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The study sought to evaluate the utility of a single supine radiograph in determining curve flexibility in early-onset scoliosis (EOS) patients.EOS patients with upright (standing/seated), supine, and side-bending radiographs who underwent spinal deformity surgery were identified. Coronal parameters included: proximal thoracic (PT) curve, main thoracic (MT) curve, and thoracolumbar/lumbar (TL/L) curve. Each radiograph was measured twice by 2 different raters. Correlation coefficients were utilized to investigate associations between the different radiographs. Interrater Correlation Coefficient (ICC) assessed intrarater and interrater reliability.Thirty-seven EOS patients were identified (age at diagnosis: 7.0±2.9 y, preoperative age: 13.0±2.9 y; 73% female; etiologies: 54% idiopathic, 30% syndromic, and 16% neuromuscular). Supine PT and MT curve measurements were highly associated with corresponding side-bending measurements (PT: r=0.75, P0.001; MT: r=0.80, P0.001), and TL/L curves were very highly associated (TL/L: r=0.92, P0.001). The mean absolute differences between supine and side-bending measurements were PT: 11.3±7.8 degrees, MT: 14.8±8.3 degrees, and TL/L: 16.2±7.6 degrees, where the side-bending was on average smaller than the supine measurement. The intrarater reliabilities were excellent, with an ICC ranging from 0.93 to 0.96 for side-bending films and 0.94 to 0.97 for supine films. The interrater reliability was excellent with ICC value of 0.88 for side-bending films and 0.93 for supine films.A single, preoperative supine radiograph was highly predictive of side-bending radiographs in patients with EOS. Supine curves measured an average of 15 degrees larger than bending curves in the MT and TL/L region. A single supine film may eliminate the need for effort-related, dual side-bending radiographs.Level II-retrospective study.

Atherosclerosis is the underlying etiology of cardiovascular disease, the leading cause of death worldwide. Atherosclerosis is a heterogeneous disease in which only a small fraction of lesions lead to heart attack, stroke, or sudden cardiac death. A distinct type of plaque containing large necrotic cores with thin fibrous caps often precipitates these acute events. Here, we show that Ca2+/calmodulin-dependent protein kinase gamma (CaMKII gamma) in macrophages plays a major role in the development of necrotic, thin-capped plaques. Macrophages in necrotic and symptomatic atherosclerotic plaques in humans as well as advanced atherosclerotic lesions in mice demonstrated activation of CaMKII. Western diet-fed LDL receptor-deficient (Ldlr(-/-)) mice with myeloid-specific deletion of CaMKII had smaller necrotic cores with concomitantly thicker collagen caps. These lesions demonstrated evidence of enhanced efferocytosis, which was associated with increased expression of the macrophage efferocytosis receptor MerTK. Mechanistic studies revealed that CaMKII gamma-deficient macrophages and atherosclerotic lesions lacking myeloid CaMKII gamma had increased expression of the transcription factor ATF6. We determined that ATF6 induces liver X receptor-alpha (LXR alpha), an Mertk-inducing transcription factor, and that increased MerTK expression and efferocytosis in CaMKII gamma-deficient macrophages is dependent on LXR alpha. These findings identify a macrophage CaMKII gamma/ATF6/LXR alpha/MerTK pathway as a key factor in the development of necrotic atherosclerotic plaques.

Continual efferocytic clearance of apoptotic cells (ACs) by macrophages prevents necrosis and promotes injury resolution. How continual efferocytosis is promoted is not clear. Here, we show that the process is optimized by linking the metabolism of engulfed cargo from initial efferocytic events to subsequent rounds. We found that continual efferocytosis is enhanced by the metabolism of AC-derived arginine and ornithine to putrescine by macrophage arginase 1 (Arg1) and ornithine decarboxylase (ODC). Putrescine augments HuR-mediated stabilization of the mRNA encoding the GTP-exchange factor Dbl, which activates actin-regulating Rac1 to facilitate subsequent rounds of AC internalization. Inhibition of any step along this pathway after first-AC uptake suppresses second-AC internalization, whereas putrescine addition rescues this defect. Mice lacking myeloid Arg1 or ODC have defects in efferocytosis in vivo and in atherosclerosis regression, while treatment with putrescine promotes atherosclerosis resolution. Thus, macrophage metabolism of AC-derived metabolites allows for optimal continual efferocytosis and resolution of injury.

Emerging data suggest that hypercholesterolemia has stimulatory effects on adaptive immunity and that these effects can promote atherosclerosis and perhaps other inflammatory diseases. However, research in this area has relied primarily on inbred strains of mice whose adaptive immune system can differ substantially from that of humans. Moreover, the genetically induced hypercholesterolemia in these models typically results in plasma cholesterol levels that are much higher than those in most humans. To overcome these obstacles, we studied human immune system-reconstituted mice (hu-mice) rendered hypercholesterolemic by treatment with adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and a high-fat/high-cholesterol Western-type diet (WD). These mice had a high percentage of human T cells and moderate hypercholesterolemia. Compared with hu-mice that had lower plasma cholesterol, the PCSK9-WD mice developed a T cell-mediated inflammatory response in the lung and liver. Human CD4+ and CD8+ T cells bearing an effector memory phenotype were significantly elevated in the blood, spleen, and lungs of PCSK9-WD hu-mice, whereas splenic and circulating regulatory T cells were reduced. These data show that moderately high plasma cholesterol can disrupt human T cell homeostasis in vivo. This process may not only exacerbate atherosclerosis, but also contribute to T cell-mediated inflammatory diseases in the hypercholesterolemia setting.

Summary Regulatory T (Treg) cell responses and apoptotic cell clearance (efferocytosis) represent critical arms of the inflammation resolution response. We sought to determine whether these processes might be linked through Treg-cell-mediated enhancement of efferocytosis. In zymosan-induced peritonitis and lipopolysaccharide-induced lung injury, Treg cells increased early in resolution, and Treg cell depletion decreased efferocytosis. In advanced atherosclerosis, where defective efferocytosis drives disease progression, Treg cell expansion improved efferocytosis. Mechanistic studies revealed the following sequence: (1) Treg cells secreted interleukin-13 (IL-13), which stimulated IL-10 production in macrophages; (2) autocrine-paracrine signaling by IL-10 induced Vav1 in macrophages; and (3) Vav1 activated Rac1 to promote apoptotic cell engulfment. In summary, Treg cells promote macrophage efferocytosis during inflammation resolution via a transcellular signaling pathway that enhances apoptotic cell internalization. These findings suggest an expanded role of Treg cells in inflammation resolution and provide a mechanistic basis for Treg-cell-enhancement strategies for non-resolving inflammatory diseases.