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Abstract Background Interleukin (IL)-17 is an important factor in rheumatoid arthritis (RA) pathogenesis. MicroRNA (miRNA)s are a family of non coding RNAs and associated with human diseases including RA. The purpose of this study is to identify the miRNAs in the differentiation of IL-17 producing cells, and analyze their expression pattern in the peripheral blood mononuclear cells (PBMC) and synovium from RA patients. Methods IL-17 producing cells were expanded from CD4+T cell. MiRNA microarray was performed to identify the miRNAs in the differentiation of IL-17 producing cells. Quantitative polymerase chain reaction was performed to examine the expression patterns of the identified miRNAs in the PBMC and synovium from RA and osteoarthritis (OA) patients. Double staining combining in situ hybridization and immunohistochemistry of IL-17 was performed to analyze the expression pattern of identified miRNA in the synovium. Results Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up regulated in the IL-17 producing T cells. The expression of miR-146a and IL-17 was higher than in PBMC in the patients with low score of Larsen grade and short disease duration. MiR-146a intensely expressed in RA synovium in comparison to OA. MiR-146a expressed intensely in the synovium with hyperplasia and high expression of IL-17 from the patients with high disease activity. Double staining revealed that miR-146a expressed in IL-17 expressing cells. Conclusion These results indicated that miR-146a was associated with IL-17 expression in the PBMC and synovium in RA patients. There is the possibility that miR-146a participates in the IL-17 expression.

Background: Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ failure, which is triggered by immunotherapy or certain infections. Immune checkpoint inhibitors rarely cause immune-related adverse event- cytokine release syndrome (irAE-CRS). This article presents a case report of irAE-CRS triggered by coronavirus disease 2019 (COVID-19)., Case Presentation: A 60-year-old man with type 2 diabetes received nivolumab treatment for esophagogastric junction carcinoma and experienced two immune-related adverse events: hypothyroidism and skin disorder. Eleven days before his visit to our hospital, he had a fever and was diagnosed with COVID-19. Five days before his visit, he developed a fever again, along with general malaise, water soluble diarrhea, and myalgia of the extremities. On admission, the patient was in a state of multiple organ failure, and although the source of infection was unknown, a tentative diagnosis of septic shock was made. The patient's condition was unstable despite systemic management with antimicrobial agents, high-dose vasopressors, and intravenous fluids. We suspected CRS due to irAE (irAE-CRS) based on his history of nivolumab use. Steroid pulse therapy (methylprednisolone 1 g/day) was started, and the patient temporarily recovered. However, his respiratory condition worsened; consequently, he was placed on a ventilator and tocilizumab was added to the treatment. His muscle strength recovered to the point where he could live at home, and was subsequently discharged., Conclusion: In patients previously treated with immune checkpoint inhibitors, irAE-CRS should be considered as a differential diagnosis when multiple organ damage is observed in addition to inflammatory findings. It is recommended to start treatment with steroids; if the disease is refractory, other immunosuppressive therapies such as tocilizumab should be introduced as early as possible., (© 2024. The Author(s).)

Purpose: The aims of the present controlled clinical study were to (1) compare patella laxity determined in the outpatient clinic with that in anaesthetized patients and (2) evaluate patella laxity before and after lateral release., Method: The study evaluated data on 33 knees from 33 patients (average age 19.7 years) between 2007 and 2011. All patients were diagnosed with recurrent dislocation of the patella. Patellar stability was evaluated in each patient thrice: patellas were first imaged in the outpatient clinic prior to surgery at 45° knee flexion with 20 N stress from the medial to lateral side and from the lateral to medial side; then, at the time of surgery, patella stress images were obtained in the same manner before and after the lateral release procedure. Radiological assessments were performed using the medial stress shift ratio (MSSR) and lateral stress shift ratio (LSSR)., Results: There were no significant differences in the LSSR and MSSR before surgery (outpatient data) and in anaesthetized patients before the lateral release procedure. Furthermore, there was no significant difference in MSSR at the time of surgery before and after the lateral release procedure. However, LSSR increased significantly after the lateral release procedure., Conclusion: The results of the present study suggest that quantitative patella stress radiography in the outpatient clinic is useful when it comes to investigating laxity of the patella, and that lateral release significantly increases lateral, but not medial, laxity in patients with recurrent patellar dislocation., Level of Evidence: IV.

Purpose: To identify the relationship between knee flexion angle and femoral tunnel length, as well as the exit points of guidewires, when using a far anteromedial portal technique for posterolateral femoral tunnel drilling in double-bundle anterior cruciate ligament reconstruction., Methods: Using the far anteromedial portal technique in 8 cadaveric knees, femoral tunnel drilling for the posterolateral bundle was performed at 3 knee flexion angles: 90°, 110° and 130°. We measured the femoral tunnel length and the distances from each guidewire to the closest relevant structures., Results: The mean tunnel length at 90° knee flexion (25.8 ± 1.8 mm) was significantly shorter than the length at 110° and 130° knee flexion (32.1 ± 2.6 and 33.1 ± 2.5 mm, respectively). The average distance between the exit point of the guidewire and the posterior articular cartilage of the lateral femoral condyle was the shortest at 90° knee flexion (3.3 ± 2.2 mm). The distance between the guidewire and the centre of the origin of the lateral collateral ligament was the shortest at 130° knee flexion (8.0 ± 1.8 mm). The guidewires penetrated the origin of the lateral gastrocnemius tendon in 2 cases at 110° knee flexion and in 1 case each at 90° and 130° knee flexion., Conclusions: When using the far anteromedial portal technique, more than 110° knee flexion is desirable to achieve ideal femoral tunnel length and avoid articular cartilage injury. In addition, the risk of damage to the origin of the lateral collateral ligament increases when the knee flexion angle increases to 130°. A knee flexion angle between 110° and 120° was recommended when using the far anteromedial portal technique.

Background: It is known from clinical and experimental studies that the healing potential of the anterior cruciate ligament (ACL) is extremely poor and that early phases of ligament healing require an augmented blood supply. MicroRNA (miRNA) is a type of small, noncoding RNA that negatively regulates gene expression, and miRNA (miR)-210 is reported to be crucial for cell response to hypoxia, vascular endothelial growth factor (VEGF)-driven endothelial cell migration, and formation of capillary-like structures., Purpose: The purpose of this study was to examine the effect of intra-articular injection of miRNA miR-210 on acceleration of ACL healing., Study Design: Controlled laboratory study., Methods: Two experiments were performed in this study. The ACLs of 12-week-old male LEW/CrlCrlj rats were partially transected. First, the temporal expression change of miR-210 after ACL injury was analyzed using real-time polymerase chain reaction (PCR) on day zero, and 1, 2, and 4 weeks after injury (n = 5 at each time point). Next, intra-articular injection of double-stranded (ds) miR-210 with atelocollagen was performed soon after injury. The control group was injected with control small interfering RNA (siRNA). Four weeks after injection, biomechanical and histological assessments of samples stained with H&E as well as Masson trichrome, and immunohistochemistry for VEGF, fibroblast growth factor 2 (FGF2), isolectin B4, and collagen type I, were performed. Real-time PCR analysis was also performed for quantitative evaluation of miR-210, VEGF-A, and collagen type I., Results: Real-time PCR analysis revealed that miR-210 expression was decreased soon after injury but gradually increased thereafter. Histological analysis confirmed that the transected area was covered with healing tissue in the miR-210 group but remained devoid of any tissue in the control group 4 weeks after injury. Biomechanical analysis confirmed the improvement of biomechanical properties in the miR-210 group; the ultimate failure loads 4 weeks after injection were 30.5 ± 3.1 N in the miR-210 group and 22.8 ± 3.1 N in the control group (P < .05). Real-time PCR analysis showed that endogenous miR-210, VEGF, and collagen type I were highly expressed compared with controls, and immunohistochemistry for VEGF, FGF2, isolectin B4, and collagen type I showed that VEGF and FGF2 were highly upregulated, and there were abundant blood vessels and fibrotic deposition in the miR-210 group., Conclusion: Injection of ds miR-210 was effective in promoting the healing of partially torn ACLs through enhancement of angiogenesis via upregulation of VEGF and FGF2., Clinical Relevance: It might represent a potential therapeutic approach for treatment of ACL injury.

MicroRNAs (miRNAs) are a family of non-coding RNAs that play an important role in human diseases, including osteoarthritis (OA). The objective of this study was to investigate the expression patterns of miRNAs in the peripheral blood mononuclear cells (PBMCs) of OA patients. PBMCs were isolated from 36 patients with OA, 6 RA patients, and 36 healthy controls. The expression patterns of miR-146a, 155, 181a, and 223 in PBMCs were analyzed using quantitative reverse transcription-polymerase chain reaction (qPCR). We investigated the expression patterns of the miRNAs in OA progression, and their relationships with the parameters of age, body mass index (BMI), the femorotibial angle (FTA), and serum keratan sulfate (KS). The relative expression levels of miR-146a, 155, 181a, and 223 in the OA patients were significantly higher than those found in healthy controls. In the early stages of OA, miR-146a and 223 expressions were significantly higher than they were at later stages. There was a significant correlation between the expression of miR-223 and KS. This study demonstrated that high expression levels of miR-146a, 155, 181a, and 223 in the PBMCs of OA patients might be related to the pathogenesis of OA. This evidence could lead to the elucidation of the mechanism underlying OA pathogenesis and hence to a novel therapeutic strategy for OA.

Background: There are various indirect signs of a discoid lateral meniscus in radiographs, for example lateral joint space widening, hypoplasia of the LFC, etc. There has, however, been no previous report of the characteristic shape of the lateral femoral condyle (LFC) in patients with osteochondritis dissecans (OCD) accompanied by a discoid lateral meniscus. The purpose of this study was to evaluate the characteristic shape of the LFC in patients with OCD accompanied by a discoid lateral meniscus, and sex differences associated with the shape of the LFC in those patients., Methods: This study included 29 males (31 knees) and 29 females (32 knees) of average age 17.7 years. There were 15 knees in 15 patients that were accompanied by OCD of the LFC (9 males, 9 knees; 6 females, 6 knees; average age 14.9 years; OCD group). There were 48 knees in 43 patients that were not accompanied by OCD of the LFC (20 males, 22 knees; 23 females, 26 knees; average age 17.6 years; non-OCD group). Standardized Rosenberg view radiographs of the knee were obtained for all patients. We evaluated the shape of LFC using the Rosenberg view and measured the condylar prominence ratio of the medial and lateral condyles adjacent to the intercondylar notch, in accordance with Ha's procedure., Results: The OCD group had a significantly larger prominence ratio than the non-OCD group. The prominence ratio for males was significantly larger than that for females., Conclusion: We clearly demonstrated that the prominence ratio in the OCD group was significantly larger than that in the non-OCD group, indicating that the shape of the LFC and OCD in the LFC may be associated with the development of these lesions.

Purpose: The objective of this study was to determine the safe penetration depth of the FasT-Fix meniscal suture repair system during all-inside repair of the posterior part of the lateral meniscus., Methods: Thirty-one knees from 17 embalmed and formalin-fixed cadavers (11 women, 6 men) were used. In each case, the circumference of the cadaver knee was measured before dissection. After dissection, 41 Fast-Fix meniscal repair devices were used in different predetermined penetration depths ranging from 8 to 16 mm. In this study, non-involvement of the popliteal neurovascular bundle, common peroneal nerve or the inferior lateral genicular vessels by either needle penetration or affixment by the suture bar anchors was considered to be a safe trial., Results: Out of the 41 FasT-Fix devices used in this study, only one device bent during introduction and was excluded from the study. For the remaining 40 trials, 27 of them were considered safe, while 13 trials were considered unsafe. The ratio of the average penetration depth to the average circumference of the cadaver knee was found to be >0.05 for the unsafe penetrations, and this was statistically significant P < 0.05. Additionally, for the first point, which is more central, there was a trend for the straight needles through the direct lateral approach to be less safe, and this was found to be statistically significant P < 0.05., Conclusions: Correlating the needle-penetration depth to the measured circumference of the cadaver knee may be an important clinical predictor of safety whereby a ratio of less than 0.05 might be useful as a guide to determine the safe penetration depth of the FasT-Fix suture repair needle during repair of the posterior horn lateral meniscus. Also, it is better to avoid using straight needles through the direct lateral approach during repair of the more central portion of the posterior horn lateral meniscus.

Objective: MicroRNA, a class of noncoding RNA, play a role in human diseases. MicroRNA-146a (miR-146a) is a negative regulator of immune and inflammatory responses, and is strongly expressed in rheumatoid arthritis (RA) synovium and peripheral blood mononuclear cells (PBMCs). This study was undertaken to examine whether miR-146a expression inhibits osteoclastogenesis, and whether administration of miR-146a prevents joint destruction in mice with collagen-induced arthritis (CIA)., Methods: PBMCs from healthy volunteers were isolated and seeded in culture plates. The following day, double-stranded miR-146a was transfected and cultured in the presence of macrophage colony-stimulating factor and either tumor necrosis factor α or RANKL. After 3 weeks, tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells were counted. Three days after miR-146a culture, the expression of c-Jun, nuclear factor of activated T cells c1 (NF-ATc1), PU.1, and TRAP was evaluated by quantitative reverse transcriptase-polymerase chain reaction. After the onset of distinct arthritis in mice with CIA, double-stranded miR-146a or nonspecific double-stranded RNA was administered twice by intravenous injection. Radiographic and histologic examinations were performed at 4 weeks., Results: The number of TRAP-positive multinucleated cells in human PBMCs was significantly reduced by miR-146a in a dose-dependent manner. The expression of c-Jun, NF-ATc1, PU.1, and TRAP in PBMCs was significantly down-regulated by miR-146a. Administration of miR-146a prevented joint destruction in mice with CIA, although it did not completely ameliorate inflammation., Conclusion: Our findings indicate that expression of miR-146a inhibits osteoclastogenesis and that administration of double-stranded miR-146a prevents joint destruction in arthritic mice. Administration of miR-146a has potential as a novel therapeutic target for bone destruction in RA., (Copyright © 2011 by the American College of Rheumatology.)

In the present study, we studied the effect of valerian extract preparation (BIM) containing valerian extract, golden root (Rhodiola rosea L.) extract and L-theanine (gamma-glutamylethylamide) on the sleep-wake cycle using sleep-disturbed model rats in comparison with that of valerian extract. A significant shortening in sleep latency was observed with valerian extract and the BIM at a dose of 1000 mg/kg. On the other hand, valerian extract and the BIM caused no significant effects on total times of wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep. Valerian extract and the BIM at a dose of 1000 mg/kg also had no significant effect on delta activity. In conclusion, it became clear that the BIM could be useful as a herbal medicine having a sleep-inducing effect without causing an alteration of the sleep-wakefulness cycle.

Mice were fed a diet supplemented with palm oil (control diet), n-3 polyunsaturated fatty acids (PUFA)-, or n-9 PUFA-rich oil for 3 weeks. The n-3 PUFA-rich diet suppressed the generation of both leukotrienes (LT) and prostaglandins (PG), but the n-9 PUFA-rich diet did LT but not PG generation during acute inflammation. Leukocyte accumulation during acute inflammation was not different in the n-3 or n-9 PUFA-rich diet group as compared with the control group. The n-3 PUFA-rich diet but not the n-9 PUFA-rich diet suppressed Freund's adjuvant-induced granuloma formation. The n-9 PUFA-rich diet significantly attenuated galactosamine/lipopolysaccharide-induced liver injury more effectively than the n-3 PUFA-rich diet as compared with the control diet. The present study revealed the differential modification of experimentally induced inflammation in mice by dietary n-3 PUFA and n-9 PUFA, which may be due to their different effects on 5-lipoxygenease and cyclooxygenase metabolism of arachidonic acid during inflammatory processes.