多节段腰椎间盘突出症的责任节段治疗与整体治疗的临床疗效比较

目的:研究和比较不同的治疗方式(责任节段治疗与整体治疗)治疗多节段腰椎间盘突出症(Herniation of Mutisegmented Lumber Intervertebral Disc,HMLD)的临床疗效及安全性。方法:对2010.01年至2013.01在我科明确诊断为多节段腰椎间盘突出且行手术治疗的共计78例患者进行回顾性分析。按照治疗方式的不同分为责任节段组(实验组,42例)和整体治疗组(对照组,36例)。结合手术前后的随访资料,评价并比较两组患者的疼痛模拟评分(VAS)、JOA功能评分及围手术期的手术时间、术中出血量、术后下地时间,花费,并发症等指标。结果:实验结果显示,实验组与对照组在术后6月,12月及36月的VAS疼痛评分及JOA评分的比较中并无显著性差异(P0.05)。但术后第二日实验组患者的疼痛程度显著好于对照组(P0.05)。实验组的术中出血量、花费及下地时间显著优于对照组(P0.05)。在并发症方面,术后1年内,实验组的并发症发生率显著优于对照组(P0.05);术后1年后,对照组的发生率较好,但两组间均无统计学差异(P0.05)。结论:对于多节段椎间盘突出症,找到责任节段并针对责任节段进行治疗较整体治疗来讲,能够在取得相似治疗效果和安全性的同时,能够有效的减少花费,手术创伤及术后疼痛指标,并能有效减少短期并发症的发生。在多节段腰椎间盘突出症的治疗中可以作为一种推荐的手术术式。     

Characterization of Cre recombinase mouse lines enabling cell type-specific targeting of postnatal intervertebral discs

Cre/loxP technology is an important tool for studying cell type-specific gene functions. Cre recombinase mouse lines, including Agc1-CreER^T2, Col2a1-Cre; Col2a1-CreER^T2, Shh-Cre, Shh-CreER^T2, and Osx-Cre, have been proven to be valuable tools to elucidate the biology of long bones, yet the information for their activity in postnatal intervertebral disc (IVD) tissues was very limited. In this study, we used R26-mTmG fluorescent reporter to systematically analyze cell specificity and targeting efficiency of these six mouse lines in IVD tissues at postnatal growing and adult stages. We found that Agc1-CreER^T2 is effective to direct recombination in all components of IVDs, including annulus fibrosus (AF), nucleus pulposus (NP), and cartilaginous endplate (CEP), upon tamoxifen induction at either 2 weeks or 2 months of ages. Moreover, Col2a1-Cre targets most of the cells in IVDs, except for some cells in the outer AF (OAF) and NP. In contrast, the activity of Col2a1-CreER^T2 is mainly limited to the IAF of IVD tissues at either stage of tamoxifen injection. Similarly, Shh-Cre directs recombination specifically in all NP cells, whereas Shh-CreER^T2 is active only in a few NP cells when tamoxifen is administered at either stage. Finally, Osx-Cre targets cells in the CEP, but not in the NP or AF of IVDs tissues at these two stages. Thus, our data demonstrated that all these Cre lines can direct recombination in IVD tissues at postnatal stages with different cell type specificity and/or targeting efficiency, and can, therefore, serve as valuable tools to dissect cell type-specific gene functions in IVD development and homeostasis.     

Temporal changes of mechanical signals and extracellular composition in human intervertebral disc during degenerative progression

In this study, a three-dimensional finite element model was used to investigate the changes in tissue composition and mechanical signals within human lumbar intervertebral disc during the degenerative progression. This model was developed based on the cell-activity coupled mechano-electrochemical mixture theory. The disc degeneration was simulated by lowering nutrition levels at disc boundaries, and the temporal and spatial distributions of the fixed charge density, water content, fluid pressure, Von Mises stress, and disc deformation were analyzed. Results showed that fixed charge density, fluid pressure, and water content decreased significantly in the nucleus pulposus (NP) and the inner to middle annulus fibrosus (AF) regions of the degenerative disc. It was found that, with degenerative progression, the Von Mises stress (relative to that at healthy state) increased within the disc, with a larger increase in the outer AF region. Both the disc volume and height decreased with the degenerative progression. The predicted results of fluid pressure change in the NP were consistent with experimental findings in the literature. The knowledge of the variations of temporal and spatial distributions of composition and mechanical signals within the human IVDs provide a better understanding of the progression of disc degeneration.     

腰椎旁神经阻滞联合超短波对腰椎间盘突出症患者疼痛及腰背肌生物力学性能的影响

目的:探讨腰椎旁神经阻滞联合超短波对腰椎间盘突出症疼痛及腰背肌生物力学性能的影响。方法:选择我院2014年2月~2016年8月收治的98例腰椎间盘突出症患者,按抽签法分组对照组与研究组。对照组采用腰椎旁神经阻滞治疗,研究组基于对照组加用超短波治疗。观察两组的临床疗效、治疗前后视觉模拟评分(VAS)、60°/s角速、120°/s角速平均功率(AP)、峰力矩(PT)、腰背屈/伸比值(F/E)、血清P物质(SP)、β-内啡肽(β-EP)、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平的变化及不良反应的发生情况。结果:研究组总有效率为95.91%,显著高于对照组,差异有统计学意义(P0.05)。治疗后,两组F/E值、血清SP、IL-6、TNF-α水平均较治疗前显著降低,且研究组以上指标均明显低于对照组,两组AP、PT、血清β-EP水平均较治疗前明显上升,且研究组以上指标显著高于对照组,差异均有统计学意义(P0.05)。两组不良反应的发生率比较差异无统计学意义(P0.05)。结论:腰椎旁神经阻滞联合超短波治疗腰椎间盘突出症的效果明显优于单用腰椎旁神经阻滞治疗,其可有效缓解疼痛及改善腰背肌生物力学性能,并减轻炎症反应。     

Autophagy and KRT8/keratin 8 protect degeneration of retinal pigment epithelium under oxidative stress

Contribution of autophagy and regulation of related proteins to the degeneration of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD) remain unknown. We report that upregulation of KRT8 (keratin 8) as well as its phosphorylation are accompanied with autophagy and attenuated with the inhibition of autophagy in RPE cells under oxidative stress. KRT8 appears to have a dual role in RPE pathophysiology. While increased expression of KRT8 following autophagy provides a cytoprotective role in RPE, phosphorylation of KRT8 induces pathologic epithelial-mesenchymal transition (EMT) of RPE cells under oxidative stress, which is mediated by MAPK1/ERK2 (mitogen-activated protein kinase 1) and MAPK3/ERK1. Inhibition of autophagy further promotes EMT, which can be reversed by inhibition of MAPK. Thus, regulated enhancement of autophagy with concurrent increased expression of KRT8 and the inhibition of KRT8 phosphorylation serve to inhibit oxidative stress-induced EMT of RPE cells as well as to prevent cell death, suggesting that pharmacological manipulation of KRT8 upregulation through autophagy with combined inhibition of the MAPK1/3 pathway may be attractive therapeutic strategies for the treatment of AMD.     

Basal forebrain cholinergic system in the dementias: Vulnerability,resilience, and resistance

The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD-TAU) and the TDP-43 proteinopathy of FTLD-TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD-TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD-TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.

     

性别因素对GRK5缺陷小鼠AD样病理改变的影响

目的性别在阿尔茨海默病（AD）的发病中是一不容忽视的危险因素。研究揭示G蛋白偶联受体（GPCRs）激酶5（GRK5）缺陷引起的相关GPCRs脱敏障碍在早期AD病理发生机制中具有重要作用，而且GRK5敲除／缺陷（GRK5KO）小鼠表现出早期AD样病理特征和短时期记忆功能损害。但这种病理变化在不同性别间有无差异，目前不得而知。本研究旨在探讨GRK5KO小鼠出现的AD样病理变化是否存在性别差异。方法用Campbell-Switzer银染来观察老龄GRK5KO小鼠海马内肿胀轴突的病理变化；Western blotting检测海马内突触蛋白水平和数个胆碱能标记物的变化；同时对上述改变在不同性别间进行深入比较。结果雌性GRK5KO小鼠海马内肿胀轴突数目比雄性小鼠高出2．5倍；而且雌性GRK5KO小鼠海马内数个突触蛋白水平比雄性小鼠显著减低。双因素方差分析显示性别和GRK5缺陷双因素之间呈显著协同效应，共同促进了雌性GRK5KO小鼠轴突缺陷和部分突触蛋白水平的降低。另外，胆碱能标记物检测显示，雌性GRK5KO小鼠毒蕈碱受体2、4以及乙酰胆碱酯酶水平较雄性小鼠显著增高。结论在促进早期AD病理发生的过程中，GRK5缺陷和性别双因素表现出协同效应，共同加剧了雌性GRK5KO小鼠脑内的AD样病理改变。     

Functional role of hedgehog pathway in osteoarthritis

The hedgehog signalling pathway is one of the key regulators of metazoan development, and it plays an important role in the regulation of a variety of developmental and physiological processes. But it is aberrantly activated in many human diseases, including osteoarthritis (OA). In this study, we have reviewed the association of hedgehog signalling pathway in the development and progression of OA and evaluated the efforts to target this pathway for the prevention of OA. Usually in OA, activation of hedgehog induces up-regulation of the expression of hypertrophic markers, including type X collagen, increases production of nitric oxide and prostaglandin E2, several matrix-degrading enzymes including matrix metalloproteinase and a disintegrin and metalloproteinase with thrombospondin motifs in human knee joint cartilage leading to cartilage degeneration, and thus contributes in OA. Targeting hedgehog signalling might be a viable strategy to prevent or treat OA. Chemical inhibitors of hedgehog signalling is promising, but they cause severe side effects. Knockdown of HH gene is not an option for OA treatment in humans because it is not possible to delete HH in larger animals. Efficient knockdown of HH achieved by local delivery of small interfering RNA in future studies utilizing large animal OA models might be a more efficient approach for the prevention of OA. However, it remains a major problem to develop one single scaffold due to the different physiological functions of cartilage and subchondral bones possess. More studies are necessary to identify selective inhibitors for efficiently targeting the hedgehog pathway in clinical conditions.     

Finite elements/Taguchi method based procedure for the identification of the geometrical parameters significantly affecting the biomechanical behavior of a lumbar disc

The aim of this work is to show a quick and simple procedure able to identify the geometrical parameters of the intervertebral disc that strongly affect the behavior of the FEM model. First, we allocated a selection criterion for the minimum number of geometrical parameters that describe, with a good degree of approximation, a healthy human vertebra. Next, we carried out a sensitivity analysis using the ‘Taguchi orthogonal array’ to arrive at a quick identification of the parameters that strongly affect the behavior of the Fem model.     

A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization

Elevated vascular endothelial growth factor (VEGF) and complement activation are implicated in the pathogenesis of different ocular diseases. The objective of this study was to investigate the hypothesis that dual inhibition of both VEGF and complement activation would confer better protection against ocular inflammation and neovascularization. In this study, we engineered a secreted chimeric VEGF inhibitor domain (VID), a complement inhibitor domain (CID) and a dual inhibitor (ACVP1). Vectors expressing these three inhibitors were constructed and packaged into AAV2 (sextY‐F) particles. The expression and secretion of the proteins were validated by Western blot. The effects of these inhibitors expressed from AAV2 vectors were examined in endotoxin‐induced uveitis (EIU), experimental autoimmune uveoretinitis (EAU) and choroidal neovascularization (CNV) mouse models. The AAV2 vectors expressing the CID‐ and ACVP1‐attenuated inflammation in EIU and EAU model, whereas the vector expressing VID showed improved retinal structure damaged by EAU, but not affect the infiltration of inflammatory cells in EAU or EIU eyes. Both VID and CID vectors improved laser‐induced retinal and choroid/RPE injuries and CNV, whereas ACVP1 vector provided significantly better protection. Our results suggest that gene therapy targeting VEGF and complement components could provide an innovative and long‐term strategy for ocular inflammatory and neovascular diseases.