Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis.

OBJECTIVES: Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. METHODS AND RESULTS: Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-ß pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10(-5)). CONCLUSIONS: Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-ß/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-ß-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.

Phenols of virgin olive oil protects nuclear DNA against oxidative damage in HeLa cells.

Oxidative DNA damage is an inescapable consequence for cells constantly exposed to oxidative stress derived from normal metabolic processes and from environmental factors. Phenolic compounds, which have strong antioxidant activity, prevent DNA damage by protecting the cells against harmful effects of oxidative stress. In this study, the effect of virgin olive oil phenolic extract (OOPE) was investigated on H2O2-induced mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in HeLa cells. DNA damage was assessed in mitochondria and two nuclear regions by using quantitative PCR (QPCR) assay. The cells were pre-treated with non-cytotoxic doses of OOPE for 4 h, and DNA damage was determined. OOPE alone does not change the steady-state level of DNA damage. The oxidative stress generated with 750 µM H2O2 caused two times greater damages in mtDNA compared to nDNA, which included the nonexpressed ß-globin region (1.507±0.110 lesions/10 kb) and the expressed APEX1 gene (1.623±0.243 lesions/10 kb) with respect to the control region. When cells were preincubated with OOPE for 4 h, nDNA damage under stress condition was completely inhibited; however, mtDNA damage was not affected by this procedure. These results suggest that OOPE has a protective effect against nDNA damage in HeLa cells.

Protective effects of olive oil phenolics and gallic acid on hydrogen peroxide-induced apoptosis.

PURPOSE: Olive oil contains several phenolic compounds possessing antioxidant activity. The aim of this study was to investigate the protective effects of olive oil phenolic extract (OOPE) and one of its constituents, gallic acid (GA) against H(2)O(2)-induced oxidative stress and apoptotic cell death in HeLa cells, a model for human epithelial cells. METHODS: The cells were pretreated with nontoxic doses of OOPE or GA for 4, 24 and 48 h, and the intracellular reactive oxygen species (ROS) level was determined, before and after oxidative stress induction with H(2)O(2). As an indicator of apoptosis, caspase 9 activity was measured. RESULTS: All pretreatments reduced ROS generation. Four hour incubation with OOPE or GA completely inhibited ROS generation. Increases in caspase 9 activity by OOPE and GA pretreatment under harsh stress conditions were inhibited 92 and 67.8%, respectively. CONCLUSIONS: These results suggest that OOPE and GA act as powerful antioxidants against oxidative stress and exert anti-apoptotic effects.

Is there any correlation between the elevated plasma levels and gene variations of factor VIII in Turkish thrombosis patients?

We investigated factor VIII (FVIII) gene mutations in 20 thrombosis patients with high level of FVIII and 20 control healthy participants. Blood samples were used for the determination of FVIII levels using static timing analyze (STA) kits. Informed consent forms were collected from all participants. Factor VIII level was 237 ± 46 IU/dL in patients group; however, it was 122 ± 38 IU/dL in healthy control participants. Isolated genomic DNAs were screened using 37 pairs of primers covering promoter region and 26 exons of FVIII gene. Single-strand conformation analysis (SSCA) technique was performed for polymorphism/mutation analyses. We observed polymorph patterns in exon 6, exon 13, exon 14F, exon 19, and exon 25 regions. However, we found no evidence of an association between observed single nucleotide polymorphisms and high thrombosis levels. In conclusion, observed exons polymorphisms do not seem to be associated with a venous thromboembolism.