Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age.

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible through iatrogenic routes due to abundant infectious prions [misfolded forms of the prion protein (PrPSc)] in the central nervous system (CNS). Some epidemiological studies have associated sCJD risk with non-CNS surgeries. We explored the potential prion seeding activity and infectivity of skin from sCJD patients. Autopsy or biopsy skin samples from 38 patients [21 sCJD, 2 variant CJD (vCJD), and 15 non-CJD] were analyzed by Western blotting and real-time quaking-induced conversion (RT-QuIC) for PrPSc. Skin samples from two patients were further examined for prion infectivity by bioassay using two lines of humanized transgenic mice. Western blotting revealed dermal PrPSc in one of five deceased sCJD patients and one of two vCJD patients. However, the more sensitive RT-QuIC assay detected prion seeding activity in skin from all 23 CJD decedents but not in skin from any non-CJD control individuals (with other neurological conditions or other diseases) during blinded testing. Although sCJD patient skin contained ~103- to 105-fold lower prion seeding activity than did sCJD patient brain tissue, all 12 mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation. Our study demonstrates that the skin of sCJD patients contains both prion seeding activity and infectivity, which raises concerns about the potential for iatrogenic sCJD transmission via skin.

Growth impairment and micronutrient deficiencies are prevalent among schoolchildren in Himalayan villages of India.

At baseline in 1992-1994, the authors assessed the combined effects of complement factor H (CFH) genotypes with smoking, fish consumption, and inflammatory markers on the risk of age-related macular degeneration (AMD) in 3,654 persons aged > or =49 years. They reexamined 75% of the survivors after 5 and 10 years, confirming incident AMD by side-by-side photographic grading. Of the 2,452 persons followed in the Blue Mountains Eye Study, 1,881 were genotyped (rs1061170), with CC, CT, and TT identified in 13.6%, 46.7%, and 39.7%, respectively. AMD risk increased with each additional C allele (early AMD: age- and sex-adjusted relative risk (RR) = 1.6, 95% confidence interval (CI): 1.2, 1.9; late AMD: RR = 2.3, 95% CI: 1.5, 3.6). Late AMD risk among current smokers with the CC/CT genotypes (RR = 10.7, 95% CI: 3.4, 33.9) was 5-fold that for genotypically similar nonsmokers (RR = 2.2, 95% CI: 0.9, 5.5) versus current nonsmokers with TT genotypes. Weekly compared with less than weekly consumption of fish was associated with reduced late AMD risk in participants with the CC genotype (RR = 0.15, 95% CI: 0.03, 0.8) but not the CT (RR = 0.7, 95% CI: 0.3, 2.0) or TT (RR = 1.3, 95% CI: 0.2, 7.2) genotypes. This study documents joint contributions from genetic and systemic factors in determining the progression of AMD.