The airway microbiome and pediatric asthma.

Purpose Of Review: Asthma is the most common chronic disease of childhood. Investigations of the lower and upper airway microbiomes have significantly progressed over recent years, and their roles in pediatric asthma are becoming increasingly clear.

Recent Findings: Early studies identified the existence of upper and lower airway microbiomes, including imbalances in both associated with pediatric asthma.

Functional analysis and transcriptomic profiling of iPSC-derived macrophages and their application in modeling Mendelian disease.

Rationale: An efficient and reproducible source of genotype-specific human macrophages is essential for study of human macrophage biology and related diseases.

Objective: To perform integrated functional and transcriptome analyses of human induced pluripotent stem cell-derived macrophages (IPSDMs) and their isogenic human peripheral blood mononuclear cell-derived macrophage (HMDM) counterparts and assess the application of IPSDM in modeling macrophage polarization and Mendelian disease.

Methods And Results: We developed an efficient protocol for differentiation of IPSDM, which expressed macrophage-specific markers and took up modified lipoproteins in a similar manner to HMDM.

Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Background: Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD.

Activation of innate immunity modulates insulin sensitivity, glucose effectiveness and pancreatic β-cell function in both African ancestry and European ancestry healthy humans.

Objective: Insulin resistance is a risk factor for type 2 diabetes, and is associated with inflammatory cardiometabolic disease. Given differences between African ancestry (AA) and European ancestry (EA) in the epidemiology of type 2 diabetes as well as in response to inflammatory stress, we investigated potential race differences in glucose homeostasis responses during experimental endotoxemia in humans.

Methods: Healthy volunteers (age 18-45 years, BMI 18-30 kg/m(2), 47% female, African-ancestry (AA, n=42) and European-ancestry (EA, n=106)) were recruited as part of the Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) Study.

Human experimental endotoxemia in modeling the pathophysiology, genomics, and therapeutics of innate immunity in complex cardiometabolic diseases.

Inflammation is a fundamental feature of several complex cardiometabolic diseases. Indeed, obesity, insulin resistance, metabolic dyslipidemia, and atherosclerosis are all closely linked inflammatory states. Increasing evidence suggests that the infectious, biome-related, or endogenous activation of the innate immune system may contribute to the development of metabolic syndrome and cardiovascular disease.

Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study.

Aims: Genome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown.

Methods And Results: We analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients.

Omega-3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers.

Scope: Fish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity. However, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans.

Race and gender variation in response to evoked inflammation.

Background: Race- and gender-variation in innate immunity may contribute to demographic differences in inflammatory and cardiometabolic disease; yet their influence on dynamic responses during inflammatory stress is poorly understood. Our objective was to examine race and gender influence on the response to experimental endotoxemia.

Methods: The Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) study was designed to investigate regulation of inflammatory and metabolic responses during low-grade endotoxemia (LPS 1 ng/kg intravenously) in healthy individuals (median age 24, IQR=7) of European (EA; n=193, 47% female) and African ancestry (AA; n=101, 59% female).

Peroxisome Proliferator-Activated Receptor-α Agonism With Fenofibrate Does Not Suppress Inflammatory Responses to Evoked Endotoxemia.

Background: Data conflict with regard to whether peroxisome proliferator-activated receptor-α agonism suppresses inflammation in humans. We hypothesized that in healthy adults peroxisome proliferator-activated receptor-α agonism with fenofibrate would blunt the induced immune responses to endotoxin (lipopolysaccharide [LPS]), an in vivo model for the study of cardiometabolic inflammation.

Methods And Results: In the Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) trial, 36 healthy volunteers (mean age 26±7 years, mean body mass index 24±3 kg/m(2), 44% female, 72% white) were randomized to fenofibrate 145 mg or placebo daily.

A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial.

Background: Chronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-grade but asymptomatic inflammatory response and thus provide an experimental model for future tests of pharmacologic and genomic modulation of cardio-metabolic traits in humans.

Methods: Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.

Translational studies of lipoprotein-associated phospholipase A₂ in inflammation and atherosclerosis.

Objectives: This study sought to examine the role of lipoprotein-associated phospholipase A₂ (Lp-PLA₂/PLA2G7) in human inflammation and coronary atherosclerosis.

Background: Lp-PLA₂ has emerged as a potential therapeutic target in coronary heart disease. Data supporting Lp-PLA₂ are indirect and confounded by species differences; whether Lp-PLA₂ is causal in coronary heart disease remains in question.

Quantitative angiography in South Asians reveals differences in vessel size and coronary artery disease severity compared to Caucasians.

South Asians are one of the highest risk ethnic groups for development of coronary artery disease (CAD) mortality and morbidity. Previous studies have investigated whether South Asians exhibit differences in angiographic coronary artery disease compared to Caucasians, with inconsistent results. We conducted a retrospective observational study comparing South Asians undergoing cardiac catheterization at a tertiary care institution with Caucasians who underwent catheterization at the same time and location to assess whether South Asians demonstrated smaller coronary artery size and/or increased angiographic coronary artery disease.

Deconstructing sociability, an autism-relevant phenotype, in mouse models.

Reduced sociability is a core feature of autism spectrum disorders (ASD) and is highly disabling, poorly understood, and treatment refractory. To elucidate the biological basis of reduced sociability, multiple laboratories are developing ASD-relevant mouse models in which sociability is commonly assessed using the Social Choice Test. However, various measurements included in that test sometimes support different conclusions.

The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels.

Aims: Two single-nucleotide polymorphisms (SNPs), rs1746048 and rs501120, from genome wide association studies of coronary artery disease (CAD) map to chromosome 10q11 ∼80 kb downstream of chemokine CXCL12. Therefore, we examined the relationship between these two SNPs and plasma CXCL12 levels.

Methods And Results: We tested the association of two SNPs with plasma CXCL12 levels in a two-stage study (n= 2939): first in PennCath (n= 1182), a Caucasian, angiographic CAD case-control study, and second in PennCAC (n= 1757), a community-based study of CAD risk factors.