple analytes in a single sample. We sought to validate a specific multiplex cytokine immunoassay (Human 9-plex cytokine array on the Searchlight® platform by Thermoscientific) prior to use in a large clinical study.

Methods: We compared spike and recovery of recombinant proteins on the Searchlight® platform to singleplex immunoassays purchased from R&D Systems, measured identical patient samples on the two different platforms, and measured identical patient samples on different days to measure intra- and inter-assay variability.

Ethnic differences in perception of lung function: a factor in pediatric asthma disparities?

Rationale: Disparities in pediatric asthma exist in that Latino children have higher prevalence and greater morbidity from asthma than non-Latino white children. The factors behind these disparities are poorly understood, but ethnic-related variations in children's ability to accurately recognize and report their pulmonary functioning may be a contributing process.

Objectives: To determine (1) if differences exist between Latino and non-Latino white children's perceptual accuracy and (2) whether these differences are related to asthma outcomes.

Acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis.

Background: The diagnosis of acute lung injury (ALI) is based on a consensus clinical definition. Despite the simplicity of this definition, ALI remains underdiagnosed and undertreated. Severe trauma is a well-described cause of ALI that represents a relatively homogeneous subset of patients with ALI.

Nuclear factor kappa B induction in airway epithelium increases lung inflammation in allergen-challenged mice.

Nuclear factor kappa B (NF-kappa B) is a critical transcription factor for the production of many inflammatory cytokines. It is activated in the airway epithelium of human asthmatics and in mice after allergic stimulation. To examine the role of NF-kappa B activation in allergic inflammation, the authors generated transgenic mouse lines that allowed for the inducible stimulation of NF-kappa B in airway epithelial cells.

Issues and methods in disparities research: the Rhode Island-Puerto Rico asthma center.

Background: Epidemiologic studies have documented higher rates of asthma prevalence and morbidity in minority children compared to non-Latino white (NLW) children. Few studies focus on the mechanisms involved in explaining this disparity, and fewer still on the methodological challenges involved in rigorous disparities research.

Objectives And Methods: This article provides an overview of challenges and potential solutions to research design for studies of health disparities.

STAT1 negatively regulates lung basophil IL-4 expression induced by respiratory syncytial virus infection.

IL-4 contributes to immunopathology induced in mice by primary respiratory syncytial virus (RSV) infection. However, the cellular source of IL-4 in RSV infection is unknown. We identified CD3(-)CD49b(+) cells as the predominant source of IL-4 in the lungs of RSV-infected BALB/c mice.

Attenuation of chronic pulmonary inflammation in A2B adenosine receptor knockout mice.

Pharmacologic evidence suggests that activation of A(2B) adenosine receptors results in proinflammatory effects relevant to the progression of asthma, a chronic lung disease associated with elevated interstitial adenosine concentrations in the lung. This concept has been challenged by the finding that genetic removal of A(2B) receptors leads to exaggerated responses in models of acute inflammation. Therefore, the goal of our study was to determine the effects of A(2B) receptor gene ablation in the context of ovalbumin-induced chronic pulmonary inflammation.

Pediatric Asthma and Problems in Attention, Concentration, and Impulsivity: Disruption of the Family Management System.

RATIONALE: This study assesses the relationships between ADHD symptoms, specific family asthma management domains, and pediatric asthma morbidity. METHODS: Participants were 110 children with asthma and a respective parent (ages 7-17, X = 11.6 years, 25% ethnic/racial minority).

Symptom perception and functional morbidity across a 1-year follow-up in pediatric asthma.

The purpose of this study was to examine the association between asthma symptom perception measured during a 5-6 week baseline and functional morbidity measured prospectively across a 1-year follow-up. Symptom perception was measured by comparing subjective ratings with peak expiratory flow rate (PEFR) and forced expiratory volume in one second (FEV(1)). We hypothesized that accurate symptom perception (ASP) would be associated with less functional morbidity.

Oxidant stress modulates murine allergic airway responses.

The allergic inflammation occurring in asthma is believed to be accompanied by the production of free radicals. To investigate the role of free radicals and the cells affected we turned to a murine model of allergic inflammation produced by sensitization to ovalbumin with subsequent aerosol challenge. We examined oxidant stress by measuring and localizing the sensitive and specific marker of lipid peroxidation, the F2-isoprostanes.

Allergen-induced airway hyperresponsiveness mediated by cyclooxygenase inhibition is not dependent on 5-lipoxygenase or IL-5, but is IL-13 dependent.

Cyclooxygenase (COX) inhibition during allergic sensitization and allergen airway challenge results in augmented allergic inflammation. We hypothesized that this increase in allergic inflammation was dependent on increased generation of leukotrienes that results from COX inhibition, as leukotrienes are important proinflammatory mediators of allergic disease. To test this hypothesis, we allergically sensitized and challenged mice deficient in 5-lipoxygenase (5-LO).