Identification of KIF3A as a Novel Candidate Gene for Childhood Asthma Using RNA Expression and Population Allelic Frequencies Differences

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.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.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

Meïr Goldschmidt and the main currents in 19th-century Judaism

Although the noted nineteenth-century Danish-Jewish writer Meïr Goldschmidt (1819–1887) made his entry into literature with a novel on Jewish themes, his later novels treated non-Jewish subjects, and his Jewish heritage appeared progressively to recede into the background of his public image. Literary historians have paid little attention to his complex perception of his own Jewishness and have made no effort to discover the immense significance he himself felt that Judaism had for his life and for his literary works. Moreover, no previous study has comprehensively treated Goldschmidt’s far-reaching network of interrelationships with an astonishing number of other major Jewish cultural figures of nineteenth-century Europe. During his restless travels crisscrossing Europe, which were facilitated by his phenomenal knowledge of the major European languages, he habitually sought out and associated with the leading Jewish figures in literature, the arts, journalism, and religion, but this fact and the resulting mutually influential connections he formed have been overlooked and ignored. This is the first focused and documented study of the Jewish aspect of Goldschmidt’s life, so vitally important to Goldschmidt himself and so indispensable to a complete understanding of his place in Danish and in world literatures

Neonatal Fc Receptor Mediates Internalization of Fc in Transfected Human Endothelial Cells

The neonatal Fc receptor, FcRn mediates an endocytic salvage pathway that prevents degradation of IgG, thus contributing to the homeostasis of circulating IgG. Based on the low affinity of IgG for FcRn at neutral pH, internalization of IgG by endothelial cells is generally believed to occur via fluid-phase endocytosis. To investigate the role of FcRn in IgG internalization, we used quantitative confocal microscopy to characterize internalization of fluorescent Fc molecules by HULEC-5A lung microvascular endothelia transfected with GFP fusion proteins of human or mouse FcRn. In these studies, cells transfected with FcRn accumulated significantly more intracellular Fc than untransfected cells. Internalization of FcRn-binding forms of Fc was proportional to FcRn expression level, was enriched relative to dextran internalization in proportion to FcRn expression level, and was blocked by incubation with excess unlabeled Fc. Because we were unable to detect either surface expression of FcRn or surface binding of Fc, these results suggest that FcRn-dependent internalization of Fc may occur through sequestration of Fc by FcRn in early endosomes. These studies indicate that FcRn-dependent internalization of IgG may be important not only in cells taking up IgG from an extracellular acidic space, but also in endothelial cells participating in homeostatic regulation of circulating IgG levels

Argon Laser Photocoagulation For Macular Edema In Branch Vein Occlusion

The Branch Vein Occlusion Study is a multi-center, randomized, controlled clinical trial designed to answer several questions regarding the management of complications of branch vein occlusion. This report discusses the question, “Is argon laser photocoagulation useful in improving visual acuity in eyes with branch vein occlusion and macular edema reducing vision to 20/40 or worse?” One hundred thirty-nine eligible eyes were assigned randomly to either a treated or an untreated control group. Comparing treated patients to control patients (mean follow-up 3.1 years for all study eyes), the gain of at least two lines of visual acuity from baseline maintained for two consecutive visits was significantly greater in treated eyes (P = .00049, logrank test). Because of this improvement in visual acuity with argon laser photocoagulation of macular edema from branch vein occlusion, we recommend laser photocoagulation for patients with macular edema associated with branch vein occlusion who meet the eligibility criteria of this study