Over 200 million people suffer from osteoporosis worldwide, one third of which will develop osteoporotic bone fractures. Unfortunately, no effective cure exists. Mutations in plastin 3 (PLS3), an F-actin binding and bundling protein, cause X-linked primary osteoporosis in men and predisposition to osteoporosis in postmenopausal women. Moreover, the strongest association so far for osteoporosis in elderly women after menopause was connected to a rare SNP in PLS3, indicating a possible role of PLS3 in complex osteoporosis as well. Interestingly, 5% of the general population are overexpressing PLS3, with yet unknown consequences. Here, we studied ubiquitous Pls3 knockout and PLS3 overexpression in mice and demonstrate that both conditions influence bone remodeling and structure: while Pls3 knockout mice exhibit osteoporosis, PLS3 overexpressing mice show thickening of cortical bone and increased bone strength. We show that unbalanced PLS3 levels affect osteoclast development and function, by misregulating the NFκB pathway. We found upregulation of RELA (NFκB subunit p65) in PLS3 overexpressing mice-known to stimulate osteoclastogenesis-but strikingly reduced osteoclast resorption. We identify NFκB repressing factor (NKRF) as a novel PLS3 interactor, which increasingly translocates to the nucleus when PLS3 is overexpressed. We show that NKRF binds to the NFκB downstream target and master regulator of osteoclastogenesis nuclear factor of activated T cells 1 (Nfatc1), thereby reducing its transcription and suppressing osteoclast function. We found the opposite in Pls3 knockout osteoclasts, where decreased nuclear NKRF augmented Nfatc1 transcription, causing osteoporosis. Regulation of osteoclastogenesis and bone remodeling via the PLS3-NKRF-NFκB-NFATC1 axis unveils a novel possibility to counteract osteoporosis.

ABBREVIATIONS. CT, computed tomography (scan); MRI, magnetic resonance imaging.

BACKGROUND:Published information evaluating frequency of and risk factors for vancomycin-induced acute kidney injury (AKI) in the pediatric intensive care unit (PICU) population is conflicting. OBJECTIVES: The primary objective was to describe the proportion of our PICU patients who developed AKI with intravenous (IV) vancomycin. The secondary objective was to describe the associated potential risk factors. METHODS: Pediatric patients (0-18 years) who received their first IV vancomycin dose in the PICU were evaluated in this retrospective chart review. AKI was defined based on Pediatric-Modified RIFLE (pRIFLE) criteria. Patient demographics, vancomycin trough concentrations, concomitant nephrotoxins, and estimated creatinine clearance changes were analyzed. RESULTS: Of 265 patients included, the primary outcome of AKI (defined by meeting any pRIFLE criteria) occurred in 62 (23.4%) patients (48 category R, 11 category I, 3 category F). Patients who received vancomycin treatment for ≥ 5 days were more likely to develop AKI (unadjusted odds ratio [uOR]: 2.52; 95% confidence interval [CI]: 1.11-5.73), as were patients with a maximum vancomycin trough level ≥ 20 mg/L (OR: 2.99; 95% CI: 1.54-5.78) and patients on 1 (uOR: 2.29; 95% CI: 1.12-4.66) or more concurrent nephrotoxin (uOR: 3.11; 95% CI: 1.43-6.77). Among nephrotoxins, patients receiving furosemide concomitantly with vancomycin were more likely to develop AKI (uOR: 3.47; 95% CI: 1.92-6.27). After adjustment, only furosemide was a significant predictor of risk of AKI/AKI (adjusted OR: 3.52; 95% CI: 1.88-6.62). The study was limited by its retrospective and observational design, and confounding variables. CONCLUSIONS: Patients who were receiving vancomycin with concurrent furosemide were at highest risk of developing AKI.INDEX TERMS: acute kidney injury, critical illness, drug monitoring, pediatrics, vancomycin J Pediatr Pharmacol Ther 2016;21(6): [486][487][488][489][490][491][492][493]

BackgroundTransfusion is a common procedure for neonates receiving intensive care management. Recognising a paucity of patient blood management (PBM) programmes in neonates, we aimed to embed blood management and best transfusion principles in the neonatal intensive care unit (NICU) by aligning local policies, providing targeted education and partnering with parents.MethodsPractice-based evidence for clinical practice improvement (PBE-CPI) methodology was used. Previous hospital accreditation audits were reviewed and a neonate-specific transfusion audit was developed. Audit was performed at baseline and repeated following the intervention period. NICU clinicians received targeted education in obtaining informed consent, prescription and safe administration of blood components during a ‘Blood Month’ awareness period. A neonate-specific parent handout about transfusion was developed in partnership with parents. A pilot video demonstrating a shared consent discussion was also developed to assist in the consent process. Parents’ knowledge, concerns and feedback regarding transfusion practice was sought at baseline (survey) and on project completion (experience trackers).ResultsNeonate-specific baseline transfusion audit showed inconsistent consent, monitoring and documentation processes in neonatal transfusions. Post-targeted education audit showed improvement in these parameters. The targeted PBM and transfusion-related education delivered during ‘Blood Month’ was well-received by staff. Parents’ feedback about the NICU transfusion consenting process was consistently positive. NICU medical and nursing clinicians (n=25) surveyed agreed that the parent handout was well set out, easy to understand and recommended that it be used to complement practice.ConclusionPBE-CPI tools aligned with Australian PBM guidelines for clinicians and parents were well-accepted by clinical stakeholders and were associated with practice improvement in PBM awareness and transfusion consent processes. This PBE-CPI project developed NICU-specific consent information, not previously available, by partnering with parents to ensure quality of care in transfusion practice. Adoption of this also helps to meet accreditation for Australian Blood Management Standards. These strategies and tools translate readily into other NICUs to embed and support best PBM and transfusion practice.