Improvement in Clinical and Radiographic Outcomes After Isolated Realignment Surgery in Patients With Large Cystic Osteochondral Lesion of the Talar Shoulder and Concurrent Malalignment.

Background: Malalignment has been suggested as a predisposing factor for the development of osteochondral lesions of the talus (OLTs). Purpose: To evaluate the clinical and radiographic outcomes of realignment surgery in patients with a large cystic OLT of the talar shoulder and concurrent malalignment of the foot and ankle. Study Design: Case series; Level of evidence, 4. Methods: The authors reviewed consecutive patients with large cystic OLTs (diameter, >10 mm) of the talar shoulder and concurrent malalignment of the foot and ankle who underwent realignment surgery between September 2013 and April 2021. The type of realignment procedure was determined based on patient symptoms and findings on plain radiographs and weightbearing computed tomography. Clinical improvement was assessed using pre- and postoperative Foot Function Index (FFI) scores and the visual analog scale (VAS) for pain. The OLT location was categorized according to Raikin zone, and the OLT area and volume were measured and compared pre- and postoperatively. The comparative analysis was performed using the Wilcoxon signed-rank test. Results: In total, 27 ankles in 27 patients (mean age, 34.4 ± 11.9 years) were included in the analysis. There were 25 patients with a medial lesion (zone 4 [n = 19], zone 7 [n = 5], and zone 1 [n = 1]), and 2 patients with a lateral lesion (zone 6). Despite OLT location, patients' symptoms varied; 15 (55.6%) patients reported both medial- and lateral-sided pain, 10 (37%) reported lateral-sided pain, and 2 (7%) reported medial-sided pain. Supramalleolar osteotomy was performed in 18 patients, while foot and hindfoot correction without supramalleolar osteotomy was performed in 9 patients. Postoperatively, both the median FFI (from 44.4 [interquartile range (IQR), 35.7-52.2] to 9.1 [IQR, 5.2-13.9]) and median VAS pain score (from 6 [IQR, 5-6] to 1 [IQR, 1-2]) improved significantly (P < .0001 for both), and the median lesion size (from 25.8 mm2 [IQR, 19.3-45.2 mm2] to 13.8 mm2 [IQR, 6.8-26.5 mm2]) and median volume (from 2226.8 mm3 [IQR, 1311-3104 mm3] to 1326.5 mm3 [IQR, 714-2100 mm3]) decreased significantly (P < .0001 for both). During the mean follow-up of 4.1 ± 2.1 years, no subsequent surgery for OLT was necessary. Conclusion: The results suggest that realignment procedures can improve the symptoms and radiographic profile of OLTs in patients with large cystic OLTs of the talar shoulder and malalignment of the foot and ankle.

Pharmacological potential of ginseng and ginsenosides in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by hepatic fat accumulation, while nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD characterized by hepatic inflammation, fibrosis, and liver injury, resulting in liver cirrhosis and hepatocellular carcinoma (HCC). Given the evidence that ginseng and its major bioactive components, ginsenosides, have potent anti-adipogenic, anti-inflammatory, anti-oxidative, and anti-fibrogenic effects, the pharmacological effect of ginseng and ginsenosides on NAFLD and NASH is noteworthy. Furthermore, numerous studies have successfully demonstrated the protective effect of ginseng on these diseases, as well as the underlying mechanisms in animal disease models and cells, such as hepatocytes and macrophages. This review discusses recent studies that explore the pharmacological roles of ginseng and ginsenosides in NAFLD and NASH and highlights their potential as agents to prevent and treat NAFLD, NASH, and liver diseases caused by hepatic steatosis and inflammation.

Maclurin inhibits caspase-11 non-canonical inflammasome in macrophages and ameliorates acute lethal sepsis in mice.

Maclurin is a natural phenolic compound isolated from Morus alba(white mulberry) andGarcinia mangostana (purple mangosteen) and has been reported to regulate cancer progression, oxidative stress, and melanogenesis. The regulatory role of maclurin, however, has never been demonstrated. This study investigated in vitro and in vivo anti-inflammatory roles of maclurin and the underlying mechanism in caspase-11 non-canonical inflammasome-stimulated inflammatory responses in macrophages and an animal model of acute lethal sepsis. Maclurin protected J774A.1 macrophages from LPS-induced cytotoxicity and suppressed caspase-11 non-canonical inflammasome-stimulated pyroptosis. Maclurin decreased the secretion and mRNA expression of pro-inflammatory cytokines and inflammatory mediators, such as IL-1ß, IL-18, TNF-α, IL-6, nitric oxide (NO), and inducible NO synthase (iNOS) in caspase-11 non-canonical inflammasome-stimulated J774A.1 macrophages. Mechanistic studies revealed that maclurin markedly suppressed the proteolytic activation of caspase-11 and gasdermin D (GSDMD) in caspase-11 non-canonical inflammasome-stimulated J774A.1 macrophages, while it did not inhibit caspase-11-mediated direct sensing of LPS. In vivo study revealed that maclurin ameliorated acute lethal sepsis in mice by increasing the survival rate and decreasing the serum levels of IL-1ß and IL-18 without significant toxicity. In conclusion, this study suggests that maclurin is a novel anti-inflammatory agent in inflammatory responses and against acute lethal sepsis via the inhibition of the caspase-11 non-canonical inflammasome in macrophages, which justifies its potential as an anti-inflammatory therapeutic agent in traditional medicine.

A Novel Model for Predicting the Sagittal Length of the Distal Tibia Using CT Imaging and Statistics.

The purpose of this study was to determine the ratio of sagittal length to coronal length of the distal tibia for predicting the sagittal length of the distal tibia. A total of 202 ankles were measured based on CT imaging availability. We measured the coronal length (Width, W) parallel to the Chaput tubercle from CT scans. Sagittal length was divided into 3 points (Diameter D1, D2, D3) in the axial plane on the same level. The relationship between coronal length and each sagittal length was determined through correlation analysis. A prediction model was then developed using multiple regression. We also analyzed the quality of the prediction model and validated the prediction model with a validation cohort. Each sagittal length (D1, D2, D3) and coronal length had a significant positive correlation (p < .01). In the prediction model, sex, height, and W were significantly associated with D1, D2, and D3 (p < .05). Prediction models were made for each sagittal length (D1, D2, D3). Concordance correlation coefficient (CCC) values of prediction models for D1, D2, and D3 were 0.78, 0.72, and 0.72 for the derivation cohort and 0.69, 0.63, and 0.61 for the validation cohort, respectively. Accuracies of models as ± 2SD for D1, D2, and D3 were 93.9%, 94.9%, and 94.9%, respectively. This study predicted the sagittal length of the distal tibia for preoperative planning by measuring the coronal length of the distal tibia. Prediction of the sagittal length of the distal tibia can help foot and ankle surgeons fixate screws stably to prevent iatrogenic injury of posterior structures of the distal tibia.

Change in intestinal alkaline phosphatase activity is a hallmark of antibiotic-induced intestinal dysbiosis.

OBJECTIVE: Intestinal alkaline phosphatase (IAP) maintains intestinal homeostasis by detoxifying bacterial endotoxins and regulating gut microbiota, and lipid absorption. Antibiotics administered to animals can cause gut dysbiosis and barrier disruption affecting animal health. Therefore, the present study sought to investigate the role of IAP in the intestinal environment in dysbiosis. METHODS: Young male mice aged 9 weeks were administered a high dose of antibiotics to induce dysbiosis. They were then sacrificed after 4 weeks to collect the serum and intestinal organs. The IAP activity in the ileum and the level of cytokines in the serum samples were measured. Quantitative real-time polymerase chain reaction analysis of RNA from the intestinal samples was performed using primers for tight junction proteins (TJPs) and proinflammatory cytokines. The relative intensity of IAP and toll-like receptor 4 (TLR4) in intestinal samples was evaluated by western blotting. RESULTS: The IAP activity was significantly lower in the ileum samples of the dysbiosisinduced group compared to the control. The interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha concentrations were significantly higher in the ileum samples of the dysbiosis-induced group. The RNA expression levels of TJP2, claudin-3, and claudin-11 showed significantly lower values in the intestinal samples from the dysbiosis-induced mice. Results from western blotting revealed that the intensity of IAP expression was significantly lower in the ileum samples of the dysbiosis-induced group, while the intensity of TLR4 expression was significantly higher compared to that of the control group without dysbiosis. CONCLUSION: The IAP activity and relative mRNA expression of the TJPs decreased, while the levels of proinflammatory cytokines increased, which can affect intestinal integrity and the function of the intestinal epithelial cells. This suggests that IAP is involved in mediating the intestinal environment in dysbiosis induced by antibiotics and is an enzyme that can potentially be used to maintain the intestinal environment in animal health care.

Anti-inflammatory role of Artemisia argyi methanol extract by targeting the caspase-11 non-canonical inflammasome in macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia argyi possesses pharmacological activities against various immunopathological conditions associated with inflammation. AIM OF THE STUDY: This study explored the inhibitory role of Artemisia argyi methanol extract (Aa-ME) in inflammatory responses and the underlying mechanism in macrophages. MATERIALS AND METHODS: Caspase-11 non-canonical inflammasome was activated in J774A.1 macrophage by Pam3CSK4 treatment and lipopolysaccharide (LPS) transfection. Aa-ME-mediated in vitro anti-inflammatory action was examined using MTT assay, lactate dehydrogenase (LDH) activity assay, enzyme-linked immunosorbent assay (ELISA), nitric oxide (NO) generation assay, and quantitative real-time polymerase chain reaction (qPCR). Aa-ME-mediated in vivo anti-inflammatory action was examined in LPS-stimulated lethal septic mice. RESULTS: Aa-ME inhibited caspase-11 non-canonical inflammasome-stimulated pyroptosis and the secretion of IL-1ß and IL-18 in J774A.1 macrophages. Aa-ME also inhibited NO generation by downregulating inducible NO synthase (iNOS) expression in LPS-primed and caspase-11 non-canonical inflammasome-triggered J774A.1 cells. The mechanism study revealed Aa-ME suppressed the auto-proteolytic activation of caspase-11 and gasdermin D (GSDMD) in J774A.1 cells and also interfered with caspase-11-mediated direct recognition of LPS. Moreover, Aa-ME alleviated LPS-induced lethal sepsis in mice by increasing their survival rate without significant toxicity. CONCLUSION: These results suggest a novel mechanism by which Aa-ME alleviates inflammatory responses by deactivating caspase-11 non-canonical inflammasome in macrophages.

Korean Red Ginseng Saponins Play an Anti-Inflammatory Role by Targeting Caspase-11 Non-Canonical Inflammasome in Macrophages.

We previously reported that Korean red ginseng (KRG) exerts an anti-inflammatory role through inhibiting caspase-11 non-canonical inflammasome in macrophages; however, the components responsible for the anti-inflammatory role remained unclear. This study explored the anti-inflammatory activity of the KRG saponin fraction (KRGSF) in caspase-11 non-canonical inflammasome-activated macrophages. KRGSF inhibited pyroptosis, pro-inflammatory cytokine secretion, and inflammatory mediator production in caspase-11 non-canonical inflammasome-activated J774A.1 cells. A mechanism study revealed that KRGSF-induced anti-inflammatory action was mediated via suppressing the proteolytic activation of caspase-11 and gasdermin D (GSDMD) in caspase-11 non-canonical inflammasome-activated J774A.1 cells. Moreover, KRGSF increased the survival of lethal septic mice. Taken together, these results reveal KRGSF-mediated anti-inflammatory action with a novel mechanism, by inhibiting caspase-11 non-canonical inflammasome in macrophages.

Syk promotes phagocytosis by inducing reactive oxygen species generation and suppressing SOCS1 in macrophage-mediated inflammatory responses.

OBJECTIVE: Inflammation, a vital innate immune response against infection and injury, is mediated by macrophages. Spleen tyrosine kinase (Syk) regulates inflammatory responses in macrophages; however, its role and underlying mechanisms are uncertain. MATERIALS AND METHODS: In this study, overexpression and knockout (KO) cell preparations, phagocytosis analysis, confocal microscopy, reactive oxygen species (ROS) determination, mRNA analysis, and immunoprecipitation/western blotting analyses were used to investigate the role of Syk in phagocytosis and its underlying mechanisms in macrophages during inflammatory responses. RESULTS: Syk inhibition by Syk KO, Syk-specific small interfering RNA (siSyk), and a selective Syk inhibitor (piceatannol) significantly reduced the phagocytic activity of RAW264.7 cells. Syk inhibition also decreased cytochrome c generation by inhibiting ROS-generating enzymes in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and ROS scavenging suppressed the phagocytic activity of RAW264.7 cells. LPS induced the tyrosine nitration (N-Tyr) of suppressor of cytokine signaling 1 (SOCS1) through Syk-induced ROS generation in RAW264.7 cells. On the other hand, ROS scavenging suppressed the N-Tyr of SOCS1 and phagocytosis. Moreover, SOCS1 overexpression decreased phagocytic activity, and SOCS1 inhibition increased the phagocytic activity of RAW264.7 cells. CONCLUSION: These results suggest that Syk plays a critical role in the phagocytic activity of macrophages by inducing ROS generation and suppressing SOCS1 through SOCS1 nitration during inflammatory responses.

Comparison of Radiological and Clinical Outcomes in Patients Treated with Standard Plating versus Intramedullary Nailing in Distal Tibial Fracture.

OBJECTIVE: To evaluate clinical and radiological outcomes including hindfoot alignment after plate vs intramedullary nailing (IMN) for distal tibia fracture and to define radiologic parameters that influence changes in hindfoot alignment. METHODS: Among 92 patients with distal tibia metaphyseal fractures treated from 2002 to 2015, 39 cases of intramedullary nailing and 53 cases of standard plate osteosynthesis were performed. Union rate and complication rate were compared in both groups. Radiographic measurements including hindfoot angulation, moment arm, calcaneal pitch angle, and Meary angle were evaluated at a minimum of 1-year follow-up. Hindfoot alignment changes after surgery were compared between both groups using student t-test. Correlation and regression were analyzed between fracture alignment parameters and hindfoot alignment. RESULTS: All patients ultimately healed, with an average union period of 26 weeks in both groups. The AOFAS and VAS scores were not significantly different between the two groups. Complications were similar between the two groups. Hindfoot alignment angle, calcaneal pitch, and Meary angle showed no significant differences between the groups. The hindfoot moment arm increased with valgus in the IMN group. A low correlation was detected between angulation at the fracture site in the coronal view and hindfoot alignment (angulation and moment arm) changes (R = 0.38). A significantly high correlation was noted only between transverse rotation and hindfoot alignment changes (R = 0.79). CONCLUSIONS: Rotation in the transverse plane notably influenced changes in hindfoot alignment. And this suggests that patients with distal tibia fracture should be closely monitored for hindfoot alignment changes caused by intraoperative transverse rotation regardless of the fixation method.

Niclosamide and Pyrvinium Are Both Potential Therapeutics for Osteosarcoma, Inhibiting Wnt-Axin2-Snail Cascade.

Osteosarcoma, the most common primary bone malignancy, is typically related to growth spurts during adolescence. Prognosis is very poor for patients with metastatic or recurrent osteosarcoma, with survival rates of only 20-30%. Epithelial-mesenchymal transition (EMT) is a cellular mechanism that contributes to the invasion and metastasis of cancer cells, and Wnt signaling activates the EMT program by stabilizing Snail and ß-catenin in tandem. Although the Wnt/Snail axis is known to play significant roles in the progression of osteosarcoma, and the anthelmintic agents, niclosamide and pyrvinium, have been studied as inhibitors of the Wnt pathway, their therapeutic effects and regulatory mechanisms in osteosarcoma remain unidentified. In this study, we show that both niclosamide and pyrvinium target Axin2, resulting in the suppression of EMT by the inhibition of the Wnt/Snail axis in osteosarcoma cells. Axin2 and Snail are abundant in patient samples and cell lines of osteosarcoma. The treatment of niclosamide and pyrvinium inhibits the migration of osteosarcoma cells at nanomolar concentrations. These results suggest that Axin2 and Snail are candidate therapeutic targets in osteosarcoma, and that anthelminthic agents, niclosamide and pyrvinium, may be effective for osteosarcoma patients.

Calcifying aponeurotic fibroma around posterior tibialis tendon in an elderly patient with flatfoot: A case report.

RATIONALE: Calcifying aponeurotic fibroma (CAF) is a rare benign fibroblastic tumor that is commonly in the hand or foot of children or adolescents. PATIENT CONCERNS: A 74-year-old female presented with a progressive pain on the medial foot for 3 years ago. The pain aggravated while walking or in a standing position for more than 20 minutes. She also complained of skin contact along the medial aspect of the foot while trying to wear a shoe. DIAGNOSIS: Physical examination revealed a firm, immobile, nontender mass accompanied with flexible flatfoot. On the single heel raise test, loss of the balance and intensification of the pain were observed. Faintly calcified soft tissue mass is shown in plain radiographs without bone involvement. Magnetic resonance imaging revealed a subcutaneous mass with ill-defined circumscribed subcutaneous mass adherent to the thickened PTT. INTERVENTIONS: The patient underwent a complete excisional biopsy, followed by medial displacement calcaneal osteotomy. OUTCOMES: The excised mass was diagnosed to be CAF on the histologic examination. At the 1-year follow-up, patient remained asymptomatic with no evidence of recurrence and all the radiographic parameters demonstrating flat foot improved. LESSONS: This is the first case of CAF located at PTT presenting with both foot pain and functional disability. In this case, complete excision of the causative structure along with alignment correction can contribute to successful postoperative outcome.

Three-Dimensional Anatomically Pre-Contoured Locking Plate for Isolated Weber B Type Fracture.

We aimed to evaluate the functional and radiographic outcomes of a three-dimensionally (3D) pre-contoured lateral locking plate fixation for isolated Weber B type fractures and to evaluate the necessity of an interfragmentary lag screw in the use of the plate. Patients who underwent surgery for isolated Weber B type fracture were divided into two groups: 41 patients treated with the 3D plate and lag screw (Group A) and 31 patients treated with the 3D plate only (Group B). The included patients were evaluated regarding the functional and radiographic outcomes. According to the McLennan and Ungersma criteria, the majority of patients showed good or fair outcomes in both groups. Comparing the two groups, Group B showed better functional outcomes (p < 0.0046), while no difference between the two groups was found in terms of the radiographic outcomes (p = 0.143). The operation time was significantly shorter in Group B (p < 0.001) and the time to bony union was within 14 months in all patients with no significant difference between the two groups (p = 0.0821). No postoperative complication was observed in both groups. In conclusion, the use of a 3D pre-contoured lateral locking plate fixation for isolated Weber B type fractures demonstrated satisfactory functional and radiographic outcomes, regardless of lag screw insertion.

14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS: Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS: Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS: This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

Joint Preservation Surgery for Varus Ankle Arthritis with Large Talar Tilt.

BACKGROUND: Varus ankle arthritis with large talar tilt (TT) is a challenging condition when considering joint preservation surgery. Three-dimensional deformity of the talus has been demonstrated with weightbearing computed tomography in varus ankle arthritis with large TT. The aim of this study was to investigate the clinical and radiographic results of posterior tibial tendon (PTT) transfer generally combined with bony realignment for varus ankle arthritis with large TT in nonparalytic ankle arthritis and to determine the indications for PTT transfer. METHODS: This study includes 23 ankles with varus arthritis and TT larger than 7.5 degrees. Patients were categorized into improved (19 ankles) and unimproved (4 ankles) groups according to the postoperative clinical results at the last follow-up. Clinical and radiographic results were compared between the groups. A cut-off point for preoperative TT that indicated a borderline between improved and unimproved groups was determined to suggest the appropriate indication for joint preservation surgery. RESULTS: In the improved group, TT, radiographic stage, Meary angle, and hindfoot alignment significantly improved at 6 months after surgery and were maintained at the last follow-up. In the unimproved group, the radiographic parameters mentioned above did not improve at 6 months after surgery, and TT decreased to 0.8 degrees as radiographic stage had progressed to end-stage arthritis at the last follow-up. In this small series, the cut-off point for predicting failure of surgery was 14.3 degrees of preoperative TT. CONCLUSION: PTT transfer often combined with bony realignment procedures may be a reasonable option for treating painful varus ankle arthritis with TT less than 14 degrees and hindfoot varus. LEVEL OF EVIDENCE: Level IV, case series.

New mechanisms of ginseng saponin-mediated anti-inflammatory action via targeting canonical inflammasome signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is an ethnopharmacological herbal plant in Asian countries, particularly in Korea, China, and Japan. Ginseng saponins, including ginsenosides, are major active components in ginseng and have been demonstrated to have numerous pharmacological effects on various human diseases. AIM OF THE REVIEW: Many previous studies investigating the anti-inflammatory effect of ginseng saponins have mostly focused on the 'priming' step rather than the 'triggering' step. This review aims to discuss the studies investigating an inhibitory role of ginseng saponins in inflammasome activation of the triggering step. MATERIALS AND METHODS: The literature was explored using the search strings, such as "ginseng saponins and inflammasomes" and "ginsenosides and inflammasomes" in several resources, such as PubMed, Google Scholar, and Scopus databases. RESULTS: Various ginseng saponins of Panax ginseng, Panax japonicas, and Panax quinquefolius alleviated inflammatory responses and diseases by inhibiting the nucleotide-binding oligomerization domain-like receptor (NLR) P3 (NLRP3) inflammasome activation. Also, ginseng saponin, Rg1 of Panax ginseng alleviated neuroinflammation and diseases by inhibiting NLRP1 inflammasome activation. Finally, ginseng saponins, Rh1 and Rg3 in Korea red ginseng (KRG) of Panax ginseng ameliorated sepsis by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. CONCLUSION: The studies discussed in this review provide insight into the new paradigm of the ginseng saponins as the promising anti-inflammatory agents that could be ethnopharmacologically used to prevent and treat inflammatory and inflammation-induced disorders via targeting inflammasomes.

TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity.

TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPß activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway.

Caspase-11 Noncanonical Inflammasome: A Novel Key Player in Murine Models of Neuroinflammation and Multiple Sclerosis.

Inflammasomes are intracellular protein complexes consisting of the pattern recognition receptors and inflammatory molecules in the inflamed cells. In response to various ligands, inflammasomes play a pivotal role to execute the inflammatory responses by inducing the pyroptosis and the secretion of pro-inflammatory cytokines, interleukin (IL)-1ß, and IL-18. Unlike canonical inflammasomes, including NOD-like receptor family inflammasomes, such as NLRP1, NLRP3, NLRC4, and absence in melanoma 2 inflammasomes, noncanonical inflammasomes, such as mouse caspase-11 and human caspase-4/5 were recently discovered, and their roles in the inflammatory responses have been poorly understood. However, emerging studies have been successfully demonstrating the regulatory roles of these noncanonical inflammasomes on inflammatory responses and the pathogenesis of inflammatory/autoimmune diseases. This review summarizes and discusses the recent studies investigating the regulatory roles of the caspase-11 noncanonical inflammasome in neuroinflammation and the pathogenesis of multiple sclerosis (MS), which provides the insight for the validation of caspase-11 noncanonical inflammasome to develop novel and promising therapeutics for MS.

The Usefulness of the QR Code in Orthotic Applications after Orthopedic Surgery.

The purpose of this study is to evaluate the utility of QR (quick response) codes in explaining the proper method for orthotic use after orthopedic surgery. A questionnaire survey was adopted to evaluate patient satisfaction with education and training in orthotic applications after orthopedic surgery. The study periods were 1 April to 30 April 2017, and 1 October to 31 October 2017. The oral training involving the conventional orthoses was conducted in April, and the videos with the orthosis on the QR code were captured in October. The QR code containing the data was distributed and the education was conducted. A total of 68 patients (QR-code group: 33) participated in the questionnaire survey. After the QR code application, the number of retraining cases increased from 62.9 to 93.9% (p-value < 0.01). The mean scores of the four items measuring the comprehension increased from 10.97 to 14.39. The satisfaction level rose from 7.14 to 9.30, and the performance increased from 7.14 to 9.52 (p-value < 0.01). The QR code is expected to be a valuable method for explaining the orthotic application after orthopedic surgery, and especially when repeated explanations are needed for elderly patients.

Fixation of isolated Lisfranc ligament injury with the TightRope™: A technical report.

Treatment of Lisfranc ligament injury is still debatable. For this reason, we applied a standard suture button (TightRope™, Arthrex, Naples, FL), a device originally designed for syndesmosis fixation, in treating isolated Lisfranc ligament (ILL) injuries. Twelve patients diagnosed as having an ILL injury were recruited. All patients regained their previous activity level within 3 months after the surgery without any complications. We propose that standard suture button device in an ILL injury is an easy technique to perform with short learning curve, accompanied with satisfactory outcomes.

A Novel Prediction Model for Determining Coronal Length of Calcaneus Using CT: A Guide for Surgery of Calcaneal Fracture.

The objective of this study was to determine the anatomical relationship between the calcaneus and its neighboring bones. Furthermore we tested a prediction model that enables to estimate safe screw length during the surgery of calcaneus fractures. A total of 169 feet were used for the study based on CT scans. We measured two horizontal and two parallel lines. The coronal length of the cuboid bone (CL) was a horizontal line anterior to the calcaneocuboidal joint, and W1 of calcaneus was a horizontal line posterior to the articular surface of the calcaneocuboidal joint. The subtalar articular length (STA) was a parallel line above the talocalcaneal joint, and W2 of calcaneus was a parallel line below to the talocalcaneal joint. Relationship of each measurement was determined through correlation analysis. A prediction model was developed based on observed correlations and the quality analyzed and validated. The CL and W1 had a significant positive correlation (r = 0.899, p < .001). The STA and W2 also had a significant positive correlation (r = 0.939, p < .001). Based on these correlations, the prediction model was made. In the quality analysis, the values of concordance correlation coefficient (CCC) for W1 and W2 were 0.894, and 0.937 respectively. In the validation analysis, the values of CCC for W1, W2 were 0.79, and 0.8, respectively. This study made it possible to predict the anatomical reference point using preoperative coronal length of the calcaneus to guide safety margin of screw length, and thereby to prevent the iatrogenic injuries on medial neurovascular structures of the calcaneus.