We found that hypoxia can enhance the angiogenic ability of IVD during inflammatory reactions, and cause progress in development of DDD via extracellular matrix regulation in this in vitro study.

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Ligamentum flavum hypertrophy (LFH) is the most important component of lumbar spinal canal stenosis. Although the pathophysiology of LFH has been extensively studied, no method has been proposed to prevent or treat it. Since the transforming growth factor‐β (TGF‐β) pathway is known to be critical in LFH pathology, we investigated whether LFH could be prevented by blocking or modulating the TGF‐β mechanism. Human LF cells were used for the experiments. First, we created TGF‐β receptor 1 (TGFBR1) knock out (KO) cells with CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 biotechnology and treated them with TGF‐β1 to determine the effects of blocking the TGF‐β pathway. Subsequently, we studied the effect of CCN5, which has recently been proposed to modulate the TGF‐β pathway. To assess the predisposition toward fibrosis, α‐smooth muscle actin (αSMA), fibronectin, collagen‐1, collagen‐3, and CCN2 were evaluated with quantitative real‐time polymerase chain reaction, western blotting, and immunocytochemistry. The TGFBR1 KO LF cells were successfully constructed with high KO efficiency. In wild‐type (WT) cells, treatment with TGF‐β1 resulted in the overexpression of the messenger RNA (mRNA) of fibrosis‐related factors. However, in KO cells, the responses to TGF‐β1 stimulation were significantly lower. In addition, CCN5 and TGF‐β1 co‐treatment caused a notable reduction in mRNA expression levels compared with TGF‐β1 stimulation only. The αSMA protein expression increased with TGF‐β1 but decreased with CCN5 treatment. TGF‐β1 induced LF cell transdifferentiation from fibroblasts to myofibroblasts. However, this cell transition dramatically decreased in the presence of CCN5. In conclusion, CCN5 could prevent LFH by modulating the TGF‐β pathway. © 2019 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2634–2644, 2019

Physicians often encounter surgical candidates with lumbar disc herniation (LDH) who request non-surgical management even though surgery is recommended. However, second opinions may differ among doctors. Therefore, a prospective comprehensive cohort study (CCS) was designed to assess outcomes of nonsurgical treatment for surgical candidates who were recommended to undergo surgery for LDH but requested a second opinion. The CCS includes both randomized and observational cohorts, comprising a nonsurgery cohort and surgery cohort, in a parallel fashion. Crossover between the nonsurgery and surgery cohorts was allowed at any time. The present study was an as-treated interim analysis of 128 cases (nonsurgery cohort, n = 71; surgery cohort, n = 57). Patient-reported outcomes included visual analogue scores for the back (VAS-B) and leg (VAS-L), the Oswestry Disability Index, the EuroQol 5-Dimension instrument, and the 36-Item Short-Form Health Survey (SF-36), which were evaluated at baseline and at 1, 3, 6, 12, and 24 months. At baseline, age and SF-36 physical function were significantly lower in the surgery cohort than in the nonsurgery cohort (p < 0.05). All adjusted outcomes significantly improved after both nonsurgical and surgical treatment (p < 0.05). The nonsurgery cohort showed less improvement of VAS-B and VAS-L scores at 1 month (p < 0.01), but no difference between cohorts was observed thereafter for 24 months (p > 0.01). Nonsurgical management may be a negotiable option even for surgical candidates in the shared decision-making process.

Objective : Since the first discovery of the 2019 novel coronavirus (COVID-19), rapid and wide spread of the disease has been reported and the World Health Organization announced that a 'pandemic' has started. Up to date there is little known regarding the impact of this outbreak on spinal specialists' daily clinical practice. We intended to evaluate how COVID-19 has affected the number of spinal disease patients we meet and operate in daily practice. Methods : The de-identified data regarding number of patients visiting the spine clinic at a tertiary referral hospital and a secondary level hospital from January, February and March of 2017 to 2020 were retrospectively reviewed. The number of outpatient department (OPD) visits, number of emergency room (ER) visits as well as number of surgeries performed during the reviewed period were collected and analyzed, comparing 2020 to the previous 3 years. Results : The number of daily OPD visits showed a steady decrease starting from January, and presented a statistically significant decrease by early March 2020, compared to the previous 3 years. During the same period, decrease in number of daily ER visits was statistically significant as well. The number of elective surgeries or number of surgeries for patients admitted via ER during COVID-19 outbreak remained similar to that of 2017-2019 suggesting, despite the decrease of patients visiting the hospital for spinal diseases, those whom required surgery still visited the hospital. The results were consistant among other hospital level. Conclusion : The outbreak of COVID-19 affected our daily practice as OPD and ER visits reduced but did not affect the number of surgeries. We believe that this report will be informative to spinal specialists worldwide fighting the COVID-19 pandemic.

The aneurysm arising from fenestrated proximal anterior cerebral artery (ACA) is considered to be unique. The authors report a case of a 59-year-old woman who presented with a subarachnoid hemorrhage (SAH) secondary to a ruptured aneurysm originating from the fenestrated A1 segment of right ACA. The patient had another unruptured aneurysm which was located at the right middle cerebral artery bifurcation. She was successfully treated with surgical clipping for both aneurysms. From the previously existing literatures, we found 18 more cases (1983-2011) of aneurysms associated with fenestrated A1 segment. All cases represented saccular type of aneurysms, and 79% of the patients had SAH. There were three subtypes of the fenestrated A1 aneurysms depending on the anatomical location, relative to the fenestrated segment. The most common type was the aneurysms located on the proximal end of fenestrated artery (82%). Azygos ACA and hypoplastic A1 were frequently accompanied by the aneurysm (33% and 31%, respectively), and multiple aneurysms were shown in three cases (16%). Considering that fenestrated A1 segment is likely to develop an aneurysm, which has high risk of rupture, early management may benefit patients with aneurysms accompanied by fenestrated proximal ACA.

This study was designed to investigate (i) extracellular matrix to specify adhesive substrates to human dura mater cell (hDMC); (ii) the alteration on adhesion‐related molecules in hDMC; and (iii) secreted matrix metalloproteinases (MMPs) linked with extracellular matrix remodeling after exposure to inflammation. The hDMC was cultured from human dura mater tissue, and the studies were performed with hDMC after co‐culturing with macrophage like THP‐1 cells (Mϕ). The adhesion of co‐cultured hDMC through collagen I increased 6.4‐fold and through collagen IV increased 5.0‐fold compared with the adhesion of naïve cells (p < 0.001). Integrin subtype α2β1 expression was increased 6.3‐fold (p < 0.001) and α1 expression was decreased 2.0‐fold (p < 0.001) in the co‐cultured cells compared with the naïve cells. Co‐culturing induced significant increases in MMP‐1 (13.9‐fold, p < 0.01), MMP‐3 (7.6‐fold, p < 0.01), and VEGF (VEGF: 3.8‐fold, p < 0.05) expression and decreases in MMP‐9 (0.1‐fold, p < 0.01) compared with the sum of naïve hDMC and Mϕ values. Increased hDMC adhesion under inflammatory conditions is caused by an increased cellular affinity for collagen I and IV mediated by increased hDMC levels of integrin subtype α2β1 and environmental MMP‐1, ‐3 and decreased MMP‐9. Selective integrin subtype α2β1 inhibition assay showed 37.8% and 35.7% reduction in adhesion of co‐cultured hDMC to collagen I (p < 0.001) and IV (p = 0.057), respectively. The present study provides insight into the pathological conditions related to dura mater adhesion in inflammation. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1–11, 2019.