BackgroundChronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing.Methodology/Principal FindingsMacrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocytosis switched wound macrophages from pro-inflammatory to an anti-inflammatory mode.Conclusions/SignificanceTaken together, this study presents first evidence demonstrating that diabetic wounds suffer from dysfunctional macrophage efferocytosis resulting in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates wound healing.

Teprotumumab attenuates the actions of both IGF-1 and TSH in fibrocytes. Specifically, it blocks the induction of proinflammatory cytokines by TSH. These results provide, at least in part, the molecular rationale for interrogating the therapeutic efficacy of this antibody in TAO.

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Purpose To characterize the presenting characteristics, pre-operative clinical activity score (CAS), surgical approach, and visual outcomes in patients with thyroid eye disease undergoing repeat orbital decompression for recurrent or recalcitrant compressive optic neuropathy. Methods The medical records of patients with recurrent or recalcitrant compressive optic neuropathy (CON) undergoing repeat orbital decompressions were retrospectively reviewed. The primary outcome measures included pre- and post-operative Humphrey visual field mean deviation, visual acuity measured in logarithm of the minimal angle of resolution, color vision measured by Ishihara plates, and presence of relative afferent pupillary defect. Details of the surgical procedure and each patient’s CAS at presentation were also recorded. Results Six patients, 9 orbits, with a mean pre-operative CAS of 3.8 were included in this review. The mean time between initial decompression and presentation to our center for recurrent or persistent CON symptoms was 8.6 years (range, 1–15 years). At presentation, the average HVF mean deviation was −16.5 (standard deviation (SD): 8.8), improving to −3.8 (2.4) post-operatively with a mean of 9.3 months follow-up (mean improvement of 75%). Pre-operative visual acuity was 0.34 (0.23) LogMAR, improving to 0.05 (0.10) logMAR with a mean follow up of 10.4 months. Pre- to post-operative comparisons of clinical measures all showed statistically significant improvement (p<0.05). Eight eyes presented with decreased visual acuity (any VA < 20/20), 4 with decreased color vision (any color vision < 11), and 1 with a relative afferent pupillary defect and all of these patients demonstrated improvement following repeat orbital decompression. Conclusions In patients with thyroid eye disease, symptoms of recurrent compressive optic neuropathy occurred up to 15 years following initial orbital decompression underscoring the smoldering, progressive nature of the disease. Repeat decompression which focused on the orbital apex resulted in visual improvement in all 6 patients. Despite clinical evidence of compressive optic neuropathy, the mean CAS of these patients at presentation was only 3.8, highlighting the importance of close monitoring of patients with thyroid eye disease following decompression regardless of the external manifestations of disease activity.