The PX domains of p47phox and p40phox bind to lipid products of PI(3)K.

PX domains are found in a variety of proteins that associate with cell membranes, but their molecular function has remained obscure. We show here that the PX domains in p47phox and p40phox subunits of the phagocyte NADPH oxidase bind to phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P(2)) and phosphatidylinositol-3-phosphate (PtdIns(3)P), respectively. We also show that an Arg-to-Gln mutation in the PX domain of p47phox, which is found in patients with chronic granulomatous disease, eliminates phosphoinositide binding, as does the analogous mutation in the PX domain of p40phox. The PX domain of p40phox localizes specifically to PtdIns(3)P-enriched early endosomes, and this localization is disrupted by inhibition of phosphoinositide-3-OH kinase (PI(3)K) or by the Arg-to-Gln point mutation. These findings provide a molecular foundation to understand the role of PI(3)K in regulating neutrophil function and inflammation, and to identify PX domains as specific phosphoinositide-binding modules involved in signal transduction events in eukaryotic cells.

Epidural analgesia in vascular surgery patients actively taking clopidogrel.

The administration of anti-platelet agents to surgical patients with a history of coronary artery disease or peripheral vascular disease represents an everyday challenge to anaesthesiologists when epidural anaesthesia or analgesia is to be considered. Practice guidelines suggest stopping clopidogrel at least 7 days before placing an epidural catheter. Withholding anti-platelet drugs represents a great risk to many of these patients. On the other hand, withholding perioperative epidural analgesia denies the patients its benefits including faster resolution of postoperative ileus, earlier ambulation, decreased risk of thromboembolism and vascular graft thrombosis, and decreased hospital stay. The charts of 306 vascular surgical patients who received epidural analgesia without withholding clopidogrel perioperatively were reviewed for the presence of any postoperative complications related to the continued intake of clopidogrel. No postoperative neurological complications resulting from the use of epidural analgesia were found in any of these patients. The point estimate (95% confidence limits) for the risk of epidural haematoma or other complications for this study is 0 (0-1)%. No neurological complications were found as a result of placing an epidural catheter in patients actively taking clopidogrel. Owing to the small sample size, we cannot recommend the liberal use of epidural analgesia with ongoing clopidogrel administration at this time. Further prospective studies, with larger sample size, are needed in order to substantiate our findings.