No abstract

Background: Platelet activation with subsequent neutrophilic adherence to the vasculature initiates ischemia-reperfusion injury. We hypothesized that higher plasma P-selectin levels reflecting platelet activation would therefore be associated with primary graft dysfunction (PGD) after lung transplantation.

Dysbindin (DTNBP1) is a positional candidate gene for 6p22.3-linked schizophrenia (SZ). However, so far, no disease-causing alleles have been identified. DTNBP1 is immediately adjacent to JARID2, a member of the ARID (AT-rich interaction domain) family of transcription modulators. We have previously suggested that proteins which bind to AT-rich domains could play a role in SZ pathogenesis. Consequently, we explored the possibility that JARID2 itself could be a candidate gene for 6p22.3-linked SZ. We used a case control design to analyze single nucleotide polymorphisms (SNPs) and insertion/deletion variants affecting AT-rich domains in both the DTNBP1 and JARID2 genes. Three of the DTNBP1 SNPs analyzed had previously been shown to be associated with SZ. We did not detect any significant difference in allele, genotype or haplotype distribution for any of these DTNBP1 markers. However, we did detect a significant difference in allele distribution for a tetranucleotide repeat polymorphism in the JARID2 gene that affects an AT-rich domain. A significant increase in short alleles (less than 11 repeats) was found in patients with SZ (v 2 ¼ 7.02; P ¼ 0.008). No other JARID2 marker displayed statistically significant allele and genotype distributions. Our findings suggest that JARID2 should be viewed as a candidate gene for 6p22.3-linked SZ.

Purpose:The Receptor for Advanced Glycation End-Products (RAGE) is an important marker of lung epithelial injury, and may be associated with impaired alveolar fluid clearance. Blockade of RAGE may attenuate lung injury in animal models. We hypothesized that PGD patients would have higher RAGE levels in plasma than non-PGD patients. Methods and Materials: Prospective, multicenter cohort study. We measured plasma levels of RAGE at 6 and 24 hours following allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was Grade 3 PGD (PaO 2 /FiO 2 Ͻ200 with alveolar infiltrates) at 72 hours after transplantation. Multivariable logistic regression was used to adjust for confounding. Results: Patients who developed PGD had higher levels of RAGE than patients without PGD in both the immediate post-transplantation period (mean 21,246 Ϯ 27,761 pg/mL in PGD vs 12,394 Ϯ 14,767 in those without, pϭ0.005) and the 24 hour time period (12,240 Ϯ 26,505 in those with PGD versus 4265 Ϯ 10,122 in those without, pϽ0.001). RAGE levels at 6 hours were significantly associated with the use of cardiopulmonary bypass. Multivariable analyses indicated that the relationship between 24 hour levels of RAGE and PGD was independent of clinical variables (Adjusted OR for each 10,000 pg/mL ϭ 1.23 (95%CI: 1.05, 1.45; pϽ0.01); whereas levels were attenuated by both the right heart pressures and use of CPB at the 6 hour time point. Conclusions: Elevated plasma levels of RAGE are associated with PGD following lung transplantation. In addition, use of cardiopulmonary bypass was associated with higher RAGE levels, suggesting either alveolar injury that is caused by cardiopulmonary bypass, or, alternately, systemic endothelial production of RAGE in the setting of bypass use.