The NEET proteins mitoNEET (mNT) and nutrient-deprivation autophagy factor-1 (NAF-1) are required for cancer cell proliferation and resistance to oxidative stress. NAF-1 and mNT are also implicated in a number of other human pathologies including diabetes, neurodegeneration and cardiovascular disease, as well as in development, differentiation and aging. Previous studies suggested that mNT and NAF-1 could function in the same pathway in mammalian cells, preventing the over-accumulation of iron and reactive oxygen species (ROS) in mitochondria. Nevertheless, it is unknown whether these two proteins directly interact in cells, and how they mediate their function. Here we demonstrate, using yeast two-hybrid, in vivo bimolecular fluorescence complementation (BiFC), direct coupling analysis (DCA), RNA-sequencing, ROS and iron imaging, and single and double shRNA lines with suppressed mNT, NAF-1 and mNT/NAF-1 expression, that mNT and NAF-1 directly interact in mammalian cells and could function in the same cellular pathway. We further show using an in vitro cluster transfer assay that mNT can transfer its clusters to NAF-1. Our study highlights the possibility that mNT and NAF-1 function as part of an iron-sulfur (2Fe-2S) cluster relay to maintain the levels of iron and Fe-S clusters under control in the mitochondria of mammalian cells, thereby preventing the activation of apoptosis and/or autophagy and supporting cellular proliferation.
Study Design. Retrospective review of a single-center spine database.Objective. Investigate the intersections of chronological age and physiological age via frailty to determine the influence of surgical invasiveness on patient outcomes Summary of Background Data. Frailty is a well-established factor in preoperative risk stratification and prediction of postoperative outcomes. The surgical profile of operative patients with adult spinal deformity (ASD) who present as elderly and not frail (NF) has yet to be investigated. Our aim was to examine the surgical profile and outcomes of patients with ASD who were NF and elderly. Methods. Patients with ASD 18 years or older, four or greater levels fused, with baseline (BL) and follow-up data were included. Patients were categorized by ASD frailty index: NF, Frail (F), severely frail (SF]. An elderly patient was defined as 70 years or older. Patients were grouped into NF/elderly and F/elderly. SRS-Schwab modifiers were assessed at BL and 1 year (0, þ, þþ). Logistic regression analysis assessed the relationship between increasing invasiveness, no reoperations, or major complications, and improvement in SRS-Schwab modifiers [Good Outcome]. Decision tree analysis assessed thresholds for an invasiveness risk/benefit cutoff point. Results. A total of 598 patients with ASD included (55.3 yr, 59.7% F, 28.3 kg/m 2 ). 29.8% of patients were older than 70 years. At BL, 51.3% of patients were NF, 37.5% F, and 11.2% SF. Sixtysis (11%) patients were NF and elderly. About 24.2% of NFelderly patients improved in SRS-Schwab by 1 year and had no reoperation or complication postoperatively. Binary regression analysis found a relationship between worsening SRS-Schwab, postop complication, and reoperation with invasiveness score (odds ratio: 1.056 [1.01-1.102], P ¼ 0.011). Risk/benefit cut-off was 10 (P ¼ 0.004). Patients below this threshold were 7.9 (2.2-28.4) times more likely to have a Good Outcome. 156 patients were elderly and F/SF with 16.7% having good outcome, with a risk/benefit cut-off point of less than 8 (4.4 [2.2-9.0], P < 0.001). Conclusion.Frailty status impacted the balance of surgical invasiveness relative to operative risk in an inverse manner, whereas the opposite was seen amongst elderly patients with a frailty status less than their chronologic age. Surgeons should perhaps consider incorporation of frailty status over age status when determining realignment plans in patients of advanced age.
Background: Recent studies have evaluated the correlation of health-related quality of life (HRQL) scores with radiographic parameters. This relationship may provide insight into the connection of patient-reported disability and disease burden caused by cervical diagnoses. Purpose: To evaluate the association between spinopelvic sagittal parameters and HRQLs in patients with primary cervical diagnoses. Methods: Patients ≥18 years meeting criteria for primary cervical diagnoses. Cervical radiographic parameters assessed cervical sagittal vertical axis, TS-CL, chin-to-brow vertical angle, C2-T3, CL, C2 Slope, McGregor's slope. Global radiographic alignment parameters assessed PT, SVA, PI-LL, T1 Slope. Pearson correlations were run for all combinations at baseline (BL) and 1 year (1Y) for continuous BL and 1Y modified Japanese Orthopaedic Association scale (mJOA) scores, as well as decline or improvement in those HRQLs at 1Y. Multiple linear regression models were constructed to investigate BL and 1Y alignment parameters as independent variables. Results: Ninety patients included 55.6 ± 9.6 years, 52% female, 30.7 ± 7kg/m 2 . By approach, 14.3% of patients underwent procedures by anterior approach, 56% posterior, and 30% had combined approaches. Average anterior levels fused: 3.6, posterior: 4.8, and mean total number of levels fused: 4.5. Mean operative time for the cohort was 902.5 minutes with an average estimated blood loss of 830 ccs. The mean BL neck disability index (NDI) score was 56.5 and a mJOA of 12.81. While BL NDI score correlated with gender ( P = 0.050), it did not correlate with BL global or cervical radiographic factors. An increased NDI score at 1Y postoperatively correlated with BL body mass index ( P = 0.026). A decreased NDI score was associated with 1Y T12-S1 angle ( P = 0.009) and 1Y T10 L2 angle ( P = 0.013). Overall, BL mJOA score correlated with the BL radiographic factors of T1 slope ( P = 0.005), cervical lordosis ( P = 0.001), C2-T3 ( P = 0.008), C2 sacral slope ( P = 0.050), SVA ( P = 0.010), and CL Apex ( P = 0.043), as well as gender ( P = 0.050). Linear regression modeling for the prior independent variables found a significance of P = 0.046 and an R 2 of 0.367. Year 1 mJOA scores correlated with 1Y values for maximum kyphosis ( P = 0.043) and TS-CL ( P = 0.010). At 1Y, a smaller mJOA score correlated with BL S1 sacral slope ( P = 0.014), pelvic incidence ( P = 0.009), L1-S1 ( P ...
INTRODUCTION: Following the introduction of biological DMARDs in Rheumatoid Arthritis (RA) treatment, cervical spine deformity seems to be less prevalent in those patients. It seems that this vast decline in patients with Atlanto-axial Subluxation (AAS), Subaxial Subluxation (SAS) or Vertical Subluxation (VS) is correlated to better control of systemic disease activity (DAS). The aim of the current study is to correlate the frequency of flare-ups in DAS to cervical spine deformity.METHODS: 272 RA patients were included and cervical deformity (AAS and/or SAS) was observed in 108 patients. 84 (31%) patients were in remission at 10 years FU and 206 (75%) of patients reached remission at least once during 10 years FU. Patients with cervical spine deformity at 10 years had less flare-ups (1.26) in DAS than patients without cervical spine deformity (1.58; 95% CI: 0.013-0.627).RESULTS: So, even though the BeSt Trial was designed to optimize treatment, 40% of the patients still developed RA-associated cervical spine deformity. However, remarkably, patients with more flares had less cervical deformity. This may be explained by the treatment regimen that anti-inflammatory medication is augmented upon measuring a systemic flare-up.CONCLUSIONS: This raises the hypothesis that RA medication treatment regimes should not be solely aimed at DAS values, as they are currently defined, in order to avoid cervical deformity in RA in the long term.
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