Impact of central venous catheter repair in pediatric intestinal failure.

OBJECTIVES: Patients with intestinal failure (IF) require long-term parenteral nutrition through central venous catheters (CVCs). When damaged, catheter replacement or repair is considered. Limited literature exists on repair outcomes in this population. We aimed to assess the impact of repair on durability of exiting CVCs and infection rates. METHODS: This was a retrospective cohort study of pediatric IF patients with tunneled silicone CVCs over 10 years. Outcomes were evaluated by assessing CVC longevity, repair success, replacement, and postrepair infection rates. RESULTS: One hundred thirty-eight repairs and 45 replacements were conducted in 37 patients with repair and replacement rates of 4.7 and 1.5 per 1000 catheter days, respectively. Twenty patients (54%) required ≥1 repair. For CVCs requiring repair, median CVC durability without and with repairs were at 123 and 391 days, respectively (P < .0001). Overall repair success rate was 96% with significantly lower success in the emergency department at 81% (P = .007). The 7-day postrepair infection rate was 2.2% without specific risk factors identified. Most repairs (76%) were performed by the Pediatric Gastroenterology division. Variability in practice was noted among services, including frequency of periprocedural antibiotic use and performance of temporary repairs before permanent repairs. A gradual increase in CVC repair rate was noted over time. CONCLUSIONS: Our study showed that CVC repair is effective in prolonging CVC durability in pediatric IF patients without increasing infection rates. Incorporating a temporary repair as a step before permanent repair may offer a route to address potential intraluminal thrombosis before permanent repair.

Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation.

The role of the mitochondrial Ca2+ uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption, and Ca2+ uptake increased in wild-type cells but not in cells lacking MCU. In proliferating wild-type control cells, the addition of the growth factors promoted the activation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser616 The lack of the MCU was associated with baseline activation of CaMKII, mitochondrial fragmentation due to increased Drp1 phosphorylation, and impaired mitochondrial respiration and glycolysis. The mitochondrial fission/fusion ratio and proliferation in MCU-deficient cells recovered after MCU restoration or inhibition of mitochondrial fragmentation or of CaMKII in the cytosol. Our data highlight a key function for the MCU in mitochondrial adaptation to the metabolic demands during cell cycle progression. Cytosolic CaMKII and the MCU participate in a regulatory circuit, whereby mitochondrial Ca2+ uptake affects cell proliferation through Drp1.

Endothelial CaMKII as a regulator of eNOS activity and NO-mediated vasoreactivity.

The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase important in transducing intracellular Ca2+ signals. While in vitro data regarding the role of CaMKII in the regulation of endothelial nitric oxide synthase (eNOS) are contradictory, its role in endothelial function in vivo remains unknown. Using two novel transgenic models to express CaMKII inhibitor peptides selectively in endothelium, we examined the effect of CaMKII on eNOS activation, NO production, vasomotor tone and blood pressure. Under baseline conditions, CaMKII activation was low in the aortic wall. Consistently, systolic and diastolic blood pressure, heart rate and plasma NO levels were unaltered by endothelial CaMKII inhibition. Moreover, endothelial CaMKII inhibition had no significant effect on NO-dependent vasodilation. These results were confirmed in studies of aortic rings transduced with adenovirus expressing a CaMKII inhibitor peptide. In cultured endothelial cells, bradykinin treatment produced the anticipated rapid influx of Ca2+ and transient CaMKII and eNOS activation, whereas CaMKII inhibition blocked eNOS phosphorylation on Ser-1179 and dephosphorylation at Thr-497. Ca2+/CaM binding to eNOS and resultant NO production in vitro were decreased under CaMKII inhibition. Our results demonstrate that CaMKII plays an important role in transient bradykinin-driven eNOS activation in vitro, but does not regulate NO production, vasorelaxation or blood pressure in vivo under baseline conditions.