Association between ischemic stroke and pyogenic spondylitis in Korea: Nationwide longitudinal cohort study.

OBJECTIVE: The purpose of this nationwide age- and sex- matched longitudinal study was to determine the pyogenic spondylitis (PS) increases the incidence of ischemic stroke (IS) in Korea. METHODS: From the National Health Insurance Service (NHIS), we collected the patient data for the period from January 1, 2004 to December 31, 2015. PS was classified according to the International Classification of Disease codes M46.2-M46.8, M49.2, and M49.3. By using a 1:5 age- and sex- stratified matching, a total of 628 patients and 3140 control subjects were included in the study. The IS incidence rates in PS and control group was calculated by using the Kaplan-Meier method. The outcome of hazard ratio of IS was estimated by Cox proportional hazards regression analyses. This study did not exclude PS as a result of postoperative complications. RESULTS: According to the study, 51 patients (8.12%) in the PS group and 201 patients (6.4%) in the control group experienced IS. The adjusted hazard ratio of IS in the PS group was 3.419 (95% CI: 2.473-4.729) after adjusting individual medical condition and demographics. Following the results of subgroup analysis, the risk ratio of IS was greater in most of the subgroup categories (male, female, age <65, age >65, non-diabetic, hypertensive, non-hypertensive, dyslipidemic and non-dyslipidemic subgroup). However, the risk of IS did not differ significantly in diabetic subgroup (95% CI: 0.953-4.360). CONCLUSIONS: The risk rate of IS increased in patient with pyogenic spondylitis.

Transplantation of neuron-inducing grafts embedding positively charged gold nanoparticles for the treatment of spinal cord injury.

In this study, we aimed to investigate the recovery after traumatic spinal cord injury (SCI) by inducing cellular differentiation of transplanted neural stem cells (NSCs) into neurons. We dissociated NSCs from the spinal cords of Fisher 344 rat embryos. An injectable gel crosslinked with glycol chitosan and oxidized hyaluronate was used as a vehicle for NSC transplantation. The gel graft containing the NSC and positively charged gold nanoparticles (pGNP) was implanted into spinal cord lesions in Sprague-Dawley rats (NSC-pGNP gel group). Cellular differentiation of grafted NSCs into neurons (stained with ß-tubulin III [also called Tuj1]) was significantly increased in the NSC-pGNP gel group (***p < 0.001) compared to those of two control groups (NSC and NSC gel groups) in the SCI conditions. The NSC-pGNP gel group showed the lowest differentiation into astrocytes (stained with glial fibrillary acidic protein). Regeneration of damaged axons (stained with biotinylated dextran amines) within the lesion was two-fold higher in the NSC-pGNP gel group than that in the NSC gel group. The highest locomotor scores were also found in the NSC-pGNP gel group. These outcomes suggest that neuron-inducing pGNP gel graft embedding embryonic spinal cord-derived NSCs can be a useful type of stem cell therapy after SCI.

The Relationship between Parkinson's Disease and Acute Myocardial Infarction in Korea : A Nationwide Longitudinal Cohort Study.

OBJECTIVE: The goal of the following statewide age and gender-coordinated cohort study in Korea is to find out if there is a link between acute myocardial infarction (AMI) and Parkinson's disease (PD). METHODS: Utilizing the National Health Insurance Sharing Service cohort, patient data were collected. Six thousand four hundred seventy-five individuals with PD were distinguished by utilizing the International Classification of Diseases 10 code G20 and have enrolled in the PD group. The number of participants decreased to 5259 after excluding 1039 patients who were hospitalized less than one time or who visited an outpatient clinic less than twice. Then, 26295 individuals were selected as part of the control group after case control matching was conducted through 1 : 5 age- and gender-coordinated matching. The Cox proportional hazard regression analysis and Kaplan-Meier method were utilized to analyze the likelihood of AMI in PD. RESULTS: After controlling for age and gender, the hazard ratio of AMI in the PD group was 3.603 (95% confidence interval [CI], 2.837-4.577). After that, the following hazard ratio of AMI in the PD group was modified against for co-morbid medical disorders, resulting in 3.551 (95% CI, 2.795-4.511). According to a subgroup analysis, in males and females aged <65 and aged ≥65 and in the non-diabetes and diabetes, hypertension and non-hypertension, dyslipidemia and non-dyslipidemia subgroups, the AMI incidence rates were dramatically higher in the PD group compared to that of the control. CONCLUSION: Individuals with PD have a greater chance of AMI, according to this cross-national study.

Association of Parkinson's disease with ischemic stroke in Korea: A nationwide longitudinal cohort study in Korea.

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.

Direct Injection of Hydrogels Embedding Gold Nanoparticles for Local Therapy after Spinal Cord Injury.

In this study, we created a hydrogel composed of glycol chitosan (gC) and oxidized hyaluronate (oHA). Gold nanoparticles (GNPs) were conjugated with ursodeoxycholic acid (UDCA). The GNP-UDCA complex was embedded into gC-oHA (CHA) hydrogels to form a CHA-GNP-UDCA gel. This CHA-GNP-UDCA gel was injected once into an epicenter of an injured region in SCI rats. Near-infrared (NIR) irradiation was then applied to the lesion as a means of local therapy. To optimize the viscosity for injection into a lesion, several volume ratios of gC and oHA were investigated using scanning electron microscopy and a rotating rheometer. The optimally synthesized CHA-GNP-UDCA gel under NIR irradiation suppressed the production of inflammatory cytokines in vitro. In addition, the optimized CHA-GNP-UDCA gel under NIR irradiation inhibited the cystic cavity of the lesion and significantly improved the hindlimb function. The production of inflammatory cytokines following SCI was significantly inhibited in the CHA-GNP-UDCA gel + NIR group. CHA-GNP-UDCA gels with NIR irradiation can therefore have therapeutic effects for those with spinal cord injuries.

Transplantation of tauroursodeoxycholic acid-inducing M2-phenotype macrophages promotes an anti-neuroinflammatory effect and functional recovery after spinal cord injury in rats.

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.

Association between ischemic stroke and seropositive rheumatoid arthritis in Korea: A nationwide longitudinal cohort study.

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.

Inhibitory Effects of Gold and Silver Nanoparticles on the Differentiation into Osteoclasts In Vitro.

Gold nanoparticles (GNPs) have been widely studied to inhibit differentiation into osteoclasts. However, reports of the inhibitory effects of silver nanoparticles (SNPs) during the process of differentiation into osteoclasts are rare. We compared the inhibitory effect of GNPs and SNPs during the process of differentiation into osteoclasts. Bone marrow-derived cells were differentiated into osteoclasts by the receptor activator of the nuclear factor-kappa-Β ligand (RANKL). The inhibitory effect of GNPs or SNPs during the process of differentiation into osteoclasts was investigated using tartrate-resistant acid phosphatase (TRAP) and actin ring staining. The formation of TRAP positive (+) multinuclear cells (MNCs) with the actin ring structure was most inhibited in the SNP group. In addition, the expression of specific genes related to the differentiation into osteoclasts, such as c-Fos, the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), TRAP, and Cathepsin K (CTSK) were also inhibited in the SNP groups. As a result, the levels related to differentiation into osteoclasts were consistently lower in the SNP groups than in the GNP groups. Our study suggests that SNPs can be a useful material for inhibiting differentiation into osteoclasts and they can be applied to treatments for osteoporosis patients.

Usefulness of Oblique Lumbar Interbody Fusion as Revision Surgery: Comparison of Clinical and Radiological Outcomes Between Primary and Revision Surgery.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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 (P < 0.05). 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 (P < 0.05). 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 (P < 0.05). 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). CONCLUSIONS: 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.

Resolvin D3 Promotes Inflammatory Resolution, Neuroprotection, and Functional Recovery After Spinal Cord Injury.

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, IL1ß) 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-ß) 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.

Development of Neuromonitoring Pedicle Screw - Results of Electrical Resistance and Neurophysiologic Test in Pig Model.

OBJECTIVE: To analyze the electrical resistance of a newly developed neuromonitoring pedicle screw (Neuro-PS) and to verify the electrophysiologic properties of the Neuro-PS in a pig model. METHODS: We developed 2 types of the Neuro-PS in which a gold lead was located internally (type I) and externally (type II). We measured the electrical resistance of the Neuro-PS and the conventional screw and analyzed the electrical thresholds of triggered EMG (t-EMG) of each screw by intentionally penetrating the medial pedicle wall and contacting the exiting nerve root in a pig model. RESULTS: The electrical resistances of the Neuro-PS were remarkably lower than that of the conventional screw. In electrophysiologic testing, only the type II Neuro-PS under the leadnerve contact condition showed a significantly lower stimulation threshold as compared to the conventional screw. CONCLUSION: The Neuro-PS demonstrated lower electrical resistances than the conventional screw. The type II Neuro-PS under the lead-nerve contact condition showed a significantly lower stimulation threshold compared to that of the other screws in the t-EMG test.

CORM-2-entrapped ultradeformable liposomes ameliorate acute skin inflammation in an ear edema model via effective CO delivery.

The short release half-life of carbon monoxide (CO) is a major obstacle to the effective therapeutic use of carbon monoxide-releasing molecule-2 (CORM-2). The potential of CORM-2-entrapped ultradeformable liposomes (CORM-2-UDLs) to enhance the release half-life of CO and alleviate skin inflammation was investigated in the present study. CORM-2-UDLs were prepared by using soy phosphatidylcholine to form lipid bilayers and Tween 80 as an edge activator. The deformability of CORM-2-UDLs was measured and compared with that of conventional liposomes by passing formulations through a filter device at a constant pressure. The release profile of CO from CORM-2-UDLs was evaluated by myoglobin assay. In vitro and in vivo anti-inflammatory effects of CORM-2-UDLs were assessed in lipopolysaccharide-stimulated macrophages and TPA-induced ear edema model, respectively. The deformability of the optimized CORM-2-UDLs was 2.3 times higher than conventional liposomes. CORM-2-UDLs significantly prolonged the release half-life of CO from 30 s in a CORM-2 solution to 21.6 min. CORM-2-UDLs demonstrated in vitro anti-inflammatory activity by decreasing nitrite production and pro-inflammatory cytokine levels. Furthermore, CORM-2-UDLs successfully ameliorated skin inflammation by reducing ear edema, pathological scores, neutrophil accumulation, and inflammatory cytokines expression. The results demonstrate that CORM-2-UDLs could be used as promising therapeutics against acute skin inflammation.

Combined Treatment with Fasudil and Menthol Improves Functional Recovery in Rat Spinal Cord Injury Model.

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.

Injectable Hydrogel Containing Tauroursodeoxycholic Acid for Anti-neuroinflammatory Therapy After Spinal Cord Injury in Rats.

We investigate the anti-inflammatory effects of injectable hydrogel containing tauroursodeoxycholic acid (TUDCA) in a spinal cord injury (SCI) model. To this end, TUDCA-hydrogel (TC gel) is created by immersing the synthesized hydrogel in a TUDCA solution for 1 h. A mechanical SCI was imposed on rats, after which we injected the TC gel. After the SCI and injections, motor functions and lesions were significantly improved in the TC gel group compared with those in the saline group. The TC gel significantly decreased pro-inflammatory cytokine levels compared with the saline; TUDCA and glycol chitosan-oxidized hyaluronate were mixed at a ratio of 9:1 (CHA) gel independently. In addition, the TC gel significantly suppressed the phosphorylation of extracellular signal-regulated kinase (p-ERK) and c-Jun N-terminal kinase (p-JNK) in the mitogen-activated protein kinase (MAPK) pathway compared with the saline, TUDCA, and CHA gel independently. It also decreased tumor necrosis factor-α (TNF-α) and glial fibrillary acidic protein (GFAP), inflammatory marker, at the injured sites more than those in the saline, TUDCA, and CHA gel groups. In conclusion, the results of this study demonstrate the neuroinflammatory inhibition effects of TC gel in SCI and suggest that TC gel can be an alternative drug system for SCI cases.

Association of acute myocardial infarction with seropositive rheumatoid arthritis in Korea: A nationwide longitudinal cohort study.

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.

Therapeutic Potential of Tauroursodeoxycholic Acid for the Treatment of Osteoporosis.

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 µM) 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.

Targeted Delivery of Mesenchymal Stem Cell-Derived Nanovesicles for Spinal Cord Injury Treatment.

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.

3'-UTR Polymorphisms of Vitamin B-Related Genes Are Associated with Osteoporosis and Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women.

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'-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 rs9426C>T,TCN2 rs10418C>T, SLC19A1 rs1051296G>T, and SLC19A2 rs16862199C>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, 1.533-16.430, p < 0.05) and OVCF (AOR, 5.760; 95% CI, 1.480-22.417, p < 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, 1.478-7.120, p < 0.05) and CD320 T-TCN2 C-SLC19A1 G-SLC19A2 C (OR, 2.287; 95% CI, 1.094-4.782, p < 0.05), were significantly more frequent among the osteoporosis group. Our findings suggest that SNPs within the CD320 gene in 3´-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.

Correction: "Changes in the medical burden of pyogenic and tuberculous spondylitis between 2007 and 2016: A nationwide cohort study".

BACKGROUND: This nationwide study aimed to compare the medical burdens of pyogenic spondylitis (PS) and tuberculous spondylitis (TS) between 2007 and 2016 in Korea. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

CORM-2-Solid Lipid Nanoparticles Maintain Integrity of Blood-Spinal Cord Barrier After Spinal Cord Injury in Rats.

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.