Publications

BACKGROUND

Asthma is a chronic inflammatory disease with a strong genetic predisposition. A major challenge for candidate gene association studies in asthma is the selection of biologically relevant genes.

METHODOLOGY/PRINCIPAL FINDINGS

Using epithelial RNA expression arrays, HapMap allele frequency variation, and the literature, we identified six possible candidate susceptibility genes for childhood asthma including ADCY2, DNAH5, KIF3A, PDE4B, PLAU, SPRR2B. To evaluate these genes, we compared the genotypes of 194 predominantly tagging SNPs in 790 asthmatic, allergic and non-allergic children. We found that SNPs in all six genes were nominally associated with asthma (p<0.05) in our discovery cohort and in three independent cohorts at either the SNP or gene level (p<0.05). Further, we determined that our selection approach was superior to random selection of genes either differentially expressed in asthmatics compared to controls (p = 0.0049) or selected based on the literature alone (p = 0.0049), substantiating the validity of our gene selection approach. Importantly, we observed that 7 of 9 SNPs in the KIF3A gene more than doubled the odds of asthma (OR = 2.3, p<0.0001) and increased the odds of allergic disease (OR = 1.8, p<0.008). Our data indicate that KIF3A rs7737031 (T-allele) has an asthma population attributable risk of 18.5%. The association between KIF3A rs7737031 and asthma was validated in 3 independent populations, further substantiating the validity of our gene selection approach.

CONCLUSIONS/SIGNIFICANCE

Our study demonstrates that KIF3A, a member of the kinesin superfamily of microtubule associated motors that are important in the transport of protein complexes within cilia, is a novel candidate gene for childhood asthma. Polymorphisms in KIF3A may in part be responsible for poor mucus and/or allergen clearance from the airways. Furthermore, our study provides a promising framework for the identification and evaluation of novel candidate susceptibility genes.

OBJECTIVES

To determine the prevalence and factors associated with use of potentially inappropriate medications (PIMs) in older adults undergoing surgery.

DESIGN

Retrospective cohort study.

SETTING

Three hundred seventy-nine acute care hospitals participating in the nationally representative Perspective database (2006-2008).

PARTICIPANTS

Individuals aged 65 and older undergoing major inpatient gastrointestinal, gynecological, urological, and orthopedic surgery (N=272,351).

MEASUREMENTS

Medications were classified as PIMs using previously published criteria defining 33 medications deemed potentially inappropriate in people aged 65 and older. Information about participant and provider characteristics and administration of PIMs was obtained from hospital discharge file data. Logistic regression techniques were used to examine factors associated with use of PIMs in the perioperative period.

RESULTS

One-quarter of participants received at least one PIM during their surgical admission. Meperidine was the most frequently prescribed PIM (37,855, 14% of participants). In adjusted analysis, PIM use was less likely as age advanced (adjusted odds ratio (AOR)=0.98 per year of age, 95% confidence interval (CI)=0.97-0.98) and in men (AOR=0.83, 95% CI=0.81-0.85). PIMs were more likely to be prescribed to participants cared for by orthopedic surgeons than for those cared for by general surgeons (AOR=1.22, 95% CI=1.08-1.40). Participants undergoing surgery in the West (AOR=1.79, 95% CI=1.02-3.16) and South (AOR=2.24, 95% CI=1.38-3.64) were more likely to receive a PIM than those in the Northeast.

CONCLUSION

Receipt of PIMs in older adults undergoing surgery is common and varies widely between providers and geographic regions and according to participant characteristics. Interventions aimed at reducing the use of PIMs in the perioperative period should be considered in quality improvement efforts.

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes, so there is great interest in understanding the complete spectrum of mTOR-regulated networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin inhibits only a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. A number of studies have highlighted mTORC1 as a regulator of lipid homeostasis. We show that the ATP-competitive inhibitor PP242, but not rapamycin, significantly down-regulates cholesterol biosynthesis genes in a 4E-BP1-dependent manner in NIH 3T3 cells, whereas S6 kinase 1 is the dominant regulator in hepatocellular carcinoma cells. To identify other rapamycin-resistant transcriptional outputs of mTOR, we compared the expression profiles of NIH 3T3 cells treated with rapamycin versus PP242. PP242 caused 1,666 genes to be differentially expressed whereas rapamycin affected only 88 genes. Our analysis provides a genomewide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin.

Hepcidin controls the levels and distribution of iron, an element whose availability can influence the outcome of infections. We investigated hepcidin regulation by infection-associated cytokines, pathogen-derived molecules, and whole pathogens in vitro and in vivo. We found that IL-22, an effector cytokine implicated in responses to extracellular infections, caused IL-6-independent hepcidin up-regulation in human hepatoma cells, suggesting it might represent an additional inflammatory hepcidin agonist. Like IL-6, IL-22 caused phosphorylation of STAT3 and synergized with BMP6 potentiating hepcidin induction. In human leukocytes, IL-6 caused potent, transient hepcidin up-regulation that was augmented by TGF-β1. Pathogen-derived TLR agonists also stimulated hepcidin, most notably the TLR5 agonist flagellin in an IL-6-dependent manner. In contrast, leukocyte hepcidin induction by heat-killed Candida albicans hyphae was IL-6-independent, but partially TGF-β-dependent. In a murine acute systemic candidiasis model, C albicans strongly stimulated hepcidin, accompanied by a major reduction in transferrin saturation. Similarly, hepcidin was up-regulated with concomitant lowering of serum iron during acute murine Influenza A/PR/8/34 virus (H1N1) infection. This intracellular pathogen also stimulated hepcidin expression in leukocytes and hepatoma cells. Together, these results indicate that hepcidin induction represents a component of the innate immune response to acute infection, with the potential to affect disease pathogenesis.