Mitochondrial-Targeted Metal-Phenolic Nanoparticles to Attenuate Intervertebral Disc Degeneration: Alleviating Oxidative Stress and Mitochondrial Dysfunction.

As intervertebral disc degeneration (IVDD) proceeds, the dysfunctional mitochondria disrupt the viability of nucleus pulposus cells, initiating the degradation of the extracellular matrix. To date, there is a lack of effective therapies targeting the mitochondria of nucleus pulposus cells. Here, we synthesized polygallic acid-manganese (PGA-Mn) nanoparticles via self-assembly polymerization of gallic acid in an aqueous medium and introduced a mitochondrial targeting peptide (TP04) onto the nanoparticles using a Schiff base linkage, resulting in PGA-Mn-TP04 nanoparticles. With a size smaller than 50 nm, PGA-Mn-TP04 possesses pH-buffering capacity, avoiding lysosomal confinement and selectively accumulating within mitochondria through electrostatic interactions. The rapid electron exchange between manganese ions and gallic acid enhances the redox capability of PGA-Mn-TP04, effectively reducing mitochondrial damage caused by mitochondrial reactive oxygen species. Moreover, PGA-Mn-TP04 restores mitochondrial function by facilitating the fusion of mitochondria and minimizing their fission, thereby sustaining the vitality of nucleus pulposus cells. In the rat IVDD model, PGA-Mn-TP04 maintained intervertebral disc height and nucleus pulposus tissue hydration. It offers a nonoperative treatment approach for IVDD and other skeletal muscle diseases resulting from mitochondrial dysfunction, presenting an alternative to traditional surgical interventions.

Dual-camera compressive hyperspectral imaging based on deep image prior and a guided filter.

Coded aperture snapshot spectral imaging (CASSI) aims to capture the high-dimensional (usually 3D) data cube using a 2D sensor in a single snapshot. Due to the ill-posed snapshot, the reconstruction results are not ideal. One feasible solution is to utilize additional information such as the panchromatic measurement in CASSI. In this paper, we propose a dual-camera hyperspectral reconstruction method based on the deep image prior (DIP) and a guided filter. In particular, the panchromatic measurements are used to estimate spatial detail, and spectral details are provided using CASSI measurements. These measurements are used as a priori learning by the self-supervised network. Using iteration combined with DIP, the hyperspectral reconstruction is continuously updated iteratively. Finally, the panchromatic measurement is used as the guidance image, and the reconstruction result is optimized by guide filtering. A large number of experimental results demonstrate that our method without training data can reconstruct spectral data with both high spectral accuracy and spatial resolution.

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

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

Secreted phosphoprotein 24 kD (Spp24) inhibits the growth of human osteosarcoma through the BMP-2/Smad signaling pathway.

Autocrine stimulation of tumor cells is an important mechanism for the growth of skeletal tumors. In tumors that are sensitive, growth factor inhibitors can dramatically reduce tumor growth. In this study, our aim was to investigate the effects of Secreted phosphoprotein 24 kD (Spp24) on the growth of osteosarcoma (OS) cells in the presence and absence of exogenous BMP-2 both in vitro and in vivo. Our study demonstrated that Spp24 inhibited proliferation and promoted apoptosis of OS cells as confirmed by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay and immunohistochemical staining. We found that BMP-2 increased the mobility and invasiveness of tumor cells in vitro whereas Spp24 inhibited both of these processes alone and in the presence of exogenous BMP-2. Phosphorylation of Smad1/5/8 and Smad8 gene expression was enhanced by treatment with BMP-2 but inhibited by treatment with Spp24. Subcutaneous and intratibial tumor models in nude mice demonstrated that BMP-2 promoted OS growth in vivo, while Spp24 significantly inhibited tumor growth. We conclude that the BMP-2/Smad signaling pathway is involved in the pathogenesis of OS growth and that Spp24 inhibits the growth of human OS induced by BMP-2 both in vitro and in vivo. Interruption of Smad signaling and increased apoptosis appear to be the primary mechanisms involved. These results confirm the potential of Spp24 as a therapeutic agent for the treatment of OS and other skeletal tumors.

MYC promotes fibroblast osteogenesis by regulating ALP and BMP2 to participate in ectopic ossification of ankylosing spondylitis.

BACKGROUND: Ectopic ossification is an important cause of disability in patients with ankylosing spondylitis (AS). Whether fibroblasts can transdifferentiate into osteoblasts and contribute to ossification remains unknown. This study aims to investigate the role of stem cell transcription factors (POU5F1, SOX2, KLF4, MYC, etc.) of fibroblasts in ectopic ossification in patients with AS. METHODS: Primary fibroblasts were isolated from the ligaments of patients with AS or osteoarthritis (OA). In an in vitro study, primary fibroblasts were cultured in osteogenic differentiation medium (ODM) to induce ossification. The level of mineralization was assessed by mineralization assay. The mRNA and protein levels of stem cell transcription factors were measured by real-time quantitative PCR (q-PCR) and western blotting. MYC was knocked down by infecting primary fibroblasts with lentivirus. The interactions between stem cell transcription factors and osteogenic genes were analysed by chromatin immunoprecipitation (ChIP). Recombinant human cytokines were added to the osteogenic model in vitro to evaluate their role in ossification. RESULTS: We found that MYC was elevated significantly in the process of inducing primary fibroblasts to differentiate into osteoblasts. In addition, the level of MYC was remarkably higher in AS ligaments than in OA ligaments. When MYC was knocked down, the expression of the osteogenic genes alkaline phosphatase (ALP) and bone morphogenic protein 2 (BMP2) was decreased, and the level of mineralization was reduced significantly. In addition, the ALP and BMP2 were confirmed to be the direct target genes of MYC. Furthermore, interferon-γ (IFN-γ), which showed high expression in AS ligaments, was found to promote the expression of MYC in fibroblasts in the process of ossification in vitro. CONCLUSIONS: This study demonstrates the role of MYC in ectopic ossification. MYC may act as the critical bridge that links inflammation with ossification in AS, thus providing new insights into the molecular mechanisms of ectopic ossification in AS.

Metaverse-based virtual reality experience and endurance performance in sports economy: Mediating role of mental health and performance anxiety.

Metaverse sports arena is gaining popularity globally that empowers virtual reality sporting experience through digital avatars. The main objective of the current study is to explore the impact of the Metaverse-based virtual reality sporting experience on the endurance performance of young Chinese athletes, with the mediating role of their mental health condition and performance anxiety. The study's participants mainly included Chinese athletes, especially the sample group is an accurate depiction of young athletes using a convenience sampling approach. SEM-AMOS statistical software was used for the analysis and validation of the proposed relationships. The study findings statistically validate that mental health and performance anxiety fully mediate the direct associations between virtual reality sporting experiences and the endurance performance of young Chinese athletes. Interestingly, the mental health condition of the young Chinese athletes imposes a greater impact on their endurance performance, in contrast to the adverse effects of their performance anxiety. The outcomes of the present research guide young athletes on the opportunities to enhance their virtual reality sporting abilities and boost their endurance performance. Policymakers can also build systems to dissolve physical and geographical barriers, reduce performance anxiety, and sustain mental health in virtual reality sporting events through the metaverse.

Curcumenol Mitigates the Inflammation and Ameliorates the Catabolism Status of the Intervertebral Discs In Vivo and In Vitro via Inhibiting the TNFα/NFκB Pathway.

Low back pain (LBP) caused by intervertebral disc degeneration (IVDD) is accredited to the release of inflammatory cytokines followed by biomechanical and structural deterioration. In our study, we used a plant-derived medicine, curcumenol, to treat IVDD. A cell viability test was carried out to evaluate the possibility of using curcumenol. RNA-seq was used to determine relative pathways involved with curcumenol addition. Using TNFα as a trigger of inflammation, the activation of the NF-κB signaling pathway and expression of the MMP family were determined by qPCR and western blotting. Nucleus pulposus (NP) cells and the rats' primary NP cells were cultured. The catabolism status was evaluated by an ex vivo model. A lumbar instability mouse model was carried out to show the effects of curcumenol in vivo. In general, RNA-seq revealed that multiple signaling pathways changed with curcumenol addition, especially the TNFα/NF-κB pathway. So, the NP cells and primary NP cells were induced to suffer inflammation with the activated TNFα/NF-κB signaling pathway and increased expression of the MMP family, such as MMP3, MMP9, and MMP13, which would be mitigated by curcumenol. Owing to the protective effects of curcumenol, the height loss and osteophyte formation of the disc could be prevented in the lumbar instability mouse model in vivo.

Unilateral versus bilateral pedicle screw fixation with transforaminal lumbar interbody fusion for treatment of lumbar foraminal stenosis.

BACKGROUND CONTEXT: Transforaminal lumbar interbody fusion (TLIF) with bilateral pedicle screw fixation (BPSF) is an effective treatment for lumbar foraminal stenosis (LFS). However, the effects of TLIF with unilateral pedicle screw fixation (UPSF) on LFS treatment have not been clearly elucidated. PURPOSE: We conducted this study to compare clinical outcomes and radiographic results of TLIF with UPSF and BPSF 2 years after the surgical treatment. DESIGN: Prospective randomized study. PATIENT SAMPLE: This study included 23 patients undergoing TLIF with UPSF and 25 patients undergoing TLIF with BPSF. OUTCOME MEASURES: Clinical outcomes were evaluated by visual analog scale (VAS) for low back pain and leg pain and Oswestry Disability Index (ODI) score. Radiographic outcomes included foraminal height, disc space height, segmental lordosis, and final fusion rates. METHODS: The clinical and radiographic outcomes were compared between the UPSF and BPSF group. The postoperative improvements were evaluated in either group. Intraoperative data such as duration of operation and estimated blood loss were collected. This study was registered at clinicaltrials.gov. RESULTS: Analysis of the VAS and ODI scores showed significant improvements in clinical outcomes within each group. No significant differences between the 2 groups were noted in the improvements of the VAS and ODI scores. The mean operative duration and blood loss were significantly greater in the BPSF group than in the UPSF group. There were significant improvements in the height of the foramen and intervertebral space and segmental lordosis in both groups, while there was no significant difference between the groups in amount of the improvements. No significant difference was found in the final fusion rates. CONCLUSIONS: TLIF is an appropriate procedure for LFS treatment. With balanced intervertebral support using a cage, UPSF could achieve similar and satisfactory effects on lumbar segmental stability and fusion compared to BPSF. The unilateral approach appears to be associated with slightly shorter operative time and less blood loss.

Prussian Blue Nanoparticles Stabilize SOD1 from Ubiquitination-Proteasome Degradation to Rescue Intervertebral Disc Degeneration.

Discography often destroys the hypoxic environment in the intervertebral disc and accelerates intervertebral disc degeneration (IVDD). Therefore, it often fails to meet the requirements for application in clinical practice. This technology mainly increases the reactive oxygen species (ROS) in the IVD. As so, it is particularly critical to develop strategies to avoid this degeneration mechanism. Prussian blue nanoparticles (PBNPs) are found to enhance development under magnetic resonance T1 and have antioxidant enzyme activity. The key results of the present study confirm that PBNPs alleviate intracellular oxidative stress and increase the intracellular activities of antioxidant enzymes, such as superoxide dismutase 1 (SOD1). PBNPs can rescue nucleus pulposus cell degeneration by increasing oxidoreductase system-related mRNA and proteins, especially by stabilizing SOD1 from ubiquitination-proteasome degradation, thus improving the mitochondrial structure to increase antioxidation ability, and finally rescuing ROS-induced IVDD in a rat model. Therefore, it is considered that PBNPs can be a potential antioxidation-protective discography contrast agent.

Incidence and prevalence of psoriatic arthritis in patients with psoriasis stratified by psoriasis disease severity: Retrospective analysis of an electronic health records database in the United States.

BACKGROUND: Among patients in the United States with psoriasis (PsO), limited data exist on the incidence and prevalence of psoriatic arthritis (PsA) based on disease severity. OBJECTIVE: To assess the incidence, prevalence, and predictors of PsA among patients with PsO stratified by PsO severity using treatment type. METHODS: Incidence of PsA per 100 PsO patient-years (PY) and prevalence were assessed using the Optum electronic health records database. Incidence was assessed from PsO diagnosis and 1 year after PsO diagnosis overall and stratified by mutually exclusive treatment classes as a severity surrogate. RESULTS: The overall incidence of PsA was 2.9 (95% CI, 2.9-3.0) events per 100 PY. The incidence (95% CI) by severity surrogate was 2.1 (2.1-2.1), 9.9 (9.5-10.4), and 17.6 (16.9-18.3) events per 100 PY for patients with mild, moderate, and severe PsO as determined by receiving nonsystemics, nonbiologic systemic therapy, and biologics, respectively. When excluding patients diagnosed with PsA 1 year after PsO diagnosis, overall incidence was lower (1.7 [95% CI, 1.6-1.7] events per 100 PY), with similar trends for treatment-severity surrogates. LIMITATIONS: Results may not be generalizable to a wider population. CONCLUSION: The risk of developing PsA increased with disease severity and was highest in patients with the most severe PsO.

Case Report: Identifying Andersson-Like Lesions in Diffuse Idiopathic Skeletal Hyperostosis.

Andersson lesions (ALs) in ankylosing spondylitis (AS) pose a severe risk to the stability of ankylosed spine, which might result in significant deterioration of spinal cord function after traumatic or inflammatory causes. Herein, erosive discovertebral lesions in diffuse idiopathic skeletal hyperostosis (DISH) presented important clinical similarities to AL in AS, but failed to completely recognize unstable spinal lesions. Therefore, we pioneered to identify spinal discovertebral lesions similar to Andersson-like lesions (ALLs) in DISH, followed by the characterization and summarization of the etiology, radiology, laboratory results, clinical symptoms, and treatment strategies for AL in AS with ALL in DISH. By characterizing the ALL in DISH cases, we showed that the ALL was mainly traumatic and established at the junction of focal stress between two adjacent ossified level arms. Erosive discovertebral ALLs were formed after trivial stress of direct impact and could be subdivided into transdiscal, transvertebral, and discovertebral types radiologically. Patients who presented with ALL frequently suffered from consistent back pain clinically and experienced a decrease in motion ability that could reflect skeletal stability, which received treatment effectiveness after conservative external spinal immobilization or further surgical internal fixation, indicating the significance of recognizing ALL in the ankylosed DISH spine to further maintain spinal stability in order to prevent catastrophic neurologic sequelae. Our work highlighted the clinical relevance of ALL in DISH in comparison with AL in AS, which provided broader insight to identify ALL in DISH, thus facilitating early intervention against DISH deterioration.

Polydopamine-coated UiO-66 nanoparticles loaded with perfluorotributylamine/tirapazamine for hypoxia-activated osteosarcoma therapy.

BACKGROUND: Hypoxia is a characteristic of solid tumors that can lead to tumor angiogenesis and early metastasis, and addressing hypoxia presents tremendous challenges. In this work, a nanomedicine based on oxygen-absorbing perfluorotributylamine (PFA) and the bioreductive prodrug tirapazamine (TPZ) was prepared by using a polydopamine (PDA)-coated UiO-66 metal organic framework (MOF) as the drug carrier. RESULTS: The results showed that TPZ/PFA@UiO-66@PDA nanoparticles significantly enhanced hypoxia, induced cell apoptosis in vitro through the oxygen-dependent HIF-1α pathway and decreased oxygen levels in vivo after intratumoral injection. In addition, our study demonstrated that TPZ/PFA@UiO-66@PDA nanoparticles can accumulate in the tumor region after tail vein injection and effectively inhibit tumor growth when combined with photothermal therapy (PTT). TPZ/PFA@UiO-66@PDA nanoparticles increased HIF-1α expression while did not promote the expression of CD31 in vivo during the experiment. CONCLUSIONS: By using TPZ and PFA and the enhanced permeability and retention effect of nanoparticles, TPZ/PFA@UiO-66@PDA can target tumor tissues, enhance hypoxia in the tumor microenvironment, and activate TPZ. Combined with PTT, the growth of osteosarcoma xenografts can be effectively inhibited.

Curcumenol mitigates chondrocyte inflammation by inhibiting the NF­κB and MAPK pathways, and ameliorates DMM­induced OA in mice.

At present, an increasing number of individuals are affected by osteoarthritis (OA), resulting in a heavy socioeconomic burden. OA in knee joints is caused by the release of inflammatory cytokines and subsequent biomechanical and structural deterioration. To determine its anti­inflammatory function, the current study investigated the use of the plant­derived medicine, curcumenol, in OA treatment. Curcumenol was not cytotoxic to ATDC5 chondrocytes and primary chondrocytes, as determined using a cell viability test. When these cells were treated with TNF­α and IL­1ß to induce inflammation, curcumenol treatment inhibited the progression of inflammation by inactivating the NF­κB and MAPK signaling pathways, as well as decreasing the expression levels of MMP3 (as indicated by reverse transcription­quantitative PCR and western blotting). Moreover, to analyze metabolic and catabolic status in high­density and pellet culture, catalytic changes and the degradation of the extracellular matrix induced by TNF­α and IL­1ß, were evaluated by alcian blue staining. These catalytic deteriorations were ameliorated by curcumenol. Using curcumenol in disease management, the mechanical and metabolic disruption of cartilage caused in the destabilization of medial meniscus (DMM) model was prevented in vivo. Thus, curcumenol mitigated inflammation in ATDC5 chondrocytes and primary mice chondrocytes, and also ameliorated OA in a DMM­induced mouse model.

Real world effectiveness and satisfaction with secukinumab in the treatment of patients with psoriatic arthritis: a population survey in five European countries.

OBJECTIVES: To describe the effectiveness of secukinumab in the treatment of psoriatic arthritis (PsA) and associated physician satisfaction with secukinumab treatment, in routine clinical practice across five European countries. METHODS: A retrospective analysis of PsA patients receiving secukinumab for ≥4 months in France, Germany, Italy, Spain and the UK from March to December 2018. Data based on physician-completed questionnaires at initiation of treatment and at the data collection consultation were collected and used to assess effectiveness. RESULTS: 572 PsA patients with a mean age of 47.9 years, 57.0% were male, with 5.6% of patients with mild, 55.2% with moderate and 38.1% severe PsA prior to treatment initiation were included. 33.0% of patients received a dosage of 150 mg and 67.0% a dosage of 300 mg secukinumab. Around 84% of patients received secukinumab for 6 months or longer. Symptoms seen at current assessment in over 20% of patients were tender or swollen joints or psoriatic skin lesions. Between initiation of treatment and the current consultation, improvements in skin, joint and overall severity were reported. Physician satisfaction with secukinumab's ability to control disease was very high during the study period, greater than 90%, and was seen irrespective of disease severity at initiation, prior biologic use, treatment duration, time since diagnosis or onset of symptoms, treatment history, and BMI. CONCLUSION: Physicians were satisfied with the ability of secukinumab to control disease and it was effective in the treatment of PsA patients in routine clinical settings.

Neck pain is the leading cause of disability burden in China: Findings from the Global Burden of Disease Study 2017.

BACKGROUND: Neck pain (NP) is a common musculoskeletal problem; however, the prevalence and years lived with disability (YLD) of NP in China are still unclear. This study sought to estimate the age-, sex- and province-specific prevalence and YLD of NP in China. METHODS: Adopting the methodology framework and analytical strategies used in the Global Burden of Disease (GBD), Injuries, and Risk Factors Study (2017), the prevalence and YLD of NP in China were estimated by age, sex, year, and provinces/regions. RESULTS: In China, the age-standardized point prevalence rate of NP was 4,532.6 per 100,000 persons in 1990 and increased slightly to 4,634.4 per 100,000 persons in 2017. The prevalence of NP was 48.0 million in 1990 and rose dramatically to 87.3 million in 2017 (an increase of 82.0%). The age-standardized YLD rate of NP was 454.0 per 100,000 persons in 1990, and there was a slight increase to 465.6 per 100,000 persons in 2017. The all-age YLD of NP was 4.8 million in 1990 and rose to 8.8 million in 2017 (which represents an increase of 81.1%). In 1990, NP was the third leading cause of YLD in China, and in 2017, NP was the leading cause of disability burden. CONCLUSIONS: This study estimated the prevalence and disability burden of NP in China. NP is currently the leading cause of disability burden in China; however, it is currently inadequately recognized and should receive further attention and be subject to further research.

Laminoplasty with selective fusion at unstable segment versus laminectomy with fusion for multilevel cervical myelopathy: a case-control study.

BACKGROUND: Segmental cervical instability is a risk factor for the progression of osteophytic bone spurs and development of myelopathy, and is treated as a relative contraindication of cervical laminoplasty. The aim of this study was to compare laminoplasty with selective fixation (LPSF) versus laminectomy with fusion (LCF) in patients with multilevel cervical myelopathy accompanied by segmental instability. METHODS: A case-control study was conducted by reviewing data from 63 patients who underwent LPSF (n = 30) or LCF (n = 33). Cervical alignment, range of motion (ROM), neurologic status and axial symptom severity pre-operation, 3-days after operation, and at the final follow-up (minimum 24 months) were measured and compared between groups. RESULTS: Postoperation, patients in the LPSF group lost 31.1 ± 17.3 % of cervical lordosis and 43.2 ± 10.9 % cervical ROM while patients in the LCF group lost 5.7 ± 8.2 % and 67.9 ± 15.5 %, respectively. Both LPSF and LCF groups significantly improved neurologic status and axial symptom severity at the final follow-up with similar between-group results(P > 0.05). Blood loss, operation time, hospital stay, and medical cost in the LPSF group were significantly less than in the LCF group(P < 0.05). CONCLUSIONS: In 2 years of clinical observation, LPSF was effective in maintaining the stability of the cervical spine with less sacrifice of mobility and surgical trauma for multilevel myelopathy with segmental instability compared to LCF.

Antibacterial efficacy of quaternized chitosan coating on 3D printed titanium cage in rat intervertebral disc space.

BACKGROUND CONTEXT: Infection around intervertebral fusion cages can be intractable because of the avascular nature of the intervertebral disc space. Intervertebral cages with antibacterial effects may be a method by which this complication can be prevented. PURPOSE: To investigate the bacterial load on the antibacterial coating cages for spinal interbody fusion STUDY DESIGN: An experimental in vitro and in vivo study. METHODS: Based on the micro-computed tomography (CT) data of rat caudal discs, mesh-like titanium (Ti) cages that anatomically fit into the discs were fabricated by three-dimensional (3D) printing. Additionally, an antibacterial coating was applied with quaternized chitosan (hydroxypropyltrimethyl ammonium chloride chitosan, HACC). In vitro release kinetics of the HACC was performed, and the antibacterial performance of the HACC-coated (Ti-HACC) cages (via inhibition zone assay, bacterial adhesion assay, and biofilm formation assay) was evaluated. Then, Ti-HACC- or noncoated (Ti) cages were implanted in the caudal discs of rats with bioluminescent Staphylococcus aureus. Bacterial survival was investigated using an in vivo imaging system (IVIS) on postoperative days 1, 3, and 5. On day 5, the infection-related changes (bone destruction and migration of cages) were assessed using micro-CT, and the healing status of the surgical wounds was also assessed. After the removal of the cages, the quantification of bacteria attached to the cages was obtained by IVIS. Histological evaluation was performed by hematoxylin and eosin staining and TRAP (tartrate-resistant acid phosphatase) staining. RESULTS: Release kinetic analysis showed the sustained release of HACC over 3 days from Ti-HACC cages. Antibacterial effects of Ti-HACC cages were demonstrated in all in vitro assays. IVIS evaluation indicated that the in vivo implantation of Ti-HACC cages with S. aureus exhibited better wound healing, less infection-related changes on micro-CT, and reduced bacterial quantity in the extracted cages compared to Ti cages. Histological evaluation demonstrated an increased number of TRAP-positive osteoclasts and severe bone destruction in the rats treated with Ti cages. CONCLUSIONS: We developed a novel antibacterial HACC-coated intervertebral cage that exhibited prominent antibacterial efficacy and prevented the structural damage caused by the infection in rat caudal discs. CLINICAL SIGNIFICANCE: HACC-coated titanium intervertebral cages may be a promising option for preventing intractable postoperative infection in spinal interbody fusion surgery.

Bleomycin induces fibrotic transformation of bone marrow stromal cells to treat height loss of intervertebral disc through the TGFßR1/Smad2/3 pathway.

BACKGROUND: Lower back pain is often accredited to loss of intervertebral disc (IVD) height and compromised spine stability as a result of intervertebral disc degeneration (IVDD). We aim to locally use bleomycin to induce the fibrotic transformation of bone marrow stromal cells (BMSCs) as a means to induce reparative fibrosis to slow down the height loss. METHODS: IVDs from patients were gathered for histological examination. The expression of the transforming growth factor beta 1 (TGF-ß) signaling pathway was determined by qPCR and western blotting. Nucleus pulposus (NP) cells, annulus fibrosus (AF) cells, and the rats' bone marrow stromal cells (BMSC) were cultured and their responsiveness to bleomycin was evaluated by Cell Counting Kit-8, comet assay, transwell migration, and wound healing assays. Rat IVDD models were created by puncture and rescued by bleomycin injection, and the effectiveness was evaluated by images (X-ray and MRI) and atomic force microscope. RESULTS: Histological examination showed increased levels of pro-fibrotic markers in IVDD tissues from patients. AF cells and BMSC cells were induced to adopt a pro-fibrotic phenotype with increased expression fibrotic markers Col1a1, Col3a1, and FSP1. The pro-fibrotic effect of bleomycin on AF cells and BMSCs was in part due to the activation of the TGFß-TGFßR1-SMAD2/3 signaling pathway. Pharmacological inhibition or gene knock-down of TGFßR1 could mitigate the pro-fibrotic effects. CONCLUSION: Locally, injection of bleomycin in rats' IVD induced rapid fibrosis and maintained its height through the TGFß-TGFßR1-SMAD2/3 signaling pathway.

Characterization of insufficient responders to ustekinumab in patients with moderate-to-severe psoriasis in the US Corrona Psoriasis Registry.

OBJECTIVE: Biologic therapies have revolutionized the management of moderate-to-severe psoriasis; however, there are a limited number of US real-world studies characterizing patients based on response to these treatments. This study examined characteristics at enrollment and change in outcomes of US patients with moderate-to-severe psoriasis who achieved insufficient responses with ustekinumab. METHODS: This study included patients enrolled in the Corrona Psoriasis Registry from April 2015 to June 2018 who initiated ustekinumab at enrollment and who were stratified based on achievement of psoriasis body surface area improving to <3% or by 75% from enrollment to the 6-month follow-up visit (response vs insufficient response). Patient demographics and disease characteristics were described at enrollment, and changes in outcomes were assessed at 6-month follow-up for ustekinumab responders and insufficient responders. RESULTS: Of the 178 patients who initiated ustekinumab in the Corrona Psoriasis Registry and had ≥1 follow-up visit, 99 (55.6%) were classified as responders at the 6-month follow-up visit. Logistic regression modeling showed that increasing age was significantly associated with a decreased likelihood of achieving a response (OR, 0.981 [95%CI, 0.962-0.999]; p = .049). CONCLUSIONS: These findings may help dermatologists characterize patients with moderate-to-severe psoriasis who have inadequate responses to biologic treatments.

Characterization of insufficient responders to anti-tumor necrosis factor therapies in patients with moderate to severe psoriasis: real-world data from the US Corrona Psoriasis Registry.

OBJECTIVE: Biologic therapies have dramatically changed the management of moderate to severe psoriasis; however, few US real-world studies characterize the unmet needs of patients who do not respond to biologic therapies. This study examined the characteristics at enrollment of patients with moderate to severe psoriasis who had insufficient responses to anti-tumor necrosis factor therapies (anti-TNFs). METHODS: Patients enrolled in the Corrona Psoriasis Registry from April 2015 to June 2018 who initiated an anti-TNF at enrollment were stratified on the basis of body surface area (BSA) improvement to <3% or a 75% improvement from enrollment to the 6-month follow-up visit (response versus insufficient response). Patient demographics and disease characteristics were described at enrollment, and changes in outcomes were assessed at 6-month follow-up for those who received anti-TNFs. RESULTS: Of 180 anti-TNF initiators who had ≥1 follow-up visit, 50.6% were classified as responders. Logistic regression modeling showed that female sex was significantly associated with a decreased likelihood of achieving a response (OR = 0.534, 95% CI = 0.289-0.988, p = .046). CONCLUSION: Despite the small sample size and short follow-up period, these findings may help dermatologists to identify patients with moderate to severe psoriasis who have unmet treatment needs.