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Objective: The aim of this nationwide age- and sex- matched longitudinal follow up study is to determine the risk of Parkinson’s disease (PD) associated with ischemic stroke in Korea.Methods: Patient data were collected from the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). PD was identified using the International Classification of Diseases (ICD) 10-CM code G 20. In total, 6,475 patients were enrolled in the PD group from the NHISS. After subtracting 1,039 patients who underwent hospitalization less than once or those who visited an outpatient clinic less than two times, 5,259 patients who were diagnosed after January 1, 2004 ultimately participated in this study. After case-control match was done through 1:5 age- and sex- stratified matching, 26,295 individuals were chosen as control. Kaplan-Meier method and Cox proportional hazard regression analysis were performed to evaluate the risk of ischemic stroke in PD.Results: The hazard ratio of ischemic stroke in the PD group was 3.848 (95% confidence interval (confidence interval [CI]): 3.14-4.70) after adjusting for age and sex. The adjusted hazard ratio of ischemic stroke in PD group was 3.885 (95% CI: 3.17-4.75) after adjusting for comorbidities. According to subgroup analysis, in male and female and non-diabetes and diabetes and non-hypertension and hypertension and dyslipidemia and non-dyslipidemia subgroups, ischemic stroke incidence rates were significantly higher in the PD group than those in the control group.Conclusions: This nationwide longitudinal study suggests an increased risk of ischemic stroke in PD patients.

Osteoporotic vertebral compression fractures (OVCFs) are serious health problems. We conducted a randomized, open‐label, phase I/IIa study to determine the feasibility, safety, and effectiveness of Wharton's jelly‐derived mesenchymal stem cells (WJ‐MSCs) and teriparatide (parathyroid hormone 1‐34) in OVCFs. Twenty subjects with recent OVCFs were randomized to teriparatide (20 μg/day, daily subcutaneous injection for 6 months) treatment alone or combined treatment of WJ‐MSCs (intramedullary [4 × 107 cells] injection and intravenous [2 × 108 cells] injection after 1 week) and teriparatide (20 μg/day, daily subcutaneous injection for 6 months). Fourteen subjects (teriparatide alone, n = 7; combined treatment, n = 7) completed follow‐up assessment (visual analog scale [VAS], Oswestry Disability Index [ODI], Short Form‐36 [SF‐36], bone mineral density [BMD], bone turnover measured by osteocalcin and C‐terminal telopeptide of type 1 collagen, dual‐energy x‐ray absorptiometry [DXA], computed tomography [CT]). Our results show that (a) combined treatment with WJ‐MSCs and teriparatide is feasible and tolerable for the patients with OVCFs; (b) the mean VAS, ODI, and SF‐36 scores significantly improved in the combined treatment group; (c) the level of bone turnover markers were not significantly different between the two groups; (d) BMD T‐scores of spine and hip by DXA increased in both control and experimental groups without a statistical difference; and (e) baseline spine CT images and follow‐up CT images at 6 and 12 months showed better microarchitecture in the combined treatment group. Our results indicate that combined treatment of WJ‐MSCs and teriparatide is feasible and tolerable and has a clinical benefit for fracture healing by promoting bone architecture. Clinical trial registration: https://nedrug.mfds.go.kr/, MFDS: 201600282‐30937., Combined treatments of Wharton's jelly‐derived mesenchymal stem cells (WJ‐MSCs) and parathyroid hormone (PTH) increased the T‐scores of the spine and hip and improved the microarchitecture in the fractured vertebral body. These effects provided satisfactory improvement of pain, function, and quality of life for patients with osteoporotic vertebral compression fractures (OVCFs). Combined treatment of WJ‐MSCs and PTH is feasible and tolerable and has a clinical benefit for treatment of OVCFs.

Resolvins, a new family from the endogenous specialized pro-resolving mediators (SPMs), promote the resolution of the inflammatory response. Resolvin D3 (RvD3), a docosahexaenoic acid (DHA) product, has been known to suppress the inflammatory response. However, the anti-inflammatory and neuroprotective effects of RvD3 are not known in a model of spinal cord injury (SCI). Here, we investigated the anti-inflammatory and neuroprotective effect of RvD3 in a mouse model of SCI. Processes associated with anti-inflammation and angiogenesis were studied in RAW 264.7 cells and the human brain endothelial cell line hCMEC/D3, respectively. Additionally, female C57BL/6 mice were subjected to moderate compression SCI (20-g weight compression for 1 min) followed by intrathecal injection of vehicle or RvD3 (1 μg/20 μL) at 1 h post-SCI. RvD3 decreased the lipopolysaccharide (LPS)-induced production of inflammatory mediators and nitric oxide (NO) in RAW 264.7 cells and promoted an angiogenic effect in the hCMEC/D3 cell line. Treatment with RvD3 improved locomotor recovery and reduced thermal hyperalgesia in SCI mice compared with vehicle treatment at 14 days post-SCI. Remarkably, RvD3-treated mice exhibited reduced expression of inflammatory cytokines (TNF-α, IL6, IL1β) and chemokines (CCL2, CCL3). Also, RvD3-treated mice exhibited increased expression of tight junction proteins such as zonula occludens (ZO)-1 and occludin. Furthermore, immunohistochemistry showed a decreased level of gliosis (GFAP, Iba-1) and neuroinflammation (CD68, TGF-β) and enhanced neuroprotection. These data provide evidence that intrathecal injection of RvD3 represents a promising therapeutic strategy to promote inflammatory resolution, neuroprotection, and neurological functional recovery following SCI.

Intervertebral disc (IVD) degeneration (IVDD) is a leading cause of chronic low back pain. There is a strong clinical demand for more effective treatments for IVDD as conventional treatments provide only symptomatic relief rather than arresting IVDD progression. This study shows that senolytic therapy with local drug delivery can inhibit IVDD and restore IVD integrity. ABT263, a senolytic drug, was loaded in poly(lactic-co-glycolic acid) nanoparticles (PLGA-ABT) and intradiscally administered into injury-induced IVDD rat models. The single intradiscal injection of PLGA-ABT may enable local delivery of the drug to avascular IVD, prevention of potential systemic toxicity caused by systemic administration of senolytic drug, and morbidity caused by repetitive injections of free drug into the IVD. The strategy resulted in the selective elimination of senescent cells from the degenerative IVD, reduced expressions of pro-inflammatory cytokines and matrix proteases in the IVD, inhibits progression of IVDD and even restores the IVD structure. This study demonstrates for the first time that local delivery of senolytic drug can effectively treat senescence-associated IVDD. This approach could be extended to treat other types of senescence-associated degenerative diseases. This article is protected by copyright. All rights reserved.

Objective We attempted to discover that Ankylosing spondylitis (AS) has a comprehensive relationship with congestive heart failure and death. Methods We used a nationwide database managed by the Korean National Health Insurance Service from 2010 to 2014. Twelve thousand nine hundred eighty-eight patients with a diagnosis of AS and 64940 age- and sex- stratified matching subjects without AS were enrolled in the AS and control groups. Incidence probabilities of 6 years congestive heart failure and death in each group were calculated. The Cox proportional hazard regression analysis was used to estimate the hazard ratio. We divided the AS and control groups into subgroups according to sex, age, income, and comorbidities. Results During the follow-up period, 102 patients (0.79%) in the AS group and 201 patients (0.32%) in the control group developed congestive heart failure (p

Objectives In this study, we study the transplantation of tauroursodeoxycholic acid (TUDCA)‐induced M2‐phenotype (M2) macrophages and their ability to promote anti‐neuroinflammatory effects and functional recovery in a spinal cord injury (SCI) model. Methods To this end, compared to the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), we evaluated whether TUDCA effectively differentiates bone marrow–derived macrophages (BMDMs) into M2 macrophages. Results The M2 expression markers in the TUDCA‐treated BMDM group were increased more than those in the GM‐CSF‐treated BMDM group. After the SCI and transplantation steps, pro‐inflammatory cytokine levels and the mitogen‐activated protein kinase (MAPK) pathway were significantly decreased in the TUDCA‐induced M2 group more than they were in the GM‐CSF‐induced M1 group and in the TUDCA group. Moreover, the TUDCA‐induced M2 group showed significantly enhanced tissue volumes and improved motor functions compared to the GM‐CSF‐induced M1 group and the TUDCA group. In addition, biotinylated dextran amine (BDA)–labelled corticospinal tract (CST) axons and neuronal nuclei marker (NeuN) levels were increased in the TUDCA‐induced M2 group more than those in the GM‐CSF‐induced M1 group and the TUDCA group. Conclusions This study demonstrates that the transplantation of TUDCA‐induced M2 macrophages promotes an anti‐neuroinflammatory effect and motor function recovery in SCI. Therefore, we suggest that the transplantation of TUDCA‐induced M2 macrophages represents a possible alternative cell therapy for SCI., Bone marrow–derived monocytes were differentiated into M2‐phenotype (M2) macrophages using tauroursodeoxycholic acid (TUDCA). TUDCA‐induced M2 macrophages were directly transplanted to a lesion in an injured spinal cord. The pro‐inflammatory cytokine levels were significantly decreased in the TUDCA‐induced M2 group. We suggest that the transplantation of TUDCA‐induced M2 macrophages represents a possible alternative cell therapy for SCI.

Intervertebral disc (IVD) degeneration can cause chronic lower back pain (LBP), leading to disability. Despite significant advances in the treatment of discogenic LBP, the limitations of current treatments have sparked interest in biological approaches, including growth factor and stem cell injection, as new treatment options for patients with chronic LBP due to IVD degeneration (IVDD). Gene therapy represents exciting new possibilities for IVDD treatment, but treatment is still in its infancy. Literature searches were conducted using PubMed and Google Scholar to provide an overview of the principles and current state of gene therapy for IVDD. Gene transfer to degenerated disc cells in vitro and in animal models is reviewed. In addition, this review describes the use of gene silencing by RNA interference (RNAi) and gene editing by the clustered regularly interspaced short palindromic repeats (CRISPR) system, as well as the mammalian target of rapamycin (mTOR) signaling in vitro and in animal models. Significant technological advances in recent years have opened the door to a new generation of intradiscal gene therapy for the treatment of chronic discogenic LBP.

The purpose of this longitudinal follow-up study was to investigate the risk of ischemic stroke nationwide in patients with seropositive rheumatoid arthritis (RA) and controls who were matched in age and sex. Patient data were collected from the National Health Insurance Service (NHIS) Health Screening (HEALS) cohort. Using the International Classification of Diseases code M05 (seropositive RA), with a prescription of any disease-modifying anti-rheumatic drug (DMARD), RA was identified. A total of 2,765 patients and 13,825 control subjects were included in our study. The 12-year incidence of ischemic stroke in each group was calculated using the Kaplan–Meier method. The risk ratio of ischemic stroke was estimated using Cox proportional hazards regression. Sixty-four patients (2.31%) in the seropositive RA group and 512 (3.70%) in the control group experienced ischemic stroke (P < 0.001) during the follow-up period. The hazard ratio of ischemic stroke in the seropositive RA group was 1.32 (95% confidence interval (CI), 1.02–1.73) after adjusting for age and sex. The adjusted hazard ratio of ischemic stroke in the seropositive RA group was 1.40 (95% CI, 1.07–1.82) after adjusting for demographics and comorbid medical disorders. According to the subgroup analysis, the hazard ratios of ischemic stroke risks in the female and hypertensive subgroups were 1.44 (95% CI, 1.05–1.97) and 1.66 (95% CI, 1.16–2.38), respectively. In the non-diabetes and non-dyslipidemia subgroups, the corresponding hazard ratios of ischemic stroke were 1.47 (95% CI, 1.11–1.95) and 1.43 (95% CI, 1.07–1.91). Seropositive RA patients have an increased risk of ischemic stroke. In female, hypertension, non-diabetes, and non-dyslipidemia RA subgroups, even without the traditional risk factors for stroke (except for hypertension), increased the risk, which could be potentially attributed to RA.

Oblique lumbar interbody fusion (OLIF) is useful as surgical treatment of degenerative lumbar disease. However, revision surgery has often resulted in worse surgical outcomes than primary surgery. Thus, we compared the usefulness of OLIF as primary surgery (PS) versus revision surgery (RS).We retrospectively investigated 173 patients who had undergone single-level OLIF from 2016 to 2018. The radiological and clinical outcomes were compared between PS (n = 152) and RS (n = 21). The effects of RS on the clinical outcomes (Oswestry Disability Index [ODI] cutoff, 12) after surgery were investigated.The ODI and visual analog scale score at 6 and 12 months after surgery was worse in the RS group than in the PS group (P0.05). In the RS group, the visual analog scale score for leg pain of the previous laminectomy side was worse than that of the virgin side at 6 and 12 months after surgery (P0.05). The disc height, ligamentum flavum, and subsidence did not differ between the 2 groups. However, the cross-sectional area enlargement differed between the 2 groups (P0.05). Multivariate logistic regression analysis showed that RS and severe subsidence were risk factors for differences in the ODI (P = 0.006 and P = 0.017, respectively).Most radiological outcomes were similar between the RS and PS groups, with no differences in complications or the requirement for additional posterior decompression. However, OLIF resulted in relatively poor clinical outcomes when used as RS. Thus, revision spine surgery tends to result in poor outcomes compared with those of primary spine surgery; however, OLIF can be a tolerable option for revision spine surgery.

Osteoporosis is a complex multifactorial condition of the musculoskeletal system. Osteoporosis and osteoporotic vertebral fracture (OVF) are associated with high medical costs and can lead to poor quality of life. Genetic factors are important in determining bone mass and structure, as well as any predisposition for bone degradation and OVF. However, genetic factors are not enough to explain osteoporosis development and OVF occurrence. Epigenetics describes a mechanism for controlling gene expression and cellular processes without altering DNA sequences. The main mechanisms in epigenetics are DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). Recently, alterations in epigenetic mechanisms and their activity have been associated with osteoporosis and OVF. Here, we review emerging evidence that epigenetics contributes to the machinery that can alter DNA structure, gene expression, and cellular differentiation during physiological and pathological bone remodeling. A progressive understanding of normal bone metabolism and the role of epigenetic mechanisms in multifactorial osteopathy can help us better understand the etiology of the disease and convert this information into clinical practice. A deep understanding of these mechanisms will help in properly coordinating future individual treatments of osteoporosis and OVF.

Intervertebral disc (IVD) degeneration is one of the predominant causes of chronic low back pain (LBP), which is a leading cause of disability worldwide. Despite substantial progress in cell therapy for the treatment of IVD degeneration, significant challenges remain for clinical application. Here, we investigated the effectiveness of hyaluronan&ndash, methylcellulose (HAMC) hydrogels loaded with Wharton&rsquo, s Jelly-derived mesenchymal stromal cell (WJ-MSCs) in vitro and in a rat coccygeal IVD degeneration model. Following induction of injury-induced IVD degeneration, female Sprague-Dawley rats were randomized into four groups to undergo a single intradiscal injection of the following: (1) phosphate buffered saline (PBS) vehicle, (2) HAMC, (3) WJ-MSCs (2 &times, 104 cells), and (4) WJ-MSCs-loaded HAMC (WJ-MSCs/HAMC) (n = 10/each group). Coccygeal discs were removed following sacrifice 6 weeks after implantation for radiologic and histologic analysis. We confirmed previous findings that encapsulation in HAMC increases the viability of WJ-MSCs for disc repair. The HAMC gel maintained significant cell viability in vitro. In addition, combined implantation of WJ-MSCs and HAMC significantly promoted degenerative disc repair compared to WJ-MSCs alone, presumably by improving nucleus pulposus cells viability and decreasing extracellular matrix degradation. Our results suggest that WJ-MSCs-loaded HAMC promotes IVD repair more effectively than cell injection alone and supports the potential clinical use of HAMC for cell delivery to arrest IVD degeneration or to promote IVD regeneration.

As life expectancy increases, the prevalence of osteoporosis is increasing. In addition to vitamin D which is well established to have an association with osteoporosis, B vitamins, such as thiamine, folate (vitamin B9), and cobalamin (vitamin B12), could affect bone metabolism, bone quality, and fracture risk in humans by influencing homocysteine/folate metabolism. Despite the crucial role of B vitamins in bone metabolism, there are few studies regarding associations between B vitamin-related genes and osteoporosis. In this study, we investigated the genetic association of four single nucleotide polymorphisms (SNPs) within the 3&rsquo, untranslated regions of vitamin B-related genes, including TCN2 (encodes transcobalamin II), CD320 (encodes transcobalamin II receptor), SLC19A1 (encodes reduced folate carrier protein 1), and SLC19A2 (encodes thiamine carrier 1), with osteoporosis and osteoporotic vertebral compression fracture (OVCF). We recruited 301 postmenopausal women and performed genotyping of CD320 rs9426 C&gt, T, TCN2 rs10418 C&gt, T, SLC19A1 rs1051296 G&gt, T, and SLC19A2 rs16862199 C&gt, T using a polymerization chain reaction-restriction fragment length polymorphism assay. There was a significantly higher incidence of both osteoporosis (AOR 5.019, 95% CI, 1.533&ndash, 16.430, p &lt, 0.05) and OVCF (AOR, 5.760, 95% CI, 1.480&ndash, 22.417, p &lt, 0.05) in individuals with genotype CD320 CT+TT and high homocysteine concentrations. Allele combination analysis revealed that two combinations, namely CD320 C-TCN2 T-SLC19A1 T-SLC19A2 C (OR, 3.244, 95% CI, 1.478&ndash, 7.120, p &lt, 0.05) and CD320 T-TCN2 C-SLC19A1 G-SLC19A2 C (OR, 2.287, 95% CI, 1.094&ndash, 4.782, p &lt, 0.05), were significantly more frequent among the osteoporosis group. Our findings suggest that SNPs within the CD320 gene in 3&acute, UTR may contribute to osteoporosis and OVCF occurrences in some individuals. Furthermore, specific allele combinations of CD320, TCN2, SLC19A1, and SLC19A2 may contribute to increased susceptibility to osteoporosis and OVCF.

Due to the safety issues and poor engraftment of mesenchymal stem cell (MSC) implantation, MSC-derived exosomes have been spotlighted as an alternative therapy for spinal cord injury (SCI). However, insufficient productivity of exosomes limits their therapeutic potential for clinical application. Moreover, low targeting ability of unmodified exosomes is a critical obstacle for their further applications as a therapeutic agent. In the present study, we fabricated macrophage membrane-fused exosome-mimetic nanovesicles (MF-NVs) from macrophage membrane-fused umbilical cord blood-derived MSCs (MF-MSCs) and confirmed their therapeutic potential in a clinically relevant mouse SCI model (controlled mechanical compression injury model). MF-NVs contained larger quantity of ischemic region-targeting molecules compared to normal MSC-derived nanovesicles (N-NVs). The targeting molecules in MF-NVs, which were derived from macrophage membranes, increased the accumulation of MF-NVs in the injured spinal cord after the in vivo systemic injection. Increased accumulation of MF-NVs attenuated apoptosis and inflammation, prevented axonal loss, enhanced blood vessel formation, decreased fibrosis, and consequently, improved spinal cord function. Synthetically, we developed targeting efficiency-potentiated exosome-mimetic nanovesicles and present their possibility of clinical application for SCI.

Background The aim of this nationwide age- and sex matched longitudinal follow up study is to determine the risk of acute myocardial infarction (AMI) associated with the seropositive rheumatoid arthritis (RA) population in Korea. Methods Patient data were collected from the National Health Insurance Service Health Screening cohort. RA was identified using the International Classification of Diseases code M05 (seropositive RA), with a prescription of any disease-modifying anti-rheumatic drug (DMARD). A total of 2,765 patients were enrolled in the seropositive RA group from January 1, 2004 to December 31, 2015 from the NHIS. The control group consisted of 13,825 subjects. The 12-years AMI incidence rate for each group was calculated using the Kaplan-Meier method. A Cox proportional-hazards regression analysis was used to estimate the hazard ratio of AMI. Results During the follow-up period, 39 patients (1.41%) in the seropositive RA group and 111 (0.80%) in the control group experienced AMI (P = 0.003). The hazard ratio of AMI in the seropositive RA group was 3.879 (95% confidence interval (CI): 2.64–5.68) after adjusting for age and sex. The adjusted hazard ratio of AMI in the seropositive RA group was 4.212 (95% CI: 2.86–6.19) after adjusting for demographics and comorbid medical disorders. According to subgroup analysis, in male and female and the non-diabetes and non-hypertension and hypertension and dyslipidemia and non-dyslipidemia subgroups, AMI incidence rates were significantly higher in the seropositive RA group than in the control group. Conclusion Our nationwide longitudinal study suggests an increased risk of AMI in seropositive RA patients.

Traumatic spinal cord injury (SCI) can cause permanent disabilities that seriously reduce quality of life. We evaluated the effects of chronic hyperglycemia before SCI on inflammatory markers and functional recovery after SCI in human patients and a rat model. In the human study, multivariate logistical regression analysis revealed that hemoglobin A1c (HbA1c) values, reflecting average plasma glucose concentration over a 3 month period, at admission were a significant risk factor for poor functional recovery. Moreover, patients with chronic hyperglycemia (HbA1c ≥ 6.5%) had high concentrations of inflammatory biomarkers (interleukin [IL]-6 and IL-8) of cerebrospinal fluid after SCI. Consistent with patient findings, chronic hyperglycemia before SCI in rats was associated with increased inflammatory responses and oxygen-free radicals in the spinal cord and blood, thus resulting in poor functional recovery and histological outcomes. Tight glucose control before SCI decreased the harmful effects of hyperglycemia after SCI in both human and rat studies. Our findings suggest that chronic hyperglycemia before SCI may be a significant prognostic factor with a negative impact on functional and histological outcomes, highlighting the importance of tight glucose control before SCI.

After spinal cord injury (SCI), neutrophil elastase (NE) released at injury site disrupts vascular endothelium integrity and stabilization. Angiopoietins (ANGPTs) are vascular growth factors that play an important role in vascular stabilization. We hypothesized that neutrophil elastase is one of the key determinants of vascular endothelium disruption/destabilization and affects angiopoietins expression after spinal cord injury. To test this, tubule formation and angiopoietins expression were assessed in endothelial cells exposed to different concentrations of recombinant neutropil elastase. Then, the expression of angiopoietin-1, angiopoietin-2, and neutrophil elastase was determined at 3 h and at 1, 3, 5, 7, 14, 21, and 28 days in a clinically relevant model of moderate compression (35 g for 5 min at T10) spinal cord injury. A dichotomy between the levels of angiopoietin-1 and angiopoietin-2 was observed; thus, we utilized a specific neutrophil elastase inhibitor (sivelestat sodium; 30 mg/kg, i.p., b.i.d.) after spinal cord injury. The expression levels of neutropil elastase and angiopoietin-2 increased, and that of angiopoietin-1 decreased after spinal cord injury in rats. The sivelestat regimen, optimized via a pharmacokinetics study, had potent effects on vascular stabilization by upregulating angiopoietin-1 via the AKT pathway and preventing tight junction protein degradation. Moreover, sivelestat attenuated the levels of inflammatory cytokines and chemokines after spinal cord injury and hence subsequently alleviated secondary damage observed as a reduction in glial scar formation and the promotion of blood vessel formation and stabilization. As a result, hindlimb locomotor function significantly recovered in the sivelestat-treated animals as determined by the Basso, Beattie, and Bresnahan scale and footprint analyses. Furthermore, sivelestat treatment attenuated neuropathic pain as assessed by responses to von Frey filaments after spinal cord injury. Thus, our result suggests that inhibiting neutropil elastase by administration of sivelestat is a promising therapeutic strategy to inhibit glial scar and promote functional recovery by upregulating angiopoietin-1 after spinal cord injury. Electronic supplementary material The online version of this article (10.1186/s40478-018-0576-3) contains supplementary material, which is available to authorized users.

Spinal epidermoid tumors are rare, benign tumors that are either acquired from trauma, surgery, or lumbar puncture or arise as congenital lesions, particularly spinal dysraphisms. We report a case of a massive spinal epidermoid tumor and review the literature with a focus on the surgical outcomes. A 71-year-old female patient presented after a fall with subsequent symptoms of severe back and hip pain, as well as loss of motor strength in the left leg. Her magnetic resonance imaging demonstrated a T2/short tau inversion recovery hyperintense mass extending from the level of the T10–11 disc caudally through S2. A biopsy was recommended to determine whether the tumor was radio- or chemo-sensitive. The patient underwent a L4 laminectomy and a pearly-white tumor was encountered, with a subsequent biopsy confirming it to be an epidermoid tumor. The following conclusions can be drawn from a review of the literature. Spinal epidermoid tumors are more common in women and tend to present in younger patients (median age of 23). The majority of patients had acquired lesions (46%). In terms of surgical outcomes for adherent tumors, gross total resection was found to provide optimal outcomes, with 90% of patients improving clinically after surgery.

Vitamin D deficiency (VDD) has been closely linked with skeletal muscle atrophy in many studies, but to date no study has focused on the paraspinal muscle.To verify paraspinal muscle changes according to serum vitamin D level.A cross-sectional study of patients who visited our hospital and an in vivo animal study.We measured serum vitamin D concentration in 91 elderly women and stratified them according to their vitamin D status in three groups, control, vitamin D insufficiency, and VDD, and obtained magnetic resonance imaging data of the lumbar spine and evaluated the quality and quantity of the paraspinal muscles. Additionally, we designed experimental rat models for VDD and VDD replacement. Then, we analyzed the microcomputed tomography data and histologic data of paraspinal muscles, and the histologic data and reverse transcription-quantitative polymerase chain reaction data of intramyonuclear vitamin D receptor (VDR) in paraspinal muscle through comparison with control rats (n=25, each group). This work was supported by a Biomedical Research Institute grant ($40,000), Kyungpook National University Hospital (2014).In the human studies, a significant decrease was noted in the overall paraspinal muscularity (p.05) and increase in fatty infiltration in the VDD group as compared with the other groups (p.05). In the rat experiment, a decrease was noted in paraspinal muscle fiber size and VDR concentration and VDR gene expression level, and total muscle volume of the VDD rats as compared with the control rats (p.05). Vitamin D replacement after VDD could partially restore the muscle volume, muscle fiber size, and intramyonuclear VDR concentration levels (p.05) of the paraspinal muscles.VDD induces paraspinal muscle atrophy and decreases the intramyonuclear VDR concentration and VDR gene expression level in these muscles. Vitamin D replacement contributes to the recovery from atrophy and restoration of intramyonuclear VDR concentration in VDD status.

We aim to provide sagittal and pelvic parameters according to different age groups in an asymptomatic population all over 30 years old and to investigate the possible causes of changes in these parameters. Whole-spine, standing lateral radiographs were taken in 128 asymptomatic Korean people over 30 years old. The spinal parameters (the total thoracic kyphosis (TTK), maximal lumbar lordosis (MLL), total lumbar lordosis (TLL), lower lumbar lordosis (LLL), thoracolumbar junctional angle (TLJA), and lumbar inclination (LI)), pelvic parameters (pelvic incidence (PI), sacral slope (SS), and pelvic tilt (PT)), and spinal balance parameters (spinal balance, sacropelvic balance, and spinopelvic balance) were measured. The body mass index, body protein mass, waist line, skeletal muscle mass, and body fat mass were also measured for potential causes. TTK and TLJA were significantly increased in the group over 70 years of age compared to the other age groups (p = 0.0002

Purpose The purpose of this study is to investigate the effect of the cross-link position on the rod fracture phenomenon during pedicle subtraction osteotomy (PSO) surgery using finite element model (FEM). Methods A three-dimensional finite element model of a lumbar spine with sagittal imbalance was constructed using computed tomography data of a 65-year-old female patient. After simulating the standard PSO at the L4 level, we constructed four models, specifically a model without a cross-link and three models with a cross-link at three different sites. The peak von Mises stress (PVMS) of the rod around the PSO site was measured after applying physiological loads (flexion, extension, axial rotation, and lateral bending) in each model. Results The measured PVMS outcomes at the PSO site were 135.8, 135.9, 208.9, and 384.7 MPa for model 1, 2, 3, and 4 during flexion, and 180.0, 180.1, 210.1, and 445.7 MPa during extension. These results show that when the cross-link is located at the PSO site, the rod stress at the PSO site increases significantly during flexion and extension. As the cross-link moved away from the PSO site, the effect on the rod stress decreased. When the cross-link was placed two levels away from the PSO site, the rod stress was scarcely affected. Conclusion When the cross-link during PSO surgery was positioned two levels away from the PSO site, the risk of rod fracture did not increase.

Spinal cord injury (SCI) is a devastating condition of the central nervous system that can lead to permanent motor and sensory deficits. Carbon monoxide–releasing molecule-2 (CORM-2) has been shown to have anti-inflammatory, anti-apoptotic, and angiogenic properties that may be useful for the treatment of SCI. However, it has a short carbon monoxide (CO) release half-life (approximately 1 min). To address this challenge, we developed a CORM-2-incorporated solid lipid nanoparticle (CORM-2-SLN) and evaluated its ameliorating effects for preventing blood-spinal cord barrier (BSCB) disruption and endothelial cell death following SCI. After a moderate compression injury of the spinal cord (compression with a 35-g impounder for 5 min), groups of rats were treated with a CORM-2-solution and CORM-2-SLNs at an equal dose of 10 mg/kg each via an intraperitoneal injection for 8 consecutive days. Behavior analysis was performed and animals were later sacrificed at different time points and evaluated for whether the CORM-2-SLNs prevented BSCB disruption and rescued endothelial cell damage following SCI. The CORM-2-SLN-treated group showed significantly diminished extravasation of Evans Blue dye with enhanced expression of tight junction proteins following SCI. Likewise, significantly diminished endothelial cell markers after SCI were optimally stabilized at 21 days. Additionally, lipopolysaccharide (LPS)-induced loss of tight junction integrity was significantly preserved after CORM-2-SLN treatment in human cerebral microvascular endothelial cell line (hCMEC/D3). Clinically, CORM-2-SLNs were associated with a significantly improved functional recovery, as compared with the CORM-2-solution. CORM-2-SLNs may help potentially to maintain BSCB integrity following SCI.

This nationwide study aimed to compare the medical burdens of pyogenic spondylitis (PS) and tuberculous spondylitis (TS) between 2007 and 2016 in Korea.We used a national database managed by the National Health Insurance Service (NHIS) with data from the years 2007 and 2016. A total of 9655 newly diagnosed patients with PS or TS were correspondingly enrolled in the PS or TS group. Chi square test analyses were used to compare the PS and TS groups.The overall incidence of infectious spondylitis during the study period was 9655 persons. The PS and TS groups consisted of 7305 and 2350 cases, respectively. Individual medical costs in the PS group (USD 10,049 ± 94 vs. USD 16,672 ± 17,729, P 0.001) and the TS group (USD 4882 ± 6869 vs. USD 8531 ± 10,709, P 0.001) both increased. The total medical cost for the PS group increased significantly between 2007 and 2016 in Korea (USD 24,428,560 vs. USD 81,044,196, P 0.001). In contrast, the total medical cost for the TS group decreased between 2007 and 2016 in Korea (USD 8,573,038 vs. USD 4,879,520, P 0.001).This nationwide study shows that the total medical cost of PS has increased and that the total medical cost of TS has decreased between 2007 and 2016 in Korea.

STUDY DESIGN Prospective observational cohort study. OBJECTIVE In this study, an educational and interactive informed consent (EIC) program was proposed for patients with cervical spondylotic myelopathy caused by ossification of the posterior longitudinal ligament (OPLL-CSM) to improve their comprehension level during the informed consent process. SUMMARY OF BACKGROUND DATA OPLL-CSM is a slow progressive disease, and it is difficult for patients to understand the disease. Few studies have evaluated very specific programs to improve the informed consent process for these patients. METHODS This prospective study evaluated patients with OPLL-CSM who either underwent the proposed EIC process (n = 63) or the standard consent process (n = 124). The standard consent process only included a physician-patient interview. During the EIC process, information was provided regarding OPLL-CSM through information booklets, a video, verbal information, and initial and second physician-patient interviews. After the second physician-patient interview, the patient was requested to answer 14 medical questions to assess their knowledge about OPLL-CSM. The proposed EIC process took approximately 90 minutes. They were asked to report the most useful educational method and the most effective method of reinforcing verbal communication. RESULTS The mean questionnaire scores were higher in the EIC group than in the control group (P

Currently, the role of transient receptor potential vanilloid type 4 (TRPV4), a nonselective cation channel in the pathology of spinal cord injury (SCI), is not recognized. Herein, we report the expression and contribution of TRPV4 in the pathology of scarring and endothelial and secondary damage after SCI. TRPV4 expression increased during the inflammatory phase in female rats after SCI and was expressed primarily by cells at endothelial-microglial junctions. Two-photon microscopy of intracellular-free Ca2+levels revealed a biphasic increase at similar time points after SCI. Expression of TRPV4 at the injury epicenter, but not intracellular-free Ca2+, progressively increases with the severity of the injury. Activation of TRPV4 with specific agonist altered the organization of endothelial cells, affected tight junctions in the hCMEC/D3 BBB cell linein vitro, and increases the scarring in rat spinal cord as well as induced endothelial damage. By contrast, suppression of TRPV4 with a specific antagonist or in femaleTrpv4KO mouse attenuated inflammatory cytokines and chemokines, prevented the degradation of tight junction proteins, and preserve blood–spinal cord barrier integrity, thereby attenuate the scarring after SCI. Likewise, secondary damage was reduced, and behavioral outcomes were improved inTrpv4KO mice after SCI. These results suggest that increased TRPV4 expression disrupts endothelial cell organization during the early inflammatory phase of SCI, resulting in tissue damage, vascular destabilization, blood–spinal cord barrier breakdown, and scarring. Thus, TRPV4 inhibition/knockdown represents a promising therapeutic strategy to stabilize/protect endothelial cells, attenuate nociception and secondary damage, and reduce scarring after SCI.SIGNIFICANCE STATEMENTTRPV4, a calcium-permeable nonselective cation channel, is widely expressed in both excitable and nonexcitable cells. Spinal cord injury (SCI) majorly caused by trauma/accidents is associated with changes in osmolarity, mechanical injury, and shear stress. After SCI, TRPV4 was increased and were found to be linked with the severity of injury at the epicenter at the time points that were reported to be critical for repair/treatment. Activation of TRPV4 was damaging to endothelial cells that form the blood–spinal cord barrier and thus contributes to scarring (glial and fibrotic). Importantly, inhibition/knockdown of TRPV4 prevented these effects. Thus, the manipulation of TRPV4 signaling might lead to new therapeutic strategies or combinatorial therapies to protect endothelial cells and enhance repair after SCI.

Rationale: Atlantoaxial transarticular screw fixation has been an effective and appealing method for inducing fusion of the C1-C2 complex. This technique is usually performed with Gallie fusion. In performing Gallie fusion using sublaminar wiring, a major concern is the risk of dural tear associated with passing sublaminar wires through the epidural space. We present the first report on symptomatic symptomatic subdural hygroma (SDH) due to transarticular screw fixation with posterior wiring. Patients concerns: A 50-year-old man had sustained dens fracture 20 years ago and presented with severe neck pain following a recent traffic accident. The images showed atlantoaxial instability due to nonunion of the dens fracture and the patient underwent transarticular screw fixation with posterior sublaminar wiring using Gallie technique. When the U-shaped wire was passed under the arch of C1 from inferior to superior, a dural tear and cerebrospinal fluid (CSF) leak occurred. The site of dural tear was repaired by direct application of sutures. The patient was discharged in good condition. Fifteen day after surgery, the patient was readmitted with a history of a progressive headache associated with vomiting and vertigo. Diagnonsis: Brain CT and MRI showed bilateral posterior fossa and a right-sided supratentorial SDH. Interventions: The patient underwent right occipital burr hole and evacuation of posterior fossa SDH due to deteriorating neurological status. Outcomes: The patient's condition gradually improved after the operation and became asymptomatic at 3-year follow-up. Lessons: Posterior fossa and supratentorial SDH could occur resulting from any intraoperative dural tear and CSF leakage during posterior cervical spinal surgery. Symptomatic SDH after posterior cervical spinal surgery should be cautiously assessed and treated. Level of Evidence: 5

Curcumin has anti-inflammatory and antioxidant activities.This study aimed to investigate the effects of curcumin on the histological changes and functional recovery following spinal cord injury (SCI).One hundred twenty-eight Sprague-Dawley rats were distributed into a sham, SCI only, SCI-hyperglycemia, and SCI-hyperglycemia-curcumin (200 mg/kg/day, i.p.) groups.SCI was induced using a clip at T9-10 and hyperglycemia was induced by streptozotocin (60-70 mg/kg, i.v.). Plasma malondialdehyde levels and superoxide dismutase activity was measured to determine oxidative stress. The activity of macrophages in the spinal cord after SCI was stained by the anti-CD68 antibody (ED-1). The tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 levels were measured by enzyme-linked immunosorbent assay and Western blot was used to verify the levels of mitogen-activated protein kinases and STAT3. The glial fibrillary acidic protein expression was evaluated by immunofluorescence analysis. Functional recovery was assessed according to the Basso, Beattie, and Bresnahan scale and histologic outcome was evaluated by the lesion volume and spared tissue area.Superoxide dismutase activity increased, the malondialdehyde level decreased, and ED-1 macrophage marker level decreased in the SCI-hyperglycemia-curcumin group than in the SCI-hyperglycemia group at 2 weeks after SCI (p.01). The SCI-hyperglycemia-curcumin group showed a statistically significant reduction in IL-6, IL-8, and TNF-α levels compared with the SCI-hyperglycemia group after SCI. The phosphorylated-extracellular signal-regulated kinase, phosphorylated-JNK, and phospho-p38 levels were significantly lower in the SCI-hypoglycemia-curcumin group than in the SCI-hypoglycemia group. The SCI-hyperglycemia-curcumin group showed a decrease in glial fibrillary acidic protein expression after SCI compared with the SCI-hyperglycemia group. The SCI-hyperglycemia-curcumin group showed a lower lesion volume, higher spared tissue, and better functional recovery than the SCI-hyperglycemia group.Curcumin may have a potential neuroprotective effect in SCI with hyperglycemia.Curcumin decreased the inflammatory response and decreased astrogliosis and improved the functional recovery and histologic outcomes in SCI with hyperglycemia.

Neuropathic pain (NP) is a complex, debilitating, chronic pain state, heterogeneous in nature and caused by a lesion or disease affecting the somatosensory system. Its pathogenesis involves a wide range of molecular pathways. NP treatment is extremely challenging, due to its complex underlying disease mechanisms. Current pharmacological and nonpharmacological approaches can provide long-lasting pain relief to a limited percentage of patients and lack safe and effective treatment options. Therefore, scientists are focusing on the introduction of novel treatment approaches, such as stem cell therapy. A growing number of reports have highlighted the potential of stem cells for treating NP. In this review, we briefly introduce NP, current pharmacological and nonpharmacological treatments, and preclinical studies of stem cells to treat NP. In addition, we summarize stem cell mechanisms—including neuromodulation in treating NP. Literature searches were conducted using PubMed to provide an overview of the neuroprotective effects of stem cells with particular emphasis on recent translational research regarding stem cell-based treatment of NP, highlighting its potential as a novel therapeutic approach.

Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain (LBP) that results in serious disability and significant economic burden. IVD degeneration alters the disc structure and spine biomechanics, resulting in subsequent structural changes throughout the spine. Currently, treatments of chronic LBP due to IVD degeneration include conservative treatments, such as pain medication and physiotherapy, and surgical treatments, such as removal of herniated disc without or with spinal fusion. However, none of these treatments can completely restore a degenerated disc and its function. Thus, although the exact pathogenesis of disc degeneration remains unclear, there are studies examining the effectiveness of biological approaches, such as growth factor injection, gene therapy, and cell transplantation, in promoting IVD regeneration. Furthermore, tissue engineering using a combination of cell transplantation and biomaterials has emerged as a promising new approach for repair or restoration of degenerated discs. The main purpose of this review was to provide an overview of the current status of tissue engineering applications for IVD regenerative therapy by performing literature searches using PubMed. Significant advances in tissue engineering have opened the door to a new generation of regenerative therapies for the treatment of chronic discogenic LBP.

The side predilections of various offending arteries in hemifacial spasm (HFS) have not been well studied. The relationship between clinical and radiological features of HFS and offending arteries were investigated in the present study. A retrospective analysis of 370 patients who underwent microvascular decompression for HFS was performed. The patients were divided into four groups based on the offending arteries, namely anterior inferior cerebellar artery (AICA), posterior inferior cerebellar artery (PICA), vertebral artery, and multiple offending arteries. Affected side, age at onset, presence of hypertension, and sigmoid sinus area and dominance were compared between groups. The mean age of patients with a left HFS was significantly greater than that of patients with a right HFS (P=0.009). The AICA affected primarily the right side and PICA and multiple offending arteries the left side (P

The blood-spinal cord barrier (BSCB) is a specialized protective barrier that regulates the movement of molecules between blood vessels and the spinal cord parenchyma. Analogous to the blood-brain barrier (BBB), the BSCB plays a crucial role in maintaining the homeostasis and internal environmental stability of the central nervous system (CNS). After spinal cord injury (SCI), BSCB disruption leads to inflammatory cell invasion such as neutrophils and macrophages, contributing to permanent neurological disability. In this review, we focus on the major proteins mediating the BSCB disruption or BSCB repair after SCI. This review is composed of three parts. Section 1. SCI and the BSCB of the review describes critical events involved in the pathophysiology of SCI and their correlation with BSCB integrity/disruption. Section 2. Major proteins involved in BSCB disruption in SCI focuses on the actions of matrix metalloproteinases (MMPs), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), angiopoietins (Angs), bradykinin, nitric oxide (NO), and endothelins (ETs) in BSCB disruption and repair. Section 3. Therapeutic approaches discusses the major therapeutic compounds utilized to date for the prevention of BSCB disruption in animal model of SCI through modulation of several proteins.

The rates of pseudarthrosis remain high despite recent advances in bone graft substitutes for spinal fusion surgery. The aim of this single center, non-randomized, open-label clinical trial was to determine the feasibility of combined use of stromal vascular fraction (SVF) and &beta, tricalcium phosphate (&beta, TCP) for patients who require posterior lumbar interbody fusion (PLIF) and pedicle screw fixation. Two polyetheretherketone (PEEK) cages were inserted into the intervertebral space following complete removal of the intervertebral disc. The PEEK cage (SVF group) on the right side of the patient was filled with &beta, TCP in combination with SVF, and the cage on the left side (control group) was filled with &beta, TCP alone. Fusion rate and cage subsidence were assessed by lumbar spine X-ray and CT at 6 and 12 months postoperatively. At the 6-month follow-up, 54.5% of the SVF group (right-sided cages) and 18.2% of the control group (left-sided cages) had radiologic evidence of bone fusion (p = 0.151). The 12-month fusion rate of the right-sided cages was 100%, while that of the left-sided cages was 91.6% (p = 0.755). Cage subsidence was not observed. Perioperative combined use of SVF with &beta, TCP is feasible and safe in patients who require spinal fusion surgery, and it has the potential to increase the early bone fusion rate following spinal fusion surgery.

Neuroprotective measures by preventing secondary spinal cord injury (SCI) are one of the main strategies for repairing an injured spinal cord. Fasudil and menthol may be potent neuroprotective agents, which act by inhibiting a rho-associated protein kinase (ROCK) and suppressing the inflammatory response, respectively. We hypothesized that combined treatment of fasudil and menthol could improve functional recovery by decreasing inflammation, apoptosis, and glial scar formation. We tested our hypothesis by administering fasudil and menthol intraperitoneally (i.p.) to female Sprague Dawley rats after moderate static compression (35 g of impounder for 5 min) of T10 spinal cord. The rats were randomly divided into five experimental groups: (i) sham animals received laminectomy alone, (ii) injured (SCI) and untreated (saline 0.2 mL/day, i.p.) rats, (iii) injured (SCI) rats treated with fasudil (10 mg/kg/day, i.p.) for two weeks, (iv) injured (SCI) rats treated with menthol (10 mg/kg/day, i.p.) for twoweeks, (v) injured (SCI) rats treated with fasudil (5 mg/kg/day, i.p.) and menthol (10 mg/kg/day, i.p.) for two weeks. Compared to single treatment groups, combined treatment of fasudil and menthol demonstrated significant functional recovery and pain amelioration, which, thereby, significantly reduced inflammation, apoptosis, and glial/fibrotic scar formation. Therefore, combined treatment of fasudil and menthol may provide effective amelioration of spinal cord dysfunction by a synergistic effect of fasudil and menthol.

Tauroursodeoxycholic acid (TUDCA) is a US FDA-approved hydrophilic bile acid for the treatment of chronic cholestatic liver disease. In the present study, we investigate the effects of TUDCA on the proliferation and differentiation of osteoblasts and its therapeutic effect on a mice model of osteoporosis. Following treatment with different concentrations of TUDCA, cell viability, differentiation, and mineralization were measured. Three-month-old female C57BL/6 mice were randomly divided into three groups (n = 8 mice per group): (i) normal mice as the control group, (ii) ovariectomy (OVX) group (receiving phosphate-buffered saline (PBS) treatment every other day for 4 weeks), and (iii) OVX group with TUDCA (receiving TUDCA treatment every other day for 4 weeks starting 6 weeks after OVX). At 11 weeks post-surgery, serum levels of procollagen type I N-terminal propeptides (PINP) and type I collagen crosslinked C-telopeptides (CTX) were measured, and all mice were sacrificed to examine the distal femur by micro-computed tomography (CT) scans and histology. TUDCA (100 nM, 1 &micro, M) significantly increased the proliferation and viability of osteoblasts and osteoblast differentiation and mineralization when used in vitro. Furthermore, TUDCA neutralized the detrimental effects of methylprednisolone (methylprednisolone-induced osteoblast apoptosis). In the TUDCA treatment group the PINP level was higher and the CTX level was lower, but these levels were not significantly different compared to the PBS treatment group. Micro-CT and histology showed that the TUDCA treatment group preserved more trabecular structures in the distal femur compared to the PBS treatment group. In addition, the TUDCA treatment group increased the percentage bone volume with respect to the total bone volume, bone mineral density, and mice distal femur trabeculae compared with the PBS treatment group. Taken together, our findings suggest that TUDCA may provide a favorable effect on bones and could be used for the prevention and treatment of osteoporosis.

α-asarone, a bioactive compound found in Acorus plant species, has been shown to exhibit neuroprotective, anti-oxidative, anti-inflammatory, and cognitive-enhancing effects. However, the effects of α-asarone on spinal cord injury (SCI) have not yet been elucidated. The present study investigated the effects of α-asarone on the mRNA of pro-inflammatory cytokines, macrophage polarization toward an anti-inflammatory M2 phenotype, and angiogenesis in rats with compressive SCI. α-Asarone was orally administered (10 mg/kg) once per day for 14 days following moderate static compression SCI. Compared to controls, α-asarone treatment significantly improved locomotor score, prevented neuroinflammation, and facilitated angiogenesis in the spinal cord at 14 days after SCI. Furthermore, α-asarone significantly reduced the TNF-α, IL-1β, IL-6, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and inducible nitric oxide synthase (iNOS) levels but increased the IL-4, IL-10, and arginase 1 levels at 24 h after SCI. At 7 and 14 days after SCI, immunohistochemistry showed reduced reactive gliosis and neuroinflammation and an increased expression of M2 macrophage markers and angiogenesis. The results suggest that the inhibition of pro-inflammatory cytokines, macrophage polarization toward an anti-inflammatory M2 phenotype, and angiogenesis by α-asarone may be some of the mechanisms underlying the α-asarone-mediated neuroprotective effects on an injured spinal cord.

Human mesenchymal stem cell (hMSC)-derived exosomes have been spotlighted as a promising therapeutic agent for cell-free regenerative medicine. However, poor organ-targeting ability and insufficient therapeutic efficacy of systemically injected hMSC-exosomes were identified as critical limitations for their further applications. Therefore, in this study we fabricated iron oxide nanoparticle (IONP)-incorporated exosome-mimetic nanovesicles (NV-IONP) from IONP-treated hMSCs and evaluated their therapeutic efficacy in a clinically relevant model for spinal cord injury. Compared to exosome-mimetic nanovesicles (NV) prepared from untreated hMSCs, NV-IONP not only contained IONPs which act as a magnet-guided navigation tool but also carried greater amounts of therapeutic growth factors that can be delivered to the target cells. The increased amounts of therapeutic growth factors inside NV-IONP were attributed to IONPs that are slowly ionized to iron ions which activate the JNK and c-Jun signaling cascades in hMSCs. In vivo systemic injection of NV-IONP with magnetic guidance significantly increased the amount of NV-IONP accumulating in the injured spinal cord. Accumulated NV-IONP enhanced blood vessel formation, attenuated inflammation and apoptosis in the injured spinal cord, and consequently improved spinal cord function. Taken together, these findings highlight the development of therapeutic efficacy-potentiated extracellular nanovesicles and demonstrate their feasibility for repairing injured spinal cord.

We have reported previously that bone marrow mesenchymal stem cell (MSC)-derived neural network scaffold not only survived in the injury/graft site of spinal cord but also served as a “neuronal relay” that was capable of improving the limb motor function in a complete spinal cord injury (SCI) rat model. It remained to be explored whether such a strategy was effective for repairing the large spinal cord tissue loss as well as restoring motor function in larger animals. We have therefore extended in this study to construct a canine MSC-derived neural network tissue in vitro with the aim to evaluate its efficacy in treating adult beagle dog subjected to a complete transection of the spinal cord. The results showed that after co-culturing with neurotropin-3 overexpressing Schwann cells in a gelatin sponge scaffold for 14 days, TrkC overexpressing MSCs differentiated into neuron-like cells. In the latter, some cells appeared to make contacts with each other through synapse-like structures with trans-synaptic electrical activities. Remarkably, the SCI canines receiving the transplantation of the MSC-derived neural network tissue demonstrated a gradual restoration of paralyzed limb motor function, along with improved electrophysiological presentation when compared with the control group. Magnetic resonance imaging and diffusion tensor imaging showed that the canines receiving the MSC-derived neural network tissue exhibited robust nerve tract regeneration in the injury/graft site. Histological analysis showed that some of the MSC-derived neuron-like cells had survived in the injury/graft site up to 6.5 months. Implantation of MSC-derived neural network tissue significantly improved the microenvironment of the injury/graft site. It is noteworthy that a variable number of them had integrated with the regenerating corticospinal tract nerve fibers and 5-HT nerve fibers through formation of synapse-like contacts. The results suggest that the transplanted MSC-derived neural network tissue may serve as a structural and functional “neuronal relay” to restore the paralyzed limb motor function in the canine with complete SCI.

The authors regret to state that an incorrect image was uploaded in Fig. 2. Please see a newly updated Fig. 2. All statements including Figure Legends are correct.

Pertaining to an association between Acute Myocardial Infarction (AMI) and Ankylosing Spondylitis (AS) is sparse. The purpose of this nationwide longitudinal study was to investigate the prevalence of AMI in newly diagnosed AS patients. A total of 12,988 patients were enrolled in the AS group from January 1, 2010 to December 31, 2014 from the Korean National Health Insurance Service (NHIS). The control group consisted of 64,940 subjects according to 1:5 age-sex stratified matching. The AMI incidence rates in AS and control group were compared using the Kaplan-Meier method. The hazard ratio of AMI and the control group was estimated by Cox proportional hazards regression analyses. During a 6 year follow up, 62 patients (0.48%) in the AS group and 157 persons (0.24%) in the control group developed AMI. The hazard ratio of AMI in the AS group was 1.99 (95% confidence interval [95% CI], 1.48–2.67) after adjusting for sex and age. The hazard ratio of AMI in the AS group was 1.81 (95% CI, 1.34–2.43) after adjusting for demographics and comorbid medical disorders. The incidence rate of AMI increases in newly diagnosed AS patients.

Postmenopausal osteoporosis is one of the most prominent diseases in postmenopausal women and it is increasing in prevalence with the aging population. Furthermore, osteoporosis and osteoporotic vertebral compression fractures (OVCFs) are related to mortality and decreased quality of life. Therefore, searching for biomarkers that are able to identify postmenopausal women who are at high risk of developing OVCFs is an effective strategy for improving the quality of life of patients and alleviating social and economic burdens. In this study, we investigated methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) gene polymorphisms in postmenopausal women with OVCF. We recruited 301 postmenopausal women and performed genotyping for the presence of MTHFR 2572C>A, 4869C>G and TS 1100C>T, 1170A>G. Genotyping was analyzed using the polymerization chain reaction restriction fragment length polymorphism assay. MTHFR 2572C>A and TS 1100C>T were associated with the prevalence of osteoporosis (MTHFR 2572CC versus CA+AA: odd ratio [OR] adjusted age, hypertention [HTN], and diabetes mellitus [DM] = 0.49, p = 0.012) and the occurrence of OVCFs (MTHFR 2572CC versus CA+AA: OR adjusted age, HTN, and DM = 0.38, p = 0.013; TS 1100CC versus CT+TT: OR adjusted age, HTN, and DM = 0.46, p = 0.02). Our novel finding is the identification of MTHFR and TS genetic variants that decrease susceptibility to OVCFs. Our findings suggest that polymorphisms in the MTHFR and TS genes are associated with susceptibility to osteoporosis and OVCFs in postmenopausal women.

We aim to characterize the biomechanical properties of a modified iliac screw fixation method compared with the classic iliac screw fixation and the S2 alar iliac screw (S2AI) fixation using a FEM. A three-dimensional, non-linear FEM of lumbosacral spine and pelvis (L1-pelvis) was modified to simulate 3 different iliac screw fixations based on posterior screw fusion. The peak von Mises stress (PVMS) values of the iliac screws in the 3 different iliac screw fixations were recorded in during flexion/extension/axial rotation/lateral bending. The interaction stress which arose between the screw head and the shaft of iliac screws, was also measured for each case. The PVMS values of the 3 different iliac screw fixation techniques were lower than the fatigue strength levels under physiological loadings. PVMS of iliac screws was observed in the screw shaft for S2AI, in the screw neck for the modified iliac screw technique, and in the offset connectors of the classic iliac screw technique. The interaction between the screw head and the neck was compressed in modified iliac screw fixation technique. On the other hand, distraction force was observed in the S2AI technique between the screw head and the screw shaft. This FEM study supports our previous clinical results, which found that the modified iliac screw fixation technique can be an effective alternative sacropelvic fixation technique comparable to the classic iliac screw and the S2AI technique.

Background Context Diabetes and menopause can cause severe osteoporosis. In general, menopause and diabetes can lead to an imbalance in bone turnover, which results in secondary osteoporosis. However, the efficacy of antiresorptive drugs against this form of osteoporosis has not been extensively evaluated. Objective The aim of this study was to determine the changes in vertebral bone remodeling when postmenopausal osteoporosis is accompanied by diabetes and to compare the efficacy of bisphosphonates and selective estrogen-receptor modulators (SERMs) against these outcomes. Study design Streptozotocin-induced diabetic, ovariectomized Sprague-Dawley rats were used as the disease model. Alendronate and raloxifene were used as the bisphosphonate and SERM, respectively. Methods We divided 62 female rats into five groups: (1) control (n=14), (2) DM (diabetes) (n=12), (3) DM+OVX (diabetes+ovariectomy) (n=12), (4) DM+OVX+A (diabetes+ovariectomy+alendronate) (n=12), and (5) DM+OVX+R (diabetes+ovariectomy+raloxifene) (n=12). Serum biochemical markers of bone turnover, including osteocalcin and the C-telopeptide of type I collagen (CTX-1), were analyzed. We measured histomorphometric parameters of the fourth lumbar vertebrae using microcomputed tomography. Mechanical strength was evaluated by a compression test. Results In the DM and DM+OVX group, only the levels of osteocalcin significantly decreased compared with those of the control group at 8 weeks after OVX. At 12 weeks, the serum CTX-1 levels in the DM+OVX+A and DM+OVX+R groups were significantly lower than those of the DM+OVX group, but there were no changes in the levels of osteocalcin. Bone mineral density and mechanical strength were higher in the DM+OVX+A and DM+OVX+R groups than in the DM and DM+OVX groups (p Conclusions Even if postmenopausal osteoporosis is accompanied by diabetes in this animal model, both alendronate and raloxifene seem to show antiresorptive effects, decreased bone turnover rates, and improved bone mechanical strength. Therefore, alendronate and raloxifene are effective in the treatment of osteoporosis even for bone loss caused by DM and postmenopausal osteoporosis.

Transforaminal lumbar interbody fusion (TLIF) is a widely accepted surgical procedure, but cage migration (CM) and cage retropulsion (CR) are associated with poor outcomes.This study seeks to identify risk factors associated with these serious events.A prospective observational longitudinal study.Over a 5-year period, 881 lumbar levels in 784 patients were treated using TLIF at three spinal surgery centers.We evaluated the odds ratio of the risk factors for CM with and without subsidence and CR in multivariate analysis.Our study classified CM into two subgroups: CM without subsidence and CM with subsidence. Cases of spinal canal and/or foramen intrusion of the cage was defined separately as CR. Patient records, operative notes, and radiographs were analyzed for factors potentially related to CM with subsidence, CM without subsidence, and CR.Of 881 lumbar levels treated with TLIFs, CM without subsidence was observed in 20 (2.3%) and CM with subsidence was observed in 36 (4.1%) patients. Among the CM cases, CR was observed in 17 (17/56, 30.4%). The risk factors of CM without subsidence were osteoporosis (OR 8.73, p.001) and use of a unilateral single cage (OR 3.57, p.001). Osteoporosis (OR 5.77, p.001) and endplate injury (OR 26.87, p.001) were found to be significant risk factors for CM with subsidence. Risk factors of CR were osteoporosis (OR 7.86, p.001), pear-shaped disc (OR 8.28, p = .001), endplate injury (OR 18.70, p.001), unilateral single cage use (OR 4.40, p = .03), and posterior cage position (OR 6.45, p = .04). A difference in overall fusion rates was identified, with a rate of 97.1% (801 of 825) for no CM, 55.0% (11 of 20) for CM without subsidence, 41.7% (15 of 36) for CM with subsidence, and 17.6% (3 of 17) for CR at 1.5 years postoperatively.Our results suggest that osteoporosis is a significant risk factor for both CM and CR. In addition, a pear-shaped disc, posterior positioning of the cage, the presence of endplate injury and the use of a single cage were correlated with the CM with and without subsidence and CR.

Intervertebral disk (IVD) degeneration is a common, chronic, and complex degeneration process that frequently leads to back pain and disability, resulting in a major public health issue. In this review we describe biological therapies under preclinical or clinical development with an emphasis on stem cell-based multimodal approaches that target prevention and treatment of IVD degeneration. Systematical review of the basic science and clinical literature was performed to summarize the current status of devising biological approaches to treating IVD degeneration. Since the exact mechanisms underlying IVD degeneration have not yet been fully elucidated and conservative managements appear to be mostly ineffective, current surgical treatment focuses on removal of the pathological disk tissues combined with spinal fusion. The treatment options, however, often produce insufficient efficacy and even serious complications. Therefore, there have been growing demands and endeavors for developing novel regenerative biology-guided strategies for repairing the IVD via delivery of exogenous growth factors, introduction of therapeutic genes, and transplantation of stem cells, or combinatorial therapies. Overall, the data suggest that when applied under a recovery neurobiology principle, multimodal regimens comprising ex vivo engineered stem cell-based disks hold a high potential promise for efficacious clinical translations.

We report an efficient and effective device to reproducibly model clinically relevant spinal cord injury (SCI) via controlled mechanical compression. In the present study, following skin incision, dorsal laminectomy was performed to expose T10 spinal cord of adult female Sprague–Dawley rats (230–250 g). The vertebral column was suspended and stabilized by Allis clamps at T8 and 12 spinous processes. A metal impounder was then gently loaded onto T10 dura (20, 35 or 50 g × 5 min; n = 7/group), resulting in acute mild, moderate, or severe standing weight compression, respectively. Neurobehavioral outcomes were evaluated using the BBB locomotor scale and inclined plane test for coordinated hindlimb function, and a battery of spinal reflex tests for sensorimotor functions, at 1 day following SCI and weekly thereafter for 7 weeks. Quantitative histopathology was used to assess injury-triggered loss of white matter, gray matter and ventral horn motor neurons. Immunocytochemical levels of glial fibrillary acidic protein (GFAP) and β-amyloid precursor protein (APP) at the cervical and lumbar regions were measured to determine the distal segment impact of T10 compression. The data demonstrates that the standardized protocol generates weight-dependent hindlimb motosensory deficits and neurodegeneration primarily at and near the lesion epicenter. Importantly, there are significantly increased GFAP and APP expressions in spinal cord segments involved in eliciting post-SCI allodynia. Therefore, the described system reliably produces compression trauma in manners partially emulating clinical quasi-static insults to the spinal cord, providing a pragmatic model to investigate pathophysiological events and potential therapeutics for compression SCI.

Objective Epidural injection of hyaluronic acid may prevent adhesion formation after spine surgery, but the compounds used to stabilize hyaluronidase could interfere with its anti-adhesion effects. The present study was conducted as a clinical trial to evaluate the efficacy and safety of an experimental medical gel in preventing adhesion formation. Methods This study was designed as a multicenter, randomized, double-blind, and comparative controlled clinical trial with an observation period of 6 weeks. Subjects were randomly assigned into two groups: group A with sodium hyaluronate + 1,4-butanediol diglycidyl ether (BDDE) and group B with sodium hyaluronate + sodium carboxymethylcellulose (CMC). Visual analogue scale (VAS) of back and leg pain and the Oswestry disability index (ODI) and scar score ratings were assessed after surgery. Results Mean scar grade was 2.37±1.13 in group A and 2.75±0.97 in group B, a statistically significant difference (p=0.012). VAS of back and leg pain and ODI scores decreased significantly from baseline to 3 and 6 weeks postoperatively in both groups (p0.3). The number of adverse reactions related to the anti-adhesion gels was not statistically different (p=0.569), but subsequent analysis of nervous adverse reactions showed group B was superior with a statistically difference (p=0.027). Conclusion Sodium hyaluronate with BDDE demonstrated similar anti-adhesion properties to sodium hyaluronate with CMC. But, care should be used to nervous adverse reactions by using sodium hyaluronate with BDDE.

Selective peripheral denervation (SPD) and deep brain stimulation of the globus pallidus (GPi-DBS) are available surgical options for patients with medically refractory cervical dystonia (CD). There are few data available concerning whether patients who have unsatisfactory treatment effects after primary surgery benefit from a different type of subsequent surgery. The aim of this study was to assess whether combining these surgical procedures (SPD plus GPi-DBS) was effective in patients with unsatisfactory treatment effects after their initial surgery. Forty-one patients with medically refractory idiopathic CD underwent SPD and/or GPi-DBS. Patients who were dissatisfied with their primary surgery (SPD or GPi DBS) elected to subsequently undergo a different type of surgery. These patients were assessed with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). SPD alone and GPi-DBS alone were performed in 16 and 21 patients, respectively. Four patients had unsatisfactory treatment effects after the initial surgery and subsequently underwent another type of surgery. Among them, two patients with persistent dystonia after SPD subsequently underwent GPi-DBS, and two other patients who had insufficient treatment effects following GPi-DBS were subsequently treated with SPD. All of these patients experienced sustained improvement from the combined surgical procedures according to the TWSTRS score during a long-term follow-up of 12–90 months. Patients with unsatisfactory treatment effects after an SPD or GPi-DBS experienced improvement from subsequently undergoing other types of surgery. Therefore, combined surgical procedures are additional surgical options with good outcomes in the treatment of patients with residual symptoms after their initial surgery.