Cyclic compressive loading induces a mature meniscal cell phenotype in mesenchymal stem cells with an atelocollagen-based scaffold.

Introduction: Biomechanical stimulation is reportedly pivotal in meniscal regeneration, although its effect on mesenchymal stem cell (MSC) meniscal differentiation remains elusive. In this study, we investigated how cyclic compressive loading (CCL) could impact MSCs using three-dimensional cultures in atelocollagen-based meniscal substitute (ACMS). Methods: We extracted MSCs from the meniscus, synovium, and articular cartilage, cultured them in three-dimensional cultures, and exposed them to CCL for 7 days. We then compared the transcriptomes of MSCs treated with and without CCL. Results: Our RNA-seq analysis revealed that CCL induced significant transcriptome changes, significantly affecting chondrocyte-related genes, including SOX9, TGFB1, and PRG4 upregulation. CCL induced transcriptional differentiation of meniscus progenitors toward mature meniscal cells. Conclusion: This study unveils the potential of mechanical stress in promoting MSC meniscal differentiation within ACMS. Our investigations provide new insights for mechanisms underlying meniscal regeneration with ACMS.

Iguratimod suppresses sclerostin and receptor activator of NF-κB ligand production via the extracellular signal-regulated kinase/early growth response protein 1/tumor necrosis factor alpha pathway in osteocytes and ameliorates disuse osteoporosis in mice.

Disuse osteoporosis is a prevalent complication among patients afflicted with rheumatoid arthritis (RA). Although reports have shown that the antirheumatic drug iguratimod (IGU) ameliorates osteoporosis in RA patients, details regarding its effects on osteocytes remain unclear. The current study examined the effects of IGU on osteocytes using a mouse model of disuse-induced osteoporosis, the pathology of which crucially involves osteocytes. A reduction in distal femur bone mass was achieved after 3 weeks of hindlimb unloading in mice, which was subsequently reversed by intraperitoneal IGU treatment (30 mg/kg; five times per week). Histology revealed that hindlimb-unloaded (HLU) mice had significantly increased osteoclast number and sclerostin-positive osteocyte rates, which were suppressed by IGU treatment. Moreover, HLU mice exhibited a significant decrease in osteocalcin-positive cells, which was attenuated by IGU treatment. In vitro, IGU suppressed the gene expression of receptor activator of NF-κB ligand (RANKL) and sclerostin in MLO-Y4 and Saos-2 cells, which inhibited osteoclast differentiation of mouse bone marrow cells in cocultures. Although IGU did not affect the nuclear translocation or transcriptional activity of NF-κB, RNA sequencing revealed that IGU downregulated the expression of early growth response protein 1 (EGR1) in osteocytes. HLU mice showed significantly increased EGR1- and tumor necrosis factor alpha (TNFα)-positive osteocyte rates, which were decreased by IGU treatment. EGR1 overexpression enhanced the gene expression of TNFα, RANKL, and sclerostin in osteocytes, which was suppressed by IGU. Contrarily, small interfering RNA-mediated suppression of EGR1 downregulated RANKL and sclerostin gene expression. These findings indicate that IGU inhibits the expression of EGR1, which may downregulate TNFα and consequently RANKL and sclerostin in osteocytes. These mechanisms suggest that IGU could potentially be used as a treatment option for disuse osteoporosis by targeting osteocytes.

Vibration acceleration enhances proliferation, migration, and maturation of C2C12 cells and promotes regeneration of muscle injury in male rats.

Vibration acceleration (VA) using a whole-body vibration device is beneficial for skeletal muscles. However, its effect at the cellular level remains unclear. We aimed to investigate the effects of VA on muscles in vitro and in vivo using the C2C12 mouse myoblast cell line and cardiotoxin-induced injury in male rat soleus muscles. Cell proliferation was evaluated using the WST/CCK-8 assay and proportion of Ki-67 positive cells. Cell migration was assessed using wound-healing assay. Cell differentiation was examined by the maturation index in immunostained cultured myotubes and real-time polymerase chain reaction. Regeneration of soleus muscle in rats was assessed by recruitment of satellite cells, cross-sectional area of regenerated muscle fibers, number of centrally nucleated fibers, and conversion of regenerated muscle from fast- to slow-twitch. VA at 30 Hz with low amplitude for 10 min promoted C2C12 cell proliferation, migration, and myotube maturation, without promoting expression of genes related to differentiation. VA significantly increased Pax7-stained satellite cells and centrally nucleated fibers in injured soleus muscles on Day 7 and promoted conversion of fast- to slow-twitch muscle fibers with an increase in the mean cross-sectional area of regenerated muscle fibers on Day 14. VA enhanced the proliferation, migration, and maturation of C2C12 myoblasts and regeneration of injured rat muscles.

Characteristics of physical activity during beginner-level group tennis lessons and the effect daily activity.

Tennis is a popular leisure sport, and studies have indicated that playing tennis regularly provides many health benefits. We aimed to clarify the characteristics of physical activity during beginner-level group tennis lessons and daily physical activity of the participants. Physical activity was measured using an accelerometer sensor device for four weeks, including the 80-min duration tennis lessons held twice a week. Valid data were categorized for tennis and non-tennis days. The mean physical activity intensity during the tennis lesson was 3.37 METs. The mean ratio of short-bout rest periods to the tennis lesson time in 90 and 120 s was 7% and 4%, respectively. The mean physical activity intensity was significantly higher (p < 0.0001) and the duration of vigorous-intensity physical activity (VPA) was increased in 76% of participants on days with tennis lessons compared to without tennis lessons. Beginner-level tennis lesson has characteristics of less short-bout rest physical activity than previously reported competitive tennis match and increased the duration of VPA in daily activity compared to without tennis lessons, suggesting that beginner-level tennis lessons contribute physical activity of health benefits.

Association of Stability and Size of Unhealed Area With Failure After Internal Fixation for Osteochondritis Dissecans Lesions of the Knee: Radiological Evaluation Using Computed Tomography.

BACKGROUND: Open reduction and internal fixation (ORIF) has been widely performed because the osteochondral component of the osteochondritis dissecans (OCD) lesion is the most suitable for reconstructing the joint structure. PURPOSE: To evaluate radiological healing in terms of reconstructed bony structure after ORIF with bone graft by computed tomography (CT), to identify preoperative prognostic factors for failure, and to determine the cutoff value of radiological healing for risk of failure. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A retrospective cohort study of 42 patients (44 knees) who underwent internal fixation with bone graft for OCD lesions of the knee from 2004 to 2018 was conducted. All patients were evaluated 6 months postoperatively, and if not healed 6 months after surgery, they were evaluated by CT periodically thereafter. Radiological healing was judged according to the following 3 criteria: (1) reossification of the OCD lesion, (2) bony continuity between the OCD lesion and basal floor, and (3) reconstructed bony surface of the femoral condyle reconstructed to match the normal joint. Then, the percentage of the radiological healing area was calculated as the ratio of the healing length to the total lesion length. The nonhealing area was calculated by multiplying the sum of the total nonhealing length. Clinical failure was defined as any definitive reoperation for the same OCD lesion, such as fragment excision, or a cartilage restoration procedure. After 6 months, all eligible patients underwent arthroscopy to check for protrusion of the absorbable pin into the joint; the removal of an absorbable pin protruding into the joint was not considered a failure. RESULTS: Clinical failure was recorded for 4 cases (9.1%). The mean overall percentage of the radiological healing area of OCD 6 months after ORIF with bone graft was 79.5% ± 24.4%, and the mean overall nonhealing area at 6 months was 87.8 ± 107.9 mm2. The percentages of radiological healing area of stable (International Cartilage Regeneration & Joint Preservation Society OCD II) lesions and femoral condylar (lateral femoral condyle + medial femoral condyle) lesions were significantly lower than unstable lesions and femoral groove lesions, respectively (P = .01 and P = .03, respectively). On receiver operating characteristic curve analysis, the cutoff points for predicting a significantly increased risk of failure were 33.9% (sensitivity, 100%; specificity, 100%; area under the curve, 1) for the percentage of radiological healing area and 222.9 mm2 (sensitivity, 95%; specificity, 100%; area under the curve, 0.956) for the nonhealing area 6 months postoperatively. CONCLUSION: A stable lesion and a femoral condylar lesion were the predictors of poor radiological healing on CT images 6 months after ORIF with bone graft. The risk of failure was increased significantly in cases with only approximately one-third of the lesion healed or in cases with large nonhealing areas at 6 months postoperatively.

Anti-NF-κB peptide derived from nuclear acidic protein attenuates ovariectomy-induced osteoporosis in mice.

NF-κB is a transcription factor that is activated with aging. It plays a key role in the development of osteoporosis by promoting osteoclast differentiation and inhibiting osteoblast differentiation. In this study, we developed a small anti-NF-κB peptide called 6A-8R from a nuclear acidic protein (also known as macromolecular translocation inhibitor II, Zn2+-binding protein, or parathymosin) that inhibits transcriptional activity of NF-κB without altering its nuclear translocation and binding to DNA. Intraperitoneal injection of 6A-8R attenuated ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation, promoting osteoblast differentiation, and inhibiting sclerostin production by osteocytes in vivo with no apparent side effects. Conversely, in vitro, 6A-8R inhibited osteoclast differentiation by inhibiting NF-κB transcriptional activity, promoted osteoblast differentiation by promoting Smad1 phosphorylation, and inhibited sclerostin expression in osteocytes by inhibiting myocyte enhancer factors 2C and 2D. These findings suggest that 6A-8R has the potential to be an antiosteoporotic therapeutic agent with uncoupling properties.

Basic fibroblast growth factor promotes meniscus regeneration through the cultivation of synovial mesenchymal stem cells via the CXCL6-CXCR2 pathway.

OBJECTIVE: To investigate the efficacy of basic fibroblast growth factor (bFGF) in promoting meniscus regeneration by cultivating synovial mesenchymal stem cells (SMSCs) and to validate the underlying mechanisms. METHODS: Human SMSCs were collected from patients with osteoarthritis. Eight-week-old nude rats underwent hemi-meniscectomy, and SMSCs in pellet form, either with or without bFGF (1.0 × 106 cells per pellet), were implanted at the site of meniscus defects. Rats were divided into the control (no transplantation), FGF (-) (pellet without bFGF), and FGF (+) (pellet with bFGF) groups. Different examinations, including assessment of the regenerated meniscus area, histological scoring of the regenerated meniscus and cartilage, meniscus indentation test, and immunohistochemistry analysis, were performed at 4 and 8 weeks after surgery. RESULTS: Transplanted SMSCs adhered to the regenerative meniscus. Compared with the control group, the FGF (+) group had larger regenerated meniscus areas, superior histological scores of the meniscus and cartilage, and better meniscus mechanical properties. RNA sequencing of SMSCs revealed that the gene expression of chemokines that bind to CXCR2 was upregulated by bFGF. Furthermore, conditioned medium derived from SMSCs cultivated with bFGF exhibited enhanced cell migration, proliferation, and chondrogenic differentiation, which were specifically inhibited by CXCR2 or CXCL6 inhibitors. CONCLUSION: SMSCs cultured with bFGF promoted the expression of CXCL6. This mechanism may enhance cell migration, proliferation, and chondrogenic differentiation, thereby resulting in superior meniscus regeneration and cartilage preservation.

Changes in patellar height after anatomical ACL reconstruction with BTB autograft with a focus on patellar tendon removal volume.

BACKGROUND: Although anatomical anterior cruciate ligament reconstruction (ACLR) can provide satisfactory outcomes, little is known about how this procedure impacts patellar height. Since harvesting bone-patellar tendon-bone (BTB) autografts is a potential risk factor for decreased patellar height, we examined changes in patellar height after anatomical ACLR with BTB autograft with a focus on the size of the harvested graft. METHODS: Subjects were 84 patients (49 males, 35 females; mean age, 23 years) who underwent primary anatomical ACLR with central third BTB autograft. Preoperative to postoperative Caton-Deschamps index (CDI) ratio was calculated using lateral knee radiographs before and 6 months after surgery. The length and cross-sectional area (CSA) of the graft were measured intraoperatively, and the CSA of the contralateral patellar tendon was measured by ultrasound 6 months postoperatively. The difference in graft CSA relative to the contralateral tendon CSA, expressed as a percentage (gCSA:ctCSA percentage), was also calculated. RESULTS: Patellar height decreased slightly after surgery (preoperative CDI: 0.856 ± 0.113; postoperative CDI: 0.841 ± 0.113), with a mean difference between preoperative and postoperative CDIs of -0.015 (range: -0.293 to 0.101). Although the CDI of male subjects significantly decreased after surgery (preoperative: 0.852 ± 0.117; postoperative: 0.827 ± 0.115), no significant changes were noted in female subjects (preoperative: 0.862 ± 0.108; postoperative: 0.861 ± 0.108). Graft length and CSA did not significantly impact the CDI ratio (r = -0.138 and r = -0.038, respectively). Moreover, no significant relationship was observed between the gCSA:ctCSA percentage and CDI ratio (r = 0.118). CONCLUSIONS: Although patellar height slightly, but significantly, decreased at 6 months after anatomical ACLR with BTB autograft, it was not affected by the length and CSA of harvested grafts. The decrease in postoperative patellar height was observed only in male subjects, suggesting the potential importance of sex differences in soft tissue healing during the postoperative period.

Ultrasound-Guided Needle Aspiration of Subperiosteal Abscess in a Child with Acute Osteomyelitis of the Fibula: A Case Report.

CASE: An 8-year-old boy with left lateral ankle pain was diagnosed with acute osteomyelitis after methicillin-susceptible Staphylococcus aureus was identified in a subperiosteal abscess in the distal fibula that had been aspirated using an ultrasound-guided needle. Symptoms improved after 2 weeks of intravenous and 4 weeks of oral antimicrobial therapy; no additional treatment was required. No growth retardation or sequelae were observed at the 6-year follow-up. CONCLUSIONS: In acute osteomyelitis, the identification of subperiosteal abscess is key for early diagnosis. Ultrasound evaluation of the distal fibula should also be considered in the diagnosis of lateral ankle pain in children.

Articular surface integrity assessed by ultrasound is associated with biological characteristics of articular cartilage in early-stage degeneration.

Early diagnosis of articular cartilage damage and repeated evaluation of treatment efficacy are essential for osteoarthritis treatment. In this study, we established a simple ultrasound grading system for early degenerative articular cartilage and investigated its relationship with cartilage biological characteristics. The ultrasound grading system were based on surface integrity (S1a: continuous high-echo lines, S1b: discontinuous or weak high-echo lines, S2: surface irregular) and cartilage echogenicity (E1: with > 50%, E2: < 50% hypoechoic area of total cartilage layer) and verified by surface roughness (Ra; µm) and histological staining. Ra was lower in S1 than in S2, and the percentage of hypoechoic and safranin O-stained areas was positively correlated. Then we examined its relationship with histopathological evaluation (OARSI grade), gene expression, and protein production in responded to pro-inflammatory cytokine (IL-1ß) stimulation. OARSI grades were different among S grades. The superficial layer of S1 had higher expression of Collagen10, aggrecan, Sox9, and lower expression of Collagen1 and BMP2 than that of S2. S1 responded more pronouncedly to IL-1ß in IL-6, IL-8, and CCL2 production than S2. There was no difference among the E-grades. Taken together, our findings indicate that ultrasound assessment using surface integrity can reflect the biological characteristics of early degenerative articular cartilage.

Meniscus surface texture is associated with degenerative changes in biological and biomechanical properties.

Meniscal degeneration is defined by semi-quantitative assessment of multiple histological findings and has been implicated in biomechanical dysfunction, yet little is known about its relationship with biological properties. This paper aimed to quantitatively evaluate degenerative findings in human meniscus to examine their relationship with gene expression and biomechanical properties, and to extract histological findings that reflect biological properties like gene expression and cytokine secretion. This study included lateral menisci of 29 patients who underwent total knee arthroplasty. The menisci were divided into six samples. For each sample, Pauli's histological evaluation and corresponding quantitative assessment (surface roughness, DNA content, collagen orientation, and GAG content) were performed, with surface roughness showing the highest correlation with the histological evaluation in a single correlation analysis (r = 0.66, p < 0.0001) and multivariate analysis (p < 0.0001). Furthermore, surface roughness was associated with gene expression related to meniscal degeneration and with tangent modulus which decreases with increasing degeneration (r = - 0.49, p = 0.0002). When meniscal tissue was classified by surface integrity, inflammatory cytokine secretion tended to be higher in severe degenerated menisci. These results suggest that the evaluation of meniscal surface texture could predict the degree of degeneration and inflammatory cytokine secretion.

The Wound Dressing Influenced Effectiveness of Cryotherapy After Anterior Cruciate Ligament Reconstruction: Case-Control Study Comparing Gauze Versus Film Dressing.

Purpose: To compare the clinical effectiveness of cryotherapy after anterior cruciate ligament reconstruction using 2 different wound dressings, conventional postoperative gauze dressings and polyurethane semipermeable transparent film dressings. Methods: In total, 60 patients who had undergone arthroscopic anterior cruciate ligament reconstruction with an autogenous patellar tendon were assigned to 2 groups. The surgical wound was covered with 5 sheets of gauze with an elastic bandage (control group) in 30 patients and film dressing was used (film group) in the remaining 30 patients. Silicone drainage catheters were inserted at the intercondylar notch, beside the distal outlet of the tibial tunnel for 2 days. After 1 hour of cooling using the device, the knee was chilled with an ice bag every 2 hours until the next morning. The severity of pain was evaluated by the number of times an analgesic, 50 mg of diclofenac sodium suppositories, had to be administered in the 24 hours after surgery. The amount of drainage during the following 2 days, the range of motion at 21 days, the change of hemoglobin concentration at 1 and 7 days, and C-reactive protein (CRP) at 1 and 7 days were examined. Results: The number of patients who used an analgesic was 18 in the control group and 7 in the film group (P = .003). The amount of drainage was 165.2 ± 72.9 mL in the control group and 289.7 ± 77.6 mL in the film group (P < .001). The postoperative CRP value was 0.77 ± 0.65 mg/dL at 1 day in the control group and 0.39 ± 0.42 mg/dL in the film group (P = .009). No statistical difference was seen for hemoglobin concentration at 1 or 7 days, CRP at 7 days or range of motion at 21 days. Conclusions: In this study, we found that film dressing enhanced the effect of cryotherapy with respect to pain control, wound drainage, and inflammation immediately after surgery compared with traditional gauze dressing with elastic wrap. Level of Evidence: III, case-control study.

Acute effects of whole body vibration exercise on post-load glucose metabolism in healthy men: a pilot randomized crossover trial.

PURPOSE: Exercise on a whole body vibration (WBV) platform, namely WBV exercise (WBVE), has long-term beneficial effects on glucose metabolism, similarly to conventional moderate-intensity exercise. Conventional moderate-intensity exercise reduces post-load plasma glucose levels at the acute phase. This study aimed to reveal acute effects of WBVE on post-load glucose metabolism. METHODS: This randomized crossover trial enrolled 18 healthy men. They completed the following three interventions in a random order: (1) a 2-hour 75-g oral glucose tolerance test (OGTT) without WBVE (OGTT-alone), (2) 20-minute WBVE before an OGTT (WBVE → OGTT), and (3) 20-minute WBVE during an OGTT (OGTT → WBVE). Post-load glucose metabolism in the WBVE → OGTT and OGTT → WBVE interventions were compared with that in the OGTT-alone intervention. RESULTS: Plasma glucose levels in the WBVE → OGTT and OGTT → WBVE interventions were not significantly different from those in the OGTT-alone intervention at any time point except 15 min, wherein the WBVE → OGTT intervention had higher glucose levels (111 [interquartile range, 102-122] mg/dL vs 122 [111-134] mg/dL, P = 0.026). Higher plasma glucagon levels were observed at 0 min in the WBVE → OGTT intervention and at 60 min in the OGTT → WBVE intervention (P = 0.010 and 0.015). Cortisol, Growth hormone, and adrenaline levels were significantly increased after WBVE, whereas noradrenaline levels were not. Serum insulin levels in the WBVE → OGTT intervention were significantly higher than those in the OGTT-alone intervention at 0 min (P = 0.008). CONCLUSIONS: WBVE did not decrease post-load plasma glucose levels at the acute phase. Acute effects of WBVE on post-load glucose metabolism would not be identical to those of conventional exercise. The unique trial number and the name of the registry: UMIN000036520, www.umin.ac.jp , date of registration, June 12, 2019.

Measurement of various intensities of physical activities and categorization of "Locomotive" and "Household" activities provide a subject-specific detailed assessment.

This study aimed to compare the physical activity (PA) measured by a wearable sensor device (WSD) and the step count measurement, and to investigate the association between PAs and lifestyle. Data of 301 participants were collected from March 2019 to March 2021. Step counts, sedentary behavior, performance time of light/moderate/vigorous PA, METs × hour of "Locomotive" and "Household" categorized activities, and energy expenditure (EE) were measured by the WSD, respectively. Furthermore, the participants were classified into student, standing worker, and sitting worker groups. Data were analyzed using the Steel-Dwass and Pearson correlation coefficient tests. The correlation between the performance time of each PA and step count was weak, except for moderate PA. "Household" EE and step count also had a weak correlation. In the comparison of lifestyle, there was a significant difference in the mean performance time of each type of PA between the groups. Additionally, the standing worker and sitting worker groups had a significant difference in METs × hour of "Household" activities, indicating that the difference between the occupations is reflected in "Household" activities. The WSD measurement can be used to evaluate detailed individual PA, whereas the step count measurement showed weakness in the PA estimation.

Predicting 10-2 Visual Field From Optical Coherence Tomography in Glaucoma Using Deep Learning Corrected With 24-2/30-2 Visual Field.

Purpose: To investigate whether a correction based on a Humphrey field analyzer (HFA) 24-2/30-2 visual field (VF) can improve the prediction performance of a deep learning model to predict the HFA 10-2 VF test from macular optical coherence tomography (OCT) measurements. Methods: This is a multicenter, cross-sectional study. The training dataset comprised 493 eyes of 285 subjects (407, open-angle glaucoma [OAG]; 86, normative) who underwent HFA 10-2 testing and macular OCT. The independent testing dataset comprised 104 OAG eyes of 82 subjects who had undergone HFA 10-2 test, HFA 24-2/30-2 test, and macular OCT. A convolutional neural network (CNN) DL model was trained to predict threshold sensitivity (TH) values in HFA 10-2 from retinal thickness measured by macular OCT. The predicted TH values was modified by pattern-based regularization (PBR) and corrected with HFA 24-2/30-2. Absolute error (AE) of mean TH values and mean absolute error (MAE) of TH values were compared between the CNN-PBR alone model and the CNN-PBR corrected with HFA 24-2/30-2. Results: AE of mean TH values was lower in the CNN-PBR with HFA 24-2/30-2 correction than in the CNN-PBR alone (1.9dB vs. 2.6dB; P = 0.006). MAE of TH values was lower in the CNN-PBR with correction compared to the CNN-PBR alone (4.2dB vs. 5.3 dB; P < 0.001). The inferior temporal quadrant showed lower prediction errors compared with other quadrants. Conclusions: The performance of a DL model to predict 10-2 VF from macular OCT was improved by the correction with HFA 24-2/30-2. Translational Relevance: This model can reduce the burden of additional HFA 10-2 by making the best use of routinely performed HFA 24-2/30-2 and macular OCT.

Chronic musculoskeletal pain, catastrophizing, and physical function in adult women were improved after 3-month aerobic-resistance circuit training.

Although exercise is beneficial for chronic musculoskeletal pain (CMP), the optimal type and amount of exercise are unclear. This study aimed to determine the impact of circuit training that combines aerobic and resistance exercises on adult women with CMP. A total of 139 women with CMP underwent circuit training for 3 months and were asked to complete the following questionnaires at baseline and 3 months later: Numeric Rating Scale (NRS), Pain Catastrophizing Scale (PCS), Roland-Morris Disability Questionnaire (RDQ), Shoulder36, and Knee injury and Osteoarthritis Outcome Score (KOOS). Significant improvements were observed in NRS, PCS, RDQ, and KOOS activities of daily living (ADL) scores after the intervention relative to baseline (p < 0.0001, p = 0.0013, 0.0004, and 0.0295, respectively), whereas shoulder function did not improve. When considering the impact of exercise frequency, NRS scores improved regardless of exercise frequency. Furthermore, PCS, RDQ, and KOOS scores improved in participants who exercised at least twice a week (24 sessions over the course of 3 months). In conclusion, CMP, pain catastrophizing, and physical function in adult female fitness club participants with CMP of NRS 4 or higher improved after 3 months of aerobic-resistance circuit training.

Effects of iguratimod on glucocorticoid-induced disorder of bone metabolism in vitro.

INTRODUCTION: Glucocorticoids are widely used to treat various diseases including rheumatoid arthritis (RA); however, one of the most frequent and severe adverse effects is glucocorticoid-induced osteoporosis (GIOP). Iguratimod (IGU) is a novel conventional synthetic disease-modifying anti-rheumatic drug developed in Japan. The aim of this study is to investigate the effects of IGU on glucocorticoid-induced disorder of bone metabolism in vitro. MATERIALS AND METHODS: In osteoclastogenesis of mouse bone marrow-derived cells, tartrate-resistant acid phosphatase staining, resorption pit assay, western blotting, real-time polymerase chain reaction (PCR), and mRNA sequencing were performed. In osteoblastogenesis of MC3T3-E1 cells, alkaline phosphatase (ALP) staining and activity, alizarin red staining, and mRNA sequencing were performed, and real-time PCR and western blotting were conducted in MC3T3-E1 cells and murine osteocyte-like cell line MLO-Y4 cells. RESULTS: IGU significantly suppressed a dexamethasone-induced increase in osteoclasts, differentiation, and bone resorption activity by inhibition of the receptor activator of the nuclear factor kappa-B (RANK)/tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)/nuclear factor kappa-B (NFκB)-p52 pathway. In MC3T3-E1 cells, IGU significantly upregulated dexamethasone-induced downregulation of ALP activity, bone mineralization, and osteoblast-related gene and protein expression. In MLO-Y4 cells, IGU significantly upregulated dexamethasone-induced downregulation of the gene expression of ALP and osteocalcin, and also downregulated receptor activator of NFκB ligand (RANKL)/osteoprotegerin gene expression ratio without dexamethasone. CONCLUSION: These results suggest that IGU may improve glucocorticoid-induced disorder of bone metabolism and may exhibit positive effects against GIOP associated with RA.

Predicting the central 10 degrees visual field in glaucoma by applying a deep learning algorithm to optical coherence tomography images.

We aimed to develop a model to predict visual field (VF) in the central 10 degrees in patients with glaucoma, by training a convolutional neural network (CNN) with optical coherence tomography (OCT) images and adjusting the values with Humphrey Field Analyzer (HFA) 24-2 test. The training dataset included 558 eyes from 312 glaucoma patients and 90 eyes from 46 normal subjects. The testing dataset included 105 eyes from 72 glaucoma patients. All eyes were analyzed by the HFA 10-2 test and OCT; eyes in the testing dataset were additionally analyzed by the HFA 24-2 test. During CNN model training, the total deviation (TD) values of the HFA 10-2 test point were predicted from the combined OCT-measured macular retinal layers' thicknesses. Then, the predicted TD values were corrected using the TD values of the innermost four points from the HFA 24-2 test. Mean absolute error derived from the CNN models ranged between 9.4 and 9.5 B. These values reduced to 5.5 dB on average, when the data were corrected using the HFA 24-2 test. In conclusion, HFA 10-2 test results can be predicted with a OCT images using a trained CNN model with adjustment using HFA 24-2 test.

Integrin α2ß1 plays an important role in the interaction between human articular cartilage-derived chondrocytes and atelocollagen gel.

Although atelocollagen gel is used as a scaffold for culturing human articular cartilage-derived chondrocytes, little is known about cell-gel interactions. In this study, we investigated the mechanism via which atelocollagen gel affects human articular cartilage-derived chondrocytes. Two types of three-dimensional cultures of human articular cartilage-derived chondrocytes (i.e., with and without atelocollagen gel) were compared. While the amount of atelocollagen gel in culture gradually decreased with time, it promoted the expression of matrix metalloproteinases (MMPs) during the early stages of culture. Genome-wide differential gene expression analysis revealed that cell membrane- and extracellular matrix-related genes were highly ranked among up- and down-regulated groups in cells cultured in the presence of atelocollagen gel. Among the integrin family of genes, the expression of integrin subunit alpha 2 and integrin subunit alpha 10 was significantly increased in the presence of atelocollagen gel. Blocking α2ß1 integrin with the specific inhibitor BTT 3033 had a significant effect on cell proliferation, MMP expression, and cell shape, as well as on the response to mechanical stimulation. Taken together, our findings indicate that the α2ß1 integrin pathway plays an important role in the interaction of atelocollagen gel with human articular cartilage-derived chondrocytes and may be a potential therapeutic target for articular cartilage disorders.

A Joint Multitask Learning Model for Cross-sectional and Longitudinal Predictions of Visual Field Using OCT.

Purpose: We constructed a multitask learning model (latent space linear regression and deep learning [LSLR-DL]) in which the 2 tasks of cross-sectional predictions (using OCT) of visual field (VF; central 10°) and longitudinal progression predictions of VF (30°) were performed jointly via sharing the deep learning (DL) component such that information from both tasks was used in an auxiliary manner (The Association for Computing Machinery's Special Interest Group on Knowledge Discovery and Data Mining [SIGKDD] 2021). The purpose of the current study was to investigate the prediction accuracy preparing an independent validation dataset. Design: Cohort study. Participants: Cross-sectional training and testing data sets included the VF (Humphrey Field Analyzer [HFA] 10-2 test) and an OCT measurement (obtained within 6 months) from 591 eyes of 351 healthy people or patients with open-angle glaucoma (OAG) and from 155 eyes of 131 patients with OAG, respectively. Longitudinal training and testing data sets included 7984 VF results (HFA 24-2 test) from 998 eyes of 592 patients with OAG and 1184 VF results (HFA 24-2 test) from 148 eyes of 84 patients with OAG, respectively. Each eye had 8 VF test results (HFA 24-2 test). The OCT sequences within the observation period were used. Methods: Root mean square error (RMSE) was used to evaluate the accuracy of LSLR-DL for the cross-sectional prediction of VF (HFA 10-2 test). For the longitudinal prediction, the final (eighth) VF test (HFA 24-2 test) was predicted using a shorter VF series and relevant OCT images, and the RMSE was calculated. For comparison, RMSE values were calculated by applying the DL component (cross-sectional prediction) and the ordinary pointwise linear regression (longitudinal prediction). Main Outcome Measures: Root mean square error in the cross-sectional and longitudinal predictions. Results: Using LSLR-DL, the mean RMSE in the cross-sectional prediction was 6.4 dB and was between 4.4 dB (VF tests 1 and 2) and 3.7 dB (VF tests 1-7) in the longitudinal prediction, indicating that LSLR-DL significantly outperformed other methods. Conclusions: The results of this study indicate that LSLR-DL is useful for both the cross-sectional prediction of VF (HFA 10-2 test) and the longitudinal progression prediction of VF (HFA 24-2 test).