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Purpose This study aimed to examine the prosthetic orientations, limb alignment, intraoperative soft tissue balance, and early clinical outcomes associated with the use of the relatively new handheld robot technique compared to those associated with the use of the conventional alignment guide for bi-cruciate stabilized total knee arthroplasty (TKA). Methods This retrospective cohort study compared the prosthetic orientation and limb alignment of 35 patients who underwent TKA using robotic assistance (robot group) with those of patients who underwent TKA using a conventional alignment guide (control group). The coronal femoral component alignment (FCA), coronal tibial component alignment (TCA), and the hip-knee-ankle (HKA) angle were compared between groups. Intraoperative soft tissue balance, including the joint component gap and varus/valgus balance assessed by an offset-type tensor, were also compared between groups. One year postoperatively, the clinical outcomes, including the range of motion and 2011 Knee Society Score (KSS), were compared between groups. Results The HKA angle and FCA were 0.1° varus and 0.1° varus, respectively, in the robot group and 1.3° varus and 1.3° varus, respectively, in the control group. The difference in the HKA angle and the FCA, but not the TCA, between groups was statistically significant (p Conclusion The accuracy of the implantations and stable soft tissue balance in the robot group were superior to those of the control group. The robot group also had superior patient-reported scores for early clinical outcomes.

This study aimed to evaluate the relationship between the radiographical features of combination of the acetabular coverage and the femoral head-neck shape and the occurrence of femoroacetabular impingement (FAI). In this study, 114 patients who had FAI with or without labral tear and mild osteoarthritis were analyzed. Plain radiographs and computed tomography (CT) were taken for evaluation of acetabular coverage and femoral head-neck measurements. The relationship between the combination angle of acetabular coverage and femoral head-neck measurements and the occurrence of FAI was evaluated. The prevalence of FAI patients with the combination angle of CT-anterior CE + α angle ≥100° was 6.1% (7/114 patients). Receiver operator characteristic curve analysis demonstrated a higher area under the curve for combination of CT-anterior center edge angle (ACEA) with the α angle at 0.94 (CT-ACEA +α angle). A threshold for the occurrence of FAI was determined using the combination CT-ACEA + α angle at 100°. The frequency of FAI surgery was significantly higher in patients with a combination angle ≥100° than in those with a smaller angle. The average modified Harris hip score was significantly lower in patients with a combination angle ≥100° than in those with a smaller angle. We suggest that the combination of lateral center edge angle ≥40°, α angle ≥50° and combined angles of CT-ACEA and α angle ≥100° may help diagnosis of FAI. Level of evidence III: retrospective cohort study.

Hepatitis B virus (HBV) infection can cause arthritis, but it is rarely reported. In the current report, we present a case of chronic polyarthritis in a patient with untreated HBV infection. A 63-year-old woman suffering from polyarthritis in her fingers visited our institution. She had experienced exacerbations and remissions of polyarthritis for more than 20 years. She had been diagnosed with rheumatoid arthritis and had been treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and nonsteroidal anti-inflammatory drugs by her primary care doctor, but the csDMARDs were discontinued at the request of the patient 10 years before the first visit to our hospital. The blood test showed negative for rheumatoid factor and anticyclic citrullinated peptides antibody but positive for hepatitis B surface antigen. Hepatitis B surface antigen and HBV-Deoxyribo Nucleic Acid (DNA) were increased to 312.6 (IU/ml) and 4.6 (log copies/ml), respectively. Based on the results of abdominal computed tomography and echography, she was diagnosed with liver cirrhosis. Treatment for HBV infection was begun with oral tenofovir at 25 mg/day. The polyarthritis in her fingers gradually disappeared and has not relapsed for 6 months after the initiation of treatment for HBV infection. When polyarthritis is diagnosed, the possibility that chronic HBV infection can be one of the causes of polyarthritis should be considered.

JOURNEY II bi-cruciate stabilized (BCS) knee system, a guided motion total knee arthroplasty (TKA), has been reported to reproduce physiological knee kinematic motion with good clinical outcomes. However, this guided system may be sensitive to the femorotibial rotational alignment.Forty-four patients (50 knees) who underwent JOURNEY II BCS TKA were included in this retrospective study. The 2011 Knee Society Score (KSS) and range of motion were assessed pre-operatively and one year postoperatively. The femoral component rotational angle relative to the surgical epicondylar axis and the tibial component rotational angle relative to Akagi's line were measured postoperatively. The absolute difference between the femoral and tibial component rotational angles was defined as femorotibial component rotational mismatch. The correlation between the parameters of these rotational alignments and postoperative clinical outcomes was evaluated. Additionally, receiver operating characteristic curve analysis was performed to determine the optimal cut-off point of the femorotibial component rotational mismatch.Mean femoral and tibial component rotational angles were 0.4° (internal rotation) and 0.7° (external rotation), respectively. The rotational mismatch of the femorotibial component was 3.2°. There were negative correlations between femorotibial rotational mismatch and clinical outcomes, including objective knee indicators, patient satisfaction, functional activities, and total 2011 KSS. The area under the curve of the femorotibial component rotational mismatch was 0.768 and the cut-off value identified by the Youden index was 2.8°.Excessive rotational mismatch between the femoral and tibial components can negatively influence the clinical outcomes of JOURNEY II BCS TKA.

Background The stromal-vascular fraction (SVF), comprising heterogeneous cell populations and adipose-derived stem cells (ADSCs), has therapeutic potential against osteoarthritis (OA); however, the underlying mechanism remains elusive. This study investigated the therapeutic effects of the heterogeneous cells in rabbit SVF on rabbit chondrocytes and compared them with those of two different ADSCs adjusted for their stem cell content.Methods Animals were divided into control, low-dose ADSCs (lADSC; 1×104 ADSCs), high-dose ADSCs (hADSC; 1×105 ADSCs), and SVF (1×105 SVF) groups. SVF and ADSCs isolated from rabbits were autografted into the knees after OA onset, and the animals were sacrificed 8 and 12 weeks after OA onset. OA progression and synovitis was analyzed by macroscopic and histological analyses, and the expression of collagen type II, SOX9, MMP-13, CD86 (M1) and CD163 (M2) was assessed using immunohistochemical and real-time polymerase chain reaction (RT-PCR). In vitro, chondrocytes were either co-cultured with SVF or lADSCs or alone (control), and the pellet size was evaluated. TGF-β and IL-10 concentrations in the medium were evaluated using an enzyme-linked immunosorbent assay. Additionally, immune-fluorescent double staining was performed for SVF and lADSCs to stain macrophages with F4/80, CD86, and CD163.Results OA progression was significantly suppressed, and synovitis was reduced in the SVF and hADSC groups. Compared to those in the control and lADSC groups, immunohistochemistry and RT-PCR revealed higher expression of collagen type Ⅱ and SOX9, lower expression of MMP-13 in cartilage, lower macrophage M1/M2 ratio, and higher expression of TGF-β, IL-10 in the synovium in the SVF and the hADSC groups. In the SVF group, the pellet size and TGF-β and IL-10 concentrations were significantly higher than those in the control and lADSC groups. Immune-fluorescent double staining revealed a significantly higher number of M2 than M1 macrophages in SVF.Conclusions The therapeutic effects of SVF and hADSCs superior on chondrocytes was superior with enhanced anabolic and inhibited catabolic factors than those of controls and lADSCs. Heterogeneous cells, mainly M2 macrophages in SVF, contributed to the therapeutic effect on chondrocytes and knee joint homeostasis by enhancing the growth factors and chondrocyte protective cytokines secretion.

Background: Synovial hyperplasia caused by rheumatoid arthritis (RA), an autoimmune inflammatory disease, leads to the destruction of the articular cartilage and bone. A member of the tumor necrosis factor superfamily, Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells (LIGHT) has been shown to correlate with the pathogenesis of RA. Methods: We used cDNA microarray analysis to compare the expression of genes in RA rheumatoid fibroblast-like synoviocytes with and without LIGHT stimulation. Results: Significant changes in gene expression (P-values < 0.05 and fold change ≥ 2.0) were associated mainly with biological function categories of glycoprotein, glycosylation site as N-linked, plasma membrane part, integral to plasma membrane, intrinsic to plasma membrane, signal, plasma membrane, signal peptide, alternative splicing, and topological domain as extracellular. Conclusions: Our results indicate that these gene expression in RA-FLS regulated by LIGHT may be important in the differentiation of several cell types and in cellular functions.

The adipose-derived stromal vascular fraction (SVF) is composed of a heterogeneous mix of adipose-derived stem cells (ADSCs), macrophages, pericytes, fibroblasts, blood, and other cells. Previous studies have found that the paracrine effects of SVF cells may be therapeutic, but their role in osteoarthritis treatment remains unclear. This study aimed to investigate the therapeutic effect of SVF cells on chondrocytes. Chondrocytes were seeded on culture plates alone (control) or cocultured with SVF or ADSCs on cell culture inserts. After 48 h of coculture, chondrocyte collagen II, tissue inhibitors of metalloproteinases-3 (TIMP-3), and matrix metalloproteinases-13 (MMP-13) messenger RNA (mRNA) expression levels were evaluated using reverse-transcription polymerase chain reaction, and the transforming growth factor-β (TGF-β) levels in the supernatant were measured using ELISA. Immunohistochemical staining and flow cytometry were used to evaluate the macrophages in the SVF. These macrophages were characterized according to phenotype using the F4/80, CD86, and CD163 markers. To determine whether the Smad2/3 signaling pathways were involved, the chondrocytes were pre-treated with a Smad2/3 phosphorylation inhibitor and stimulated with the SVF, and then Smad2/3 phosphorylation levels were analyzed using western blot. The mRNA expression levels of various paracrine factors and chondrocyte pellet size were also assessed. Collagen II and TIMP-3 expression were higher in the SVF group than in the ADSC group and controls, while MMP-13 expression was the highest in the ADSC group and the lowest in the controls. TGF-β levels in the SVF group were also elevated. Immunohistochemical staining and flow cytometry revealed that the macrophages in the SVF were of the anti-inflammatory phenotype. Western blot analysis showed that the SVF increased Smad2/3 phosphorylation, while Smad2/3 inhibitors decreased phosphorylation. Smad2/3 inhibitors also reduced the expression of various other paracrine factors and decreased chondrocyte pellet size. These findings suggested that the paracrine effect of heterogeneous cells, such as anti-inflammatory macrophages, in the SVF partly supports chondrocyte regeneration through TGF-β-induced Smad2/3 phosphorylation.

Purpose Assessment of the conventional mechanical axis (MA) (hip-to-talus axis) is reported to result in constitutional varus in the native knee. However, the ground MA (hip-to-calcaneus axis), which is the line from the hip center to the bottom of the calcaneus, passes through the center of the knee joint in the native knee and is a possible alternative target for total knee arthroplasty (TKA) assessments. Therefore, this study aimed to present a “ground kinematically aligned (KA)-TKA.” In this technique, the femoral component is placed on the cylindrical axis using the calipered technique and the tibial component is placed to give a neutral ground MA. Radiographical investigation was used to determine whether physiological alignment can be individually achieved with ground KA-TKA; this was compared with that of a tibia-restricted modified KA-TKA, referring to conventional MA (hip-to-talus axis) results. Methods As the primary endpoint, this prospective cohort study compared the ground MA ratios of the knee joints in 40 ground KA-TKAs (G group: Coronal Plain Alignment of the Knee (CPAK) 28 type I, 7 II, 1 IV, and 4 V) with those of the preceding 60 modified KA-TKAs (M group: CPAK 46 type I, 12 II, and 2 V) performed for patients with varus osteoarthritis (OA). The number of outliers differing over ± 5% from the neutral were compared between groups using the χ2-test. The Hip–knee–ankle (HKA) angle, coronal femoral/tibial component alignment (FCA/TCA), and joint line orientation angle (JLOA) were compared between the groups using non-paired t-tests. Statistical significance was set at p Results The G group had a higher ratio of the ground MA passing through the knee center than the M group did; outliers differing over ± 5% from the neutral of the ground MA were 2/40 cases in the G group and 20/60 cases in the M group, which was a significant difference (p = 0.001). The HKA angle, FCA/TCA, and JLOA were not significantly different between the groups. Conclusions Targeting the ground MA in KA-TKA for patients with varus OA was feasible and has the potential to provide a physiological alignment more similar to the native knee in TKA than other kinematic alignment techniques. Level of evidence Level III.

This study compared the accuracy of three dimensional (3D) mini-optical navigation and accelerometer-based portable navigation systems for cup positioning during a total hip arthroplasty (THA) in the supine position.This retrospective cohort study assessed data for 77 hips using 3D mini-optical navigation (n = 37) and accelerometer-based portable navigation (n = 40). The patients underwent THA through the mini-anterolateral approach in the supine position using a portable navigation system. We assessed the preoperative target angles, recorded intraoperative cup angles, postoperative CT imaging angles, cup angle measurement errors, and other clinical parameters.The mean absolute differences in radiographic inclination were similar between 3D mini-optical navigation and accelerometer-based portable navigation systems during THA in the supine position (2.8° ± 1.7° vs 2.8° ± 1.9°, p = 0.637). The mean absolute differences in radiographic anteversion were also similar (2.6° ± 2.3° vs 2.5° ± 1.9°, p = 0.737). Cup malalignment (absolute difference of inclination or anteversion between postoperative CT and preoperative target angle of 5°) was significantly associated with body mass index (BMI) in accelerometer-based portable navigation but not in 3D mini-optical navigation.This is the first study to compare the accuracy of cup positioning between 3D mini-optical and accelerometer-based navigations in THA in the supine position. Both portable navigation systems accurately identified the orientation of cup placement. The accuracy of 3D mini-optical navigation is not affected by high BMI and may be preferred over other options in such patients.

Introduction Kinematically aligned total knee arthroplasty (KA-TKA) has gained interest for achieving more favorable clinical outcomes than mechanically aligned TKA. One of the advantages of KA-TKA is reported to be an easy acquisition of intraoperative soft-tissue balance without excessive medial release for varus osteoarthritis. However, we hypothesized that the prosthesis type affects intraoperative soft-tissue balance even in the KA-TKA. The present study aimed to compare intraoperative soft-tissue balance and clinical outcomes of KA-TKAs using single-radius (SR) or multiradius (MR) prostheses. Materials and Methods Consecutive 70 cruciate-retaining modified KA-TKAs (31 SR and 39 MR) were performed in patients with varus-type osteoarthritis using a navigation system. Intraoperative soft-tissue balance including joint component gap and varus/valgus balance was measured with femoral component placement and patellofemoral joint reduction throughout the range of motion using offset-type tensor and compared between the two groups. Two years postoperatively, the range of motion and 2011 Knee Society Scores were compared between the two groups. Results and Conclusion Joint component gaps showed no significant differences between the two groups from 0 to 30 degrees of flexion. However, during 60 to 120 degrees of flexion, joint component gaps of SR group showed significantly larger values than those of MR group (p Interpretation Despite no difference in clinical outcomes, joint component gap showed different patterns due to the prosthesis type in modified KA-TKAs.

BACKGROUND: Periprosthetic joint infection is a difficult complication, especially in patients with rheumatoid arthritis. Life-threatening septic shock due to periprosthetic joint infection caused by group G streptococcus is rare, and there have been few reports about its treatment. We describe a successful case of sudden onset septic shock due to group G Streptococcus infection after revision total knee arthroplasty. CASE REPORT: A 61-year-old woman with rheumatoid arthritis treated with biological disease-modifying antirheumatic drugs for about 12 years presented with acute right knee pain and shock 6 months after revision total knee arthroplasty. Periprosthetic joint infection caused by group G Streptococcus was diagnosed. She was admitted to the Intensive Care Unit, treated with respiratory support and dialysis, and underwent irrigation, debridement, and polyethylene liner exchange as the first surgery. At 9 days after the first surgery, she underwent the second surgery, consisting of implant removal and antibiotic spacer placement due to failure. It took approximately 7 weeks to normalize the levels of systemic markers of inflammation with intravenous antibiotics and then oral antibiotics for further 12 weeks, but re-revision total knee arthroplasty was successfully performed 1.5 years later. At a 1-year follow-up from the final surgery, she was able to walk with a cane and had no symptoms of infection. CONCLUSIONS: In such cases with sudden onset of septic shock due to periprosthetic joint infection, appropriate and prompt surgical treatment should be performed to save the infected limb as well as the patient’s life.

Background The relationship between the femoral component design in total knee arthroplasty (TKA) and the patellofemoral contact force, as well as the soft tissue balance, has not been well reported thus far. Methods Twenty-eight mobile-bearing posterior-stabilized (PS) TKAs using the traditional model (PFC Sigma) and 27 mobile-bearing PS TKAs using the latest model (Attune) were included. Surgeries were performed using the measured resection technique assisted with the computed tomography (CT)-based free-hand navigation system. After all the trial components were placed, patellar contact forces on the medial and lateral sides were measured using two uniaxial ultrathin force transducers with the knee at 0°, 10°, 30°, 60°, 90°, 120°, and 135° of flexion. The joint component gap and the varus ligament balance of the femorotibial joint were also measured. The non-paired Student’s t-test was conducted to compare the values of the two groups. Results The medial patellar contact force was significantly lower for Attune group than for PFC Sigma group at 120° of knee flexion (P = 0.0058). The lateral patellar contact force was also significantly lower for Attune group than PFC Sigma group at 120° and 135° of knee flexion (P = 0.0068 and P = 0.036). The joint component gap, as well as the varus ligament balance, showed no statistically significant difference between the two groups. Conclusions Reduced thickness and width of the anterior flange of the femoral component in the Attune may play a role in low patellar contact force.

Genetic polymorphisms might serve as useful prognostic markers for the timely diagnosis of RA. The purpose of this study was to identify genomic factors predictive of the occurrence of interstitial lung disease (ILD) in RA by performing a genome-wide association study of genetic variants, including single nucleotide polymorphisms (SNPs).The study population included 306 RA patients. All patients were treated with conventional DMARDs, including 6-16 mg MTX per week. Clinical data and venous blood samples were collected from all patients before administration of DMARDs. A total of 278 347 SNPs were analysed to determine their association with ILD occurrence.Several SNPs were strongly associated with ILD occurrence (

The relationship between the severity of preoperative varus deformity and the amount of its correction in unicompartmental knee arthroplasty (UKA) as well as the thickness of the insert has not been well known.One hundred and three patients who underwent medial fixed-bearing UKA with the use of the spacer block method were assessed. After the component gap in extension was measured using a UKA tensor, the pre-osteotomy gap was calculated from the thickness of the bone cuts. The relationship between the preoperative hip-knee-ankle (HKA) angle as well as the pre-osteotomy gap and the amount of change in HKA angle were analysed. Also, preoperative HKA angle and the thickness of the bone cuts were compared among groups by the insert thickness.The mean preoperative HKA angle was 7.7 ± 3.1° varus. Patients with more varus deformity and those with a wider pre-osteotomy gap showed a more valgus change in HKA angle. As for the thickness of the insert, the preoperative HKA angle of the patients with the thinnest insert was significantly smaller (less varus) than that of those with the thicker insert while no statistically significant difference was found among the insert groups regarding the amount of the bone cuts.The severity of the preoperative varus deformity as well as the intraoperative pre-osteotomy gap related to the amount of change in HKA angle. As thick inserts tended to be used in severe varus knees, the tibial bone cut can be reduced in such cases.

Objectives Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR). Methods We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (n = 54, each group). Results The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group’s 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group’s good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group’s good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up. Conclusions IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up.

Background To improve implant survival through accelerated early bone remodeling during total hip arthroplasty (THA), hydroxyapatite (HA) is widely used as a bioactive coating, which is believed to enhance initial fixation by osseointegration. We aimed to investigate the relationship between stem insertion alignment and postoperative bone mineral density (BMD) changes in patients with full hydroxyapatite-coated (HA) compaction short stem and short tapered-wedge stem. Methods This retrospective cohort study enrolled 115 consecutive patients (115 joints) undergoing THA using the full HA compaction short (n = 59) and short tapered-wedge (n = 56) stems. Stem alignment, including anteversion, valgus, and anterior tilt were measured by a three-dimensional template using computed tomography data. Post-operative peri-prosthetic BMD was measured by dual-energy X-ray absorptiometry. The relationship between stem alignment and BMD changes in the stems was analyzed. Results Patterns of peri-prosthetic BMD changes were similar in both groups. Stem insertion alignments of anteversion, valgus, and anterior tilt were different between the two stem types. Stem alignment of valgus and anterior tilt did not affect peri-prosthetic BMD in either of the stem type. An absolute anteversion difference between stem anteversion and original canal anteversion caused significant peri-prosthetic BMD loss in Gruen zones one and seven in the tapered-wedge stem. However, stem alignment of absolute anteversion difference did not affect BMD changes in the HA compaction stem. Conclusions Peri-prosthetic bone remodeling remained unaffected by stem alignment after THA with the new short full HA compaction stem.

Endochondral ossification is a complex biological phenomenon involving a variety of factors and cells. Cyclin-dependent kinase inhibitor 1 (p21) inhibits cell cycle progression and is affected by external stress. We recently reported that embryonic endochondral ossification is unaffected by endogenous p21 deficiency. In this study, we evaluated whether p21 expression affects endochondral ossification during fracture healing.Tibial fractures were introduced into p21 knockout (p21The Allen score for fracture healing was lower in p21p21 deficiency leads to delayed endochondral ossification by attenuating the Ihh-Runx2-Osterix pathway in vivo, and p21 deficiency in hypertrophic chondrocytes causes delayed differentiation of hypertrophic chondrocytes in vitro. p21 plays a role in endochondral ossification during fracture healing.

To investigate the cell types that undergo apoptosis in TNF-α inhibitor (TNFI)- and IL-6 inhibitor (IL-6I)-treated synovia of RA patients, and to observe and compare histological changes in them.Synovial tissue was collected during total knee arthroplasty from 20 RA patients who were divided into three groups based on RA treatment received: conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs, control group), TNFI, or IL-6I. Tissue samples were subjected to haematoxylin and eosin staining, terminal deoxynucleotidyl transferase fluorescein-deoxyuridine triphosphate nick end labelling (TUNEL), immuno-histochemistry (IHC) and immunofluorescence staining for, respectively, histopathological assessment, apoptosis detection and IHC evaluation and scoring.TUNEL-positive cells were detected surrounding the discoid fibrosis unique to the TNFI group, while those in the IL-6I group were distributed widely, especially surrounding the blood vessels. IHC revealed that in TNFI-treated tissue, CD86- and CD80-positive cells were detected only in the lining and sublining layer, while CD163- and CD206-positive cells were detected more broadly; in the IL-6I-treated tissue, all four were detected widely but their levels were lower than in the control group. Immunofluorescence also revealed macrophages mainly were the apoptotic cells in the lining and sublining layers of TNFI group. TUNEL Expression levels of CD20- and CD3-positive cells were remarkably lower in the IL-6I group, compared with the control and TNFI groups.TNFIs and IL-6Is target different action sites and synovial cell types, resulting in histopathological features of synovium distinct from one another.

Herpes zoster (HZ) is known as a side effect of using biologics in rheumatoid arthritis (RA). Incidence of this side effect may be different depending on genetic factors because susceptibility to HZ infection varies by race. Here, we analyzed the statistical relationships of whole genome single nucleotide polymorphisms (SNPs) with HZ infection in biologics-treated RA patients.The subjects were 321 Japanese female patients (including 56 herpes virus infected patients) of RA using biologics. The relationships of 302,814 SNPs with HZ infection were analyzed using case-control analyses by Fisher’s exact tests. We picked up SNPs (P < 10-8) significantly associated with HZ infection. Then, herpes infection was compared among the genotypes using a multivariate logistic regression analysis adjusted for onset age of RA.Rs10774580 located in 2’-5’-oligoadenylate synthetase like gene (OASL) was significantly associated with herpes virus infection. The minor allele homozygous carrier was positively associated with herpes virus infection in multivariate analysis.We for the first time showed a significant relationship between a genetic factor and HZ infection among RA patients. Rs10774580 may be one of the biomarkers for HZ infection.

We recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21−/−) (n = 16) and wild type C57BL/6 (p21+/+) mice (n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (n = 5 per group) to interleukin (IL)-1β stimulation was determined in vitro. Arthritis scores were higher in p21−/− mice than in p21+/+ mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21−/− mice compared to p21+/+ mice. p21−/− mice expressed higher levels of IL-1β, TNF-α, F4/80, CD86, p-IKKα/β, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/β and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1β, IL-6, and TNF-α.

Introduction The concept of anatomic restoration has garnered considerable interest in the form of kinematically aligned total knee arthroplasty (KA-TKA). KA-TKAs have been reported to reproduce natural alignment and kinematics. However, few randomized controlled trials (RCTs) have compared the biomechanical outcomes and the long-term clinical outcomes of KA-TKA with those of mechanically aligned TKA (MA-TKA). We aim to investigate the long-term clinical and biomechanical effects of KA-TKA and to determine whether KA-TKA or MA-TKA is more appropriate for primary TKA. Methods This trial will compare clinical and biomechanical outcomes of KA-TKA to those of MA-TKA. Two hundred patients will be enrolled in the RCT and randomized into KA-TKA or MA-TKA groups. Both the groups will be evaluated 1 week before the operation, on the day of the operation, 6 months after the operation, and 1, 5, and 10 years after the operation. The primary outcome is the difference between preoperative and 1-year postoperative functional activity scores of the 2011 Knee Society Score (2011 KSS) in both groups as well as the differences between the scores of both groups. The secondary outcomes will include differences in symptom, satisfaction, and expectation scores of the 2011 KSS, intraoperative kinematics evaluation, postoperative clinical outcomes and complications, pre- and postoperative gait analyses and radiograph evaluations between both KA-TKA and MA-TKA.

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation in synovial tissues. Hyperplasia of synovial tissue leads to the formation of pannus, which invades joint cartilage and bone resulting in joint destruction. Tumor necrosis factor-like ligand 1A (TL1A), a member of the tumor necrosis factor superfamily (TNFSF15), contributes to the pathogenesis of autoimmune diseases, including RA. In the present study, a cDNA microarray was used to search for genes whose expression in rheumatoid fibroblast-like synoviocytes (RA-FLS) were regulated by TL1A. Four individual lines of primary cultured RA-FLS were incubated either with recombinant human TL1A protein or phosphate-buffered saline, as an unstimulated control, for 12 h. Gene expression was then detected through the microarray assay. The results revealed the expression profiles of genes in RA-FLS regulated by TL1A. The present study also demonstrated the functions of those genes whose expression in RA-FLS was regulated by TL1A. Among the genes in this profile, the present study focused on the following genes: Spectrin repeat-containing nuclear envelope 1, Fc receptor-like 2, PYD (pyrin domain)-containing 1, cell division cycle 45 homolog, signal transducer and activator of transcription 5B, and interferon regulatory factor 4. These genes may affect the pathogenesis of RA, including proliferation, regulation of B cells and T cells, inflammation, and cytokine processing. The present study revealed for the first time, to the best of our knowledge, the expression profile of genes in RA-FLS regulated by TL1A. The data indicate that TL1A may regulate the gene expression of various key molecules in RA-FLS, thus affecting the pathogenesis of RA. Further investigations of the genes detected in the current profiles may provide a deeper understanding of the pathogenesis and a novel target for the treatment of RA.

Background: Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder whose progression is modulated by fibroblast-like synoviocytes (FLSs). Cyclin-dependent kinase (CDK) inhibitor 1 (p21) regulates the activation of other CDKs, and we recently reported that p21 deficiency induces susceptibility to osteoarthritis. Here, we focused on joint inflammation to determine the mechanisms associated with p21 function in synovial and cartilage tissues in RA.Methods: p21-knockout (p21-/-) mice and wild-type C57BL/6 (WT p21+/+) mice were used to establish a collagen antibody-induced arthritis (CAIA) model. The severity of arthritis was evaluated visually, and histological and immunohistological analyses performed 7, 14, and 28 days after injection with a cocktail of five monoclonal antibodies that recognize conserved epitopes on various species of type II collagen. The response of p21 siRNA-treated human RA FLSs to IL-1β stimulation was also determined.Results: Arthritis scores were higher in p21-/- mice than those in p21+/+ mice. More severe and prolonged synovitis of the knee joints and earlier loss of staining and cartilage destruction were observed in p21-/- mice than in p21+/+ mice. p21-/- mice expressed higher levels of IL-1β, F4/80, p-IKKα/β, and MMPs in cartilage and synovial tissues at each time point, except for before injection of the monoclonal antibodies, via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased MMP expression and enhanced IKKα/β phosphorylation in human FLSs.Conclusion: p21-deficient CAIA mice are susceptible to alterations in the RA phenotype, including joint cartilage destruction and severe synovitis, via IL-1β-induced inflammation. Therefore, p21 regulation may constitute a possible strategy for RA treatment.

Rationale: Giant cell arteritis (GCA)—a primary vasculitis of medium and large arteries—is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury. Objective: The MMP (matrix metalloproteinase)-9—a type IV collagenase—is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent. Methods and Results: The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts, and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from patients with GCA. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD (cluster of differentiation) 4 + T cells required MMP-9–producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID (severe combined immunodeficiency) chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting rMMP-9 (recombinant MMP-9). Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates ( P P P P P P Conclusions: In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9–producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks, and neointimal growth all require the enzymatic activity of MMP-9, identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation in synovial tissues. Hyperplasia of synovial tissues leads to the formation of pannus that invades the joint cartilage and bone, resulting in joint destruction. Fas ligand (FasL), which is a member of the tumor necrosis factor superfamily, contributes to the pathogenesis of autoimmune diseases, including RA. The current study attempted to identify genes whose expressions in rheumatoid fibroblast-like synoviocytes (RA-FLS) were regulated by FasL, using cDNA microarray. A total of four individual lines of primary cultured RA-FLS were incubated either with recombinant human FasL protein or PBS as an unstimulated control for 12 h. Gene expression was detected using a microarray assay. The results revealed the expression profiles of genes in RA-FLS regulated by Fas and investigated the functions of the genes that were regulated. Among the genes in this profile, the mRNA expression changes of the following genes were indicated to be of note using RT-qPCR: Dual specificity phosphatase 6, epiregulin, interleukin 11, angiopoietin-like 7, protein inhibitor of activated STAT 2 and growth differentiation factor 5. These genes may affect the pathogenesis of RA by affecting apoptosis, proliferation, cytokine production, cytokine-induced inflammation, intracellular signaling, angiogenesis, bone destruction and chondrogenesis. To the best of our knowledge, the current study is the first study to reveal the expression profile of genes in RA-FLS regulated by FasL. The data demonstrated that FasL may regulate the expression of a number of key molecules in RA-FLS, thus affecting RA pathogenesis. Further studies of the genes detected may improve the understanding of RA pathogenesis and provide novel treatment targets for RA.

Decoy receptor 3 (DcR3) competitively binds to Fas ligand, lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells (LIGHT) and TNF-like ligand 1A (TL1A), thereby preventing their effects. Using a microarray assay, we previously newly identified centrosomal protein 70 kDa (CEP70) as one of the genes whose expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) is reduced by DcR3. Here, we investigated the significance of DcR3 regulation of CEP70 for RA-FLS.Synovial samples were obtained from RA patients who had never been treated with biologics and from osteoarthritis (OA) patients. CEP70 mRNA expression was quantified using RT-qPCR analysis. CEP70 protein expression was assessed using immunohistochemical and western blot analyses.CEP70 was expressed predominantly in the superficial lining layer in RA synovial tissue. CEP70 expression was dose-dependently downregulated by DcR3-Fc in RA-FLS but was not downregulated in OA-FLS. TL1A antibody prevented the DcR3-Fc inhibitory effects on CEP70 expression in RA-FLS.These results indicated that DcR3 reduces CEP70 expression in RA-FLS by binding to membrane-bound TL1A and may suppress RA-FLS proliferation. The reduction in CEP70 expression by DcR3/TL1A signaling may control the hyperplasia of RA synovium.

Background Fas ligand (FasL) is a member of tumor necrosis factor superfamily (TNFSF6) and reported to contribute to synovial hyperplasia of rheumatoid arthritis (RA). Apoptosis of RA synovial cells through Fas/FasL pathway was inhibited by pro-inflammatory cytokines present within the synovium [1]. We previously reported that decoy receptor 3 overexpressed in rheumatoid synovial fibroblasts (RA-FLS) stimulated by TNFα protects the cells from Fas-induced apoptosis [2]. Objectives In this study, we investigated the gene expression profiles regulated by FasL in RA-FLS to reveal how FasL is involved in the pathogenesis of RA. Methods RA-FLS were obtained during total knee replacement surgery from patients with RA. Four individual lines of primary cultured RA-FLS were incubated either with 1000 ng/ml of recombinant human FasL protein or the same volume of phosphate buffered saline as unstimulated control in reduced serum medium for 12h. Gene expressions were detected by microarray assay (Human Genome U133 Plus 2.0, GeneChip® 3’ Expression Array; Thermo Fisher Scientific). Results Microarray data analysis revealed that FasL up-regulated or down-regulated the expression of various genes in RA-FLS. The function of regulated genes included transcriptional activator activity, positive regulation of metabolic process, positive regulation of cellular metabolic process, positive regulation of macromolecule metabolic process, positive regulation of nitrogen compound metabolic process, regulation of phosphorylation, positive regulation of biological process, regulation of phosphate metabolic process, regulation of MAPK cascade, and regulation of multicellular organismal process. The most up-regulated 3 genes by FasL were dual specificity phosphatase 6 (DUSP6), epiregulin (EREG) and interleukin11 (IL-11). The most down-regulated 3 genes by FasL were angiopoietin-like 7 (ANGPTL7), protein inhibitor of activated STAT2 (PIAS2) and growth differentiation factor 5 (GDF5). Conclusion DUSP6 regulates CD4+ T-cell activation and differentiation by inhibiting the T-cell receptor-dependent extracellular signal-regulated kinases 1 and 2 activations [3]. EREG is increased in patients with RA and associated with the development of cytokine-induced arthritis [4]. IL-11 regulates the growth and development of hematopoietic stem cells and decreases the pro-inflammatory cytokines and nitric oxide productions [5]. ANGPTL7 is pro-angiogenic factor [6] and promotes pro-inflammatory responses through the P38 signaling pathway [7]. PIAS proteins inhibit the activated STAT and are involved in the pathogenesis of RA [8]. GDF5 is associated with joint destruction of patients with OA and RA [9]. FasL regulates the expression of various genes in RA-FLS. Therefore, FasL may affect the pathogenesis of RA by regulating gene expressions of these molecules in RA-FLS. References [1] Wakisaka S. et al., Clin Exp Immunol. 1998;114:119-128. [2] Hayashi S. et al., Arthritis Rheum. 2007;56:1067-1074. [3] Bertin S. et al., Mucosal Immunol. 2015;8:505-515. [4] Harada M. et al., J Immunol. 2015;194:1039-1046. [5] Moreland L. et al., Arthritis Res. 2001;3:247-252. [6] Katoh Y, et al., Int J Mol Med. 2006;17:1145-1149. [7] Quian T, et al., Inflammation. 2016;39:974-985. [8] Lao M. et al., J Immunol. 2016;196:596-606. [9] Martinez A. et al., Ann Rheum Dis. 2008;67:1352-1353. Disclosure of Interests None declared

Improving patient health‐related quality of life (HRQOL) and prevention of bone fracture are important components of the treatment of osteoporosis. Our aim in this study was to evaluate the effect of denosumab treatment in improving HRQOL among patients with osteoporosis. Our analysis was based on 332 patients with osteoporosis, followed for 24 months. All patients received denosumab (60 mg) subcutaneously every 6 months. Bone mineral density (BMD) was assessed at the distal radius, with serum concentration of calcium, phosphate, P1NP, and TRACP5b also measured. HRQOL assessment included pain (visual analogue scale [VAS]) and the EQ‐5D questionnaire. A multivariate analysis was performed to identify the possible confounders associated with deterioration in the EQ‐5D utility score in response to denosumab treatment. Denosumab treatment yielded a 3.4% increase in BMD at 24 months. Serum levels of TRACP5b and P1NP decreased significantly, from baseline, at 6 months, with no effect on calcium and phosphate levels. Pain VAS and EQ‐5D utility score improved significantly, from baseline, at 6 months, with the EQ‐5D utility score correlating with the BMD at all time points of measurement over the 24‐month period of observation. Knee osteoarthritis and multiple comorbidities were significantly associated with a worse HRQOL in response to denosumab treatment. Denosumab treatment increased BMD, with improvements in BMD correlating with improved HRQOL, supporting a possible benefit of using denosumab for the treatment of osteoporosis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease leading to joint destruction. The aim of the present study was to identify the genomic factors predictive of susceptibility to joint destruction in patients with RA by performing a genome‑wide association study of genetic variants, including single nucleotide polymorphisms (SNPs). The study sample included 228 patients with a diagnosis of RA in the past 5 years. Patients were classified into rapid (total Sharp score/years of RA, ≥50) and slow (total Sharp score/years of RA

BackgroundNovel therapeutic strategies for the healing of nonunion, which has serious effects on the quality of life of patients, are needed. We evaluated the therapeutic effect of local transplantation of human stromal vascular fraction (SVF) cells on fracture healing in a rat non-healing fracture model and compared the effects between freshly isolated (F) and cryopreserved (C)-SVFs.MethodsNon-healing fracture model was induced in the femur of female immunodeficient rats (F344/N Jcl rnu/rnu) with cauterizing periosteum. Immediately after the creation of non-healing fracture, rats received local transplantation of F and C-SVFs suspended in phosphate-buffered saline (PBS) or the same volume of PBS without cells using the same scaffold as a control group. During 8 weeks post-surgery, radiologic, histological, immunohistochemical, and biomechanical analyses were performed to evaluate fracture healing. The comparison of radiological results was performed with a chi-square test, and the multiple comparisons of immunohistochemical, histological, and biomechanical results among groups were made using a one-way analysis of variance. A probability value of 0.05 was considered to denote statistical significance.ResultsAt week 8, in 60% of animals receiving F-SVF cells and in 50% of animals receiving C-SVF cells, the fracture radiologically healed with bone union whereas nonunion was observed in the control group. The healing potential was also confirmed by histological and biomechanical assessments. One of the mechanisms underlying healing involving intrinsic angiogenesis/osteogenesis was enhanced in F- and C-SVF groups compared with that in the control group. Human cell-derived vasculogenesis/osteogenesis, which was also confirmed in an in vitro differentiation assay, was also enhanced in the F- and C-SVF groups compared with that in the control groups and could be another mechanism for healing.ConclusionsSVF cells can enhance bone healing and cryopreserved cells have almost equal potential as fresh cells. SVF cells can be used for improving nonunion bone fracture healing as an alternative to other mesenchymal stem cells and the effect of SVF cells can be maintained under cryopreservation.

Treatment of rheumatoid arthritis (RA) is aimed at long-term remission and inhibition of joint destruction by different biologic drugs. However, the choice of a particular biologic agent based on individual cases of RA remains unestablished. Interleukin-6 (IL-6) inhibitor and tumor necrosis factor (TNF) inhibitor are common biologics used for the treatment of RA. This study aimed to investigate predictive factors for effective selection of tocilizumab (IL-6 inhibitor) and etanercept (TNF inhibitor) in patients with RA. This is a retrospective cohort study. The 196 patients analyzed in this study were divided into four groups: tocilizumab treatment as the first biologic group (TCZ first, 42 patients), tocilizumab as second/ third biologic group (TCZ second, 34 patients), etanercept as the first biologic group (ETN first, 103 patients) and etanercept as second/third group (ETN second, 17 patients). Visual analog scale (VAS), clinical disease activity index (CDAI), and modified health assessment questionnaire (mHAQ) scores at the initiation of biologic treatment and after 6 months of tocilizumab and etanercept therapy were measured and compared to clinical parameters and radiographical parameters among the four groups. CRP, MMP-3, VAS, CDAI, and HAQ were improved after 6 months of treatment in all groups. Improvement of clinical outcomes was correlated with CRP value, duration of RA, and Sharp scores at the initiation of treatment. Multivariate analysis demonstrated improvement in CDAI was significantly associated with the yearly progression of erosion according to the Sharp score in TCZ first group (OR, 1.5; 95% CI, 1.03–2.07) and was negatively associated with the duration of RA (OR, 0.49; 95% CI, 0.29–0.86) at the initiation of treatment with ETN first group. We identified the predictive factors for effective selection of tocilizumab and etanercept treatment and established the effectiveness of tocilizumab for the patients with rapid progressive joint erosion and etanercept for the early administration from diagnosis of RA.

Background:Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes hyperplasia of synovial tissue. Death receptor 3 (DR3) is a tumor necrosis factor receptor and binds to TL1A, a member of the TNF family. DR3 is involved in the mechanism of cell proliferation and apoptosis through NF-κB signaling. Suppression of DR3 in rheumatoid synovial fibroblasts (RA-FLS) is associated with hyperplasia of rheumatoid synovial tissue [1]. We previously revealed the expression profiles regulated by TL1A, suggesting that TL1A might affect the pathogenesis of RA, including proliferation, regulation of B cells and T cells, inflammation, and cytokine processing [2].Objectives:In this study, we investigated the gene expression profiles regulated by DR3 in RA-FLS to reveal how DR3 is involved in the pathogenesis of RA.Methods:RA-FLS were from patients with RA. Four individual lines of primary cultured RA-FLS were incubated either with 1000 ng/ml of human DR3-Fc protein or 1000ng/ml of human IgG1 as a control for 12h. Gene expressions were detected by microarray assay.Results:Microarray data analysis revealed that DR3 up-regulated or down-regulated the expression of various genes in RA-FLS (Figure). The function of regulated genes included protein-L-isoaspartate (D-aspartate) O-methyltransferase activity, carboxyl-O-methyltransferase activity, protein carboxyl O-methyltransferase activity, regulation of cilium assembly, O-methyltransferase activity, regulation of plasma membrane bounded cell projection assembly, regulation of cell projection assembly, regulation of organelle assembly, protein methyltransferase activity, and S-adenosylmethionine-dependent methyltransferase activity. The most up-regulated 2 genes by DR3 were KIAA1109 (KIAA1109), and adhesion G protein-coupled receptor A3 (ADGRA3). The most down-regulated 2 genes by DR3 were RNA exonuclease 2 (REXO2), and family with sequence similarity 120A (FAM120A).Conclusion:In this study, we first revealed the expression profiles of genes regulated by DR3 in RA-FLS. KIAA1109/TENR/IL2/IL21 gene is strongly associated with RA in European descent populations [3]. ADGRA3 is a member of G protein-coupled receptors (GPCRs). GPCRs associates with the regulation of cytoskeletal organization, the cell adhesion and migration, cell proliferation and apoptosis, and cell differentiation [4]. Loss of REXO2 affects cell growth and morphology [5], and REXO2 was identified as a target gene for inflammatory bowel disease-associated variants [6]. FAM120A regulates activity of Src kinase to protect cells from oxidative stress-induced apoptosis [7]. DR3 regulates the gene expressions of various key molecules in RA-FLS and may affect the pathogenesis of RA by regulating gene expression of RA-FLS.References:[1]Takami N. et al., Arthritis Rheuma. 2006;54:779-787.[2]Fukuda K. et al., Biomed Rep. 2019;1:1-5.[3]Teixeira VH. et al., Arthritis Research & Therapy. 2009;11:R45.[4]Hamann J. et al., Pharmacol Rev. 2015;67:338-367.[5]Bruni F, et al., PLoS One. 2013;8:e64670.[6]Hulur I, et al., BMC Genomics. 2015;16:138.[7]Tanaka M. et al., Mol Cell Biol. 2009;29:402-413.Disclosure of Interests:None declared

Background:Many blood vessels are generated in the hyperplastic synovial tissue of patients with rheumatoid arthritis (RA), and lead to chronic tissue inflammation and joint destruction [1]. Janus kinase (JAK) family consisting of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) are chain receptors which phosphorylate signal transducers and activators of transcription (STAT) and mediate inflammatory diseases including RA [2]. Nowadays, several JAK inhibitors such as Tofacitinib (TOF), Baricitinib (BAR) and Peficitinib (PEF) have been developed and demonstrated to have the inhibitory effects on inflammatory arthritis [3-5]. However, there were few reports concerning their effects on angiogenesis in vitro.Objectives:The purpose of the present study is to investigate the influence of JAK inhibitors on angiogenesis of human umbilical vein endothelial cell (HUVEC) activated by vascular endothelial growth factor (VEGF).Methods:The cell line of HUVECs were used for this study. The activity of proliferation and tube formation were analyzed by counting assay and tube formation assay, respectively.In counting assay, HUVECs (5 × 104cells/ml) were seeded onto 96-well cell culture plate with 20 ng/ml VEGF including various doses (0.1µM, 1µM, 5µM) of TOF, BAR or PEF. After 48 hours incubation at 37°C in a humidified atmosphere containing 5% CO2, cell proliferation of each groups was assessed using cell counting kit. In tube formation assay, HUVECs (5 × 104cells/ml) were treated with 20ng/ml VEGF including various dose (0.1µM, 1µM, 5µM) of TOF, BAR or PEF for 00 hours, then seeded onto 48-well plate applied with Matrigel. After 24 hours incubation on Matrigel, the capillary-like tube formation of each well was photographed using phase contrast microscopy. Tube formation were quantitated by measurement of the length of branch.Results:HUVECs were activated in proliferation and tube formation by VEGF treatment. And, the proliferation and tube formation of HUVECs activated by VEGF were suppressed by All of TOF, BAR and PEF. In particular, TOF and PEF could suppress them highly.Conclusion:This study showed the inhibitory effect of JAK inhibitors on proliferation and tube formation of HUVECs activated by VEGF. In particular, the angiogenesis of HUVECs activated by VEGF was highly suppressed by TOF and PEF. VEGF is reported to regulate the angiogenesis through multi JAK-STAT signaling pathways [6]. The inhibitory effects on angiogenesis of TOF, BAR and PEF might depend on the differences in their affinity for JAKs. VEGF has been shown to a have a central involvement in the angiogenic process in RA [7]. JAK inhibitors might suppress the angiogenesis in RA synovial tissues by inhibiting VEGF signaling.References:[1]Scott DL, et al. Rheumatoid arthritis. Lancet. 2010.[2]Banerjee S, et al. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs. 2017.[3]William D, et al. JAK inhibitors in dermatology: the promise of a new drug class. Journal of the American Academy of Dermatology. 2017.[4]Dhillon S. Tofacitinib: A Review in Rheumatoid Arthritis. Drugs. 2017.[5]Markham A, et al. Peficitinib: First Global Approval. Drugs. 2019.[6]Zhang HY, et al. Three important components in the regeneration of the cavernous nerve: brain-derived neurotrophic factor, vascular endothelial growth factor and the JAK/STAT signaling pathway. Asian journal of andrology. 2011.[7]Paleolog EM. Angiogenesis in rheumatoid arthritis. Arthritis research. 2002.Acknowledgments:noneDisclosure of Interests:None declared

Introduction: Analysis of predictive factors for the improvement of bone mineral density (BMD) in response to osteoporosis treatment is critical. Several studies reported on the analysis of bone turnover markers as a predictive factor for the improvement of BMD; however, few studies reported on predictive factors other than bone turnover markers. Thus, this study aimed to analyze other predictive factors for distal radial BMD improvement in response to denosumab treatment among patients with osteoporosis.Methods: We evaluated 133 patients with osteoporosis over a 24 month period. All patients received denosumab (60 mg) subcutaneously every 6 months. The BMD of the distal radius was assessed in all patients and serum concentrations of PINP and TRACP5b determined.Results: Denosumab treatment resulted in a 3.3% increase, from baseline, in distal radius BMD at 24 months. The average BMD change at 24 months was not significantly changed in relation to gender or prevalent medication. The average BMD change at 24 months was negatively correlated with patient’s age. Almost all the points of PINP and TRACP5b were not correlated with BMD except TRACP5b value at 24 months.Conclusions: We found that improvement of bone mineral density with denosumab treatment for osteoporosis is associated with young age of the patients. We recommend denosumab treatment for younger patients with osteoporosis.

Improving patient health-related quality of life (HRQOL) and prevention of bone fracture are important components of the treatment of osteoporosis. Our aim in this study was to evaluate the effect of denosumab treatment in improving HRQOL among patients with osteoporosis. Our analysis was based on 332 patients with osteoporosis, followed for 24 months. All patients received denosumab (60 mg) subcutaneously every 6 months. Bone mineral density (BMD) was assessed at the distal radius, with serum concentration of calcium, phosphate, P1NP, and TRACP5b also measured. HRQOL assessment included pain (visual analogue scale [VAS]) and the EQ-5D questionnaire. A multivariate analysis was performed to identify the possible confounders associated with deterioration in the EQ-5D utility score in response to denosumab treatment. Denosumab treatment yielded a 3.4% increase in BMD at 24 months. Serum levels of TRACP5b and P1NP decreased significantly, from baseline, at 6 months, with no effect on calcium and phosphate levels. Pain VAS and EQ-5D utility score improved significantly, from baseline, at 6 months, with the EQ-5D utility score correlating with the BMD at all time points of measurement over the 24-month period of observation. Knee osteoarthritis and multiple comorbidities were significantly associated with a worse HRQOL in response to denosumab treatment. Denosumab treatment increased BMD, with improvements in BMD correlating with improved HRQOL, supporting a possible benefit of using denosumab for the treatment of osteoporosis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

We present two-epoch maps of SiO masers (v = 1a ndv = 2, J = 1–0) associated with the M-type star IRC � 10414, which were obtained with the Japanese VLBI Network (JVN). The spatial and Doppler velocity distributions, and the intensity ratio of the v = 1t ov = 2( J = 1–0) lines have significantly changed for eight years since our previous Very Long Baseline Array (VLBA) observation. The maser proper motions revealed by these twoepoch observations with an interval of one month are quite random and too fast to be explained by ballistic motions of the maser clumps. The maser distributions seen in the present observations cannot be explained by a rotatinginfalling ring model implied in the previous work. We discuss the kinematical relation between the SiO and H2O masers in IRC � 10414. In the present observations, the scale sizes of SiO v = 1a ndv = 2 masers in IRC � 10414 were roughly equal, as observed in typical Mira variables.

We present a distance measurement for the semiregular variable S Crateris (S Crt) based on its annual parallax. With the unique dual beam system of the VLBI Exploration for Radio Astrometry (VERA) telescopes, we measured the absolute proper motion of a water maser spot associated with S Crt, referred to the quasar J1147-0724 located at an angular separation of 1.23$^{\circ}$. In observations spanning nearly two years, we have detected the maser spot at the LSR velocity of 34.7 km s$^{-1}$, for which we measured the annual parallax of 2.33$\pm$0.13 mas corresponding to a distance of 430$^{+25}_{-23}$ pc. This measurement has an accuracy one order of magnitude better than the parallax measurements of HIPPARCOS. The angular distribution and three-dimensional velocity field of maser spots indicate a bipolar outflow with the flow axis along northeast-southwest direction. Using the distance and photospheric temperature, we estimate the stellar radius of S Crt and compare it with those of Mira variables., 9 pages, 4 figures, accepted for publication in PASJ (Vol.60, No.5, October 25, VERA special issue)

We observed the SiO (v = 1 and v = 2, J = 1–0) maser emissions toward the Mira variable IK Tauri (IK Tau, NML Tau, IRC +10050) over nine epochs from 2003 November to 2005 April using the VLBI Exploration of Radio Astrometry (VERA) telescope array. We found that the SiO maser distributions around IK Tau are highly variable, depending on the stellar pulsation phase. The velocity structures were complex and also time-variable, and are inconsistent with a simply rotating shell that was suggested by previous observations. Based on fittings of the SiO maser distributions to elliptical ring models, we found that the ring size seems to vary in correlation with the pulsation phase, as previously found for TX Cam. Comparisons of the v = 1 and v = 2 maser distributions reveal that 42–50% of the maser pairs have a positional offset less than 0.5 mas, suggesting that the maser pumping in these spots is likely to be dominated by line overlapping or collisional pumping, rather than pure radiative pumping. In order to model the velocity structure of the spoke-like features observed in IK Tau, we propose a ballistic-orbit model, in which a gas clump ejected from the stellar surface moves radially outward with a gravitational deceleration, and argue that the stellar mass can be deduced from that model.

We report on results of five-epoch VLBI observations of H2O maser emission in the M-type star IRC � 10414, carried out with the VLBI Exploration of Radio Astrometry (VERA). The maser distribution extends over an area of 70 mas � 260 mas and exhibits a bipolar structure. The relative proper motions of 17 maser features were measured during the monitoring observations spanning nine months. The distance to IRC � 10414 was re-estimated on the basis of the statistical treatment of parallax and the model-fitting method, yielding D = 3.1 ˙ 0.4 kpc and D = 2.0 ˙ 0.2 kpc, respectively. The estimated distance, D = 2–3 kpc, is much larger than that previously adopted. The stellar luminosity of IRC � 10414 is also re-estimated to be L� � 9 � 10 4 (D=2 kpc) 2 Lˇ, much brighter by a factor of 10–20 than previously adopted (L� � 10000 Lˇ). The maser motions exhibit not only a spherically expanding flow with a velocity of � 10 (D=2 kpc) km s � 1 , but also a faster bipolar outflow with a major axis in the north–south direction and at a small inclination angle with respect to the celestial sphere. These characteristics of the star and the