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BackgroundEstablishing an optimal animal model for intervertebral disc (IVD) degeneration is essential for developing new IVD therapies. The intra-articular injection of monosodium iodoacetate (MIA), which is commonly used in animal models of osteoarthritis, induces cartilage degeneration and progressive arthritis in a dose- and time-dependent manner. The purpose of this study was to determine the effect of MIA injections into rabbit IVDs on the progression of IVD degeneration evaluated by radiographic, micro-computerized tomography (micro-CT), magnetic resonance imaging (MRI), and histological analyses.MethodsIn total, 24 New Zealand White (NZW) rabbits were used in this study. Under general anesthesia, lumbar discs from L1-L2 to L4-L5 had a posterolateral percutaneous injection of MIA in contrast agent (CA) (L1-L2: CA only; L2-L3: MIA 0.01 mg; L3-L4: 0.1 mg; L4-L5: 1.0 mg; L5-L6: non-injection (NI) control). Disc height was radiographically monitored biweekly until 12 weeks after injection. Six rabbits were sacrificed at 2, 4, 8, and 12 weeks post-injection and processed for micro-CT, MRI (T2-mapping), and histological analyses. Three-dimensional (3D) disc height in five anatomical zones was evaluated by 3D reconstruction of micro-CT data.ResultsDisc height of MIA-injected discs (L2-L3 to L4-L5) gradually decreased time-dependently (P < 0.0001). The disc height of MIA 0.01 mg-injected discs was significantly higher than those of MIA 0.1 and 1.0 mg-injected discs (P < 0.01, respectively). 3D micro-CT analysis showed the dose- and time-dependent decrease of 3D disc height of MIA-injected discs predominantly in the posterior annulus fibrosus (AF) zone. MRI T2 values of MIA 0.1 and 1.0 mg-injected discs were significantly decreased compared to those of CA and/or NI controls (P < 0.05). Histological analyses showed progressive time- and dose-degenerative changes in the discs injected with MIA (P < 0.01). MIA induced cell death in the rabbit nucleus pulposus with a high percentage, while the percentage of cell clones was low.ConclusionsThe results of this study showed, for the first time, that the intradiscal injection of MIA induced degenerative changes of rabbit IVDs in a time- and dose-dependent manner. This study suggests that MIA injection into rabbit IVDs could be used as an animal model of IVD degeneration for developing future treatments.

Low back pain (LBP) is now regarded as the first cause of disability worldwide and should be a priority for future research on prevention and therapy. Intervertebral disc (IVD) degeneration is an important pathogenesis of LBP. Platelet-rich plasma (PRP) is an autologous blood concentrate that contains a natural concentration of autologous growth factors and cytokines and is currently widely used in the clinical setting for tissue regeneration and repair. PRP has great potential to stimulate cell proliferation and metabolic activity of IVD cells in vitro. Several animal studies have shown that the injection of PRP into degenerated IVDs is effective in restoring structural changes (IVD height) and improving the matrix integrity of degenerated IVDs as evaluated by magnetic resonance imaging (MRI) and histology. The results of this basic research have shown the great possibility that PRP has significant biological effects for tissue repair to counteract IVD degeneration. Clinical studies for evaluating the effects of the injection of PRP into degenerated IVDs for patients with discogenic LBP have been reviewed. Although there was only one double-blind randomized controlled trial, all the studies reported that PRP was safe and effective in reducing back pain. While the clinical evidence of tissue repair of IVDs by PRP treatment is currently lacking, there is a great possibility that the application of PRP has the potential to lead to a feasible intradiscal therapy for the treatment of degenerative disc diseases. Further large-scale studies may be required to confirm the clinical evidence of PRP for the treatment of discogenic LBP.

BACKGROUND:The progression of intervertebral disc (IVD) degeneration leads to rupture within IVD tissues. The location and appearance of areas of gaseous radiolucency in the IVD, known as vacuum phenomena (VPs), are considered to indirectly indicate the position and extent of IVD rupture. The clinical significance of VPs in degenerated IVDs is not fully understood. The purpose of this study is to assess and classify the morphology of IVD ruptures by the presence of intradiscal VPs, and to examine the association between morphological VP-positive IVD ruptures and degenerative lumbar diseases. METHODS:IVD rupture was evaluated by the presence of VPs using computed tomography (CT) imaging. VP shape (spot, linear, island) was classified using sagittal imaging, and VP distribution (A-N: anterior AF-NP; N: NP only; N-P: NP-posterior AF; A-N-P: anterior and posterior AF-NP) was classified using axial imaging. The disc height index (DHI) was calculated from lateral radiographs. Disc degeneration and lumbar spinal stenosis were evaluated by MRI grade. RESULTS:In the VP shape analysis, the island type was the most common, followed by linear and spot types. In the VP distribution analysis, A-N was the most common group, followed by N, N-P and A-N-P. Intra- and inter-observer reliabilities were statistically sufficient to classify different rupture shapes and distributions. The DHI tended to be lower in discs that contained VPs, especially in the anterior AF area. The shape and distribution of intradiscal VPs were significantly associated with the degree of disc degeneration and lumbar spinal stenosis graded by MRI. Discs with VPs extending from the NP into the anterior and/or posterior AF had a significantly higher proportion of advanced disc degeneration (Pfirrmann's classification: grades IV and V). CONCLUSIONS:This is the first study to analyze the morphology of IVD rupture evaluated by the presence of intradiscal VPs using CT imaging. This classification can comprehensively present the shape and axial distribution of VPs within IVDs. Intradiscal VPs are associated with the progression of disc degeneration and lumbar spinal stenosis.

Background: We examined whether denosumab-induced hypocalcaemia is evident in osteoporosis when given loop diuretics that promote urinary calcium excretion. Methods: Japanese Spontaneous Adverse Drug Event Reports was analyzed to examine signals for denosumab-induced hypocalcaemia co-administered loop diuretics. We retrospectively included osteoporotic patients to detect predictors for denosumab-induced hypocalcaemia (corrected calcium level < 8.5 mg/dL) using multivariate logistic regression analysis. We compared differences in corrected calcium levels (ΔCa = nadir-baseline). Results: A significant signal for hypocalcaemia was detected (Reporting odds ratio = 865.8, 95% confidence interval [95% CI]: 596.8 to 1255.9, p < 0.0001). Among 164 patients (hypocalcaemia, 12%), loop diuretics have a significant association with hypocalcaemia (odds ratio [OR] = 6.410, 95% CI: 1.005 to 40.90, p = 0.0494). However, hypocalcaemia was found to be lower in high corrected calcium levels at baseline (OR = 0.032, 95% CI: 0.005 to 0.209, p < 0.0001) and calcium and vitamin D supplementation (OR = 0.285, 95% CI: 0.094 to 0.868, p = 0.0270). In the non-hypocalcaemia, ΔCa decreased significantly in the denosumab plus loop diuretics than in the denosumab alone (-0.9 [-1.3 to -0.7] mg/dL vs. -0.5 [-0.8 to -0.3] mg/dL, p = 0.0156). However, ΔCa remained comparable in the hypocalcaemia despite loop diuretics co-administration (-1.0 [-1.2 to -0.8] mg/dL vs. -0.8 [-1.5 to -0.7] mg/dL, p = 0.7904). Conclusions: Loop diuretics may predispose to developing denosumab-induced hypocalcaemia. [ABSTRACT FROM AUTHOR]

Background: Malignant chest wall tumors need to be excised with wide resection to ensure tumor free margins, and the reconstruction method should be selected according to the depth and dimensions of the tumor. Vascularized tissue is needed to cover the superficial soft tissue defect or bone tissue defect. This study evaluated differences in complications according to reconstruction strategy. Methods: Forty-five patients with 52 operations for resection of malignant tumors in the chest wall were retrospectively reviewed. Patients were categorized as having superficial tumors, comprising Group A with simple closure for small soft tissue defects and Group B with flap coverage for wide soft tissue defects, or deep tumors, comprising Group C with full-thickness resection with or without mesh reconstruction and Group D with full-thickness resection covered by flap with or without polymethyl methacrylate. Complications were evaluated for the 52 operations based on reconstruction strategy then risk factors for surgical and respiratory complications were elucidated. Results: Total local recurrence-free survival rates in 45 patients who received first operation were 83.9% at 5 years and 70.6% at 10 years. The surgical complication rate was 11.5% (6/52), occurring only in cases with deep tumors, predominantly from Group D. Operations needing chest wall reconstruction (p = 0.0016) and flap transfer (p = 0.0112) were significantly associated with the incidence of complications. Operations involving complications showed significantly larger tumors, wider areas of bony chest wall resection and greater volumes of bleeding (p < 0.005). Flap transfer was the only significant predictor identified from multivariate analysis (OR: 10.8, 95%CI: 1.05–111; p = 0.0456). The respiratory complication rate was 13.5% (7/52), occurring with superficial and deep tumors, particularly Groups B and D. Flap transfer was significantly associated with the incidence of respiratory complications (p < 0.0005). Cases in the group with respiratory complications were older, more frequently had a history of smoking, had lower FEV1.0% and had a wider area of skin resected compared to cases in the group without respiratory complications (p < 0.05). Preoperative FEV1.0% was the only significant predictor identified from multivariate analysis (OR: 0.814, 95%CI: 0.693–0.957; p = 0.0126). Conclusions: Surgical complications were more frequent in Group D and after operations involving flap transfer. Severe preoperative FEV1.0% was associated with respiratory complications even in cases of superficial tumors with flap transfer. [ABSTRACT FROM AUTHOR]

BackgroundThe receptor activator of NF-κB ligand (RANKL), a member of the TNF ligand superfamily, is known to regulate bone metabolism. The expression of each component of the RANK/RANKL/osteoprotegerin (OPG) system in the intervertebral disc (IVD) has not been examined in detail. The purposes of this study were to examine the expression of the RANK/RANKL/OPG system and to evaluate the function of RANKL in the matrix metabolism of the rat IVD.MethodsSprague-Dawley, 12-week-old, male rats were used in this study. Anulus fibrosus (AF), nucleus pulposus (NP) and cartilaginous endplate (CEP) cells isolated from dissected thoracolumbar discs were monolayer-cultured. RANK/RANKL/OPG expression in rat IVDs was examined using real-time polymerase chain reaction (PCR) and immunohistochemical analysis (cultured cells and IVD tissues). To examine the effect of interleukin-1β (IL-1β) stimulation on the mRNA levels of RANK, RANKL and OPG, the cells were cultured with or without recombinant human IL-1β (rhIL-1β). To evaluate the effect of RANKL on the mRNA expression of catabolic factors (IL-1β, matrix metalloproteinase-3 (MMP-3) and MMP-13), the cells were cultured with RANKL in the presence or absence of rhIL-1β. The immunohistochemical expression of this system was also evaluated using human IVD tissues with different grades of degeneration.ResultsmRNA expression levels of RANK, RANKL, and OPG were clearly identified in AF, NP and CEP cells. Immunoreactivity to RANK, RANKL and OPG was distributed in the cell membranes and/or cytoplasm of the three types of cells. The mRNA level of RANKL was significantly upregulated by treatment with rhIL-1β of the three types of cells. Treatment with RANKL without rhIL-1β did not induce significant effects on the mRNA expression of catabolic factors by AF, NP and CEP cells. However, the expression was significantly upregulated by stimulation with RANKL in the presence of rhIL-1β. There was a general trend for more RANK/RANKL/OPG-positive cells in human IVD tissues in an advanced stage of degeneration compared to an early stage.ConclusionsOur study showed the possibility that the RANK/RANKL/OPG system may play a part in the process of intervertebral disc degeneration.

Study designPreliminary clinical trial.PurposeTo determine the safety and initial efficacy of intradiscal injection of autologous platelet-rich plasma (PRP) releasate in patients with discogenic low back pain.Overview of literaturePRP, which is comprised of autologous growth factors and cytokines, has been widely used in the clinical setting for tissue regeneration and repair. PRP has been shown in vitro and in vivo to potentially stimulate intervertebral disc matrix metabolism.MethodsInclusion criteria for this study included chronic low back pain without leg pain for more than 3 months; one or more lumbar discs (L3/L4 to L5/S1) with evidence of degeneration, as indicated via magnetic resonance imaging (MRI); and at least one symptomatic disc, confirmed using standardized provocative discography. PRP releasate, isolated from clotted PRP, was injected into the center of the nucleus pulposus. Outcome measures included the use of a visual analog scale (VAS) and the Roland-Morris Disability Questionnaire (RDQ), as well as X-ray and MRI (T2-quantification).ResultsData were analyzed from 14 patients (8 men and 6 women; mean age, 33.8 years). The average follow-up period was 10 months. Following treatment, no patient experienced adverse events or significant narrowing of disc height. The mean pain scores before treatment (VAS, 7.5±1.3; RDQ, 12.6±4.1) were significantly decreased at one month, and this was generally sustained throughout the observation period (6 months after treatment: VAS, 3.2±2.4, RDQ; 3.6±4.5 and 12 months: VAS, 2.9±2.8; RDQ, 2.8±3.9; p

Simple Summary: Programmed death-ligand 1 (PD-L1) on the tumor cell surface binds to its receptor, programmed death-1 (PD-1), on T cells and inhibits their activity. Immunotherapy involving PD-L1 and PD-1 inhibition has provided a remarkable innovation in cancer therapy. Recently, the soluble form of PD-L1 (sPD-L1) has attracted attention for systemic immune suppression. In this study, we successfully showed that sarcoma cells can release functional exosomal PD-L1, one of the forms of sPD-L1. Furthermore, the release of exosomal PD-L1 derived from normal and sarcoma cells was shown to be induced by irradiation. These findings demonstrate that radiated cells, including normal cells and sarcoma cells, induce the systemic release of exosomal PD-L1, and combination therapy with anti-PD-1/PD-L1 antibody may block the immune activity of exosomal PD-L1. (1) Background: Exosomal PD-L1 has garnered attention owing to its role in instigating systemic immune suppression. The objective of this study is to elucidate whether bone and soft tissue sarcoma cells possess the capacity to secrete functionally active exosomal PD-L1 and whether radiotherapy (RT) induces the exosomal PD-L1 release. (2) Methods: Human osteosarcoma cell line 143B and human fibrosarcoma cell line HT1080 were utilized. Exosomes were isolated from the culture medium and blood via ultracentrifugation. The expression of PD-L1 on both tumor cells and exosomes was evaluated. The inhibitory effect on PBMC was employed to assess the activity of exosomal PD-L1. Post radiotherapy, changes in PD-L1 expression were compared. (3) Results: Exosomal PD-L1 was detected in the culture medium of tumor cells but was absent in the culture medium of PD-L1 knockout cells. Exosomal PD-L1 exhibited an inhibitory effect on PBMC activation. In tumor-bearing mice, human-derived exosomal PD-L1 was detected in the bloodstream. Following radiotherapy, tumor cells upregulated PD-L1, and human-derived exosomal PD-L1 were detected in the bloodstream. (4) Conclusions: Exosomal PD-L1 emanates from bone and soft tissue sarcoma cells and is disseminated into the circulatory system. The levels of PD-L1 in tumor cells and the release of exosomal PD-L1 were augmented after irradiation with RT. [ABSTRACT FROM AUTHOR]

Study Design: Multicenter prospective study. Objective: The influence of central sensitization (CS) on neurological symptoms and surgical outcomes in patients with degenerative cervical myelopathy (DCM) remains unknown. This study aimed to investigate the effects of preoperative CS on surgical outcomes of patients with DCM following posterior decompression surgery. Methods: 77 consecutive patients with DCM (mean age 67.1) who received posterior decompression surgery were included in this study. The participants completed CS inventory (CSI) scores and the following patient-reported outcome measures (PROMs) preoperatively and 12 months postoperatively: the Japanese Orthopaedic Association (JOA) score for cervical myelopathy and JOA cervical myelopathy evaluation questionnaire (JOACMEQ) for cervical spinal diseases. The association of preoperative CSI scores with preoperative and postoperative PROMs was analyzed, and their changes were statistically evaluated. Results: The preoperative CSI score was significantly decreased at 12 months postoperatively, and it was significantly associated with the JOA score and JOACMEQ preoperatively and at 12 months postoperatively. However, no significant association was observed between preoperative CSI and the postoperative change of any PROMs at 12 months. The posterior decompression surgery significantly improved the JOA scores and 'lower extremity function' and 'quality of life (QOL)' domains of the JOACMEQ, independent of the severity of preoperative CSI score. Multiple regression analysis demonstrated that preoperative CSI was significantly associated with the 'QOL' domain of JOACMEQ and original JOA score at 12 months postoperatively. Conclusion: The CSI score can be an auxiliary indicator of surgical outcomes of patients with DCM following posterior decompression surgery. [ABSTRACT FROM AUTHOR]