Siglecs are a family of sialic acid-binding immunoglobulin-like lectins that regulate the functions of cells in the innate and adaptive immune systems through glycan recognition. Here we show that Siglec-15 regulates osteoclast development and bone resorption by modulating receptor activator of nuclear factor kB ligand (RANKL) signaling in association with DNAX-activating protein 12 kDa (DAP12), an adaptor protein bearing an immunoreceptor tyrosine-based activation motif (ITAM). Among the known Siglecs expressed in myeloid lineage cells, only Siglec-15 was upregulated by RANKL in mouse primary bone marrow macrophages. Siglec-15-deficient mice exhibit mild osteopetrosis resulting from impaired osteoclast development. Consistently, cells lacking Siglec-15 exhibit defective osteoclast development and resorptive activity in vitro. RANKL-induced activation of phosphatidylinositol 3-kinase (PI3K)/Akt and Erk pathways were impaired in Siglec-15-deficient cells. Retroviral transduction of Siglec-15-null osteoclast precursors with wild-type Siglec-15 or mutant Siglec-15 revealed that the association of Siglec-15 with DAP12 is involved in the downstream signal transduction of RANK. Furthermore, we found that the ability of osteoclast formation is preserved in the region adjacent to the growth plate in Siglec-15-deficient mice, indicating that there is a compensatory mechanism for Siglec-15-mediated osteoclastogenesis in the primary spongiosa. To clarify the mechanism of this compensation, we examined whether osteoclast-associated receptor (OSCAR)/Fc receptor common g (FcRg) signaling, an alternative ITAM-mediated signaling pathway to DAP12, rescues impaired osteoclastogenesis in Siglec-15-deficient cells. The ligands in type II collagen activate OSCAR and rescue impaired osteoclastogenesis in Siglec-15-deficient cells when cultured on bone slices, indicating that Siglec-15-mediated signaling can be compensated for by signaling activated by type II collagen and other bone matrix components in the primary spongiosa. Our findings indicate that Siglec-15 plays an important role in physiologic bone remodeling by modulating RANKL signaling, especially in the secondary spongiosa.
Study Design: Prospective cross-sectional study. Objectives: To investigate the timing of deep vein thrombosis (DVT) onset secondary to spinal cord injury without anticoagulant therapies. Setting: Spinal Cord Injury Center in Hokkaido, Japan. Methods: Between November 2012 and June 2013, patients with spinal cord injury who were admitted to our hospital within 1 day after the injury and treated surgically within 24 h underwent a neurological examination, leg vein ultrasonography and D-dimer test 1, 3, 7, 14 and 28 days after surgery. All patients received treatment with intermittent pneumatic compression and elastic stockings, but without any anticoagulant. Results: DVT developed in 12 patients (11 men and 1 women), with a mean age of 62.2 years (range, 41-80 years; mean age of total sample, 63.2 years (range, 25-78 years)), all distal to the popliteal vein. DVT occurred more often with a more severe paralysis (66.3%, AIS A and B). The median (± standard error) length of time from the operation to DVT detection was 7.5 ± 2.2 days. The mean D-dimer level upon DVT detection was 14.6 ± 11.8 μg ml − 1 , with no significant differences between those who developed DVT and those who did not at any of the time points. Conclusion: These results suggest that DVT can develop at the very-acute stage of spinal cord injury and the incidence increases with a more severe paralysis. DVT detection was more reliable with ultrasonography, which should be used with DVT-preventive measures, beginning immediately after the injury, for the management of patients with spinal cord injury. INTRODUCTIONDeep vein thrombosis (DVT) is one of the most dangerous complications of a spinal cord injury. DVT has a high incidence in patients with spinal cord injury as compared with patients with other diseases 1 with a high mortality rate if complicated by pulmonary embolism. 2 Although prevention, early detection and timely treatment of DVT are important during the management of patients with spinal cord injury, the timing of DVT onset secondary to a spinal cord injury has not yet been determined. In order to clarify these problems, this study aimed to investigate the timing of DVT onset by prospectively analyzing the patients immediately after a spinal cord injury.
IMPORTANCEThe optimal management for acute traumatic cervical spinal cord injury (SCI) is unknown. OBJECTIVE To determine whether early surgical decompression results in better motor recovery than delayed surgical treatment in patients with acute traumatic incomplete cervical SCI associated with preexisting canal stenosis but without bone injury. DESIGN, SETTING, AND PARTICIPANTSThis multicenter randomized clinical trial was conducted in 43 tertiary referral centers in Japan from December 2011 through November 2019. Patients aged 20 to 79 years with motor-incomplete cervical SCI with preexisting canal stenosis (American Spinal Injury Association [ASIA] Impairment Scale C; without fracture or dislocation) were included. Data were analyzed from September to November 2020. INTERVENTIONS Patients were randomized to undergo surgical treatment within 24 hours after admission or delayed surgical treatment after at least 2 weeks of conservative treatment. MAIN OUTCOMES AND MEASURES The primary end points were improvement in the mean ASIA motor score, total score of the spinal cord independence measure, and the proportion of patients able to walk independently at 1 year after injury. RESULTS Among 72 randomized patients, 70 patients (mean [SD] age, 65.1 [9.4] years; age range, 41-79 years; 5 [7%] women and 65 [93%] men) were included in the full analysis population (37 patients assigned to early surgical treatment and 33 patients assigned to delayed surgical treatment).Of these, 56 patients (80%) had data available for at least 1 primary outcome at 1 year. There was no significant difference among primary end points for the early surgical treatment group compared with the delayed surgical treatment group (mean [SD] change in ASIA motor score, 53.7 [14.7] vs 48.5 [19.1]; difference, 5.2; 95% CI, −4.2 to 14.5; P = .27; mean [SD] SCIM total score, 77.9 [22.7] vs 71.3 [27.3]; P = .34; able to walk independently, 21 of 30 patients [70.0%] vs 16 of 26 patients [61.5%]; P = .51). A mixed-design analysis of variance revealed a significant difference in the mean change in ASIA motor scores between the groups (F 1,49 = 4.80; P = .03). The early surgical treatment group, compared with the delayed surgical treatment group, had greater motor scores than the delayed surgical treatment group at 2 weeks (mean [SD] score, 34.2 [18.8] vs 18.9 [20.9]), 3 months (mean [SD] score, 49.1 [15.1] vs 37.2 [20.9]), and 6 months (mean [SD] score, 51.5 [13.9] vs 41.3 [23.4]) after injury. Adverse events were common in both groups (eg, worsening of paralysis, 6 patients vs 6 patients; death, 3 patients vs 3 patients).
The selective estrogen receptor modulator raloxifene is therapeutically beneficial for postmenopausal connective tissue degradation, such as osteoporosis, vascular sclerosis, and dermal degradation; however, the effects of raloxifene on postmenopausal tendon metabolism have not been clarified. In this study, we investigated the effects of raloxifene analogue (LY117018) on cell proliferation and collagen metabolism using cultured rat Achilles tendon fibroblasts. 17beta-Estradiol (E(2); 10(-11)-10(-9) M) and LY117018 (10(-9)-10(-7) M) had no significant effects on tendon fibroblast proliferation, based on a BrdU (5-bromo-2'-deoxyuridine) incorporation assay (24 hr) and a WST-8 colorimetric assay (2 or 6 days). Neither E(2) nor LY117018 significantly altered the expression of type I collagen, which is a main component of the tendon extracellular matrix (ECM), whereas both E(2) and LY117018 significantly increased the expression of matrix metalloproteinase (MMP)-13, which is responsible for tendon collagen degradation in rat. Also, both E(2) and LY117018 increased the expression of type III collagen and elastin, which are minor components of tendon ECM, but are considered to govern the elastic properties of tendons. These changes in collagen and MMP induced by either E(2) or LY117018 were attenuated by the estrogen receptor alpha blocker ICI 182,780. The results of this study suggest that postmenopausal estrogen deficiency might downregulate tendon collagen turnover and decrease tendon elasticity. Further, raloxifene treatment might restore these changes to premenopausal levels.
The objective of this study was to investigate the effect of landiolol on the cardiovascular responses to emergence from anesthesia and tracheal extubation. Fifty-nine patients without cardiovascular disorders who were scheduled for tympanoplasty were randomly allocated to receive a loading dose of landiolol at 0.125 mg x kg(-1) x min(-1) for 1 min, followed by an infusion at 0.01 mg x kg(-1) x min(-1) (group L1), 0.02 mg x kg(-1) x min(-1) (group L2), 0.03 mg x kg(-1) x min(-1) (group L3), or 0.04 mg x kg(-1) x min(-1) (group L4). At the end of surgery, sevoflurane and nitrous oxide were discontinued, and landiolol was started. The mean arterial pressure (MAP), heart rate (HR), and rate pressure product (RPP) in the four groups were compared before anesthesia induction, just after extubation, 5 min after extubation, 10 min after extubation, and at discharge from the operating room. Just after extubation compared with the baseline, the MAP increased significantly in all groups; the HR increased in groups L1 and L2; and the RPP increased in all groups, except for group L4. Continuous administration of landiolol, at 0.03 or 0.04 mg x kg(-1) x min(-1), may prevent the increases in HR and RPP, respectively, that occur at the emergence from anesthesia and tracheal extubation.
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