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Background Chronic lateral ankle instability (CLAI) is caused by lateral ankle ligament weakness or rupture secondary to recurrent sprains. The surgical management has traditionally involved a modified Broström-Gould (MBG) procedure with or without internal brace (IB) augmentation. This study aims to demonstrate the improved outcomes for patients undergoing an MBG procedure with IB augmentation for CLAI. Methodology A retrospective analysis was performed among 40 patients undergoing an MBG procedure with or without IB for CLAI at a large teaching hospital between January 2012 and June 2019. Functional outcomes were measured using the Manchester-Oxford Foot Questionnaire (MOxFQ). Clinic letters were reviewed to assess additional outcomes including postoperative complications, revision surgery rate, time in a plaster cast, and time to full weight-bearing. Results A total of 23 patients were included in the study, with seven undergoing both MBG and IB procedures and 16 undergoing MBG intervention alone. The average age was 37.1 years in the IB group and 35.7 years in the MBG group. The mean MOxFQ overall raw scores (10.9 vs. 33.6, p < 0.016), standing and walking MOxFQ subscale (4 vs. 15.2, p < 0.012), pain MOxFQ subscale (4.86 vs. 10.9, p < 0.042), and social interaction subscale (2 vs. 7.5 p < 0.023) all showed significantly better results for the IB group versus the MBG group. Patients in the IB group had significantly less number of weeks in plaster than the MBG group and were able to fully weight bear sooner (4.14 vs. 6, p < 0.01). The MBG group suffered a postoperative complication in seven patients compared to zero in the IB group (p < 0.057). There were three re-ruptures in the MBG group requiring further revision surgery compared to zero in the IB group (3 vs. 0, p < 0.53). Conclusions MBG surgery with IB augmentation for CLAI appears to have better outcomes in terms of overall function and may have fewer overall complications. The IB group displayed a lower recurrence of pain, less time in a plaster cast, and a quicker return to walking., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Flaherty et al.)

Inflammation skews bone marrow hematopoiesis increasing the production of myeloid effector cells at the expense of steady-state erythropoiesis. A compensatory stress erythropoiesis response is induced to maintain homeostasis until inflammation is resolved. In contrast to steady-state erythroid progenitors, stress erythroid progenitors (SEPs) utilize signals induced by inflammatory stimuli. However, the mechanistic basis for this is not clear. Here we reveal a nitric oxide (NO)-dependent regulatory network underlying two stages of stress erythropoiesis, namely proliferation, and the transition to differentiation. In the proliferative stage, immature SEPs and cells in the niche increased expression of inducible nitric oxide synthase ( Nos2 or iNOS ) to generate NO. Increased NO rewires SEP metabolism to increase anabolic pathways, which drive the biosynthesis of nucleotides, amino acids and other intermediates needed for cell division. This NO-dependent metabolism promotes cell proliferation while also inhibiting erythroid differentiation leading to the amplification of a large population of non-committed progenitors. The transition of these progenitors to differentiation is mediated by the activation of nuclear factor erythroid 2-related factor 2 (Nfe2l2 or Nrf2). Nrf2 acts as an anti-inflammatory regulator that decreases NO production, which removes the NO-dependent erythroid inhibition and allows for differentiation. These data provide a paradigm for how alterations in metabolism allow inflammatory signals to amplify immature progenitors prior to differentiation., Key Points: Nitric-oxide (NO) dependent signaling favors an anabolic metabolism that promotes proliferation and inhibits differentiation.Activation of Nfe2l2 (Nrf2) decreases NO production allowing erythroid differentiation.

Macrophages play a pivotal role in mediating inflammation and subsequent resolution of inflammation. The availability of selenium as a micronutrient and the subsequent biosynthesis of selenoproteins, containing the 21 st amino acid selenocysteine (Sec), are important for the physiological functions of macrophages. Selenoproteins regulate the redox tone in macrophages during inflammation, the early onset of which involves oxidative burst of reactive oxygen and nitrogen species. SELENOW is a highly expressed selenoprotein in bone marrow-derived macrophages (BMDMs). Beyond its described general role as a thiol and peroxide reductase and as an interacting partner for 14-3-3 proteins, its cellular functions, particularly in macrophages, remain largely unknown. In this study, we utilized Selenow knock-out (KO) murine bone marrow-derived macrophages (BMDMs) to address the role of SELENOW in inflammation following stimulation with bacterial endotoxin lipopolysaccharide (LPS). RNAseq-based temporal analyses of expression of selenoproteins and the Sec incorporation machinery genes suggested no major differences in the selenium utilization pathway in the Selenow KO BMDMs compared to their wild-type counterparts. However, selective enrichment of oxidative stress-related selenoproteins and increased ROS in Selenow -/- BMDMs indicated anomalies in redox homeostasis associated with hierarchical expression of selenoproteins. Selenow -/- BMDMs also exhibited reduced expression of arginase-1, a key enzyme associated with anti-inflammatory (M2) phenotype necessary to resolve inflammation, along with a significant decrease in efferocytosis of neutrophils that triggers pathways of resolution. Parallel targeted metabolomics analysis also confirmed an impairment in arginine metabolism in Selenow -/- BMDMs. Furthermore, Selenow -/- BMDMs lacked the ability to enhance characteristic glycolytic metabolism during inflammation. Instead, these macrophages atypically relied on oxidative phosphorylation for energy production when glucose was used as an energy source. These findings suggest that SELENOW expression in macrophages may have important implications on cellular redox processes and bioenergetics during inflammation and its resolution., Competing Interests: Conflict-of-interest statement All the authors have read the manuscript and approved its final version before the submission. None of the authors have any potential conflict-of-interests to declare., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)