Hypoxia-induced ALKBH5 aggravates synovial aggression and inflammation in rheumatoid arthritis by regulating the m6A modification of CH25H.

Previous studies have shown that epigenetic factors are involved in the occurrence and development of rheumatoid arthritis (RA). However, the role of N6-methyladenosine (m6A) methylation in RA has not been determined. The aim of this study was to investigate the role and regulatory mechanisms of hypoxia-induced expression of the m6A demethylase alkB homolog 5 (ALKBH5) in RA fibroblast-like synoviocytes (FLSs). Synovial tissues were collected from RA and osteoarthritis (OA) patients, and RA FLSs were obtained. ALKBH5 expression in RA FLSs and collagen-induced arthritis (CIA) model rats was determined using quantitative reverse transcription-PCR (qRT-PCR), western blotting and immunohistochemistry (IHC). Using ALKBH5 overexpression and knockdown, we determined the role of ALKBH5 in RA FLS aggression and inflammation. The role of ALKBH5 in RA FLS regulation was explored using m6A-methylated RNA sequencing and methylated RNA immunoprecipitation coupled with quantitative real-time PCR. The expression of ALKBH5 was increased in RA synovial tissues, CIA model rats and RA FLSs, and a hypoxic environment increased the expression of ALKBH5 in FLSs. Increased expression of ALKBH5 promoted the proliferation and migration of RA-FLSs and inflammation. Conversely, decreased ALKBH5 expression inhibited the migration of RA-FLSs and inflammation. Mechanistically, hypoxia-induced ALKBH5 expression promoted FLS aggression and inflammation by regulating CH25H mRNA stability. Our study elucidated the functional roles of ALKBH5 and mRNA m6A methylation in RA and revealed that the HIF1α/2α-ALKBH5-CH25H pathway may be key for FLS aggression and inflammation. This study provides a novel approach for the treatment of RA by targeting the HIF1α/2α-ALKBH5-CH25H pathway.

The Comparative Analysis of Antegrade Versus Retrograde Approach for a Failed Porous Tantalum Rod Removal During Conversion to Total Hip Arthroplasty.

BACKGROUND The failure of porous tantalum rods applied to patients with osteonecrosis of the femoral head (ONFH) has been increasingly reported during the last few years. Very few studies have reported methods for implant removal. This study aimed at comparing 2 procedures used for the removal of a failed tantalum rod during conversion to total hip arthroplasty (THA). MATERIAL AND METHODS A total of 65 patients (65 hips), who underwent THA after failed implantation of a tantalum rod between June 2007 and December 2016, were retrospectively evaluated. These patients were classified into 2 groups depending on whether the antegrade approach (removal of the tantalum rod from the tip to the butt at the lateral femoral cortex, n=27) or retrograde approach (removal of the tantalum rod from the butt at the lateral femoral cortex to the proximal tip, n=38) was used for rod extraction. These 2 groups were compared for incision length, operation time, blood loss, fracture, tantalum debris, Harris hip scores, and the presence of osteolysis and/or radiolucency. RESULTS These 2 groups did not present any significant differences in terms of Harris hip score and incision length. However, the operation time (P=0.000), blood loss (P=0.000), amount of tantalum debris (P=0.000), and presence of radiolucency (P=0.046) were greater for the retrograde approach than for the antegrade approach. CONCLUSIONS The risk of conversion to THA following failed tantalum rod implantation is high. In such cases, the antegrade procedure was found to be a simple and efficient method for removing the trabecular metal rod with the use of a trephine.

Short-Term Efficacy and Safety of Secukinumab for Ankylosing Spondylitis: A Systematic Review and Meta-Analysis of RCTs.

Secukinumab is a novel IL-17A inhibitor that has been confirmed to be effective for treating PsA and RA. Several studies have demonstrated that secukinumab also provides benefits for AS patients. Thus, we performed a meta-analysis of RCTs to evaluate the short-term efficacy and safety of secukinumab for the management of AS. The PubMed, Medline, Embase, Web of Science, and Cochrane Library databases were searched for RCTs published prior to March 2020 on the treatment of AS with secukinumab. The primary outcome was the ASAS20 response, and the secondary outcomes included the ASAS40 response, ASAS5/6 response, SF-36 PCS score, ASQoL score, and AEs. Dichotomous data were expressed as pooled RRs with 95% CIs, while continuous data were expressed as pooled MDs with 95% CIs. Subgroup analysis was conducted based on whether the AS patients previously underwent treatment with TNFi. A total of 4 RCTs with 1166 patients were included in our meta-analysis. At week 16, secukinumab 150 mg yielded significant improvements in the clinical response and patient-reported outcomes for AS patients. There was no increased risk of AEs. Consistent results were detected in the meta-analysis of secukinumab 75 mg versus a placebo. Furthermore, no significant difference was detected between the secukinumab 75 mg group and secukinumab 150 mg group. We concluded that secukinumab is effective for treating AS and generally well tolerated by AS patients in the short term, regardless of whether they previously underwent TNFi treatment. The superiority of secukinumab 150 mg over secukinumab 75 mg seems to be limited, since no significant difference in any endpoint was detected between the two groups.

Synergistic Chemotherapy and Photodynamic Therapy of Endophthalmitis Mediated by Zeolitic Imidazolate Framework-Based Drug Delivery Systems.

Endophthalmitis, derived from the infections of pathogens, is a common complication during the use of ophthalmology-related biomaterials and after ophthalmic surgery. Herein, aiming at efficient photodynamic therapy (PDT) of bacterial infections and biofilm eradication of endophthalmitis, a pH-responsive zeolitic imidazolate framework-8-polyacrylic acid (ZIF-8-PAA) material is constructed for bacterial infection-targeted delivery of ammonium methylbenzene blue (MB), a broad-spectrum photosensitizer antibacterial agent. Polyacrylic acid (PAA) is incorporated into the system to achieve higher pH responsiveness and better drug loading capacity. MB-loaded ZIF-8-PAA nanoparticles are modified with AgNO3 /dopamine for in situ reduction of AgNO3 to silver nanoparticles (AgNPs), followed by a secondary modification with vancomycin/NH2 -polyethylene glycol (Van/NH2 -PEG), leading to the formation of a composite nanomaterial, ZIF-8-PAA-MB@AgNPs@Van-PEG. Dynamic light scattering, transmission electron microscopy, and UV-vis spectral analysis are used to explore the nanoparticles synthesis, drug loading and release, and related material properties. In terms of biological performance, in vitro antibacterial studies against three kinds of bacteria, i.e., Escherichia coli, Staphylococcus aureus, and methicillin-resistant S. aureus, suggest an obvious superiority of PDT/AgNPs to any single strategy. Both in vitro retinal pigment epithelium cellular biocompatibility experiments and in vivo mice endophthalmitis models verify the biocompatibility and antibacterial function of the composite nanomaterials.

Construction of High Drug Loading and Enzymatic Degradable Multilayer Films for Self-Defense Drug Release and Long-Term Biofilm Inhibition.

Bacterial infections and biofilm formation on the surface of implants are important issues that greatly affect biomedical applications and even cause device failure. Construction of high drug loading systems on the surface and control of drug release on-demand is an efficient way to lower the development of resistant bacteria and biofilm formation. In the present study, (montmorillonite/hyaluronic acid-gentamicin)10 ((MMT/HA-GS)10) organic/inorganic hybrid multilayer films were alternately self-assembled on substrates. The loading dosage of GS was as high as 0.85 mg/cm2, which could be due the high specific surface area of MMT. The obtained multilayer film with high roughness gradually degraded in hyaluronidase (HAS) solutions or a bacterial infection microenvironment, which caused the responsive release of GS. The release of GS showed dual enzyme and bacterial infection responsiveness, which also indicated good drug retention and on-demand self-defense release properties of the multilayer films. Moreover, the GS release responsiveness to E. coli showed higher sensitivity than that to S. aureus. There was only ∼5 wt % GS release from the film in PBS after 48 h of immersion, and the amount quickly increased to 30 wt % in 105 CFU/mL of E. coli. Importantly, the high drug dosage, smart drug release, and film peeling from the surface contributed to the efficient antibacterial properties and long-term biofilm inhibition functions. Both in vitro and in vivo antibacterial tests indicated efficient sterilization function and good mammalian cell and tissue compatibility.

Total hip arthroplasty following failure of tantalum rod implantation for osteonecrosis of the femoral head with 5- to 10-year follow-up.

BACKGROUND: Total hip arthroplasty (THA) with failure of tantalum rod implant for osteonecrosis of the femoral head (ONFH) will be the only choice for patients. However,it remains unknown whether tantalum rod implantation has an adverse effect on the survival time of implants following conversion to THA. The aim of this study was to retrospectively evaluate the clinical and radiographic outcomes of conversion to THA in patients who were previously treated with implantation of a tantalum rod. METHODS: This study included 31 patients (39 hips), who underwent conversion to THA due to failure of core decompression with an implanted tantalum rod. Among these 31 patients, 26 patients were male and five patients were female. The mean age of these patients was 49.3 years old (range: 36-64 years old). The control group included 33 patients (40 hips), who underwent total hip replacement without tantalum rod implantation. The hip Harris score, implant wear, osteolysis, radiolucencies and surgical complications were recorded during the follow-up. The distribution of tantalum debris in the proximal, middle and distal periprosthetic femoral regions, radiolucent lines and osteolysis were analyzed on post-operative radiographs. RESULTS: There were no significant differences in Harris score, liner wear and complications between the two groups (P > 0.05). Osteolysis and radiolucent lines more likely occurred in patients with tantalum debris distributed in three regions than in one or two regions (P < 0.05). CONCLUSIONS: The mid-term clinical outcome of patients who underwent THA with tantalum rod implantation was not different from those without a tantalum rod, suggesting that tantalum debris did not increase the liner wear rate. However, the distribution of periprosthetic tantalum debris in the proximal, middle and distal femoral regions may increase the risk of femoral osteolysis and radiolucent lines.

Investigating clinical failure of core decompression with autologous bone marrow mononuclear cells grafting for the treatment of non-traumatic osteonecrosis of the femoral head.

OBJECTIVE: This study aimed to analyze the clinical factors related to the failure of autologous bone marrow mononuclear cells grafting (BMMCG) following core decompression (CD) in early stage osteonecrosis of the femoral head (ONFH). METHODS: In total, 148 patients (192 hips) underwent CD with autologous BMMCG for treatment of non-traumatic ONFH. The patients were classified by their ARCO staging and China-Japan Friendship Hospital (CJFH) typing system. All patients were clinically and radiographically followed up every three months during the first year and every six months in the following years. The clinical evaluation was conducted by pre- and post-operative Harris hip scores (HHS), while serial anteroposterior (AP) and frog lateral radiographs were used for post-operative radiographic evaluation. RESULTS: There were 56 hips as clinical failure cases, and 50 hips (89.29%) of failure cases developed between three and ten months after operation. Based on CJFH classification system, type L2 showed more failure rate with 60.0% (9 of15). The Cox risk model showed that disease type was an independent risk factor for post-operative clinical failure (P = 0.042). Multivariate analysis of the Cox proportional-hazards model showed that type L1 had a hazard ratio (HR) of 0.286 (95% CI 0.100-0.816), type L3 with HR of 0.245 (95% CI 0.079-0.759), respectively. CONCLUSION: Disease type is an important risk factor for autologous BMMCG combined with CD, and the degree of lateral pillar necrosis is a significant reference index for prognosis evaluation in early stage of ONFH.

Hip Osteonecrosis Is Associated with Increased Plasma IL-33 Level.

The recently discovered IL-33 as an IL-1 cytokine family member has been proved to be specifically released from osteonecrotic bones. We aimed to investigate the potential role of IL-33 in the development of osteonecrosis of femoral head (ONFH). Forty patients diagnosed with ONFH and forty age-, sex-, and body mass index- (BMI-) matched healthy subjects were included in this prospective study between March 2016 and September 2016. A commercially available ELISA kit was used to test the level of plasma IL-33. The IL-33 levels were compared among different ARCO stages, CJFH types, and etiology groups. Plasma IL-33 levels were significantly higher in the ONFH patients than that in the control subjects. The levels of IL-33 did not differ significantly among the ONFH patients with different ARCO stages. The IL-33 levels of patients with CJFH type L3 were significantly higher than that of patients with types L1 and L2. No significant differences were observed in IL-33 levels between steroid-induced, alcohol-induced, and idiopathic patients. Our findings seem to indicate that IL-33 effects may be detrimental during ONFH, which appeared to be associated with the prognosis of ONFH. The IL-33 deserves particular attention in the pathogenesis of ONFH.

Positive Effects of Extracorporeal Shock Wave Therapy on Spasticity in Poststroke Patients: A Meta-Analysis.

BACKGROUND: Spasticity is a common and serious complication following a stroke, and many clinical research have been conducted to evaluate the effect of extracorporeal shock wave therapy (ESWT) on muscle spasticity in poststroke patients. This meta-analysis aimed to evaluate the therapeutic effect on decreasing spasticity caused by a stroke immediately and 4 weeks after the application of shock wave therapy. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library databases for relevant studies through November 2016 using the following item: (Hypertonia OR Spasticity) and (Shock Wave or ESWT) and (Stroke). The outcomes were evaluated by Modified Ashworth Scale (MAS) grades and pooled by Stata 12.0 (Stata Corp, College Station, TX, USA). RESULTS: Six studies consisting of 9 groups were included in this meta-analysis. The MAS grades immediately after ESWT were significantly improved compared with the baseline values (standardized mean difference [SMD], -1.57; 95% confidence intervals [CIs], -2.20, -.94). Similarly, the MAS grades judged at 4 weeks after ESWT were also showed to be significantly lower than the baseline values (SMD, -1.93; 95% CIs, -2.71, -1.15). CONCLUSIONS: ESWT for the spasticity of patients after a stroke is effective, as measured by MAS grades. Moreover, no serious side effects were observed in any patients after shock wave therapy. Nevertheless, our current study with some limitations such as the limited sample size only provided limited quality of evidence; confirmation from a further systematic review or meta-analysis with large-scale, well-designed randomized control trials is required.

Direct Loading and Tunable Release of Antibiotics from Polyelectrolyte Multilayers To Reduce Bacterial Adhesion and Biofilm Formation.

Bacteria adhesion on the surface of biomaterials and following biofilm formation are important problems in biomedical applications. The charged antibiotics with small molar mass can hardly deposit alternately with polymers into multilayered films to load the drug. Herein, the (poly(acrylic acid)-gentamicin/poly(ethylenimine))n ((PAA-GS/PEI)n) multilayer film was designed and constructed via a layer-by-layer self-assembly method. Low molar mass GS cations were first combined with polyanion PAA and self-assembled with PEI to form multilayer films showing exponential growth behavior. The GS dosage could be adjusted by changing the layer number of films. Furthermore, the thermal cross-linking method was used to control the release rate of GS in PBS buffer. Owing to the diffusion of GS, a zone of inhibition of about 7.0 mm showed the efficient disinfection activity of the multilayer film. It could also be seen from the biofilm inhibition assay that the multilayer film effectively inhibited bacterial adhesion and biofilm formation. As the drug loading dosage was 160 µg/cm(2), the multilayer films showed very low cytotoxicity against human lens epithelial cells. The present work provides an easy way to load GS into multilayer films which can be applied to surface modification of implants and biomedical devices.

Cancellous and Cortical Bone Microarchitectures of Femoral Neck in Rheumatoid Arthritis and Osteoarthritis Compared with Donor Controls.

This study investigated the 3D microarchitecture of cancellous and cortical bones of the femoral neck in rheumatoid arthritis (RA), osteoarthritis (OA) and donor controls. 26 femoral necks (including heads) were harvested during total hip replacement surgeries in 11 patients with RA (mean age 66.7 ± 12.8 years) and 15 patients with OA (67.3 ± 8.4 years). Femoral heads/necks were also harvested from 8 donors (74.9 ± 10.2 years). Bone samples of 10 mm thickness were prepared from each femoral neck and scanned with micro-CT to evaluate microarchitectural parameters. The RA and OA samples showed no significant differences in microarchitectural parameters in cancellous or cortical bone. Compared with the donor controls, bone volume fraction in RA and OA cancellous bone was significantly greater, the structure model index in OA was significantly lower, and the surface density in RA was significantly greater. The RA bone tissues showed erosion and marked osteophyte formation. This study demonstrated that RA and OA have similar trends of overall microarchitectural degeneration in the femoral neck, despite marked erosion in RA bone and osteophyte formation in OA bone. However, we could not eliminate the possibility of local differences between RA and OA bone. The age-related bone loss in RA and OA was less severe than those of normal ageing and osteoporosis, suggesting a compensatory effect of the diseases to increase bone density.

[Mechanisms and influencing factors of hypoxemia after joint arthroplasty].

OBJECTIVE: To explore the mechanisms and influencing factors of hypoxemia after joint arthroplasty to further guide and improve clinical management. METHODS: From January 2013 to May 2013, 135 patients undergoing joint arthroplasty were retrospectively analyzed. Perioperative pulse oximetry (SpO2) were measured and plotted. The effects of gender, age, body mass index (BMI), blood group, disease diagnosis, anesthesia, type of surgery, surgeon, anticoagulation method, hemoglobin changes (ΔHG), hematocrit changes (ΔHCT) and platelet changes (ΔPLT) on the postoperative hypoxemia and their predictive values were analyzed. RESULTS: Univariate analysis showed that hypoxemia were associated with gender, age, diagnosis, type of surgery and anesthesia (P < 0.05). And multivariate linear regression analysis revealed that age was independently associated with postoperative hypoxemia. CONCLUSION: Perioperative SpO2 changes have certain patterns. Asymptomatic hypoxemia is likely to occur within two days, especially during knee arthroplasty. As an independent factor, age impacts the incidence of hypoxemia after primary joint arthroplasty. For elderly patients, we should strengthen timely interventions for preventing life-threatening complications.

Quality of sexual life after total hip arthroplasty in male patients with osteonecrosis of femoral head.

BACKGROUND: Patients with osteonecrosis of the femoral head (ONFH) have a severe impact on their health status, functionality and quality of life. Sexual life is an important component of the quality of life and is still a frequently neglected domain in patients with ONFH. The aims of the study were to evaluate the influence of the disease and the total hip arthroplasty (THA) surgery on quality of sexual life (QSL) in these patients. METHODS: A prospective, self-controlled study was done. 247 patients of ONFH who underwent unilateral or bilateral THA were asked to complete a standardized QSL questionnaire, and the score of QSL was evaluated preoperatively and at first year follow-up of post-THA operation. RESULTS: The mean age of the patient was 46.8 (range 25-60) years. 194 cases (78.5%, 276 hips) were alcohol-induced ONFH. There is significant decrease (p = 0.026) in sexual relationship impairment on the 0-8 scale from pre-THA (5.3 ± 0.7) to post-THA (2.3 ± 0.4). There is no significant difference for effect on sexual function (p = 0.14) between pre-THA (2.3 ± 0.4) and post-THA (1.8 ± 0.3). There is significant improvement (p = 0.018) in overall sexual satisfaction degree of patients on the 1-5 scale from pre-THA (2.7 ± 0.2) to post-THA (4.7 ± 0.6), but no significant increase for sexual partner. CONCLUSION: ONFH has impaired relationships with partner and overall sexual satisfaction degree of the male patients; THA has improved significantly relationships with partner and overall sexual satisfaction degree of the male patients, but no effect on sexual function of the patients and overall sexual satisfaction degree of sexual partner.

Relationship between post-SARS osteonecrosis and PAI-1 4G/5G gene polymorphisms.

OBJECTIVE: To explore the correlation between post-severe acute respiratory symptom (SARS) patients with osteonecrosis, investigate the etiology of post-SARS osteonecrosis and select the sensitive molecular symbols for early diagnosis and distinguish the high-risk population. METHODS: The studied subjects were divided into two groups. Sixty-two post-SARS patients with osteonecrosis were one group, and 52 age- and sex-matched healthy people were as normal controlled group. Empty stomach blood samples from cubital veins were collected from both groups. Plasminogen activator inhibitor (PAI) by means of enzyme-linked immunosorbent assay and PAI-1 4G/5G polymorphism was detected by polymerase chain reaction and solid phase oligonucleotide assay. RESULTS: The blood agents of post-SARS patients changed obviously with 15.64 ± 13.85 U/ml while the control group 7.96 ± 4.27 U/ml; 4G/4G genotype for the PAI-1 polymorphism detected in post-SARS group was more than that of the control group, but had no statistical significance. The plasma PAI activity was related to homozygote 4G/4G genotype. This reveals that homozygote 4G/4G genotype may be a susceptible gene mark to Chinese osteonecrosis patients. CONCLUSION: Plasminogen activator inhibitor-1 is sensitive blood symbol for screening high-risk susceptible population; 4G/4G PAI-1 genotype may be an etiological factor in osteonecrosis.

Correction: Ocular biocompatibility evaluation of POSS nanomaterials for biomedical material applications.

[This corrects the article DOI: 10.1039/C5RA08668J.].

Correction: Ma et al. Extracellular Vesicles from BMSCs Prevent Glucocorticoid-Induced BMECs Injury by Regulating Autophagy via the PI3K/Akt/mTOR Pathway. Cells 2022, 11, 2104.

In the original publication [...].

An Antibiotic Nanobomb Constructed from pH-Responsive Chemical Bonds in Metal-Phenolic Network Nanoparticles for Biofilm Eradication and Corneal Ulcer Healing.

In the treatment of refractory corneal ulcers caused by Pseudomonas aeruginosa, antibacterial drugs delivery faces the drawbacks of low permeability and short ocular surface retention time. Hence, novel positively-charged modular nanoparticles (NPs) are developed to load tobramycin (TOB) through a one-step self-assembly method based on metal-phenolic network and Schiff base reaction using 3,4,5-trihydroxybenzaldehyde (THBA), ε-poly-ʟ-lysine (EPL), and Cu2+ as matrix components. In vitro antibacterial test demonstrates that THBA-Cu-TOB NPs exhibit efficient instantaneous sterilization owing to the rapid pH responsiveness to bacterial infections. Notably, only 2.6 µg mL-1 TOP is needed to eradicate P. aeruginosa biofilm in the nano-formed THBA-Cu-TOB owing to the greatly enhanced penetration, which is only 1.6% the concentration of free TOB (160 µg mL-1). In animal experiments, THBA-Cu-TOB NPs show significant advantages in ocular surface retention, corneal permeability, rapid sterilization, and inflammation elimination. Based on molecular biology analysis, the toll-like receptor 4 and nuclear factor kappa B signaling pathways are greatly downregulated as well as the reduction of inflammatory cytokines secretions. Such a simple and modular strategy in constructing nano-drug delivery platform offers a new idea for toxicity reduction, physiological barrier penetration, and intelligent drug delivery.

Bacterial elimination via cell membrane penetration by violet phosphorene peripheral sub-nanoneedles combined with oxidative stress.

The effectiveness of an antibacterial agent is strongly influenced by its antibacterial mechanism, which, in turn, depends on the agent's topological structure. In the natural world, the nanoprotrusions on the surface of insect wings give them excellent antimicrobial properties through physical penetration while being compatible with host cells. Inspired by the novel nanostructure of insect wings, violet phosphorus (VP), a new member of the phosphorus family, has antibacterial potential due to the sub-nanoneedle on its edge. Here, we demonstrate that VP and its exfoliated product, violet phosphorene nanosheets (VPNSs), have superior antibacterial capability against pathogens via cell membrane penetration induced by peripheral sub-nanoneedles combined with oxidative stress. The results show that VPNSs can inactivate more than 99.9% of two common pathogens (Escherichia coli and Staphylococcus aureus) and more than 99.9% of two antibiotic-resistant bacteria (Escherichia coli pUC19 and methicillin-resistant Staphylococcus aureus), while showing almost no toxicity toward normal cells at a high concentration of 2.0 mg mL-1. Moreover, VPNSs can achieve effective treatment of induced skin wound infections and bacterial keratitis (BK) by Staphylococcus aureus and methicillin-resistant Staphylococcus aureus, respectively, showing promising potential for ocular and skin wound infection theragnostics.