Inflammation intensity-dependent expression of osteoinductive Wnt proteins is a key link between inflammation and ectopic new bone formation in AS. Activation of both the canonical Wnt/β-catenin and noncanonical Wnt/PKCδ pathways is required for inflammation-induced new bone formation.

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OBJECT The aim of this study was to evaluate the effects of rod stiffness and implant density on coronal and sagittal plane correction in patients with main thoracic curve adolescent idiopathic scoliosis (AIS). METHODS The authors conducted a retrospective study of 77 consecutive cases involving 56 female and 21 male patients with Lenke Type 1 main thoracic curve AIS who underwent single-stage posterior correction and instrumented spinal fusion with pedicle screw fixation between July 2009 and July 2012. The patients' mean age at surgery was 15.79 ± 3.21 years. All patients had at least 1 year of follow-up. Radiological parameters in the coronal and sagittal planes, including Cobb angle of the major curve, side-bending Cobb angle of the major curve, thoracic kyphosis (TK), correction rates, and screw density, were measured and analyzed. Screw densities (calculated as number of screws per fusion segment × 2) of < 0.60 and ≥ 0.60 were defined as low and high density, respectively. Titanium rods of 5.5 mm and 6.35 mm diameter were defined as low and high stiffness, respectively. Patients were divided into 4 groups based on the type of rod and density of screw placement that had been used: Group A, low-stiffness rod with low density of screw placement; Group B, low-stiffness rod with high density of screw placement; Group C, high-stiffness rod with low density of screw placement; Group D, high-stiffness rod with high density of screw placement. RESULTS The mean coronal correction rate of the major curve, for all 77 patients, was (81.45% ± 7.51%), and no significant difference was found among the 4 groups (p > 0.05). Regarding sagittal plane correction, Group A showed a significant decrease in TK after surgery (p < 0.05), while Group D showed a significant increase (p < 0.05); Group B and C showed no significant postoperative changes in TK (p > 0.05). The TK restoration rate was highest in Group D and lowest in Group A (A, −39.32% ± 7.65%; B, −0.37% ± 8.25%; C, −4.04% ± 6.77%; D, 37.59% ± 8.53%). Screw density on the concave side was significantly higher than that on the convex side in all the groups (p < 0.05). CONCLUSIONS For flexible main thoracic curve AIS, both rods with high stiffness and those with low stiffness combined with high or low screw density could provide effective correction in the coronal plane; rods with high stiffness along with high screw density on the concave side could provide better outcome with respect to sagittal TK restoration.

Bone morphogenetic protein 2 (BMP-2) plays a critical role in the differentiation of precursor cells and has been approved for clinical application to induce new bone formation. To date, unexpectedly high doses of recombinant BMP-2 have been required to induce bone healing in humans. Thus, enhancing cellular responsiveness to BMP-2 potentially has critically important clinical implications. BMP responsiveness may be modulated in part by cross-talk with other signaling pathways, including mitogen-activated protein kinases (MAPKs). c-Jun NH 2 -terminal kinase (JNK) is a MAPK that has been reported to be required for late-stage differentiation of preosteoblasts and BMP-2-induced differentiation of preosteoblasts and pleuripotent cells. In this study we determined that MC3T3-E1-clone 24 cells (MC-24) can be induced by BMP-2 to differentiate into mineralizing osteoblast cultures. Using this inducible system, we employed both JNK loss-of-function and gain-of-function reagents to make three key observations: (1) JNK is required for phosphorylation of Smad1 by BMP-2 and subsequent activation of Smad1 signaling and osteoblast differentiation, (2) JNK1, but not JNK2, is required for BMP-2-induced formation of mineralized nodules, and (3) JNK1 activation decreases binding of inhibitory Smad6 to the type I BMP receptor (BMPR-I) and reciprocally increases binding of Smad1, both observations that would increase responsiveness to BMP-2. Understanding this and other pathways that lead to increased cellular responsiveness to BMPs could greatly aid more cost-effective and safe clinical delivery of these important molecules. ß

Background: The risk of relapse in major depressive disorder (MDD) is associated with high worldwide disease burden. Cognitive behavioral therapy (CBT) and its modifications might be effective in relapse prevention. The aim of this review was to evaluate the efficacy of these treatments for reducing relapse of MDD. Methods: The retrieval was performed in the databases of MEDLINE via Pubmed, EMBASE and PsycINFO via OVID, The Cochrane Library and four Chinese databases. Clinical trials registry platforms and references of relevant articles were retrieved as well. Hazard ratio (HR) and corresponding 95% confidence interval (CI) were used to pool evidences. Results: A total of 16 eligible trials involving 1945 participants were included. In the first 12 months, CBT was more efficacious than control in reducing the risk of developing a new episode of depression for MDD patients in remission (HR:0.50, 95%CI:0.35-0.72, I 2 = 11%). Mindfulness-based cognitive therapy (MBCT) was more efficacious than control only among patients with 3 or more previous depressive episodes (HR:0.46, 95%CI:0.31-0.70, I 2 = 38%). Besides, compared with maintenance antidepressant medication (m-ADM), MBCT was a more effective intervention (HR:0.76, 95%CI:0.58-0.98, I 2 = 0%). These positive effects might be only maintained at two and nearly 6 years follow up for CBT. Conclusion: The use of CBT for MDD patients in remission might reduce risk of relapse. Besides, the effect of MBCT was moderated by number of prior episodes and MBCT might only be effective for MDD patients with 3 or more previous episodes. Further exploration for the influence of previous psychological intervention is required.

Growing evidence shows that the inhibitory effect of inflammatory cytokines on new bone formation by osteogenic precursor cells is a critical cause of net bone‐density reduction. Melatonin has been proven to be a potential therapeutic candidate for osteoporosis. However, whether it is capable of antagonizing the suppressing effect of inflammatory cytokines on osteogenic precursor cells is so far elusive. In this study, using the cell culture system of human bone marrow stromal cells and MC3T3‐E1 preosteoblasts, we recorded the following vital observations that provided insights of melatonin‐induced bone formation: 1) melatonin induced bone formation in both normal and inflammatory conditions; 2) Wnt4 was essential for melatonin‐induced bone formation in inflammatory stimulation; 3) melatonin‐ and Wnt4‐induced bone formation occurred via activation of β‐catenin and p38‐JNK MAPK pathways by interaction with a distinct frizzled LDL receptor‐related protein complex; 4) melatonin suppressed the inhibitory effect of NF‐κB on osteogenesis in a Wnt4‐dependent manner; and 5) melatonin induced Wnt4 expression through the ERK1/2‐Pax2‐Egr1 pathway. In summary, we showed a novel mechanism of melatonin‐induced bone formation in an inflammatory environment. Melatonin‐induced Wnt4 expression is essential for its osteoinductive effect and the inhibitory effect of NF‐κB on bone formation. Our novel findings may provide useful information for its potential translational application.—Li, X., Li, Z., Wang, J., Li, Z., Cui, H., Dai, G., Chen, S., Zhang, M., Zheng, Z., Zhan, Z., Liu, H. Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment. FASEB J. 33, 10126–10139 (2019). http://www.fasebj.org

Study Design A multinational, multiethnic, cross-sectional image-based study was performed in 33 institutions, representing 10 countries, which were part of the AOSpine Asia Pacific Research Collaboration Consortium. Objective Lumbar facet joint orientation has been reported to be associated with the development of degenerative spondylolisthesis (DS). The role of ethnicity regarding facet joint orientation remains uncertain. As such, the following study was performed across a wide-ranging population base to assess the role of ethnicity in facet joint orientation in patients with DS in the Asia Pacific region. Methods Lateral standing X-rays and axial magnetic resonance imaging scans were obtained for patients with lumbar DS. The DS parameters and facet joint angulations were assessed from L3–S1. Sex, age, body mass index (BMI), and ethnicity were also noted. Results The study included 371 patients with known ethnic origin (mean age: 62.0 years; 64% males, 36% females). The mean BMI was 25.6 kg/m2. The level of DS was most prevalent at L4–L5 (74.7%). There were 28.8% Indian, 28.6% Japanese, 18.1% Chinese, 8.6% Korean, 6.5% Thai, 4.9% Caucasian, 2.7% Filipino, and 1.9% Malay patients. Variations in facet joint angulations were noted from L3 to S1 and between patients with and without DS (p < 0.05). No differences were noted with regards to sex and overall BMI to facet joint angulations (p > 0.05); however, increasing age was found to increase the degree of angulation throughout the lumbar spine (p < 0.05). Accounting for age and the presence or absence of DS at each level, no statistically significant differences between ethnicity and degree of facet joint angulations from L3–L5 were noted (p > 0.05). Ethnic variations were noted in non-DS L5–S1 facet joint angulations, predominantly between Caucasian, Chinese, and Indian ethnicities (p < 0.05). Conclusions This study is the first to suggest that ethnicity may not play a role in facet joint orientation in the majority of cases of DS in the Asia-Pacific region. Findings from this study may facilitate future comparative studies in other multiethnic populations. An understanding of ethnic variability may assist in identifying those patients at risk of postsurgical development or progression of DS. This study also serves as a model for large-scale multicenter studies across different ethnic groups and cultural boundaries in Asia.

Analgesic overuse often happens to migraine patients, especially chronic migraineurs, and migraine has been demonstrated to be associated with white matter lesions (WMLs). The aim of this study was to investigate the relationship between medication overuse headache (MOH) and WMLs in chronic migraine (CM) patients. Subjects were enrolled and divided into three groups: healthy controls, CM without MOH (CMwoMOH), and CM with MOH (CM-MOH). Most of the CM patients used non-steroidal anti-inflammatory drugs (NSAIDs) as acute headache medications. All the participants underwent magnetic resonance imaging scans and images were obtained for WML evaluation with semiquantitative scales. One hundred and forty-one participants were included, 45 of them for controls, 38 for CMwoMOH, and 58 for CM-MOH. In women, CMwoMOH patients had a higher prevalence of high WML load compared with controls and CM-MOH patients. In men, however, all the study groups showed no differences in the prevalence of high WML load. CMwoMOH women had increased risks of high deep white matter lesion (DWML) load compared with controls, while they had no risks of high periventricular white matter lesion (PVWML) load. CM-MOH women had no risks of high DWML load, but they had reduced risks of high PVWML load. The association of CM-MOH with high WML load in women was not changed when compared with CMwoMOH. Age was independently associated with high WML load among women. These data suggest that MOH caused by NSAIDs is not a risk factor for WMLs. Rather, NSAID overuse probably protects MOH patients from WMLs through anti-inflammatory effects.