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Exploring causal correlations between inflammatory cytokines and intervertebral disc degeneration: A Mendelian randomization 探索炎性细胞因子与椎间盘退变之间的因果关系:孟德尔随机试验
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-07-10 DOI: 10.1002/jsp2.1349
Tao Xu, Guangzi Chen, Jian Li, Yingchi Zhang

Background

Inflammatory cytokines have been reported to be related to intervertebral disc degeneration (IVDD) in several previous studies. However, it remains unclear about the causal relationship between inflammatory cytokines and IVDD. This study employs Mendelian randomization (MR) to analyze the causal link between inflammatory cytokines and the risk of IVDD.

Method

We used genetic variants associated with inflammatory cytokines from a meta-analysis of genome-wide association study (GWAS) in 8293 Finns as instrumental variables and IVDD data were sourced from the FinnGen consortium. The main analytical approach utilized Inverse-Variance Weighting (IVW) with random effects to assess the causal relationship. Additionally, complementary methods such as MR-Egger, weighted median, simple mode, weighted mode, and MR pleiotropy residual sum and outlier were employed to enhance the robustness of the final results.

Result

We found interferon-gamma (IFN-γ, p = 2.14 × 10–6, OR = 0.870, 95% CI = 0.821–0.921), interleukin-1 beta (IL-1b, p = 0.012, OR = 0.951, 95% CI = 0.914–0.989), interleukin-4 (IL-4, p = 0.034, OR = 0.946, 95% CI = 0.899–0.996), interleukin-18 (IL-18, p = 0.028, OR = 0.964, 95% CI = 0.934–0.996), granulocyte colony-stimulating factor (GCSF, p = 0.010, OR = 0.919, 95% CI = 0.861–0.980), and Stromal cell-derived factor 1a (SDF1a, p = 0.014, OR = 1.072, 95% CI = 1.014–1.134) were causally associated with risk of IVDD.

Conclusion

Our MR analyses found a potential causal relationship between six inflammation cytokines (IFN-γ, IL-1b, IL-4, IL-18, SDF1a, and GCSF) and altered IVDD risk.

背景:以前的一些研究报告称,炎性细胞因子与椎间盘退变(IVDD)有关。然而,炎性细胞因子与 IVDD 之间的因果关系仍不明确。本研究采用孟德尔随机法(MR)分析炎性细胞因子与 IVDD 风险之间的因果关系:我们使用了对8293名芬兰人进行的全基因组关联研究(GWAS)荟萃分析中与炎性细胞因子相关的基因变异作为工具变量,IVDD数据来自FinnGen联盟。主要分析方法是利用带有随机效应的逆方差加权法(IVW)来评估因果关系。此外,还采用了 MR-Egger、加权中位数、简单模式、加权模式、MR 多变量残差和离群值等补充方法,以增强最终结果的稳健性:我们发现干扰素-γ(IFN-γ,p = 2.14 × 10-6,OR = 0.870,95% CI = 0.821-0.921)、白细胞介素-1 beta(IL-1b,p = 0.012,OR = 0.951,95% CI = 0.914-0.989)、白细胞介素-4(IL-4,p = 0.034,OR = 0.946,95% CI = 0.899-0.996)、白细胞介素-18(IL-18,p = 0.028,OR = 0.964,95% CI = 0.934-0.996)、粒细胞集落刺激因子(GCSF,p = 0.010,OR = 0.919,95% CI = 0.861-0.980)和基质细胞衍生因子 1a(SDF1a,p = 0.014,OR = 1.072,95% CI = 1.014-1.134)与 IVDD 风险存在因果关系:我们的磁共振分析发现,六种炎症细胞因子(IFN-γ、IL-1b、IL-4、IL-18、SDF1a 和 GCSF)与 IVDD 风险改变之间存在潜在的因果关系。
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引用次数: 0
Development of a mouse model of chronic ventral spinal cord compression: Neurobehavioral, radiological, and pathological changes 慢性腹侧脊髓压迫小鼠模型的开发:神经行为、放射学和病理学变化
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-07-10 DOI: 10.1002/jsp2.1350
Zhongyuan He, Tao Tang, Zhengya Zhu, Fuan Wang, Jianfeng Li, Fu Zhang, Nguyen Tran Canh Tung, Shaoyu Liu, Xizhe Liu, Zhiyu Zhou

Objectives

The main objective of this study was to establish a mouse model of spinal ligament ossification to simulate the chronic spinal cord compression observed in patients with ossification of the posterior longitudinal ligament (OPLL). The study also aimed to examine the mice's neurobiological, radiological, and pathological changes.

Methods

In the previous study, a genetically modified mouse strain was created using Crispr-Cas9 technology, namely, Enpp1flox/flox/EIIa-Cre (C57/B6 background), to establish the OPLL model. Wild-type (WT) mice without compression were used as controls. Functional deficits were evaluated through motor score assessment, inclined plate testing, and gait analysis. The extent of compression was determined using CT imaging. Hematoxylin and eosin staining, luxol fast blue staining, TUNEL assay, immunofluorescence staining, qPCR, and Western blotting were performed to evaluate levels of apoptosis, inflammation, vascularization, and demyelination in the study.

Results

The results demonstrated a gradual deterioration of compression in the Enpp1flox/flox/EIIa-Cre mice group as they aged. The progression rate was more rapid between 12 and 20 weeks, followed by a gradual stabilization between 20 and 28 weeks. The scores for spinal cord function and strength, assessed using the Basso Mouse Scale and inclined plate test, showed a significant decline. Gait analysis revealed a noticeable reduction in fore and hind stride lengths, stride width, and toe spread. Chronic spinal cord compression resulted in neuronal damage and activated astrocytes and microglia in the gray matter and anterior horn. Progressive posterior cervical compression impeded blood supply, leading to inflammation and Fas-mediated neuronal apoptosis. The activation of Bcl2 and Caspase 3 was associated with the development of progressive neurological deficits (p < 0.05).

Conclusions

The study presents a validated model of chronic spinal cord compression, enabling researchers to explore clinically relevant therapeutic approaches for OPLL.

研究目的本研究的主要目的是建立脊柱韧带骨化小鼠模型,以模拟后纵韧带骨化(OPLL)患者的慢性脊髓压迫症状。研究还旨在检测小鼠的神经生物学、放射学和病理学变化:在之前的研究中,我们利用 Crispr-Cas9 技术创建了一个转基因小鼠品系,即 Enpp1 flox/flox /EIIa-Cre (C57/B6 背景),以建立 OPLL 模型。无压迫的野生型(WT)小鼠作为对照组。通过运动评分评估、倾斜板测试和步态分析评估功能障碍。通过 CT 成像确定压迫程度。研究中进行了血红素和伊红染色、鲁索快蓝染色、TUNEL检测、免疫荧光染色、qPCR和Western印迹,以评估细胞凋亡、炎症、血管化和脱髓鞘的水平:结果表明,随着年龄的增长,Enpp1 flox/flox /EIIa-Cre 小鼠组的压迫症状逐渐恶化。在12周至20周期间,恶化速度更快,随后在20周至28周期间逐渐趋于稳定。使用巴索小鼠量表和斜板试验评估的脊髓功能和力量评分显示出明显的下降。步态分析显示,前后步长、步幅和脚趾张开度明显下降。慢性脊髓压迫导致神经元损伤,激活了灰质和前角的星形胶质细胞和小胶质细胞。颈椎后部的逐渐压迫阻碍了血液供应,导致炎症和 Fas 介导的神经细胞凋亡。Bcl2 和 Caspase 3 的激活与进行性神经功能缺损的发展有关(p 结论):该研究提出了一种经过验证的慢性脊髓压迫模型,使研究人员能够探索与临床相关的 OPLL 治疗方法。
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引用次数: 0
Silibinin promotes healing in spinal cord injury through anti-ferroptotic mechanisms Silibinin 通过抗发炎机制促进脊髓损伤的愈合。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-07-01 DOI: 10.1002/jsp2.1344
Arman Vahabi, Anıl Murat Öztürk, Bünyamin Kılıçlı, Derviş Birim, Gizem Kaftan Öcal, Taner Dağcı, Güliz Armağan

Study Design

Pre-clinical animal experiment.

Objective

In this study, we investigated therapeutic effects of silibinin in a spinal cord injury (SCI) model. In SCI, loss of cells due to secondary damage mechanisms exceeds that caused by primary damage. Ferroptosis, which is iron-dependent non-apoptotic cell death, is shown to be influential in the pathogenesis of SCI.

Methods

The study was conducted as an in vivo experiment using a total of 78 adult male/female Sprague Dawley rats. Groups were as follows: Sham, SCI, deferoxamine (DFO) treatment, and silibinin treatment. There were subgroups with follow-up periods of 24 h, 72 h, and 6 weeks in all groups. Malondialdehyde (MDA), glutathione (GSH), and Fe2+ levels were measured by spectrophotometry. Glutathione peroxidase-4 (GPX4), ferroportin (FPN), transferrin receptor (TfR1), and 4-hydroxynonenal (4-HNE)-modified protein levels were assessed by Western blotting. Functional recovery was assessed using Basso–Beattie–Bresnahan test.

Results

Silibinin achieved significant suppression in MDA and 4-HNE levels compared to the SCI both in 72-h and 6 weeks group (p < 0.05). GSH, GPX4, and FNP levels were found to be significantly higher in the silibinin 24 h, 72 h, and 6 weeks group compared to corresponding SCI groups (p < 0.05). Significant reduction in iron levels was observed in silibinin treated rats in 72 h and 6 weeks group (p < 0.05). Silibinin substantially suppressed TfR1 levels in 24 h and 72 h groups (p < 0.05). Significant difference among recovery capacities was observed as follows: Silibinin > DFO > SCI (p < 0.05).

Conclusion

Impact of silibinin on iron metabolism and lipid peroxidation, both of which are features of ferroptosis, may contribute to therapeutic activity. Within this context, our findings posit silibinin as a potential therapeutic candidate possessing antiferroptotic properties in SCI model. Therapeutic agents capable of effectively and safely mitigating ferroptotic cell death hold the potential to be critical points of future clinical investigations.

研究设计临床前动物实验:本研究调查了西利宾在脊髓损伤(SCI)模型中的治疗效果。在脊髓损伤(SCI)中,继发性损伤机制造成的细胞损失超过了原发性损伤造成的细胞损失。铁凋亡是一种铁依赖性非凋亡性细胞死亡,在 SCI 的发病机制中具有重要影响:研究以体内实验的形式进行,共使用 78 只成年雄性/雌性 Sprague Dawley 大鼠。分组如下SCI、去氧胺(DFO)治疗和西利宾治疗。所有组别均设有随访期为 24 小时、72 小时和 6 周的子组。用分光光度法测量丙二醛(MDA)、谷胱甘肽(GSH)和 Fe2+ 的水平。谷胱甘肽过氧化物酶-4(GPX4)、铁蛋白(FPN)、转铁蛋白受体(TfR1)和 4-羟基壬烯醛(4-HNE)修饰蛋白水平通过 Western 印迹法进行评估。采用巴索-巴蒂-布雷斯纳汉试验评估功能恢复情况:结果:与 SCI 相比,西利宾在 72 小时组和 6 周组的 MDA 和 4-HNE 水平都有明显的抑制作用(p p p p DFO > SCI(p 结论:西利宾在 72 小时组和 6 周组的 MDA 和 4-HNE 水平都有明显的抑制作用(p p p DFO > SCI):西利宾对铁代谢和脂质过氧化的影响(两者都是铁变态反应的特征)可能有助于治疗活动。在这种情况下,我们的研究结果表明,西利宾是一种潜在的候选治疗药物,在 SCI 模型中具有抗铁细胞减少的特性。能够有效、安全地减轻铁变态反应细胞死亡的治疗药物有可能成为未来临床研究的关键点。
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引用次数: 0
Efficacy of using autologous cells with graft substitutes for spinal fusion surgery: A systematic review and meta-analysis of clinical outcomes and imaging features 在脊柱融合手术中使用自体细胞和移植物替代物的疗效:临床结果和成像特征的系统回顾和荟萃分析。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-06-28 DOI: 10.1002/jsp2.1347
F. Salamanna, D. Contartese, G. Tedesco, A. Ruffilli, M. Manzetti, G. Viroli, M. Traversari, C. Faldini, G. Giavaresi

Over the past several decades, there has been a notable increase in the total number of spinal fusion procedures worldwide. Advanced spinal fusion techniques, surgical approaches, and new alternatives in grafting materials and implants, as well as autologous cellular therapies, have been widely employed for treating spinal diseases. While the potential of cellular therapies to yield better clinical results is appealing, supportive data are needed to confirm this claim. This meta-analysis aims to compare the radiographic and clinical outcomes between graft substitutes with autologous cell therapies and graft substitutes alone. PubMed, Scopus, Web of Science, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials were searched for studies comparing graft substitutes with autologous cell therapies and graft substitutes alone up to February 2024. The risk of bias of the included studies was evaluated using the Downs and Black checklist. The following outcomes were extracted for comparison: fusion success, complications/adverse events, Visual Analog Scale (VAS) score, and Oswestry Disability Index (ODI) score. Thirteen studies involving 836 patients were included, with 7 studies considered for the meta-analysis. Results indicated that the use of graft substitutes with autologous cell therapies demonstrated higher fusion success rates at 3, 6, and 12 months, lower VAS score at 6 months, and lower ODI score at 3, 6, and 12 months. The complication rate was similar between graft substitutes with autologous cell therapies and graft substitutes alone. Although the current literature remains limited, this meta-analysis suggests that the incorporation of cellular therapies such as bone marrow and platelet derivatives with graft substitutes is associated with a higher fusion rate and significant improvements in functional status and pain following spinal fusion. Future well-designed randomized clinical trials are needed to definitively assess the clinical effectiveness of cellular therapies in spinal fusion.

过去几十年来,全球脊柱融合手术的总数显著增加。先进的脊柱融合技术、手术方法、新的移植材料和植入物以及自体细胞疗法已被广泛用于治疗脊柱疾病。虽然细胞疗法有可能产生更好的临床效果,但这一说法需要支持性数据来证实。本荟萃分析旨在比较移植物替代物与自体细胞疗法和单纯移植物替代物之间的放射学和临床效果。截至 2024 年 2 月,我们在 PubMed、Scopus、Web of Science、ClinicalTrials.gov 和 Cochrane 对照试验中央注册中心检索了比较移植物替代物与自体细胞疗法和单纯移植物替代物的研究。采用Downs和Black核对表对纳入研究的偏倚风险进行了评估。提取了以下结果进行比较:融合成功率、并发症/不良事件、视觉模拟量表(VAS)评分和Oswestry残疾指数(ODI)评分。共纳入 13 项研究,涉及 836 名患者,其中 7 项研究被纳入荟萃分析。结果表明,使用移植物替代物与自体细胞疗法在3、6和12个月时的融合成功率更高,6个月时的VAS评分更低,3、6和12个月时的ODI评分更低。伴有自体细胞疗法的移植物替代物与单纯移植物替代物的并发症发生率相似。尽管目前的文献仍然有限,但这项荟萃分析表明,在移植物替代物中加入骨髓和血小板衍生物等细胞疗法与更高的融合率以及脊柱融合术后功能状态和疼痛的显著改善有关。未来还需要进行精心设计的随机临床试验,以明确评估细胞疗法在脊柱融合术中的临床效果。
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引用次数: 0
A comprehensive review of cell transplantation and platelet-rich plasma therapy for the treatment of disc degeneration-related back and neck pain: A systematic evidence-based analysis 细胞移植和富血小板血浆疗法治疗椎间盘退变相关背痛和颈痛的综合综述:基于证据的系统分析。
IF 3.4 3区 医学 Q1 ORTHOPEDICS Pub Date : 2024-06-24 DOI: 10.1002/jsp2.1348
Jordy Schol, Shota Tamagawa, Tibo Nico Emmie Volleman, Muneaki Ishijima, Daisuke Sakai

Low back pain (LBP) and neck pain predominate as the primary causes of disability. Cell- and platelet-rich plasma (PRP) products are potential therapies with clinical trials and reviews promoting their efficacy. Nonetheless, they frequently disregard the clinical significance of reported improvements. In this systematic review, the effectuated improvements in pain, disability, quality of life (QoL), and radiographic images are comprehensively described and scored on their clinical significance. An electronic database literature search was conducted on July 2023 for in-human assessment of cell or PRP products to alleviate discogenic pain. Papers were screened on quantitative pain, disability, QoL, radiographic improvements, and safety outcomes. Risk of bias was assessed through MINORS and Cochrane Source of Bias tools. Reported outcomes were obtained, calculated, and assessed to meet minimal clinically important difference (MCID) standards. From 7623 screened papers, a total of 80 articles met the eligibility criteria, presenting 68 specific studies. These presented at least 1974 treated patients. Overall, cell/PRP injections could alleviate pain and disability, resulting in MCID for pain and disability in up to a 2-year follow-up, similar to those observed in patients undergoing spinal fusion. Included trials predominantly presented high levels of bias, involved heterogeneous study designs, and only a minimal number of randomized controlled trials. Nonetheless, a clear clinically significant impact was observed for cell- and PRP-treated cohorts with overall good safety profiles. These results highlight a strong therapeutic potential but also underline the need for future cost-effectiveness assessments to determine the benefits of cell/PRP treatments.

腰痛(LBP)和颈痛是导致残疾的主要原因。细胞和富血小板血浆(PRP)产品是一种潜在的疗法,临床试验和评论都在宣传其疗效。然而,这些临床试验和综述往往忽视了所报道的改善效果的临床意义。在这篇系统性综述中,对疼痛、残疾、生活质量(QoL)和放射影像的有效改善进行了全面描述,并对其临床意义进行了评分。2023 年 7 月,我们在电子数据库中搜索了有关细胞或 PRP 产品缓解椎间盘源性疼痛的人体评估文献。筛选的论文涉及定量疼痛、残疾、QoL、放射学改善和安全性结果。通过 MINORS 和 Cochrane 偏倚来源工具评估偏倚风险。对报告的结果进行了获取、计算和评估,以符合最小临床重要性差异 (MCID) 标准。从筛选出的 7623 篇论文中,共有 80 篇符合资格标准,其中 68 篇为具体研究。其中至少有 1974 名患者接受了治疗。总体而言,细胞/PRP注射可减轻疼痛和残疾,在长达2年的随访中,疼痛和残疾的MCID与接受脊柱融合术的患者所观察到的相似。所纳入的试验主要存在高度偏倚,研究设计不尽相同,只有极少量的随机对照试验。尽管如此,我们还是观察到细胞和 PRP 治疗组群具有明显的临床效果,而且总体安全性良好。这些结果凸显了强大的治疗潜力,但也强调了未来进行成本效益评估的必要性,以确定细胞/PRP疗法的益处。
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引用次数: 0
Static study and numerical simulation of the influence of cement distribution in the upper and lower adjacent vertebrae on sandwich vertebrae in osteoporotic patients: Finite element analysis 骨质疏松症患者上下相邻椎体骨水泥分布对三明治椎体影响的静态研究和数值模拟:有限元分析
IF 3.4 3区 医学 Q1 Medicine Pub Date : 2024-06-21 DOI: 10.1002/jsp2.1343
Shaolong Huang, Xue Wu, Chengqiang Zhou, Xu Zhang, Zhongjian Tang, Xiangyu Qi, Shuai Zhao

Objective

We analyzed the influence of the location of the upper and lower cement on the sandwich vertebrae (SV) by computer finite element analysis.

Materials and Methods

A finite element model of the spinal segment of T11-L1 was constructed and 6 mL of cement was built into T11 and L1 simultaneously. According to the various distributions of bone cement at T11 and L1, the following four groups were formed: (i) Group B-B: bilateral bone cement reinforcement in both T11 and L1 vertebral bodies; (ii) Group L-B: left unilateral reinforcement in T11 and bilateral reinforcement in L1; (iii) Group L-R: unilateral cement reinforcement in both T11 and L1 (cross); (iv) Group L-L: unilateral cement reinforcement in both T11 and L1 (ipsilateral side). The maximum von Mises stress (VMS) and maximum displacement of the SV and intervertebral discs were compared and analyzed.

Results

The maximum VMS of T12 was in the order of size: group B-B < L-B < L-R < L-L. Group B-B showed the lowest maximum VMS values for T12: 19.13, 18.86, 25.17, 25.01, 19.24, and 20.08 MPa in six directions of load flexion, extension, left and right lateral bending, and left and right rotation, respectively, while group L-L was the largest VMS in each group, with the maximum VMS in six directions of 21.55, 21.54, 30.17, 28.33, 19.88, and 25.27 MPa, respectively.

Conclusion

Compared with the uneven distribution of bone cement in the upper and lower adjacent vertebrae (ULAV), the uniform distribution of bone cement in the ULAV reduced and uniformed the stress load on the SV and intervertebral disc. Theoretically, it can lead to the lowest incidence of sandwich vertebral fracture and the slowest rate of intervertebral disc degeneration.

目的 通过计算机有限元分析,分析上下骨水泥位置对夹层椎体(SV)的影响。 材料与方法 建立 T11-L1 脊柱的有限元模型,在 T11 和 L1 中同时植入 6 mL 骨水泥。根据骨水泥在 T11 和 L1 的不同分布,分为以下四组:(i) B-B 组:T11 和 L1 椎体双侧骨水泥加固;(ii) L-B 组:T11 左侧单侧加固,L1 双侧加固;(iii) L-R 组:T11 和 L1 单侧骨水泥加固(交叉);(iv) L-L 组:T11 和 L1 单侧骨水泥加固(同侧)。对 SV 和椎间盘的最大 von Mises 应力(VMS)和最大位移进行了比较和分析。 结果 T12 的最大 VMS 依次为:B-B 组;L-B 组;L-R 组;L-L 组。B-B 组 T12 的最大 VMS 值最低,在负荷屈曲、伸展、左右侧弯、左右旋转六个方向的最大 VMS 值分别为 19.13、18.86、25.17、25.01、19.24 和 20.08 MPa,而 L-L 组是各组中 VMS 值最大的,六个方向的最大 VMS 值分别为 21.55、21.54、30.17、28.33、19.88 和 25.27 MPa。 结论 与骨水泥在上下相邻椎体(ULAV)的不均匀分布相比,骨水泥在 ULAV 的均匀分布降低并均匀了 SV 和椎间盘的应力负荷。从理论上讲,它可以使夹层椎体骨折的发生率最低,椎间盘退变的速度最慢。
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引用次数: 0
Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study 循环炎症蛋白对脊柱退行性疾病的影响:遗传相关性和孟德尔随机研究的证据。
IF 3.7 3区 医学 Q1 Medicine Pub Date : 2024-06-17 DOI: 10.1002/jsp2.1346
Qingcong Zheng, Rongjie Lin, Du Wang, Chunfu Zheng, Weihong Xu

Background

Numerous investigations have suggested links between circulating inflammatory proteins (CIPs) and spinal degenerative diseases (SDDs), but causality has not been proven. This study used Mendelian randomization (MR) to investigate the causal associations between 91 CIPs and cervical spondylosis (CS), prolapsed disc/slipped disc (PD/SD), spinal canal stenosis (SCS), and spondylolisthesis/spondylolysis.

Methods

Genetic variants data for CIPs and SDDs were obtained from the genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary method, analyzing the validity and robustness of the results through pleiotropy and heterogeneity tests and performing reverse MR analysis to test for reverse causality.

Results

The IVW results with Bonferroni correction indicated that beta-nerve growth factor (β-NGF), C-X-C motif chemokine 6 (CXCL6), and interleukin-6 (IL-6) can increase the risk of CS. Fibroblast growth factor 19 (FGF19), sulfotransferase 1A1 (SULT1A1), and tumor necrosis factor-beta (TNF-β) can increase PD/SD risk, whereas urokinase-type plasminogen activator (u-PA) can decrease the risk of PD/SD. FGF19 and TNF can increase SCS risk. STAM binding protein (STAMBP) and T-cell surface glycoprotein CD6 isoform (CD6 isoform) can increase the risk of spondylolisthesis/spondylolysis, whereas monocyte chemoattractant protein 2 (MCP2) and latency-associated peptide transforming growth factor beta 1 (LAP-TGF-β1) can decrease spondylolisthesis/spondylolysis risk.

Conclusions

MR analysis indicated the causal associations between multiple genetically predicted CIPs and the risk of four SDDs (CS, PD/SD, SCS, and spondylolisthesis/spondylolysis). This study provides reliable genetic evidence for in-depth exploration of the involvement of CIPs in the pathogenic mechanism of SDDs and provides novel potential targets for SDDs.

背景:大量研究表明,循环炎症蛋白(CIPs)与脊柱退行性疾病(SDDs)之间存在联系,但因果关系尚未得到证实。本研究采用孟德尔随机法(MR)调查了91种CIPs与颈椎病(CS)、椎间盘突出/椎间盘脱出(PD/SD)、椎管狭窄(SCS)和脊椎滑脱症/脊椎溶解症之间的因果关系:CIPs 和 SDDs 的遗传变异数据来自全基因组关联研究(GWAS)数据库。我们以反向方差加权(IVW)为主要方法,通过多向性和异质性检验分析结果的有效性和稳健性,并进行反向MR分析以检验反向因果关系:经 Bonferroni 校正的 IVW 结果表明,β-神经生长因子(β-NGF)、C-X-C 矩阵趋化因子 6(CXCL6)和白细胞介素 6(IL-6)可增加 CS 风险。成纤维细胞生长因子 19(FGF19)、磺基转移酶 1A1(SULT1A1)和肿瘤坏死因子-β(TNF-β)可增加 PD/SD 风险,而尿激酶型纤溶酶原激活剂(u-PA)可降低 PD/SD 风险。FGF19和TNF可增加SCS风险。STAM结合蛋白(STAMBP)和T细胞表面糖蛋白CD6同工酶(CD6同工酶)可增加脊柱骨化/椎体溶解风险,而单核细胞趋化蛋白2(MCP2)和潜伏相关肽转化生长因子β1(LAP-TGF-β1)可降低脊柱骨化/椎体溶解风险:磁共振分析表明,多种基因预测的 CIP 与四种 SDD(CS、PD/SD、SCS 和脊柱滑脱症/椎体溶解症)风险之间存在因果关系。这项研究为深入探讨CIPs参与SDDs的致病机制提供了可靠的遗传学证据,并为SDDs提供了新的潜在靶点。
{"title":"Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study","authors":"Qingcong Zheng,&nbsp;Rongjie Lin,&nbsp;Du Wang,&nbsp;Chunfu Zheng,&nbsp;Weihong Xu","doi":"10.1002/jsp2.1346","DOIUrl":"10.1002/jsp2.1346","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Numerous investigations have suggested links between circulating inflammatory proteins (CIPs) and spinal degenerative diseases (SDDs), but causality has not been proven. This study used Mendelian randomization (MR) to investigate the causal associations between 91 CIPs and cervical spondylosis (CS), prolapsed disc/slipped disc (PD/SD), spinal canal stenosis (SCS), and spondylolisthesis/spondylolysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Genetic variants data for CIPs and SDDs were obtained from the genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary method, analyzing the validity and robustness of the results through pleiotropy and heterogeneity tests and performing reverse MR analysis to test for reverse causality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The IVW results with Bonferroni correction indicated that beta-nerve growth factor (β-NGF), C-X-C motif chemokine 6 (CXCL6), and interleukin-6 (IL-6) can increase the risk of CS. Fibroblast growth factor 19 (FGF19), sulfotransferase 1A1 (SULT1A1), and tumor necrosis factor-beta (TNF-β) can increase PD/SD risk, whereas urokinase-type plasminogen activator (u-PA) can decrease the risk of PD/SD. FGF19 and TNF can increase SCS risk. STAM binding protein (STAMBP) and T-cell surface glycoprotein CD6 isoform (CD6 isoform) can increase the risk of spondylolisthesis/spondylolysis, whereas monocyte chemoattractant protein 2 (MCP2) and latency-associated peptide transforming growth factor beta 1 (LAP-TGF-β1) can decrease spondylolisthesis/spondylolysis risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MR analysis indicated the causal associations between multiple genetically predicted CIPs and the risk of four SDDs (CS, PD/SD, SCS, and spondylolisthesis/spondylolysis). This study provides reliable genetic evidence for in-depth exploration of the involvement of CIPs in the pathogenic mechanism of SDDs and provides novel potential targets for SDDs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11183170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A fully automatic MRI-guided decision support system for lumbar disc herniation using machine learning 利用机器学习的全自动腰椎间盘突出症 MRI 指导决策支持系统。
IF 3.7 3区 医学 Q1 Medicine Pub Date : 2024-05-30 DOI: 10.1002/jsp2.1342
Di Zhang, Jiawei Du, Jiaxiao Shi, Yundong Zhang, Siyue Jia, Xingyu Liu, Yu Wu, Yicheng An, Shibo Zhu, Dayu Pan, Wei Zhang, Yiling Zhang, Shiqing Feng

Background

Normalized decision support system for lumbar disc herniation (LDH) will improve reproducibility compared with subjective clinical diagnosis and treatment. Magnetic resonance imaging (MRI) plays an essential role in the evaluation of LDH. This study aimed to develop an MRI-based decision support system for LDH, which evaluates lumbar discs in a reproducible, consistent, and reliable manner.

Methods

The research team proposed a system based on machine learning that was trained and tested by a large, manually labeled data set comprising 217 patients' MRI scans (3255 lumbar discs). The system analyzes the radiological features of identified discs to diagnose herniation and classifies discs by Pfirrmann grade and MSU classification. Based on the assessment, the system provides clinical advice.

Results

Eventually, the accuracy of the diagnosis process reached 95.83%. An 83.5% agreement was observed between the system's prediction and the ground-truth in the Pfirrmann grade. In the case of MSU classification, 95.0% precision was achieved. With the assistance of this system, the accuracy, interpretation efficiency and interrater agreement among surgeons were improved substantially.

Conclusion

This system showed considerable accuracy and efficiency, and therefore could serve as an objective reference for the diagnosis and treatment procedure in clinical practice.

背景:与主观临床诊断和治疗相比,腰椎间盘突出症(LDH)的规范化决策支持系统将提高可重复性。磁共振成像(MRI)在腰椎间盘突出症的评估中起着至关重要的作用。本研究旨在开发一种基于磁共振成像的 LDH 决策支持系统,该系统能以可重复、一致和可靠的方式评估腰椎间盘:研究小组提出了一种基于机器学习的系统,该系统由一个人工标注的大型数据集进行训练和测试,该数据集由 217 名患者的 MRI 扫描(3255 个腰椎间盘)组成。该系统通过分析已识别椎间盘的放射学特征来诊断椎间盘突出症,并根据 Pfirrmann 等级和 MSU 分类对椎间盘进行分类。根据评估结果,系统提供临床建议:结果:诊断过程的准确率最终达到 95.83%。在 Pfirrmann 等级方面,系统预测与地面实况的一致性达到 83.5%。在 MSU 分级方面,精确度达到了 95.0%。在该系统的帮助下,外科医生的准确性、解释效率和医生间的一致性都得到了大幅提高:结论:该系统显示出相当高的准确性和效率,因此可作为临床实践中诊断和治疗程序的客观参考。
{"title":"A fully automatic MRI-guided decision support system for lumbar disc herniation using machine learning","authors":"Di Zhang,&nbsp;Jiawei Du,&nbsp;Jiaxiao Shi,&nbsp;Yundong Zhang,&nbsp;Siyue Jia,&nbsp;Xingyu Liu,&nbsp;Yu Wu,&nbsp;Yicheng An,&nbsp;Shibo Zhu,&nbsp;Dayu Pan,&nbsp;Wei Zhang,&nbsp;Yiling Zhang,&nbsp;Shiqing Feng","doi":"10.1002/jsp2.1342","DOIUrl":"10.1002/jsp2.1342","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Normalized decision support system for lumbar disc herniation (LDH) will improve reproducibility compared with subjective clinical diagnosis and treatment. Magnetic resonance imaging (MRI) plays an essential role in the evaluation of LDH. This study aimed to develop an MRI-based decision support system for LDH, which evaluates lumbar discs in a reproducible, consistent, and reliable manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The research team proposed a system based on machine learning that was trained and tested by a large, manually labeled data set comprising 217 patients' MRI scans (3255 lumbar discs). The system analyzes the radiological features of identified discs to diagnose herniation and classifies discs by Pfirrmann grade and MSU classification. Based on the assessment, the system provides clinical advice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eventually, the accuracy of the diagnosis process reached 95.83%. An 83.5% agreement was observed between the system's prediction and the ground-truth in the Pfirrmann grade. In the case of MSU classification, 95.0% precision was achieved. With the assistance of this system, the accuracy, interpretation efficiency and interrater agreement among surgeons were improved substantially.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This system showed considerable accuracy and efficiency, and therefore could serve as an objective reference for the diagnosis and treatment procedure in clinical practice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Kinematics, kinetics, and new insights from a contemporary analysis of the first experiments to produce cervical facet dislocations in the laboratory 运动学、动力学以及对首次在实验室中产生颈椎面脱位的实验进行当代分析后得出的新见解
IF 3.7 3区 医学 Q1 Medicine Pub Date : 2024-05-27 DOI: 10.1002/jsp2.1336
Ryan D. Quarrington, Robert Bauze, Claire F. Jones

Background

The first experimental study to produce cervical facet dislocation (CFD) in cadaver specimens captured the vertebral motions and axial forces that are important for understanding the injury mechanics. However, these data were not reported in the original manuscript, nor been presented in the limited subsequent studies of experimental CFD. Therefore, the aim of this study was to re-examine the analog data from the first experimental study to determine the local and global spinal motions, and applied axial force, at and preceding CFD.

Methods

In the original study, quasistatic axial loading was applied to 14 cervical spines by compressing them between two metal plates. Specimens were fixed caudally via a steel spindle positioned within the spinal canal and a bone pin through the inferior-most vertebral body. Global rotation of the occiput was restricted but its anterior translation was unconstrained. The instant of CFD was identified on sagittal cineradiograph films (N = 10), from which global and intervertebral kinematics were also calculated. Corresponding axial force data (N = 6) were extracted, and peak force and force at the instant of injury were determined.

Results

CFD occurred in eight specimens, with an intervertebral flexion angle of 34.8 ± 5.6 degrees, and a 3.1 ± 1.9 mm increase in anterior translation, at the injured level. For seven specimens, CFD was produced at the level of transition from upper neck lordosis to lower neck kyphosis. Five specimens with force data underwent CFD at 545 ± 147 N, preceded by a peak axial force (755 ± 233 N) that appeared to coincide with either fracture or soft tissue failure.

Conclusions

Re-examining this rich dataset has provided quantitative evidence that small axial compression forces, combined with anterior eccentricity and upper neck extension, can cause flexion and shear in the lower neck, leading to soft tissue rupture and CFD.

背景 首次在尸体标本中进行颈椎面脱位(CFD)的实验研究捕捉到了对了解损伤力学非常重要的椎体运动和轴向力。然而,这些数据并未在原稿中报告,也未在后续有限的 CFD 实验研究中呈现。因此,本研究旨在重新审查第一项实验研究中的模拟数据,以确定 CFD 时和之前的局部和整体脊柱运动以及施加的轴向力。 方法 在最初的研究中,通过将 14 根颈椎压缩在两块金属板之间,对其施加等静态轴向负荷。通过椎管内的钢轴和穿过最下椎体的骨针将标本固定在尾部。枕骨的整体旋转受到限制,但其前移不受任何限制。在矢状面放射摄影胶片上确定 CFD 的瞬间(N = 10),并从中计算出整体和椎体间的运动学数据。提取了相应的轴向力数据(N = 6),并确定了峰值力和损伤瞬间的力。 结果 8 个标本出现了 CFD,受伤水平的椎体间屈曲角度为 34.8 ± 5.6 度,前移增加了 3.1 ± 1.9 毫米。七个标本的 CFD 是在上颈椎前凸过渡到下颈椎后凸的水平制作的。五个有受力数据的标本在 545 ± 147 牛顿时进行了 CFD,在此之前的轴向力峰值(755 ± 233 牛顿)似乎与骨折或软组织破坏相吻合。 结论 对这一丰富数据集的重新研究提供了定量证据,证明较小的轴向压缩力加上前偏心和上颈部伸展,可导致下颈部弯曲和剪切,从而导致软组织断裂和 CFD。
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引用次数: 0
Why clinical trials in disc regeneration strive to achieve completion: Insights from publication status and funding sources 椎间盘再生临床试验为何难以完成?从发表情况和资金来源看问题
IF 3.7 3区 医学 Q1 Medicine Pub Date : 2024-05-24 DOI: 10.1002/jsp2.1329
Luca Ambrosio, Giorgia Petrucci, Fabrizio Russo, Claudia Cicione, Rocco Papalia, Gianluca Vadalà, Vincenzo Denaro

Background

Chronic discogenic low back pain (LBP) poses a significant global burden, yet effective therapeutic interventions directly targeting the underlying degenerative process remain elusive. After demonstrating promising results in preclinical studies, intradiscal injection of cell-based treatments has been increasingly investigated in the clinical setting. However, most clinical trials failed to reach publication, with the few available reports showing only minor improvements. The aim of this study was to analyze the prospective clinical trials registered on ClinicalTrials.gov investigating cell therapies for LBP, with a specific emphasis on identifying critical obstacles hindering study completion, including trial design and funding sources.

Methods

A systematic search of prospective clinical trials investigating cell-based treatments for chronic LBP due to intervertebral disc degeneration was performed on ClinicalTrials.gov. Extracted data encompassed study design, recruitment, experimental treatment modalities, investigated outcomes, current status, completion date, publication status, and funding sources. Fisher's exact test assessed associations between categorical variables, while a multiple logistic regression model aimed to identify factors potentially linked to the publication status of the studies.

Results

Our search identified 26 clinical trials. Among these, only 7 (26.9%) were published, and none of the other studies marked as completed reported any results on ClinicalTrials.gov. Fifty percent of included trials were funded by universities, whereas the rest was sponsored by industry (38.5%) or private institutions (11.5%). Experimental treatments primarily involved cell-based or cell-derived products of varying sources and concentrations. Products containing carriers, such as hyaluronic acid or fibrin, were more frequently funded by industry and private organizations (p = 0.0112). No significant differences emerged when comparing published and nonpublished studies based on funding, as well as between publication status and other variables.

Conclusion

Most clinical trials exploring cell-based disc regenerative therapies for chronic LBP have never reached completion, with only a small fraction reporting preliminary data in publications.

背景 慢性椎间盘源性腰背痛(LBP)给全球带来了沉重负担,但直接针对潜在退行性病变过程的有效治疗干预措施却仍未见踪影。椎间盘内注射细胞疗法在临床前研究中取得了可喜的成果,因此越来越多的临床研究开始关注这种疗法。然而,大多数临床试验都未能发表,仅有的几份报告也只显示出轻微的改善。本研究的目的是分析在 ClinicalTrials.go 上注册的研究椎间盘突出症细胞疗法的前瞻性临床试验,重点是找出阻碍研究完成的关键因素,包括试验设计和资金来源。 方法 在ClinicalTrials.gov上对研究椎间盘退变引起的慢性枸杞痛的细胞疗法的前瞻性临床试验进行了系统检索。提取的数据包括研究设计、招募、实验治疗方式、调查结果、当前状态、完成日期、发表状态和资金来源。费雪精确检验评估了分类变量之间的关联,而多元逻辑回归模型则旨在确定与研究发表状态相关的潜在因素。 结果 我们的搜索发现了 26 项临床试验。其中只有 7 项(26.9%)已发表,其他标注为已完成的研究均未在 ClinicalTrials.gov 上报告任何结果。50%的纳入试验由大学资助,其余试验则由企业(38.5%)或私人机构(11.5%)赞助。实验治疗主要涉及不同来源和浓度的细胞或细胞衍生产品。含有载体(如透明质酸或纤维蛋白)的产品更多地由工业界和私人机构资助(p = 0.0112)。比较已发表和未发表研究的资金情况,以及发表情况和其他变量之间的差异并不明显。 结论 大多数探索基于细胞的椎间盘再生疗法治疗慢性腰椎间盘突出症的临床试验从未完成,只有一小部分在出版物中报告了初步数据。
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引用次数: 0
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JOR Spine
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