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Heterotopic ossification is abnormal bone formation in soft tissues that occurs primarily after injury and major surgery. This condition often causes local pain and limits joint motion in the affected limb. Currently, there is no effective treatment or prophylaxis for this condition other than surgical removal of the lesion. Recent studies suggest that retinoic acid receptor (RAR) agonists are effective in suppressing heterotopic ossification in patients with Fibrodysplasia Ossificans Progressiva, a congenital disorder characterized by progressive ossification of soft tissue, by suppressing the aberrant differentiation of mesenchymal stem cells in muscle. In this study, we aimed to elucidate the potential use of RAR agonists in suppressing injury-induced ectopic tendon ossification using a mouse Achilles tenotomy model. Contrary to our initial hypothesis, administration of RAR agonists throughout the experimental period (5 weeks) accelerated ectopic tendon ossification in our model. Of note, in vitro differentiation experiments using tendon-derived mesenchymal stem cells revealed that RAR agonists play opposing roles in osteogenic and chondrogenic differentiation, promoting the former and suppressing the latter. Indeed, we found that RAR agonists suppressed tendon ossification when administered before cartilage nodule formation, but promoted it when administered after. These results suggest that RAR agonists have a dual and opposing effect on tendon ectopic ossification, depending on the duration and timing of their administration. Our data may provide a basis for further investigation of the potential use of RAR agonists in the treatment of injury-induced heterotopic ossification., (© 2024 Orthopaedic Research Society.)

Background Context: SI-6603 (condoliase) is a chemonucleolytic agent approved in Japan in 2018 for the treatment of lumbar disc herniation (LDH) associated with radicular leg pain. Condoliase, a mucopolysaccharidase with high substrate specificity for glycosaminoglycans (GAGs), offers a unique mechanism of action through the degradation of GAGs in the nucleus pulposus. As LDH management is currently limited to conservative approaches and surgical intervention, condoliase could offer a less invasive treatment option than surgery for patients with LDH., Purpose: The Discovery 6603 study (NCT03607838) evaluated the efficacy and safety of a single-dose injection of SI-6603 (condoliase) vs sham for the treatment of radicular leg pain associated with LDH., Study Design/setting: A randomized, double-blind, sham-controlled, phase 3 study conducted across 41 sites in the United States., Patient Sample: Male and female participants (N=352; aged 30-70 years) with contained posterolateral LDH and unilateral radiculopathy/radicular leg pain for greater than 6 weeks., Outcome Measures: The primary endpoint was the change from baseline (CFB) in average worst leg pain score at 13 weeks, assessed using the 100-mm visual analogue scale. Key secondary endpoints were CFB in average worst leg pain score at 52 weeks, herniation volume at 13 weeks, and Oswestry Disability Index (ODI) score at 13 weeks. Safety evaluations included adverse events (AEs) and imaging findings., Methods: Participants were randomized 1:1 to receive a single intradiscal injection of condoliase (1.25 units) or sham injection followed by 52 weeks of observation. The primary and key secondary endpoints were assessed using a mixed model for repeated measures (MMRM) analysis and a protocol-specified multiple imputation (MI) sensitivity analysis on the modified intention-to-treat (mITT) population. A prespecified serial gatekeeping algorithm was used for multiple comparisons. Safety endpoints included AEs, laboratory tests, vital signs, imaging (by X-ray and magnetic resonance imaging [MRI]), and occurrence of posttreatment lumbar surgery., Results: Of the 352 randomized participants, 341 constituted the mITT population (condoliase n=169; sham n=172) and the safety population (condoliase n=167; sham n=174). For the primary endpoint, the condoliase group showed significantly greater improvement in CFB in worst leg pain at Week 13 (least squares mean [LSM] CFB: -41.7) compared with sham injection (-34.2; LSM difference: -7.5; 95% confidence interval [CI]: -14.1, -0.9; p=.0263) based on the MMRM analysis. CFB in worst leg pain at Week 52 favored condoliase vs sham, but the difference was not statistically significant (p=.0558), which halted the serial gatekeeping testing algorithm and dictated that the CFB in herniation volume and ODI scores at Week 13 would be considered nonsignificant, regardless of their p-values. Treatment group differences in CFB in herniation volume and ODI score favored the condoliase group vs sham at all timepoints. The MI sensitivity analysis showed differences in CFB in worst leg pain at Week 13 (p=.0223) and Week 52 (p=.0433) in favor of the condoliase group. Treatment-emergent AEs (TEAEs) were more common in the condoliase group (≥1 TEAE: 71.9%; ≥1 treatment-related TEAE: 28.1%) compared with the sham group (≥1 TEAE: 60.3%; ≥1 treatment-related TEAE: 10.3%). Of the TEAEs, spinal MRI abnormalities and back pain occurred most frequently. No treatment-related serious AEs occurred., Conclusions: Condoliase met its primary endpoint of significantly improving radicular leg pain at Week 13 and was generally well tolerated in patients with LDH. Chemonucleolysis with condoliase has the potential to provide a less invasive treatment option than surgery for those unresponsive to conservative treatment strategies., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

While remarkable progress has been made in the development of peptide medicines, many problems related to peptide synthesis remain unresolved. Previously, we reported electrochemical peptide synthesis using a phosphine as a potentially recyclable coupling reagent. However, there was room for improvement from the point of view of reaction efficiency, especially in the carboxylic acid activation step and the peptide bond formation step. To overcome these challenges, we searched for the optimal phosphine. Among phosphines with various electronic properties, we found that electron-rich triaryl phosphines improved the reaction efficiency. Consequently, we successfully performed electrochemical peptide synthesis on sterically hindered and valuable amino acids. We also synthesized oligopeptides that were challenging with our previous method. Finally, we examined the effect of substituents on the phosphine cations, and gained some insights into reactivity, which will aid researchers designing reactions involving phosphine cations., (© 2024 Wiley-VCH GmbH.)

Traumatic heterotopic ossification is a condition in which extraskeletal bone formation occurs in soft tissues after injury. It most commonly occurs in patients who had major orthopedic surgery and in those with severe extremity injuries. The lesion causes local pain and can impair motor function of the affected limb, but there is currently no established prophylaxis or treatment for this condition. In this study, we show that immobilization at an early stage of the inflammatory response after injury can attenuate ossification formation in a murine Achilles tenotomy model. Gene expression analysis revealed a decrease in the expression of Tnf and an increase in the expression of Mkx, which encodes one of the master regulators of tendon differentiation, Mohawk. Notably, we found that TNF-α suppressed the expression of Mkx transcripts and accelerated the osteogenic differentiation of tendon-derived mesenchymal stem cells (MSCs), suggesting that TNF-α acts as a negative regulator of Mkx transcription. Consistent with these findings, pharmaceutical inhibition of TNF-α increased the expression of Mkx transcripts and suppressed bone formation in this mouse model. These findings reveal the previously unrecognized involvement of TNF-α in regulating tendon MSC fate through suppression of Mkx expression and suggest that TNF-α is a potential target for preventing traumatic heterotopic ossification., (© 2024 Orthopaedic Research Society.)

The LBX1 gene is located near a single nucleotide polymorphism that is highly associated with susceptibility to adolescent idiopathic scoliosis and is considered one of the strongest candidate genes involved in the pathogenesis of this condition. We have previously found that loss of LBX1 from skeletal muscle results not only in spinal deformity but also in lean body mass, suggesting a potential role for LBX1 in energy metabolism. The purpose of the present study was to test this hypothesis by analyzing the phenotype of mice lacking LBX1 in skeletal muscle with a focus on energy metabolism. We found that loss of LBX1 rendered mice more resistant to high-fat diet-induced obesity, despite comparable food intake between mutant and control mice. Notably, the mutant mice exhibited improved glucose tolerance, increased maximal aerobic capacity, and higher core body temperature compared to control mice. In addition, we found that overexpression of LBX1 decreased glucose uptake in cultured cells. Taken together, our data show that LBX1 functions as a negative regulator of energy metabolism and that loss of LBX1 from skeletal muscle increases systemic energy expenditure resulting in lean body mass. The present study thus suggests a potential association between LBX1 dysfunction and lean body mass in patients with adolescent idiopathic scoliosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nakagawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

"Cysts of the ligamentum flavum (cysts-LF)" is the term for non-neoplastic cystic lesion involving LF. The aim of the present study was to elucidate the histopathological characteristics and pathogenesis of "cysts-LF". Herein, we defined cysts-LF as spinal cysts containing degenerative LF components. From archival cases, we investigated 18 symptomatic cysts-LF surgically removed from 18 patients (13 males and five females; median age 68.5 years [range, 42-86 years]). The elastic fibers of LF components in the wall were separated and/or torn, and cyst walls were accompanied by chondroid metaplasia (17 cases), myxoid changes (13 cases), ossification (11 cases), amyloid deposits (14 cases), hemosiderosis (six cases), granular/smudgy calcification (four cases), synovial cell linings (three cases), and severe inflammatory infiltrates (one case). These histologic features of our cysts-LF were shared by previously reported "cysts-LF." Fourteen cysts-LF demonstrated vascular stenosis/occlusion, and eight showed thick hyalinized vessels, suggesting local circulatory insufficiency. Eight cases (44%) exhibited lipomembranous fat necrosis, accompanied by hyalinized vascular changes (p = 0.003). Ischemic conditions were observed in nearly half of the present cysts-LF, and may be one of the main contributing factors for the formation of cysts-LF, via degeneration and cystic changes in the LF., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: Chemonucleolysis with condoliase significantly improved clinical symptoms in patients with lumbar disc herniation. We evaluated the surgical intervention rate and outcomes for >1 year after condoliase treatment., Methods: This was a follow-up study of patients who received condoliase or placebo in two previous randomized, placebo-controlled clinical trials with 1-year follow-ups. A post-treatment surgery survey and on-site examination were administered and patients' data from the clinical trial records and additional interview data were analyzed to evaluate the surgical intervention rate. Patients' lumbar disease symptoms, Oswestry Disability Index, and imaging features were evaluated., Results: Among the patients (condoliase, n = 228; placebo, n = 128) enrolled in the clinical trials, additional post-treatment surgery data were available for 231 patients after the clinical trials ended, and 179 patients underwent post-trial examinations, at least 5 years and 17 months after the end of the clinical trials. The surgical intervention rate in the placebo and condoliase groups was 20.7% (95% confidence interval: 14.2-29.7) and 13.4% (95% confidence interval: 8.8-20.2), respectively. The mean change in Oswestry Disability Index score from pre-injection in placebo and condoliase groups was -24.7 ± 15.0 and -32.7 ± 18.6 (between-group difference: -8.0 ± 17.3; 95% confidence interval: -13.2 to -2.7). Modic Type 2 changes were observed, particularly in the condoliase group. No relationship between lumbar disease symptoms and change in imaging features was found., Conclusions: This follow-up study more than 1 year revealed no new safety concerns of condoliase. However, because the study had several limitations, such as large loss of follow-up, further research is needed., Competing Interests: Declaration of competing interest This study was funded by Seikagaku Corporation. Yukihiro Matsuyama and Kazuhiro Chiba received consulting fee from Seikagaku Corp. UMIN: 000015221., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Adolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated., Material and Methods: Mendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese., Results: Significant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10 -3 ), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10 -3 ) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10 -3 ), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI., Conclusions: Our Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Otomo, Khanshour, Koido, Takeda, Momozawa, Kubo, Kamatani, Herring, Ogura, Takahashi, Minami, Uno, Kawakami, Ito, Sato, Watanabe, Kaito, Yanagida, Taneichi, Harimaya, Taniguchi, Shigematsu, Iida, Demura, Sugawara, Fujita, Yagi, Okada, Hosogane, Kono, Nakamura, Chiba, Kotani, Sakuma, Akazawa, Suzuki, Nishida, Kakutani, Tsuji, Sudo, Iwata, Inami, Wise, Kochi, Matsumoto, Ikegawa, Watanabe and Terao.)

Over the past few decades, the clinical outcomes of patients with cancer have significantly improved mostly owing to the development of effective chemotherapeutic treatments. However, chronic health conditions such as bone mass loss and risk of fragility fractures caused by chemotherapy have also emerged as crucial issues in patients treated for cancer. In this study, we aimed to understand the effect of eribulin mesylate (ERI), a microtubule-targeting agent currently used to treat metastatic breast cancer and certain subtypes of advanced sarcomas, on bone metabolism in mice. The administration of ERI reduced bone mass in mice, mainly by promoting osteoclast activity. Gene expression analysis of skeletal tissues revealed no change in the expression levels of the transcripts for RANK ligand, one of the master regulators of osteoclastogenesis; however, the transcript levels of osteoprotegerin, which neutralizes RANK ligand, were significantly reduced in ERI-treated mice compared with those in vehicle-treated controls, indicating a relative increase in RANK ligand availability after ERI treatment. In line with the increased bone resorption in ERI-treated mice, we found that zoledronate administration effectively suppressed bone loss in these mice. These results reveal a previously unrecognized effect of ERI on bone metabolism and suggest the application of bisphosphonates for patients with cancer undergoing treatment with ERI., Competing Interests: All authors declare that they have no conflicts of interests., (© 2023 The Authors.)

LBX1 is a gene located near a single-nucleotide polymorphism, rs11190870, which is highly associated with susceptibility to adolescent idiopathic scoliosis. However, the potential involvement of LBX1 in the etiology of this spinal deformity has not been elucidated. In this study, we aimed to determine whether the lack of LBX1 in skeletal muscle results in spinal deformities in mice. We generated mutant mice in which the Lbx1 allele was conditionally excised under the control of a human muscle actin promoter. Mice lacking LBX1 from the skeletal muscle were fertile and available. The mutant mice had hypoplastic forelimbs and weighed less than control animals, but otherwise, there were no overt anomalies. The mice did not exhibit a scoliosis-like spinal deformity; however, they developed moderate kyphosis as they grew old. These observations indicated that LBX1 is involved in limb development and potentially in the maintenance of spinal curvature/alignment in mice., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Antifouling agents with low toxicity are in high demand for sustaining marine industries and the environment. This study aimed to synthesize 15 isothiocyanates derived from β-citronellol and evaluate their antifouling activities and toxicities against cypris larvae of the barnacle Amphibalanus amphitrite. The synthesized isothiocyanates exhibited effective antifouling activities (EC 50 =0.10-3.33 μg mL -1 ) with high therapeutic ratios (LC 50 /EC 50 >30). Four isothiocyanates with an amide or isocyano group showed great potential as effective antifouling agents (EC 50 =0.10-0.32 μg mL -1 , LC 50 /EC 50 =104-833). The enantiomers of the isothiocyanates only slightly differed in their antifouling activities. These results may serve as a basis for further research and development of β-citronellol-derived isothiocyanates as effective low-toxic antifouling agents. To the best of our knowledge, this study is the first to report the antifouling activities of isothiocyanates derived from accessible natural products., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Adolescent idiopathic scoliosis (AIS) is a serious health problem affecting 3% of live births all over the world. Many loci associated with AIS have been identified by previous genome wide association studies, but their biological implication remains mostly unclear. In this study, we evaluated the AIS-associated variants in the 7p22.3 locus by combining in silico, in vitro, and in vivo analyses. rs78148157 was located in an enhancer of UNCX, a homeobox gene and its risk allele upregulated the UNCX expression. A transcription factor, early growth response 1 (EGR1), transactivated the rs78148157-located enhancer and showed a higher binding affinity for the risk allele of rs78148157. Furthermore, zebrafish larvae with UNCX messenger RNA (mRNA) injection developed body curvature and defective neurogenesis in a dose-dependent manner. rs78148157 confers the genetic susceptibility to AIS by enhancing the EGR1-regulated UNCX expression. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

Background: The clinical outcomes of patients with pediatric cancer have significantly improved over the past few decades. However, the treatments are often highly intensive and can advertently pose a risk for developing various health conditions, including bone mass loss and fragility fractures. Since patients with bone malignancies, such as osteosarcoma (OS) and Ewing's sarcoma (ES), require musculoskeletal surgery as well as chemotherapy, OS/ES survivors are potentially at even greater risk of developing these musculoskeletal conditions than those with other types of cancer. However, these issues in OS/ES survivors are often overlooked by clinicians treating childhood cancers. Thus, this scoping review was designed and conducted to better understand the bone health conditions in OS/ES survivors., Design: We conducted a literature search and included the studies that describe bone mineral density in association with bone health in OS/ES survivors for analysis. Data regarding patients' demographic, diagnosis, bone mineral density, laboratory examinations, and incidence of fractures were extracted and evaluated., Results: We found that almost half of OS/ES survivors have bone mass deficit and that several factors (such as a frailer physique and younger age at diagnosis) are potentially associated with low bone mass in OS/ES survivors. On the other hand, due to a paucity of information currently available, we could not determine whether long-term OS/ES survivors would ultimately regain bone mass or be at a greater risk of fragility fractures., Conclusions: This scoping review reveals a previously unappreciated knowledge gap in our understanding of bone health conditions in OS/ES survivors and raises awareness among clinicians and care providers of this condition that OS/ES patients may encounter after successful treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest.

Background: Condoliase has been used in Japan to treat patients with lumbar disc herniation by its injection into the nucleus pulposus. The injection of condoliase together with contrast media is prohibited; because there are no data whether contrast media have any effect on condoliase activity. This study aimed to elucidate the effects of contrast media on condoliase activity., Methods: Condoliase with chondroitin sulfate (CS) and without CS were mixed with various contrast media (nonionic [iohexol or iotrolan]; ionic [amidotrizoic acid]). (i) The mixtures with CS were incubated at 37°C; (ii) the mixtures without CS were stored at 24°C for 60 min, followed by addition of CS to assess condoliase activity by measuring the amount of N -acetylhexosamines enzymatically cleaved from CS using Morgan - Elson method., Results: (i) In the presence of CS, the ionic contrast media reduced condoliase activity within 10 min in a dose-dependent manner, and the nonionic contrast media had no effect on condoliase activity for at least 120 min. (ii) In the absence of CS, the ionic contrast media almost completely inactivated condoliase within 15 min, and the nonionic contrast media also reduced condoliase activity; the residual activity was 65% with iotrolan and 35% with iohexol at 60 min., Conclusions: The ionic contrast media significantly reduced condoliase activity regardless of presence or absence of CS. Although the nonionic contrast media did not affect condoliase activity in the presence of CS, it reduced activity in the absence of CS. Mixing condoliase with contrast media, especially ionic type contrast media, should be avoided., Competing Interests: Ippei Watanabe and Taiichi Shirogane are employees of Seikagaku Corp. This study was conducted at Seikagaku Corp. Yukihiro Matsuyama and Kazuhiro Chiba received consulting fee from Seikagaku Corp., (© 2022 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Oxidative biaryl coupling of aryls with different electronic features generally fails. However, this has not been systematically studied via theoretical analysis, and thus, the crucial factor governing coupling efficiency remains unclear. Herein, we propose that the "oxidation potential gap (ΔE ox )" is a key parameter in predicting the efficiency of an intramolecular oxidative coupling reaction, with ΔE ox defined as a difference in the oxidation potentials of the relevant aromatic rings. Our experimental and computational analyses revealed that the efficiency of an aromatic intramolecular coupling reaction correlates with the activation energy (ΔE ≠ ) of C-C bond formation of the radical cation intermediates. Furthermore, ΔE ≠ correlates with ΔE ox . Therefore, we demonstrate the tuning of ΔE ox by attaching cleavable extra electron-donating/-withdrawing groups, enabling the rational synthesis of a phenanthridone skeleton using aromatic rings with an electronic gap., (© 2022 Wiley-VCH GmbH.)

Introduction: Prostate cancer often forms osteoblastic lesions that appear as a high-dense shadow upon X-ray. Although the lesions may seem to increase bone strength, pathological fracture occurs in one in four patients with prostate cancer. The aim of this study is to elucidate the factors that may increase the risk of pathological fracture in patients with prostate cancer metastases in the proximal femur by analyzing computed tomography data., Materials and Methods: Computed tomography data of the femur of 62 prostate cancer patients were retrospectively analyzed. The patients were divided into three groups based on the presence or absence of femoral metastatic lesions and pathological fracture. Surgical specimens of the proximal femur collected from patients who had a pathological fracture were histologically analyzed., Results: Bone density in the marrow area was increased in all cases with metastases compared with those with no metastases. Contrarily, the cortical bone density at the medial trochanter region was significantly lower in patients who had pathological fractures in the proximal femur than those who did not. Accordingly, histological analysis of the surgical specimens revealed that the affected cortical bone was osteopenic without any apparent new bone formation., Conclusion: These results indicate that prostate cancer is less effective in inducing bone formation in the cortex than in the marrow and that the decrease in the cortical bone density at the medial trochanter region leads to an increased risk of pathological fracture. Therefore, a previously undocumented risk factor for pathological fracture in prostate cancer patients is presented., (© 2022. The Japanese Society Bone and Mineral Research.)

Background: Postoperative lymphopenia (PL) after spine surgery is reported to be an indicator of surgical-site infection (SSI). PL without SSI is often encountered, resulting in a treatment dilemma. We focused on PL, so as to improve the accuracy of detecting SSI., Methods: In total, 329 patients underwent spine surgery, including nine patients presenting with SSI. The complete blood cell counts, differential counts, and C-reactive protein (CRP) level were measured pre-surgery and on postoperative days 2, 7, and 14. The relationships between PL and SSI were evaluated, and PL and non-PL conditions were compared among all cases. We then divided the patients into two groups: PL and non-PL, and determined the useful serological markers using receiver operating characteristic curves., Results: Sixty-one patients presented with PL, including four with SSI. However, PL was not directly suggested as a biomarker of SSI (p = 0.067). We revealed PL as a risk factor for SSI (p = 0.004, Odds ratio: 7.54). Among all cases, the lymphocyte count and CRP level differed significantly between the PL and non-PL groups at all perioperative time-points. The white blood cell count, neutrophil count, and CRP levels on postoperative day 7 significantly differed between the SSI and non-SSI cases in the PL group. The area under the curve (AUC) for CRP was greater than that of the other parameters. The neutrophil count was only effective as a marker in the non-PL group. The combination of two cutoff values (CRP: 3.7 mg/dL (PL group) and neutrophil count: 6172/μL (non-PL group)) presented high specificity (87.2%) and sensitivity (88.9%), while only one cutoff value (CRP: 2.9 mg/dL) had a specificity of 77.4% and sensitivity of 77.8%., Conclusions: Approximately one-fifth of patients developed PL post-surgery, which was a risk factor for SSI, with constant high inflammation. Grouping based on PL and establishing diagnostic cutoff values are more appropriate than establishing only one cutoff value for overall cases., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier B.V.)

Background: The accuracy rates of several effective serological markers of surgical site infection following spine surgery are unclear. We aimed to verify the accuracy of each significant marker and identify the most suitable and effective combination of these markers for the diagnosis of surgical site infection following spine surgery., Methods: This retrospective study enrolled 329 patients who underwent spine surgery for causes other than infectious spondylitis, including 9 patients with surgical site infection. Complete blood cell count, differential counts, and C-reactive protein levels were measured preoperatively and postoperatively (days 2 and 7). Serological data were compared among non-surgical site infection and surgical site infection cases. Cutoff values for items presenting significant differences were determined using receiver operating characteristic curves. Ratios in each serological factor at each time-point were compared. Combinations of these factors on postoperative day 7 and ratio items were investigated to determine the most suitable combination comprising the least number of items., Results: Significant differences were noted among four factors on postoperative day 7, except for the lymphocyte count. For the ratio items, significant differences were observed among 6 items. The combination of these ten markers was examined; each factor was assigned 1 point. The most suitable combination comprising 4 items, including neutrophil count, neutrophil-to-lymphocyte ratio, lymphocyte count ratio, and C-reactive protein ratio, presented an AUC of 0.95, with a cutoff value, sensitivity, and specificity of 3 points, 0.89, and 0.92, respectively., Conclusion: The combination of four markers is the most suitable criterion for the surgical site infection scoring system following spine surgery, where scores of ≥3 points strongly indicate surgical site infection. This criterion may be a strong tool for detecting surgical site infection., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier B.V.)

Osteosarcoma (OS) is the most common primary bone tumor that mainly affects adolescents and young adults. Although standard treatment modality can achieve up to 60%-70% 5-year survival rate, there has not been any substantial improvement over the past four decades. Furthermore, those presenting with pulmonary metastatic lesions often undergo a highly unfavorable clinical course. Therefore, there is a severely unmet clinical need to provide a more effective treatment for patients with OS. In this study, we show that trabectedin (TBD), a chemotherapeutic agent approved for soft tissue sarcomas, significantly suppresses pulmonary metastasis in a mouse OS xenograft model. In vitro experiments revealed that TBD suppresses cell migration potentially by downregulating the activity of ERK1/2, intracellular molecules that are critically involved in the regulation of cell motility. Collectively, our data may provide a basis for further investigation of TBD on the potential use for OS patients who are at great risk of pulmonary metastasis., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: Limited chondrocyte migration and impaired cartilage-to-cartilage healing is a barrier in cartilage regenerative therapy. Collagenase treatment and delivery of a chemotactic agent may play a positive role in chondrocyte repopulation at the site of cartilage damage. This study evaluated chondrocyte migratory activity after enzymatic treatment in cultured cartilage explant. Differential effects of platelet-derived growth factor (PDGF) dimeric isoforms on the migratory activity were investigated to define major chemotactic factors for cartilage., Methods: Full-thickness cartilage (4-mm 3 blocks) were harvested from porcine femoral condyles and subjected to explant culture. After 15 min or 60 min of actinase and collagenase treatments, chondrocyte migration and infiltration into a 0.5-mm cartilage gap was investigated. Cell morphology and lubricin, keratan sulfate, and chondroitin 4 sulfate expression in superficial- and deep-zone chondrocytes were assessed. The chemotactic activities of PDGF-AA, -AB, and -BB were measured in each zone of chondrocytes, using a modified Boyden chamber assay. The protein and mRNA expression and histological localization of PDGF-β were analyzed by western blot analysis, real-time reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemistry, and results in each cartilage zone were compared., Results: Superficial-zone chondrocytes had higher migratory activity than deep-zone chondrocytes and actively bridged the cartilage gap, while metachromatic staining by toluidine blue and immunoreactivities of keratan sulfate and chondroitin 4 sulfate were detected around the cells migrating from the superficial zone. These superficial-zone cells with weak immunoreactivity for lubricin tended to enter the cartilage gap and possessed higher migratory activity, while the deep-zone chondrocytes remained in the lacuna and exhibited less migratory activity. Among PDGF isoforms, PDGF-AB maximized the degree of chemotactic activity of superficial zone chondrocytes. Increased expression of PDGF receptor-β was associated with higher migratory activity of the superficial-zone chondrocytes., Conclusions: In enzymatically treated cartilage explant culture, chondrocyte migration and infiltration into the cartilage gap was higher in the superficial zone than in the deep zone. Preferential expression of PDGF receptor-β combined with the PDGF-AB dimeric isoform may explain the increased migratory activity of the superficial-zone chondrocytes. Cells migrating from superficial zone may contribute to cartilage regeneration., (© 2022. The Author(s).)

We aimed to investigate the risk factors of spontaneous osseous fusion (SOF) of the atlantoaxial joint after closed reduction under general anesthesia followed by halo fixation (remodeling therapy) for chronic atlantoaxial rotatory fixation, and to elucidate the recovery mechanism of the rotatory range of motion (ROM) after halo removal. Twelve patients who underwent remodeling therapy were retrospectively reviewed. Five patients with SOF were categorized as the fusion group and seven patients without SOF as the non-fusion group. Three dimensional CT was used to detect direct osseous contact (DOC) of facet joints before and during halo fixation, while dynamic CT at neutral and maximally rotated head positions was performed to measure rotatory ROM after halo removal. The duration from onset to initial visit was significantly longer (3.2 vs. 5.7 months, p = 0.04), incidence of DOC during halo fixation was higher (0/7 [0%] vs. 4/5 [80%], p = 0.004), and segmental rotatory ROM of Occiput/C1 (Oc/C1) at final follow-up was larger (9.8 vs. 20.1 degrees, p = 0.003) in the fusion group. Long duration from the onset to the initial visit might induce irreversible damage to the articular surface of the affected facet, which was confirmed as DOC during halo fixation and resulted in SOF. Long duration from the onset to the initial visit and DOC during halo fixation could be used to suggest the risk for SOF. Nonetheless, rotatory ROM of Oc/C1 increased to compensate for SOF.

Muraymycins and caprazamycins are strong inhibitors of MraY, which is responsible for peptidoglycan biosynthesis. Although they are promising antibacterial agents with a novel mode of action, their chemical structures are rather complex. This study investigated the simplification of these natural products by structure-based drug design, synthesis, and biological evaluation. We developed a simplified rigid scaffold with an arylalkyne moiety, which shows sub-micromolar MraY inhibitory activity. The scaffold is suitable for further investigating the structure-activity relationship by virtue of our synthetic strategy, where the substituent of interest is installed in the last stage of synthesis. This scaffold shows the potential for further use in optimizing MraY inhibitory and antibacterial activities., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Electrochemical reduction of amides was achieved by using a hydrosilane without any toxic or expensive metals. The key reactive ketyl radical intermediate was generated by cathodic reduction. Continuous reaction with anodically generated silyl radicals or zinc bromide resulted in chemoselective deoxygenation to give the corresponding amines.

Denosumab is a monoclonal antibody that has been approved to treat osteoporosis, skeletal metastasis, and giant cell tumor of bone in skeletally mature patients. Due to its potential adverse effects on normal bone growth, its use has not yet been approved in skeletally immature patients; however, the use of this agent in such patients with overt or dysregulated bone resorptive conditions has been explored in recent years. While most studies have proven the effectiveness of denosumab in controlling the progression of various disorders in skeletally immature patients, they have also revealed that refractory hypercalcemia often follows the discontinuation of denosumab treatment, raising a concern over the use of this agent in these patients. Thus, this study was designed to better understand the pathology of this condition through a systematic review of the published literature. Our analysis suggests that this condition has a potential male predisposition, that there is a correlation between the duration of denosumab treatment and patient age, and that this condition often occurs within 3 months after the last administration of denosumab in skeletally immature patients but is significantly less likely in adults. These results may further underscore that high bone formation and bone turnover rates are critically associated with hypercalcemia after the discontinuation of denosumab. In contrast, given that not all skeletally immature patients develop hypercalcemia, it is probable that other unidentified factors are involved in the pathology of this condition., Competing Interests: The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Author names: Keisuke Horiuchi, Eisuke Kobayashi, Tsukasa Mizuno, Michiro Susa, and Kazuhiro Chiba., (© 2021 Published by Elsevier Inc.)

Eribulin is a novel microtubule inhibitor that, similar to other types of microtubule inhibitors, induces apoptosis by inhibiting the mitotic division of cells. Besides this direct effect on tumor cells, previous studies have shown that eribulin has the potential to induce tumor vascular remodeling in several different cancers; however, the mechanisms underlying this phenomenon remain unclear. In the present study, we aimed to elucidate whether eribulin is effective against synovial sarcoma, a relatively rare sarcoma that often affects adolescents and young adults, and to histologically investigate the microstructure of tumor vessels after the administration of eribulin. We found that eribulin exhibits potent antitumor activity against synovial sarcoma in a tumor xenograft model and that tumor vessels frequently have intervascular pillars, a hallmark of intussusceptive angiogenesis (IA), after the administration of eribulin. IA is a distinct form of angiogenesis that is involved in normal developmental processes as well as pathological conditions. Our data indicate that IA is potentially involved in eribulin-induced vascular remodeling and thereby suggest previously unacknowledged role of IA in regulating the tumor vasculature after eribulin administration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The large amount of waste derived from coupling reagents is a serious drawback of peptide synthesis from a green chemistry viewpoint. To overcome this issue, we report an electrochemical peptide synthesis in a biphasic system. Anodic oxidation of triphenylphosphine (Ph 3 P) generates a phosphine radical cation, which serves as the coupling reagent to activate carboxylic acids, and produces triphenylphosphine oxide (Ph 3 P[double bond, length as m-dash]O) as a stoichiometric byproduct. In combination with a soluble tag-assisted liquid-phase peptide synthesis, the selective recovery of desired peptides and Ph 3 P[double bond, length as m-dash]O was achieved. Given that methods to reduce Ph 3 P[double bond, length as m-dash]O to Ph 3 P have been reported, Ph 3 P[double bond, length as m-dash]O could be a recyclable byproduct unlike byproducts from typical coupling reagents. Moreover, a commercial peptide active pharmaceutical ingredient (API), leuprorelin, was successfully synthesized without the use of traditional coupling reagents., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Adolescent idiopathic scoliosis (AIS) is a common disease causing three-dimensional spinal deformity in as many as 3% of adolescents. Development of a method that can accurately predict the onset and progression of AIS is an immediate need for clinical practice. Because the heritability of AIS is estimated as high as 87.5% in twin studies, prediction of its onset and progression based on genetic data is a promising option. We show the usefulness of polygenic risk score (PRS) for the prediction of onset and progression of AIS. We used AIS genomewide association study (GWAS) data comprising 79,211 subjects in three cohorts and constructed a PRS based on association statistics in a discovery set including 31,999 female subjects. After calibration using a validation data set, we applied the PRS to a test data set. By integrating functional annotations showing heritability enrichment in the selection of variants, the PRS demonstrated an association with AIS susceptibility (p = 3.5 × 10 -40 with area under the receiver-operating characteristic [AUROC] = 0.674, sensitivity = 0.644, and specificity = 0.622). The decile with the highest PRS showed an odds ratio of as high as 3.36 (p = 1.4 × 10 -10 ) to develop AIS compared with the fifth in decile. The addition of a predictive model with only a single clinical parameter (body mass index) improved predictive ability for development of AIS (AUROC = 0.722, net reclassification improvement [NRI] 0.505 ± 0.054, p = 1.6 × 10 -8 ), potentiating clinical use of the prediction model. Furthermore, we found the Cobb angle (CA), the severity measurement of AIS, to be a polygenic trait that showed a significant genetic correlation with AIS susceptibility (rg = 0.6, p = 3.0 × 10 -4 ). The AIS PRS demonstrated a significant association with CA. These results indicate a shared polygenic architecture between onset and progression of AIS and the potential usefulness of PRS in clinical settings as a predictor to promote early intervention of AIS and avoid invasive surgery. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Background: Shoulder 36 (Sh-36) is an original quality of life measure for shoulder lesions with high reliability and validity; however, in some cases, especially in those with a Bankart lesion, we observed no improvement in Sh-36 during the postoperative follow-up. Sh-36 may be less effective for a certain shoulder lesion. This study aimed to compare the reliability, validity, and responsiveness of Sh-36 among different representative diagnoses of shoulder lesions., Methods: Sh-36 and the Disability of the Arm, Shoulder and Hand (DASH) were measured in 192 patients with a Bankart lesion (Bankart group), rotator cuff tear (Cuff group), and SLAP lesion (SLAP group) who underwent arthroscopic surgery. Both measures were evaluated before surgery, and at 3, 6, 9, 12, 18, and 24 months postoperatively, and reliability, validity, and responsiveness of Sh-36 and the DASH were compared among the three groups., Results: Significant postoperative improvement was observed in the three groups (p < 0.0001) within 9 months. No marked improvement was observed after 9 months in the Bankart and SLAP groups due to the ceiling effect; however, most domains of Sh-36 increased continuously in the Cuff group during the whole follow-up period. Reliability and construct validity were sufficient in all the groups. The longitudinal validity was sufficient in most domains for the three groups; however, the standardized response mean in the Bankart group was lower than that in other two groups, indicating low responsiveness in this group because of the ceiling effect., Conclusions: Sh-36 was a valid and reliable instrument in patients who have undergone arthroscopic shoulder surgery, especially for patient with a rotator cuff tear with high responsiveness. However, Sh-36 had lower standard response mean representing lower responsiveness in the Bankart group due to the ceiling effect and may not be ideal for longitudinal follow-up in patients with a Bankart lesion., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration., Competing Interests: The authors have declared that no competing interest exists.

Skeletal development is a highly sophisticated process in which the expression of a variety of growth factors, signaling molecules, and extracellular matrix proteins is spatially and temporally orchestrated. In the present study, we show that ADAM10, a transmembrane protease that is critically involved in the functional regulation of various membrane-bound molecules, plays an essential role in the longitudinal growth of long bones and in skeletal development. We found that mutant mice lacking ADAM10 in osteochondroprogenitors exhibited marked growth retardation and had shorter long bones than the control mice. Histomorphometric analysis revealed that the mutant mice had a shorter hypertrophic zone and that their hypertrophic chondrocytes were smaller in size than those of the control mice. Unexpectedly, we found that the mRNA expression of the chemokine CXCL12 and its receptor CXCR4 were significantly reduced in cartilage tissues lacking ADAM10. Further, exogenous supplementation of recombinant CXCL12 rescued the defect in the ADAM10-deficient growth plate in an ex vivo culture model. Taken together, our data show a previously unknown role for ADAM10 in skeletal development that involves its regulation of the CXCL12 and CXCR4 signaling pathway., Competing Interests: Declaration of competing interest All authors declare they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Rigid pedicle screw fixation is mandatory for achieving successful spinal fusion; however, there is no reliable method predicting screw fixation before screw insertion. The purpose of the present study was to investigate the efficacy of measurement of tapping torque to predict pedicle screw fixation., Methods: First, different densities of polyurethane foam were used to measure tapping torque. The insertional torque during pedicle screw insertion and axial pullout strength were measured and compared between under-tapped and same-tapped groups. Next, for in vivo study, the tapping and insertional torque of lumbar pedicle screws using the cortical bone trajectory technique were measured intraoperatively in 45 consecutive patients. Then, correlations between tapping torque, the bone mineral density of the femoral neck and lumbar vertebrae, and insertional torque were investigated., Results: Ex vivo tapping torque significantly correlated with the insertional torque and pullout strength regardless of tapping sizes (r = 0.98, p < 0.001). The mean in vivo tapping and insertional torque were 1.48 ± 0.73 and 2.48 ± 1.25 Nm, respectively (p < 0.001). Insertional torque significantly correlated with tapping torque and two BMD parameters, and the correlation coefficient of tapping torque (r = 0.83, p < 0.001) was higher than those of femoral neck BMD (r = 0.59, p < 0.001) and lumbar BMD (r = 0.39, p < 0.001)., Conclusions: Tapping torque is a reliable predictor of pedicle screw fixation and allows surgeons to improve the integrity of the bone-screw interface by making modification prior to actual screw insertion., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Electrochemical intramolecular C(sp 2 )-H cross-coupling and dehydrogenative indole synthesis were developed. Both reactions were initiated by anodic oxidation of the same electron-rich indoline moiety, but the product selectivity was controlled by different electron-transfer processes. Intramolecular cross-coupling was achieved by the generation of a strong electrophilic radical cation intermediate in the MeNO 2 -HFIP-LiClO 4 system. Indole formation was accomplished through benzylic oxidation and continuous deprotonation. We applied these reactions to the total synthesis of natural pyrrolophenanthridone alkaloids.

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Several AIS susceptibility loci have been identified; however, they could explain only a small proportion of AIS heritability. To identify additional AIS susceptibility loci, we conduct a meta-analysis of the three genome-wide association studies consisting of 79,211 Japanese individuals. We identify 20 loci significantly associated with AIS, including 14 previously not reported loci. These loci explain 4.6% of the phenotypic variance of AIS. We find 21 cis-expression quantitative trait loci-associated genes in seven of the fourteen loci. By a female meta-analysis, we identify additional three significant loci. We also find significant genetic correlations of AIS with body mass index and uric acid. The cell-type specificity analyses show the significant heritability enrichment for AIS in multiple cell-type groups, suggesting the heterogeneity of etiology and pathogenesis of AIS. Our findings provide insights into etiology and pathogenesis of AIS.

Spontaneous regression of sarcoma is exceedingly rare. A 62-year-old male presented with myxofibrosarcoma of the thigh which regressed after open biopsy. Treatment strategy for this condition is not well-documented in the literature. In this report, we describe the case of a spontaneously regressed myxofibrosarcoma successfully treated by resection where the extent of the tumor was determined from the initial MRI. This case demonstrates that myxofibrosarcoma has the potential to regress spontaneously, and astute awareness of this phenomenon is necessary for appropriate management of this condition.

Electrode materials can have a significant impact on the course of an electrolysis reaction. Of particular interest is that different electrodes can generate different products from the same substrate. The electrode-material-selective transformations of styrene derivatives with molecular oxygen are reported. Platinum electrodes afford carbonyl products via cleavage of olefins, whereas tetrahydrofuran formation is achieved with carbon electrodes. A variety of different styrenes are available for both reactions. Electrolysis allows straightforward and mild chemical conversions that are metal- and oxidant-free. Electrochemical measurements illuminate the different effects of platinum and carbon electrodes on styrenes. The key to the differing reactions is probably that the oxidation potentials of the substrates are lower (higher HOMO energy) on carbon electrodes than on platinum electrodes. The adsorption of the substrates on carbon electrodes can also promote tetrahydrofuran formation., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Azanucleosides, the sugar-modified nucleoside analogues, have various biological activities, while their efficient synthetic strategy is still under development. Herein, a novel method for the synthesis of pharmaceutically relevant azanucleosides, β-anomers of ribo-azanucleosides, by means of site-specific anodic C-H activation by using a nitroalkane-lithium perchlorate medium is reported. A mechanistic study of the electrochemical reaction and the armed/disarmed concept from traditional glycochemistry revealed that the 2'-substituent has a significant effect on the reactivity of prolinol derivative, and suitable carboxylic acid additives can control the reactivity of the intermediate species, an iminium cation equivalent. Finally, this method was demonstrated to be applicable for the synthesis of β-anomers of ribo-azanucleosides with all four nucleobases in a stereoselective manner., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Granulocyte-colony stimulating factor (G-CSF) is a cytokine crucially involved in the regulation of granulopoiesis and the mobilization of hematopoietic stem cells from bone marrow. However, emerging data suggest that G-CSF exhibits more diverse functions than initially expected, such as conferring protection against apoptosis to neural cells and stimulating mitogenesis in cardiomyocytes and skeletal muscle stem cells after injury. In the present study, we sought to investigate the potential contribution of G-CSF to the regulation of muscle volume. We found that the administration of G-CSF significantly enhances muscle hypertrophy in two different muscle overload models. Interestingly, there was a significant increase in the transcripts of both G-CSF and G-CSF receptors in the muscles that were under overload stress. Using mutant mice lacking the G-CSF receptor, we confirmed that the anabolic effect is dependent on the G-CSF receptor signaling. Furthermore, we found that G-CSF increases the diameter of myotubes in vitro and induces the phosphorylation of AKT, mTOR, and ERK1/2 in the myoblast-like cell line C2C12 after differentiation induction. These findings indicate that G-CSF is involved in load-induced muscle hypertrophy and suggest that G-CSF is a potential agent for treating patients with muscle loss and sarcopenia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A selective dehydrogenative electrochemical functionalization of benzylic positions that employs 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) has been developed. The electrogenerated products are versatile intermediates for subsequent functionalizations as they act as masked benzylic cations that can be easily activated. Herein, we report a sustainable, scalable, and reagent- and metal-free dehydrogenative formal benzyl-aryl cross-coupling. Liberation of the benzylic cation was accomplished through the use of acid. Valuable diarylmethanes are accessible in the presence of aromatic nucleophiles. The direct application of electricity enables a safe and environmentally benign chemical transformation as oxidizers are replaced by electrons. A broad variety of different substrates and nucleophiles can be employed., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD also reported multiple heritable risk factors, including height, body mass index (BMI), bone mineral density (BMD), lipid levels, etc. Genetics can help elucidate causality between traits and suggest loci with pleiotropic effects. One such approach is polygenic score (PGS) which summarizes the effect of multiple variants by the summation of alleles weighted by estimated effects from GWAS. To investigate genetic overlaps of LDD and related heritable risk factors, we calculated the PGS of height, BMI, BMD and lipid levels in a Chinese population-based cohort with spine MRI examination and a Japanese case-control cohort of lumbar disc herniation (LDH) requiring surgery. Because most large-scale GWASs were done in European populations, PGS of corresponding traits were created using weights from European GWASs. We calibrated their prediction performance in independent Chinese samples, then tested associations with MRI-derived LDD scores and LDH affection status. The PGS of height, BMI, BMD and lipid levels were strongly associated with respective phenotypes in Chinese, but phenotype variances explained were lower than in Europeans which would reduce the power to detect genetic overlaps. Despite of this, the PGS of BMI and lumbar spine BMD were significantly associated with LDD scores; and the PGS of height was associated with the increased the liability of LDH. Furthermore, linkage disequilibrium score regression suggested that, osteoarthritis, another degenerative disorder that shares common features with LDD, also showed genetic correlations with height, BMI and BMD. The findings suggest a common key contribution of biomechanical stress to the pathogenesis of LDD and will direct the future search for pleiotropic genes.

Study Design: A randomized, double-blind, placebo-controlled, multicenter phase III clinical trial., Objective: To evaluate the efficacy and safety of chemonucleolysis with condoliase in patients with lumbar disc herniation (LDH)., Summary of Background Data: Condoliase is a pure mucopolysaccharidase derived from a bacterium, Proteus vulgaris that has high substrate specificity for chondroitin sulfate and hyaluronic acid in the nucleus pulposus of the intervertebral disc., Methods: In this study, patients aged 20 to 70 years with unilateral leg pain, positive straight leg raise test, and a contained LDH were recruited in Japan. Patients were treated with a single injection of condoliase (1.25 U) or placebo and were followed for 1 year after administration. The primary endpoint was change in worst leg pain from baseline to week 13. The secondary endpoints included responder rate, and the changes from baseline up to week 52 in the worst leg pain, worst back pain, Oswestry Disability Index, 36-Item Short-Form Health Survey, neurologic examinations, and imaging parameters., Results: A total of 82 and 81 patients received an injection of condoliase and placebo, respectively. The average changes in worst leg pain from baseline to week 13 (primary endpoint) were -49.5 mm in the condoliase group and -34.3 mm in the placebo group, and the difference of -15.2 mm was significant (95% confidence interval, -24.2 to -6.2; P = 0.001). Significant improvements were observed in the condoliase groups, compared with the placebo group, in most secondary endpoints at 1 year after administration. In the condoliase group, back pain, Modic type 1 change, and decrease in disc height were frequently reported, without any clinically relevant consequences., Conclusion: Condoliase significantly improved symptoms in patients with LDH and was well tolerated. Condoliase is a novel and potent chemonucleolytic drug for the treatment of LDH., Level of Evidence: 1.

Artificial orthogonal bond formations such as the alkyne-azide cycloaddition have enabled selective bioconjugations under mild conditions, yet naturally occurring linkages between native functional groups would be more straightforward to elaborate bioconjugates. Herein, we describe the use of a phosphodiester bond as a versatile option to access various bioconjugates. An opposite activation strategy, involving 5'-phosphitylation of the supported oligonucleotides, has allowed several biomolecules that possess an unactivated alcohol to be directly conjugated. It should be noted that there is no need to pre-install artificial functional groups and undesired and unpredictable perturbations possibly caused by bioconjugation can be minimized.

The absolute configuration of Stachybotrin C was confirmed in this study. After synthesizing the dimethyl ethers of Stachybotrin C, the C-8 epimer was analyzed by 1D NOESY. However, the stereochemistry determination was difficult through the NOE correlations. Instead, the di(4-bromobenzyl) ether of Stachybotrin C was derived and used for X-ray diffraction analysis, because its single crystal was easier to obtain than that of the original Stachybotrin C. The stereochemistry of Stachybotrin C was determined to be (8S, 9R). This derivatization approach may also be used to prepare single crystals of the analogues.

Nodular hidradenoma (NH) is a benign adnexal tumor that arises from either eccrine or apocrine sweat glands. NH can originate from any cutaneous site, but the most common sites are the head and anterior surface of the trunk, with very rare cases in the extremities. Long-standing NH has been reported to undergo malignant transformation to malignant NH (MNH); however, its occurrence in the lower leg is extremely rare with only one other case reported to date. In this report, we present a rare case of MNH occurring in the lower leg which was resected with the intent to make a diagnosis. At the final follow-up after 11 months, no local recurrence or metastasis has been observed.

Study Design: Case-only study., Objective: The aim of this study was to confirm the association of rs11190870 with adolescent idiopathic scoliosis (AIS) severity in Japanese patients with AIS., Summary of Background Data: Although the association of rs11190870 with AIS susceptibility is replicated in multiple ethnics, the association of rs11190870 with curve severity is controversial. Since the previous studies are of small, we performed a replication study using far larger number of patients than previous studies., Methods: A total of 1860 Japanese patients with AIS who had reached skeletal maturity or undergone surgical fusion were included in the study. We evaluated the association between rs11190870 and AIS progression for the entire group, and then for patients grouped according to a severe curve (a Cobb angle of ≥40°) or mild curve (a Cobb angle <30°). Because braces could affect the results of the present study, patients in the mild-curve group were divided according to whether or not they had worn a brace. We then evaluated associations between rs11190870 genotype and curve severity in these groups., Results: The mean Cobb angles were 54.8° ± 12.1° in the severe-curve group and 24.4° ± 4.0° in the mild-curve group. The difference in rs11190870 risk-allele frequency between the severe- and mild-curve groups was evaluated. No significant differences were observed. We then examined the association of rs11190870 risk-allele frequency between patients in the mild- and severe-curve groups using the χ test for three models, and found a marginal association between rs11190870 and curve severity in the dominant model (P = 0.035, odds ratio = 1.51)., Conclusion: We found no association between rs11190870 and curve severity using the criteria of previous study. However, we found a marginal association between rs11190870 and curve severity. Large-scale replication studies that consider skeletal maturity and brace history, including replication studies in other ethnic groups, would be helpful for clarifying the association., Level of Evidence: 4.

Explosive growth in the use of open shell reactivity, including neutral radicals and radical ions, in the field of synthetic organic chemistry has been observed in the past decade, particularly since the advent of ruthenium complexes in 2008. These complexes generally induce single-electron transfer (SET) processes via visible-light absorption. Additionally, recent significant advancements in organic electrochemistry involving SET processes to provide open shell reactivity offer a complementary method to traditional polarity-driven reactions described by two-electron transfer processes. In this Review, we highlight the importance of intramolecular SET processes in the field of synthetic organic chemistry, which seem to be more elusive than the intermolecular versions, since they are net redox-neutral and thus cannot simply be regarded as oxidations or reductions. Such intramolecular SET processes can rationally be understood in combination with concomitant bond formations and/or cleavages, and are regulated by a structural motif that we call a "redox tag." In order to describe modern radical-driven reactions involving SET processes, we focus on a classical formalism in which electrons are treated as particles rather than waves, which offers a practical yet powerful approach to explain and/or predict synthetic outcomes.

OBJECTIVE Chemonucleolysis with condoliase has the potential to be a new, less invasive therapeutic option for patients with lumbar disc herniation (LDH). The aim of the present study was to determine the most suitable therapeutic dose of condoliase. METHODS Patients between 20 and 70 years of age with unilateral leg pain, positive findings on the straight leg raise test, and LDH were recruited. All eligible patients were randomly assigned to receive condoliase (1.25, 2.5, or 5 U) or placebo. The primary end point was a change in the worst leg pain from preadministration (baseline) to week 13. The secondary end points were changes from baseline in the following items: worst back pain, Oswestry Disability Index (ODI), SF-36, and neurological examination. For pharmacokinetic and pharmacodynamic analyses, plasma condoliase concentrations and serum keratan sulfate concentrations were measured. The safety end points were adverse events (AEs) and radiographic and MRI parameters. Data on leg pain, back pain, abnormal neurological findings, and imaging parameters were collected until week 52. RESULTS A total of 194 patients received an injection of condoliase or placebo. The mean change in worst leg pain from baseline to week 13 was -31.7 mm (placebo), -46.7 mm (1.25 U), -41.1 mm (2.5 U), and -47.6 mm (5 U). The differences were significant at week 13 in the 1.25-U group (-14.9 mm; 95% CI -28.4 to -1.4 mm; p = 0.03) and 5-U group (-15.9 mm; 95% CI -29.0 to -2.7 mm; p = 0.01) compared with the placebo group. The dose-response improvement in the worst leg pain at week 13 was not significant (p = 0.14). The decrease in the worst leg pain in all 3 condoliase groups was observed from week 1 through week 52. Regarding the other end points, the worst back pain and results of the straight leg raise test, ODI, and SF-36 showed a tendency for sustained improvement in each of the condoliase groups until week 52. In all patients at all time points, plasma condoliase concentrations were below the detectable limit (< 100 μU/ml). Serum keratan sulfate concentrations significantly increased from baseline to 6 hours and 6 weeks after administration in all 3 condoliase groups. No patient died or developed anaphylaxis or neurological sequelae. Five serious AEs occurred in 5 patients (3 patients in the condoliase groups and 2 patients in the placebo group), resolved, and were considered unrelated to the investigational drug. Severe AEs occurred in 10 patients in the condoliase groups and resolved or improved. In the condoliase groups, back pain was the most frequent AE. Modic type 1 change and decrease in disc height were frequent imaging findings. Dose-response relationships were observed for the incidence of adverse drug reactions and decrease in disc height. CONCLUSIONS Condoliase significantly improved clinical symptoms in patients with LDH and was well tolerated. While all 3 doses had similar efficacy, the incidence of adverse drug reactions and decrease in disc height were dose dependent, thereby suggesting that 1.25 U would be the recommended clinical dose of condoliase. Clinical trial registration no.: NCT00634946 (clinicaltrials.gov).