Circular RNA PDK1 targets miR-4731-5p to enhance TNXB expression in ligamentum flavum hypertrophy.

Hypertrophic ligamentum flavum (LF) is a main factor responsible for lumbar spinal stenosis (LSS); however, the exact mechanisms of the pathogenesis of these processes remain unknown. This study aimed to elucidate whether circular RNAs and microRNAs regulate the pathogenesis of LF and LSS, especially focusing on circPDK1 (hsa_circ_0057105), a circRNA targeting pyruvate dehydrogenase kinase 1 and differentially expressed in LF tissues between lumbar disk herniation and LSS patients. The circPDK1/miR-4731 and miR-4731/TNXB (Tenascin XB) interactions were predicted and validated by luciferase reporter assay. Colony formation, wound-healing, and MTT assays were used for estimating cell proliferation and migration. Protein expression levels were evaluated using Western blotting. TNXB expression was verified using immunohistochemistry (IHC). Overexpressing circPDK1 promoted the proliferation, migration, and expression of fibrosis-related protein (alpha smooth muscle actin (α-SMA), lysyl oxidase like 2 (LOXL2), Collagen I, matrix metalloproteinase-2 (MMP-2) and TNXB) in LF whereas miR-4731-5p showed opposite effects. The expression of TNXB was promoted by circPDK1; contrary results were observed with miR-4731-5p. Co-overexpression of miR-4731-5p partially reversed the proliferative and fibrosis-prompting effects of circPDK1 or TNXB. The circPDK1-miR-4731-TNXB pathway may be proposed as a regulatory axis in LF hypertrophy, which might shed light on in-depth research of LSS, as well as providing a novel therapeutic target for LF hypertrophy-induced LSS.

Sinapic Acid Inhibits IL-1ß-Induced Apoptosis and Catabolism in Nucleus Pulposus Cells and Ameliorates Intervertebral Disk Degeneration.

BACKGROUND: Low back pain (LBP) is a very common condition and leads to serious pain, disability, and price tag all over the world. Intervertebral disk degeneration (IDD) is one of the major reasons that contributed to LBP. The levels of interleukin 1 beta (IL-1ß) increase significantly in degenerative disks. IL-1ß also accelerates IDD. Sinapic acid (SA) has the effect of anti-inflammatory, antioxidant and antimicrobial. However, the effect of SA on IDD has never been studied. Therefore, the aim of this study was to figure out whether SA has protective effect on nucleus pulposus (NP) cells and further explore the possible underlying mechanism. METHODS: The nucleus pulposus (NP) tissues of rats were collected and cultured into NP cells. The NP cells were stimulated by IL-1ß and treated with SA. In vitro treatment effects were evaluated by ELISA, Western blot assay, immunofluorescence, TUNEL method and real-time PCR. We conducted percutaneous needle puncture in the rat tail to build intervertebral disk degeneration model and treated rats with SA. In vivo treatment effects were evaluated by hematoxylin and eosin (HE) and safranin O (SO) staining and magnetic resonance imaging (MRI) method. RESULTS: Our results showed that SA not only inhibited apoptosis but also suppressed inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS) interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in IL-1ß-stimulated NP cells. As to extracellular matrix (ECM), SA could increase collagen II and aggrecan levels and reduce the expression of MMP13 and ADAMTS5 during the stimulation of IL-1ß. Furthermore, SA could activate nuclear factor-erythroid 2-related factor-2 (Nrf2) to inhibit nuclear factor κB (NF-κB) induced by IL-1ß. Nrf2 knockdown partly reduced the protective effect of SA on NP cells. Correspondingly, SA ameliorated IDD by promoting Nrf2 expression. In vivo results also showed that SA could delay the progression of IDD. CONCLUSION: In conclusion, we demonstrated that SA could protect the degeneration of NP cells and revealed the underlying mechanism of SA on Nrf2 activation in NP cells.

Real-World Evidence in Prescription Medication Use Among U.S. Adults with Neck Pain.

INTRODUCTION: Neck pain is a common condition that leads to serious pain, disability, and increased healthcare costs worldwide. Pharmacotherapy is one of the most common strategies to reduce neck pain in patients. The aim of this study was to analyze the real-world pattern of drugs prescribed for patients with neck pain in the USA. METHODS: Data on individuals who reported current neck pain in the 2009-2010 US National Health and Nutrition Examination Survey (NHANES) and with a history of persistent pain for at least 6 weeks or 3 months were extracted from the NHANES database. Those included in the study were divided into three groups based on the duration of pain: the without neck pain group (Group A); subacute group (Group B) with a history of 6 weeks of neck pain; and the chronic neck pain group (Group C) with a history of 3 months of neck pain. The use and duration of medication prescribed for Group A, B, and C patients were compared. RESULTS: The analysis revealed that opioid use was significantly more prevalent in the subacute and chronic neck pain group than in the without neck pain group (Group A) (adjusted odds ratio [aOR] 4.20, 95% confidence interval [CI] 2.07-8.52 and aOR 7.00, 95% CI 4.32-11.33, respectively). The factors strongly associated with higher opioid use included older age, low education level, and low family income. In the chronic neck group, opioids, followed in decreasing order of frequency by acetaminophen and nonsteroidal anti-infammatory drugs, were the most common analgesics used in combination with other analgesics. CONCLUSION: Our analysis of the data shows that the long-term excessive use of opioids and the underutilization of other analgesics are two major issues in the treatment of neck pain in the USA. Possible improvements include improved education of patients by healthcare professionals on the use of opioids and more consideration given to non-pharmacotherapy options. Our results reveal the potential problem in pharmacotherapy choices for neck pain treatment and may help improve the current clinical practice in the USA and other countries.

Endocrine Therapy for the Functional Recovery of Spinal Cord Injury.

Spinal cord injury (SCI) is a major cause of physical disability and leads to patient dissatisfaction with their quality of life. Patients with SCI usually exhibit severe clinical symptoms, including sensory and motor dysfunction below the injured levels, paraplegia, quadriplegia and urinary retention, which can exacerbate the substantial medical and social burdens. The major pathological change observed in SCI is inflammatory reaction, which induces demyelination, axonal degeneration, and the apoptosis and necrosis of neurons. Traditional medical treatments are mainly focused on the recovery of motor function and prevention of complications. To date, numerous studies have been conducted to explore the cellular and molecular mechanism of SCI and have proposed lots of effective treatments, but the clinical applications are still limited due to the complex pathogenesis and poor prognosis after SCI. Endocrine hormones are kinds of molecules that are synthesized by specialized endocrine organs and can participate in the regulation of multiple physiological activities, and their protective effects on several disorders have been widely discussed. In addition, many studies have identified that endocrine hormones can promote nerve regeneration and functional recovery in individuals with central nervous system diseases. Therefore, studies investigating the clinical applications of endocrine hormones as treatments for SCI are necessary. In this review, we described the neuroprotective roles of several endocrine hormones in SCI; endocrine hormone administration reduces cell death and promotes functional repair after SCI. We also proposed novel therapies for SCI.

Optimal medial transforaminal lumbar interbody fusion approach with five extensive options: A simulated study on three-dimensional digital reconstructed images.

OBJECTIVE: The objective of this study is to use 3D digital lumbar models to investigate and simulate the optimal posterior operative approach for safe decompression and insertion of an interbody cage. METHODS: Thirty lumbar spine (L3-S1) computed tomography data are collected for 3D reconstruction. We cut medial half part of the superior facet and define the distance between the margin of the operative side of the spinous process and the medial margin of the cut superior facet as "medial distance (MD)". Then, we cut the total superior facet and define the distance between the margin of the operative side of the spinous process and the lateral side of the junction of the pedicle and the vertebral body as "extend distance (ED)". The feasible insertion of the current standard width size (10 mm and 12 mm) interbody cages was assessed by the two aforementioned MD and ED approaches. Besides the ED, we also simulate four other extensive options of lateral upper, lateral lower, vertical upper and lower and transmedian contralateral decompression on 3D digital lumbar model. RESULTS: The MD increased from 13.48 ± 1.28 mm at L3/4 to 18.05 ± 1.43 mm at L5/S1, and the ED increased from 16.64 ± 1.34 mm at L3/4 to 21.12 ± 1.62 mm at L5/S1. To insert a 10-mm-wide cage, 16.7% (left) and 13.3% (right) of MD for L3/4 is not enough, 60.0% (left) and 46.7% (right) of MD for L3/4 is subsafe, 13.3% (left) and 16.7% (right) of MD for L4/5 is subsafe and all others are safe. To insert a 12-mm-wide cage, 76.7% (left) and 60.0% (right) of MD for L3/4 is not enough, 20.0% (left) and 30.0% (right) of MD for L3/4 is subsafe, 13.3%% (left) and 16.7% (right) of MD for L4/5 is not enough, 63.3% (left) and 56.7% (right) of MD for L4/5 is subsafe and 6.7% (left) and 10.0% (right) of MD for L5/S1 is subsafe, whereas 33.3%% (left) and 30.0% (right) of ED for L3/4 is subsafe, 3.3% (left) and 3.3% (right) of ED for L4/5 is subsafe and all others are safe. Besides the ED, on 3D models, four other extensive options could be simulated too and may need to be performed for different special individuals. CONCLUSION: Our 3D digital image study provides a feasible optimal medial transforaminal lumbar interbody fusion approach with five extensive options on lower lumbar region. It can provide safe lumbar decompression and interbody fusion in most population. In addition, surgeons can choose the different extensive options for special individual conditions. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Transforminal lumbar interbody fusion is very common used for lumbar degenerative diseases. The optimal medial transforminal lumbar interbody fusion with five options provide a safe and precise approach for surgeons in treatment of lumbar degenerative diseases.

The compression of L5 nerve root, single or double sites?-radiographic graded signs, intra-operative detect technique and clinical outcomes.

BACKGROUND: The L5 nerve root could be compressed at both L4-5 and L5-S1 regions. If L5 nerve root has confirmed compression at L4-5 level and questionable compression at L5-S1 foramina, performing both surgeries at L4-5 and L5-S1 levels may induce unnecessary extra surgery on L5-S1; however, ignoring foraminal stenosis of L5/S1 may require re-exploration. METHODS: Two hundred seventeen patients with L5 nerve root compressed at L4-5 lateral access were performed with L4-5 decompression and interbody fusion. Lee et al. grade classification was used to assess the foraminal stenosis of L5-S1 preoperatively. Nerve root probe was designed and used to detect if there were foraminal stenosis at L5-S1 level that compressing the exiting L5 nerve root. Visual analog scale (VAS) of low back pain, leg pain and Oswestry Disability Index (ODI) were used to assess clinical outcomes. RESULTS: For all of 217 patients who underwent L4-5 surgery, L5-S1 foramina were preoperatively assessed as: grade 0: 125 cases, grade 1: 58 cases, grade 2: 23 cases, and grade 3: 11 cases. After intra-operative L5 nerve root detection, 11/11 patients with grade 3 radiographic foraminal stenosis, 6/23 (26.1%) with grade 2 and 2/58 (3.4%) who had grade 1 underwent L4-5 and L5-S1 transforaminal lumbar interbody fusion (TLIF), the others received only L4-5 TLIF. Compared to pre-operative baseline data, both L4-5 TLIF and L4-5 and L5-S1 TLIF groups had significant decreased VAS of low back pain and leg pain, and ODI at 3 and 24 months after operation. CONCLUSIONS: We suggested that our novel nerve root probe combined with pre-operative radiographic grade may be helpful to surgeons to identify the single or double compression of L5 nerve root and make a more precise surgical strategy to improve surgical outcome than the method depended on pre-operative radiographic grade alone.

Correlation between lumbar intervertebral disc height and lumbar spine sagittal alignment among asymptomatic Asian young adults.

BACKGROUND: To investigate the distribution and characteristics of the lumbar intervertebral disc height (IDH) in asymptomatic Asian population and to determine whether the lumbar IDH is related to the lumbar spine sagittal alignment. METHODS: A cohort of 169 cases of asymptomatic volunteers was enrolled from January 2014 to July 2016. All participants underwent magnetic resonance imaging of the lumbar spine and panoramic radiography of the spine. Panoramic radiographs of the spine were taken to evaluate pelvic incidence (PI), sacral slope (SS), and pelvic tilt (PT) using Surgimap® software. Roussouly classification was utilized to categorize all subjects according to the four subtypes of sagittal alignment. The IDH was measured on the MRI mid-saggital section of the vertebral body. The relationships between lumbar IDH and spine-pelvic parameters were also assessed using the Spearman correlation analysis. RESULTS: The reference value ranges of IDH in asymptomatic Asian volunteers between L1/2, L2/3, L3/4, L4/5, and L5/S1 were (6.25, 10.99), (6.97, 12.08), (7.42, 13.3), (7.76, 14.57),and (7.11, 13.12) mm, respectively. Based on the above reference value, the high lumbar intervertebral space is defined as more than 14 mm. According to the Roussouly Classification, there are 33 cases in type I, 48 in type II, 66 in type III, and 22 in type IV. According to the definition of the high IDH, there are two cases in type I, three in type II, nine in type III, and eight in type IV. The results indicated that people in the Roussouly III and IV subtypes had greater values for IDH compared to those of Roussouly I and II subtypes, and the spinopelvic parameters were partly correlated with IDH in different subtypes. In addition, levels L4-L5 showed the highest IDH for all four groups followed by the L3-L4 and L5-S1 levels, and the value of L3-L4 is equivalent to that of L5-S1. All type groups showed moderate and positive correlations between the PI and IDH except the level of L1-L2 in type IV. CONCLUSIONS: The IDH may influence the lumbar spine sagittal alignment in asymptomatic Asian adults. Moreover, pre-operative evaluation of IDH is useful for selection of optimal cage size and reconstruction of spinal alignment.

NELL-1 based demineralized bone graft promotes rat spine fusion as compared to commercially available BMP-2 product.

BACKGROUND: Spinal fusion is among the most commonly performed orthopaedic procedures. Unfortunately, current treatments such as autologous bone grafting or recombinant proteins (BMP-2) have numerous clinical shortcomings. Here, we directly compare the efficacy of NELL-1, a novel osteoinductive growth factor, to two currently available treatments, (1) recombinant BMP-2 and (2) iliac crest bone grafting, in a spinal fusion model. METHODS: Twenty-six skeletally mature athymic rats underwent posterolateral spine fusion of L4/L5 vertebrae. Treatment groups included NELL-1 (10 and 50 µg) in a demineralized bone matrix (DBX), as compared to BMP-2 (90 µg) in an absorbable collagen sponge (ACS) or morselized iliac crest bone. Scaffolds without recombinant protein were used as controls. Animals were sacrificed at 4 weeks post-operative and fusion was assessed by manual palpation, radiography [high-resolution X-ray, micro-computed tomography (microCT)], histology (hematoxylin and eosin, Masson's trichrome) and immunohistochemistry (osteocalcin). RESULTS: Results showed 100 % fusion in all NELL-1- and BMP-2-treated samples. In contrast, lower rates of fusion were observed in scaffold-only and bone graft treatment groups. MicroCT scans revealed radiographic evidence of fusion among spines treated with NELL-1. Bone bridging was also observed with BMP-2 treatment, but was accompanied by inner radiolucency, suggesting cyst-like bone formation. Histologically, NELL-1-treated grafts showed increased bone formation, endochondral ossification and vascularization. Although BMP-2 treated grafts exhibited increased bone formation and angiogenesis, numerous adipocytes were also observed. CONCLUSION: NELL-1-based bone grafts are comparable to BMP-2 + ACS in spinal fusion efficacy. Histological differences were observed however, including robust endochondral ossification with NELL-1 treatment as compared to lipid-filled bone with BMP-2 treatment. These findings suggest NELL-1 based bone grafts show promise for future efforts in skeletal tissue engineering.

[Clinical characteristics and results of cervical spinal cord injury in the patients with ossification of the posterior longitudinal ligament].

OBJECTIVE: To investigate the clinical characteristics and results of cervical spinal cord injury (SCI) in the patients with ossification of the posterior longitudinal ligament (OPLL). METHODS: Nineteen patients with cervical SCI associated with OPLL were retrospectively analyzed. Data collection included: pre- and postoperative neurological function, OPLL-type, MRI signal changes and surgical approaches. RESULTS: Spinal cord associated with OPLL was injured severely by mild trauma. Methylprednisolone sodium succinate was used within 8 h after trauma in 12 cases. Two of them died of complications. The neurological functions were markedly improved in the other 10 cases. Seventeen cases had surgical treatment. The neurological functions (Frankel grade) were improved significantly in the operated patients except for one, who died 27 d after operation. CONCLUSIONS: The patients with OPLL are prone to have severe SCI, which directly associates with the preexisting OPLL-type and hyper-intensity signal change in the spinal cord on MRI. Both of using methylprednisolone sodium succinate administration within 8 h after trauma and surgical decompression may improve the neurological outcomes.

Effects of Ginkgo biloba extract (EGb 761) on hydroxyl radical-induced thymocyte apoptosis and on age-related thymic atrophy and peripheral immune dysfunctions in mice.

In this study, the effect of EGb 761, a standard extract of Ginkgo biloba leaf, on thymocyte apoptosis and age-related thymic atrophy and on peripheral immune dysfunctions was investigated in mice. When primary culture of thymocytes was preincubated with 100 microg/ml EGb 761 before their exposure to hydroxyl radicals (*OH) generated by Fe(2+)-mediated Fenton reaction, apoptotic cell death induced by *OH was distinctly prevented as determined by DNA laddering, the TUNEL assay and flow cytometric analysis. Furthermore, oral EGb 761 administration (about 1.5 mg/day/mouse) for 60 consecutive days led to a significant thymic regrowth in 22-month-old mice as revealed by the increment of thymus weight and total numbers of thymocytes. Partial recovery of peripheral immune capacities such as mitogen responsiveness and NK cell activity were also found in the old mice after 60 days of EGb 761 supplementation. Taken together, our study indicates that in addition to its protective and rescuing abilities on neurodegenerative disorders and cardiovascular diseases, EGb 761 was also found active in the rejuvenation of degenerated thymus and accordingly the strengthening of the immune system. These beneficial effects of EGb 761 on immune system are based on its antioxidant properties as well as the cell proliferation-stimulating effect.