The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis.

Inflammation is critical in the pathobiology of atherosclerosis. An essential player in the inflammatory process in atherosclerosis are macrophages that scavenge oxidatively modified low-density lipoproteins (OxLDL) deposited in the subendothelium of systemic arteries that secrete a myriad of pro-inflammatory mediators. Here, we identified that a subunit of the Skp-Cullin-F-box ubiquitin E3 ligase apparatus, termed FBXO3, modulates the inflammatory response in atherosclerosis. Specifically, individuals with a hypofunctioning genetic variant of FBXO3 develop less atherosclerosis. FBXO3 protein is present in cells of monocytic lineage within carotid plaques and its levels increase in those with symptomatic compared with asymptomatic atherosclerosis. Further, cellular depletion or small molecule inhibition of FBXO3 significantly reduced the inflammatory response to OxLDL by macrophages without altering OxLDL uptake. Thus, FBXO3 potentiates vascular inflammation and atherosclerosis that can be effectively mitigated by a small molecule inhibitor.

Clinical Experience with Secondary Endoscopic Reconstruction of Clival Defects with Extracranial Pericranial Flaps.

Objectives The aim of this study is to report the clinical outcome of extracranial pericranial flaps (ePCF) used for reconstruction of clival dural defects following failure of primary repair. Design Retrospective review of skull base database. Setting Academic medical center. Participants Patients undergoing reconstruction of clival defects with ePCF following endoscopic endonasal surgery (EES). Main outcome measures Postoperative cerebrospinal fluid (CSF) leak, meningitis, and flap necrosis. Results Seven patients (five males and two females) who underwent ePCF reconstruction for clival defects following EES were included. All patients (ages 8-64 years) had a postoperative CSF leak due to a failed primary clival reconstruction (five had one, one had two, and one had three failed CSF leak repairs prior to ePCF reconstruction). Nasoseptal and inferior turbinate (lateral nasal wall) flaps were not available for secondary reconstruction due to prior surgeries. The immediate success rate of ePCF for the reconstruction of clival defects in patients with multiple flap failures was 58%. Two patients developed CSF leaks that were successfully repaired endoscopically with the addition of free tissue grafts; one patient had partial flap necrosis that required debridement; none required an additional vascularized flap. Width of the defect, length of the defect, properties of the ePCF, and age did not demonstrate significance ( p > 0.05) for adverse outcome. Conclusion An ePCF is a reconstructive option for high-risk, large clival defects when other local and regional vascularized flaps are not available or fail. ePCFs can be used for reconstruction of clival defects in all populations, including pediatric patients.

Evaluation of Intranasal Flap Perfusion by Intraoperative Indocyanine Green Fluorescence Angiography.

BACKGROUND: Vascularized intranasal flaps are the primary reconstructive option for endoscopic skull base defects. Flap vascularity may be compromised by injury to the pedicle or prior endonasal surgery. There is currently no validated technique for intraoperative evaluation of intranasal flap viability. OBJECTIVE: To evaluate the efficacy of indocyanine green (ICG) near-infrared angiography in predicting the viability of pedicled intranasal flaps during endoscopic skull base surgery through a pilot study. METHODS: ICG near-infrared fluorescence endoscopy was performed during endoscopic endonasal surgery for skull base tumors. Intraoperative and postoperative data were collected regarding enhancement of the flap body and pedicle. Fluorescence was rated qualitatively. Postoperatively, flap perfusion was evaluated via MRI-contrast enhancement in addition to clinical outcomes (cerebrospinal fluid leak and endoscopic flap appearance). RESULTS: Thirty-eight patients underwent ICG fluorescence angiography. Both the body and pedicle enhanced in 20 patients (53%), while the pedicle only enhanced for 12 patients (32%), the body only for 3 (8%), and neither for 3 (8%). When both the pedicle and body enhanced with ICG, the rate of postoperative MRI contrast enhancement was 100% and the rate of flap necrosis was 0%. The sensitivity and specificity of flap pedicle ICG enhancement for predicting postoperative flap MRI enhancement were 97% and 67%, respectively. Two of 3 patients without enhancement developed flap necrosis. CONCLUSION: ICG fluorescence angiography of intraoperative flap perfusion is feasible and correlates well with outcomes of postoperative MRI flap enhancement and flap necrosis. Additional study is needed to further refine the imaging technique and optimally characterize the clinical utility.