A novel method for engineering autologous non-thrombogenic in situ tissue-engineered blood vessels for arteriovenous grafting

The durability of prosthetic arteriovenous (AV) grafts for hemodialysis access is low, predominantly due to stenotic lesions in the venous outflow tract and infectious complications. Tissue engineered blood vessels (TEBVs) might offer a tailor-made autologous alternative for prosthetic grafts. We have designed a method in which TEBVs are grown in vivo, by utilizing the foreign body response to subcutaneously implanted polymeric rods in goats, resulting in the formation of an autologous fibrocellular tissue capsule (TC). One month after implantation, the polymeric rod is extracted, whereupon TCs (length 6 cm, diameter 6.8 mm) were grafted as arteriovenous conduit between the carotid artery and jugular vein of the same goats. At time of grafting, the TCs were shown to have sufficient mechanical strength in terms of bursting pressure (2382 +/- 129 mmHg), and suture retention strength (SRS: 1.97 +/- 0.49 N). The AV grafts were harvested at 1 or 2 months after grafting. In an ex vivo whole blood perfusion system, the lumen of the vascular grafts was shown to be less thrombogenic compared to the initial TCs and ePTFE grafts. At 8 weeks after grafting, the entire graft was covered with an endothelial layer and abundant elastin expression was present throughout the graft. Patency at 1 and 2 months was comparable with ePTFE AV-grafts. In conclusion, we demonstrate the remodeling capacity of cellularized in vivo engineered TEBVs, and their potential as autologous alternative for prosthetic vascular grafts.Vascular Surger

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis

Impact of GSTM1 on aromatic-DNA adducts and p53 accumulation in human skin and lymphocytes.

Pharmacogenetics 2001 Aug;11(6):537-43 Related Articles, Books, LinkOut Impact of GSTM1 on aromatic-DNA adducts and p53 accumulation in human skin and lymphocytes. Godschalk RW, Ostertag JU, Zandsteeg AM, Van Agen B, Neuman HA, Van Straaten H, Van Schooten FJ. Department of Health Risk Analysis and Toxicology, Maastricht University, The Netherlands. The cellular response to DNA damage is often a p53-mediated cell cycle arrest to provide time for DNA repair or to direct damaged cells into apoptosis. In this study, the impact of glutathione-S-transferase M1 (GSTM1) on DNA damage and subsequent p53-protein accumulation was examined in lymphocytes of healthy volunteers in vitro exposed to benzo[a]pyrene-diol-epoxide (BPDE) and in skin of atopic eczema patients topically treated with coal tar. DNA adducts were determined by immunocytochemical staining (ICC) and 32P-postlabelling, p53 accumulation was studied by ICC and the GSTM1 genotype was assessed by polymerase chain reaction. In cultured lymphocytes treated with 2.5 microM BPDE for 18 h, increased levels of p53 were found, which were positively related to BPDE-DNA adduct levels assessed by ICC (rs = 0.66, P < 0.001) and 32P-postlabelling (rs = 0.56, P < 0.001) and appeared to be higher in GSTM1(-/-) than in GSTM1(+) subjects (P = 0.003). In skin biopsies of coal tar treated eczema patients, p53 levels were elevated in 7/10 patients and a correlation was observed between p53 and DNA adduct levels (rs = 0.50, P = 0.029). GSTM1(-/-) subjects contained higher levels of p53 in the stratum basale than GSTM1(+) individuals (P = 0.026), but no influence of GSTM1 on DNA adduct levels was observed. Thus, p53 accumulates in human skin and lymphocytes as a protective mechanism against polycyclic aromatic hydrocarbon induced DNA damage, and this is more pronounced in GSTM1(-/-) compared to GSTM1(+) individuals