KLF2/PPARγ axis contributes to trauma-induced heterotopic ossification by regulating mitochondrial dysfunction.

Trauma-induced heterotopic ossification (HO) is a complex disorder after musculoskeletal injury and characterized by aberrant extraskeletal bone formation. Recent studies shed light on critical role of dysregulated osteogenic differentiation in aberrant bone formation. Krupel-like factor 2 (KLF2) and peroxisome proliferator-activated receptor gamma (PPARγ) are master adapter proteins that link cellular responses to osteogenesis; however, their roles and relationships in HO remain elusive. Using a murine burn/tenotomy model in vivo, we identified elevated KLF2 and reduced PPARγ levels in tendon stem/progenitor cells (TSPCs) during trauma-induced HO formation. Both KLF2 inhibition and PPARγ promotion reduced mature HO, whereas the effects of PPARγ promotion were abolished by KLF2 overexpression. Additionally, mitochondrial dysfunction and reactive oxygen species (ROS) production also increased after burn/tenotomy, and improvements in mitochondrial function (ROS scavenger) could alleviate HO formation, but were abolished by KLF2 activation and PPARγ suppression by affecting redox balance. Furthermore, in vitro, we found increased KLF2 and decreased PPARγ levels in osteogenically induced TSPCs. Both KLF2 inhibition and PPARγ promotion relieved osteogenesis by improving mitochondrial function and maintaining redox balance, and effects of PPARγ promotion were abolished by KLF2 overexpression. Our findings suggest that KLF2/PPARγ axis exerts regulatory effects on trauma-induced HO through modulation of mitochondrial dysfunction and ROS production in TSPCs by affecting redox balance. Targeting KLF2/PPARγ axis and mitochondrial dysfunction can represent attractive approaches to therapeutic intervention in trauma-induced HO.

Development and Validation of a Deep-Learning Model to Predict Total Hip Replacement on Radiographs: The Total Hip Replacement Prediction (THREP) Model.

BACKGROUND: There are few methods for accurately assessing the risk of total hip arthroplasty (THA) in patients with osteoarthritis. A novel and reliable method that could play a substantial role in research and clinical routine should be investigated. The purpose of the present study was to develop a deep-learning model that can reliably predict the risk of THA with use of radiographic images and clinical symptom data. METHODS: This retrospective, multicenter, case-control study assessed hip joints on weighted-bearing anteroposterior pelvic radiographs obtained from Osteoarthritis Initiative (OAI) participants. Participants who underwent THA were matched to controls according to age, sex, body mass index, and ethnicity. Cases and controls were uniformly split into training, validation, and testing data sets at proportions of 72% (n = 528), 14% (n = 104), and 14% (n = 104), respectively. Images and clinical symptom data were passed through a detection model and a deep convolutional neural network (DCNN) model to predict the probability of THA within 9 years as well as the most likely time period for THA (0 to 2 years, 3 to 5 years, 6 to 9 years). Model performance was assessed with use of the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity in the testing set. RESULTS: A total of 736 participants were evaluated, including 184 cases and 552 controls. The prediction model achieved an overall accuracy, sensitivity, and specificity of 91.35%, 92.59% and 86.96%, respectively, with an AUC of 0.944, for THA within 9 years. The AUC of the DCNN model for assessing the most likely time period was 0.907 for 0 to 2 years, 0.916 for 3 to 5 years, and 0.841 for 6 to 9 years. Gradient-weighted class activation mapping closely corresponded to regions affecting the prediction of the DCNN model. CONCLUSIONS: The proposed DCNN model is a reliable and valid method to predict the probability of THA-within limitations. It could assist clinicians in patient counseling and decision-making regarding the timing of the intervention. In the future, by increasing the size of the data set, enhancing the ethnic and socioeconomic diversity of the participants, and improving the follow-up rate, the quality of the conclusions can be further improved. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Surgical resection outcomes of post-traumatic elbow heterotopic ossification: multicenter case series at a minimum 5-year follow-up.

BACKGROUND: Heterotopic ossification (HO), a common complication after elbow trauma, causes severe limb disability, Surgical resection is usually performed for post-traumatic elbow HO (PTEHO) to regain mobility. Though it was heavily reported, there has been no long-term (minimum 5-year) follow-up. PATIENTS AND METHODS: 173 patients who underwent PTEHO resection were followed up for minimum 5 years in 4 hospitals between January/2015 and August/2016. Demographics, disease characteristics, preoperative and minimum 5-year assessments were collected. After controlling for potential variables when dividing long-term ROM into <120° and ≥120°, risk factors for ROM recovery to modern functional arc were identified through multivariable regression analysis. RESULTS: Clinically important improvements in ROM of 39°â†’124° were obtained at final follow-up, and 74.6% achieved modern functional arc (≥120°). Mayo Elbow Performance Index (MEPI) had clinically important increases of 69→93 points at final follow-up, and 96.5% reported excellent-to-good. Pain (Numerical Rating Scale, 1.9→0.6 points) and ulnar nerve symptoms were improved. Total complication rate was 15.6%, including new-onset ulnar nerve symptoms (5.8%), HO recurrence with clinical symptoms (6.9%), elbow instability (1.7%), and joint infection (1.2%). Previously reported high body mass index (BMI, p=0.002) and long disease duration (p=0.033) were equally identified as risk factors for not achieving modern functional arc, meanwhile tobacco use (p=0.024) and ankylosed HO (p<0.001) were found to be new risk factors. CONCLUSION: Surgical resection yields satisfactory outcomes for PTEHO at long-term of minimum 5 years. High BMI, tobacco use, long disease duration, and ankylosed HO would negatively affect ROM recovery to modern functional arc (≥120°). LEVEL OF EVIDENCE: Level IV, therapeutic study.

Association Between Tranexamic Acid Use and Heterotopic Ossification Prevalence After Elbow Trauma Surgery: A Propensity-Score-Matched Cohort Study.

BACKGROUND: Heterotopic ossification (HO) is a common complication of elbow trauma that can affect limb mobility. Inflammation is an initiating factor for HO formation. Tranexamic acid (TXA) can reduce the inflammatory response after orthopaedic surgery. However, evidence regarding the effectiveness of TXA use for HO prevention after elbow trauma surgery is lacking. METHODS: This retrospective observational propensity-score-matched (PSM) cohort study was conducted from July 1, 2019, to June 30, 2021, at the National Orthopedics Clinical Medical Center, Shanghai, People's Republic of China. A total of 640 patients who underwent surgery following elbow trauma were evaluated. The present study excluded patients with an age of <18 years; those with a history of elbow fracture; those with a central nervous system injury, spinal cord injury, burn injury, or destructive injury; and those who had been lost to follow-up. After 1:1 matching on the basis of sex, age, dominant arm, injury type, open injury, comminuted fracture, ipsilateral trauma, time from injury to surgery, and nonsteroidal anti-inflammatory drug use, the TXA group and the no-TXA group comprised 241 patients each. RESULTS: In the PSM population, the prevalence of HO was 8.71% in the TXA group and 16.18% in the no-TXA group (with rates of 2.07% and 5.80% for clinically important HO, respectively). Logistic regression analyses showed that TXA use was associated with a lower rate of HO (odds ratio [OR], 0.49; 95% CI, 0.28 to 0.86; p = 0.014) than no TXA use, as well as with a lower rate of clinically important HO (OR, 0.34; 95% CI, 0.11 to 0.91; p = 0.044). None of the baseline covariates significantly affected the relationship between TXA use and HO rate (p > 0.05 for all). Sensitivity analyses supported these findings. CONCLUSIONS: TXA prophylaxis may be an appropriate method for the prevention of HO following elbow trauma. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

lncRNA MEG3 Promotes Osteogenic Differentiation of Tendon Stem Cells Via the miR-129-5p/TCF4/ß-Catenin Axis and thus Contributes to Trauma-Induced Heterotopic Ossification.

BACKGROUND: Heterotopic ossification (HO) is one of the most intractable conditions following injury to the musculoskeletal system. In recent years, much attention has been paid to the role of lncRNA in musculoskeletal disorders, but its role in HO was still unclear. Therefore, this study attempted to determine the role of lncRNA MEG3 in the formation of post-traumatic HO and further explore the underlying mechanisms. RESULTS: On the basis of high-throughput sequencing and qPCR validation, elevated expression of the lncRNA MEG3 was shown during traumatic HO formation. Accordingly, in vitro experiments demonstrated that lncRNA MEG3 promoted aberrant osteogenic differentiation of tendon-derived stem cells (TDSCs). Mechanical exploration through RNA pulldown, luciferase reporter gene assay and RNA immunoprecipitation assay identified the direct binding relationship between miR-129-5p and MEG3, or miR-129-5p and TCF4. Further rescue experiments confirmed the miR-129-5p/TCF4/ß-catenin axis to be downstream molecular cascade responsible for the osteogenic-motivating effects of MEG3 on the TDSCs. Finally, experiments in a mouse burn/tenotomy model corroborated the promoting effects of MEG3 on the formation of HO through the miR-129-5p/TCF4/ß-catenin axis. CONCLUSIONS: Our study demonstrated that the lncRNA MEG3 promoted osteogenic differentiation of TDSCs and thus the formation of heterotopic ossification, which could be a potential therapeutic target.

STING contributes to trauma-induced heterotopic ossification through NLRP3-dependent macrophage pyroptosis.

Trauma-induced heterotopic ossification (HO) is featured by aberrant bone formation at extra-skeletal site. STING is a master adaptor protein linking cellular damage to immune responses, while its role in HO remains elusive. A murine burn/tenotomy model was used to mimic trauma-induced HO in vivo. We demonstrated elevated STING expression in macrophages in inflammatory stage after burn/tenotomy, and STING inhibition significantly alleviated HO formation. Activated NLRP3-dependent macrophage pyroptosis was also found in inflammatory stage after burn/tenotomy. Either STING or NLRP3 suppression reduced mature HO by weakening macrophage pyroptotic inflammation, while protective effects of STING were abolished by NLRP3 overexpression. Further, in vitro, we also found a prominent STING level in pyroptotic BMDMs. STING suppression relieved macrophage pyroptotic inflammation, while abolished by NLRP3 overexpression. Our results reveal that STING poses regulatory effects on trauma-induced HO formation, via modulating NLRP3-dependent macrophage pyroptosis. Targeting STING-NLRP3 axis represents an attractive approach for trauma-induced HO prevention.

[The second dorsal metacarpal artery flap relaying the dorsal island flap of the index finger for the repair of soft tissue defect of thumb].

Objective: To investigate the effectiveness of the second dorsal metacarpal artery fascial vascular pedicle retrograde island flap relaying the dorsal island flap of the index finger in repairing skin and soft tissue defects of the thumb. Methods: The clinical data of 8 patients with skin and soft tissue defects of thumb between October 2019 and January 2021 were retrospectively analyzed. There were 3 males and 5 females with an average age of 35 years (range, 18-52 years). The causes of injury included machine injury in 2 cases, crush injury in 3 cases, and cutting injury in 3 cases. There were 2 cases of dorsal defect of the proximal part, 1 dorsal defect of the distal part, and 5 instances of the distal part defect. The skin and soft tissue defects ranged from 1.7 cm×1.4 cm to 3.0 cm×2.5 cm. The time from injury to flap repair was 7-21 days, with an average of 14 days. Firstly, the dorsal island flap of the index finger (dorsal side of the proximal part of the index finger) was used to repair the defect of the thumb. Then the second dorsal metacarpal artery fascia vascular pedicle retrograde island flap (near the radial side of the back of the hand) was used to repair the dorsal defect of the index finger; the donor site was sutured directly. Results: Vascular crisis of the flap occurred in 1 case within 48 hours after operation, and the flap was bloated and bruised in 1 case due to excessive suture tension, and all the flaps survived after symptomatic treatment; partial skin margin of the flap was necrotic in 1 case after operation, and the incision healed after dressing change; the other 5 flaps survived, and all the wounds in the donor and recipient sites healed by first intention. All the 8 patients were followed up 3-10 months, with an average of 6 months. One patient had mild scar; the other patients had no significant difference in the color of the flap and the surrounding skin, no adhesion of tendons, and little interference of index finger function, and there was no obvious pain and dysfunction in the donor and recipient sites of the flap. At last follow-up, the extension-flexion range of motion of the metacarpophalangeal joint of the thumb was 0°-55°, and that of the interphalangeal joint was 0°-75°; the extension-flexion range of motion of the metacarpophalangeal joint of the index finger was 0°-82°, that of the proximal interphalangeal joints was 0°-90°, and that of the distal interphalangeral joints was 0°-65°. Conclusion: The application of the second dorsal metacarpal artery fascial vascular pedicle retrograde island flap relaying the dorsal island flap of the index finger to repair skin and soft tissue defect wounds of thumb is a feasible treatment with reliable blood supply, less postoperative complications, no need for skin grafting, less interference to the function of the index finger, and satisfactory wound repair effect.

Outcomes of Eight-Plate Epiphysiodesis for Residual Clubfoot Deformities.

OBJECTIVE: The outcome of congenital clubfoot treatment is still challenging if the feet deformities are not completely corrected. Here we explore a minimal invasive procedure with an eight-plate implant to correct the residual forefoot adduction deformity after treatment of neglected or relapsed clubfoot. METHODS: We retrospectively reviewed patients with residual forefoot adduction deformity after clubfoot treatment between January 2013 and June 2016. The patients underwent temporary epiphysiodesis of the lateral column of the mid-foot, which in detail, an eight-plate was placed on each side of the calcaneocuboid joint. The foot deformities were recorded according to the weight-bearing radiographic measurements including talo-first metatarsal angle, calcaneo-fifth metatarsal angle and medial-to-lateral column length. RESULTS: A total of 13 patients (20 feet) with an average age of 7.8 years old were located with an average duration of 40.8 months follow-up (range, 28 to 54 months). The average talo-first metatarsal angle improved from 28.3° (range, 19° to 47°) preoperatively to 8.3° (range, 3° to 18°) and the calcaneo-fifth metatarsal angle improved from 29.1° (range, 19° to 40°) preoperatively to 8.4° (range, 0° to 21°) at final follow-up. The mean ratio of the medial-to-lateral column length improved from 1.14 ± 0.06 to 1.55 ± 0.09 with statistical significance (t = 3.566; P < 0.001). CONCLUSIONS: Eight-plate epiphysiodesis is an easy and effective method for the correction of residual forefoot adduction deformity after clubfoot treatment in growing children without the need of osteotomy.

Severe spaghetti wrist injury: Should we expand the terminology from wrist to proximal forearm?

OBJECTIVES: This study aims to point out the key principles for the management of multicomponent soft tissue injuries of the wrist and forearm to discuss whether we should expand the term "spaghetti" from the wrist to forearm in such terrifying cases. PATIENTS AND METHODS: Data from a total of 50 patients (44 males, 6 females; mean age: 48.5±25.7 years; range, 10 to 70 years) who were treated for multicomponent soft tissue injuries of the wrist and forearm, including at least one major artery and one major nerve, between February 2020 and December 2021 were retrospectively analyzed. The patients were divided into the wrist injury group (n=30) and forearm injury group (n=20) according to the location of laceration. Demographic characteristics, including age, sex ratio and mechanism and side of injury, total lacerated structures, and outcomes, including tendon function, opposition, intrinsic muscle function, deformities, sensation and grip strength were evaluated. RESULTS: In the wrist injury group, a mean of 12.27±3.53 structures at the volar side were injured. It took a mean time of 1.8±0.4 h for emergency surgical repair and, after a mean of 16.6±5.3 month follow-up, most patients received excellent/good outcomes in the six aspects. In the forearm injury group, a mean of 12.95±2.96 structures at the volar side were injured. It took an average time of 2.1±0.4 h for emergency surgical repair and, after a mean of 15.4±6.4 month follow-up, most patients received excellent/good outcomes and were satisfied with the functional recovery. Only surgical time (p=0.018) and final grip strength (p=0.023) between the two groups showed a statistically significant difference. CONCLUSION: We propose to merge the severe wrist and proximal forearm laceration of multiple tendons/muscles with at least one major artery and one major nerve as a whole, namely the spaghetti-ketchup injury, since the laceration of wrist and that of proximal forearm in this study share similar mechanisms and outcomes after primary repair or reconstruction.

Novel use of close-wedge osteotomy and monorail external fixator in the treatment of chronic Monteggia fracture.

OBJECTIVES: This study aims to evaluate the efficacy of close-wedge osteotomy and monorail external fixator in the treatment of chronic Monteggia fracture. PATIENTS AND METHODS: Between January 2014 and December 2021, data of a total of 22 patients (14 males, 8 females; mean age: 15.6±5.1 years; range, 6 to 25 years) who suffered from chronic Monteggia fractures were retrospectively reviewed. All the patients were treated for acute angulation of the ulna after osteotomy and gradual angulation for radial head reduction. Range of motion of the elbow and forearm, the angle between the longitudinal axis of proximal radius and the hypothesized Storen's line (RSA), Visual Analog Scale (VAS), and Mayo Elbow Performance Score (MEPS), as well as Disabilities of Arm, Shoulder and Hand (DASH) score were recorded preoperatively and at the final follow-up. RESULTS: Objective parameters were all significantly improved in the aspects of range of motions of the elbow and forearm, and RSA (21.4±4.5° preoperatively and 2.0±1.4° at the final follow-up, t=18.20, p<0.05). The level of pain due to the chronic injury was eliminated, as the mean VAS was significantly lower at the final follow-up compared to preoperative scoring (2.8±2.0 preoperatively and 0.5±0.9 at the final follow-up, t=4.86, p<0.05). The function of the elbow and upper limb was restored, which was indicated by improved MEPS (73.2±12.5 preoperatively and 96.6±6.4 at the final follow-up, t=7.70, p<0.05) and DASH (28.3±6.0 preoperatively and 4.1±2.0 at the final follow-up, t=19.35, p<0.05). No complication was observed. CONCLUSION: Close-wedge osteotomy and gradual lengthening with monorail external fixator in the treatment of chronic Monteggia fracture showed great efficacy. We also provided a specified osteotomy site aiming at PRUJ reconstruction.

Hinge positioning method of Ilizarov apparatus in correcting radial head luxation caused by multiple hereditary exostoses.

OBJECTIVES: In this study, we present a specified hinge positioning method to achieve satisfying and steerable lengthening and angulation to correct forearm multiple hereditary exostoses (MHE) combined with severe radiocapitellar joint dislocation using Ilizarov ring fixators. PATIENTS AND METHODS: Between January 2014 and December 2018, a total of 30 forearms of 23 patients (11 males, 12 females; mean age: 18.3±6.8 years; range, 8 to 35 years) who suffered from type IIa (n=2) or IIb (n=28) MHE with severe radiocapitellar joint luxation were retrospectively analyzed. All patients were treated with Ilizarov external fixators with our specified hinge positioning method. Range of motion of the elbow, forearm and wrist and Visual Analog Scale (VAS), as well as Disabilities of Arm, Shoulder, and Hand (DASH) score, and radiological parameters, including radial articular angle (RAA), ulnar variance (UV) and carpi slip (CS), were recorded preoperatively and at final follow-up and were compared. RESULTS: Clinical and radiological outcomes were evaluated. Range of motion of the elbow, forearm and wrist, VAS, DASH and radiological features, including RAA, CS, and UV were significantly improved, except for range of motion of the forearm supination. Temporary nail track infection was seen in two of the forearms and was controlled with oral antibiotics. None of the patients developed radial head dislocation again. CONCLUSION: Clinical and radiological outcomes of this novel hinge positioning method are satisfactory in treating MHE with severe radial head dislocation, and this method can be an alternative treatment for MHE by setting a milestone for accurate radiocapitellar joint reduction.

Bilateral triceps tendon approach is flexible and efficient in the treatment of type C distal humerus fractures.

PURPOSE: The purpose of this study was to assess and compare elbow range of motion, triceps extension strength and functional results of type C (AO/OTA) distal humerus fractures treated with bilateral triceps tendon (BTT) approach and olecranon osteotomy (OO). At the same time, we are also trying to know whether BTT approach can provide sufficient vision for comminuted intra-articular fractures of the distal humerus, and whether it is convenient to convert to the treatment to total elbow arthroplasty (TEA) or OO. METHODS: Patients treated with OO and BTT approaches for type C distal humerus fractures between July 2014 and December 2017 were retrospectively reviewed. Inclusion criteria include: (1) patients' age were more than 18 years old, (2) follow-up was no less than 6 months, and (3) patients were diagnosed with type C fractures (based on the AO/OTA classification). Exclusion criteria include: (1) open fractures (Gustillo type 2 or type 3), (2) treated by other approaches, and (3) presented with combined injuries of ipsilateral upper extremities, such as ulnar nerve. Elbow range of motion and triceps extension strength testing were completely valuated, when the fractures had healed. Assessment of functional results using the Mayo elbow performance score and complications were conducted in final follow-up. The data were compared using the two tailed Student's t-test. All data were presented as mean ± standard deviation. RESULTS: Eighty-six patients of type C distal humerus fractures, treated by OO and BTT approach were retrospectively reviewed between July 2014 and December 2017. Fifty-five distal humerus fractures (23 males and 32 females, mean age 52.7 years) treated by BTT approach or OO were included in this study. There were 10 fractures of type C1, 16 type C2 and 29 type C3 according to the AO/OTA classification. Patients were divided into two surgical approach groups chosen by the operators: BTT group (28 patients) and OO group (27 patients). And the mean follow-up time of all patients was 15.6 months (range, 6-36 months). Three cases in BTT group were converted to TEA, and one converted to OO. Only one case in BTT group presented poor articular reduction with a step more than 2 mm. There were not significantly different in functional outcomes according to the Mayo elbow performance score, operation time and extension flexion motion are values between BTT group and OO group (p > 0.05). Complications and reoperation rate were also similar in the two groups. Triceps manual muscle testing were no significant difference in the two groups, even subdivided in elder patients (aged >60 years old). CONCLUSION: BTT is a safe approach to achieve similar functional result comparing with OO. BTT were not suitable for every case with severe comminuted pattern, but it avoids the potential complications related to OO, and has no complications concerning with triceps tendon. It is convenient for open reduction internal fixation and flexible to be converted to OO, as well as available to be converted to TEA in elder patients.

Oriented inner fabrication of bi-layer biomimetic tendon sheath for anti-adhesion and tendon healing.

INTRODUCTION: Synthetic fibrous membranes unveil a promising field in anti-adhesion of tendons. Meanwhile, oriented nanofiber structures have been widely studied and used in the application of biomedical engineering, particularly in repairing and strengthening effects. METHODS: In this study, a bi-layer poly(L-lactic acid) (PLLA) electrospun membrane was fabricated, in which the inner oriented fibrous layer was designed to promote tendon healing while outer random aligned layer was designed to prevent peritendinous adhesion. RESULTS: It was found that fibroblasts were aligned along the oriented fiber of membranes in vitro and in a Leghorn chicken model. In biomechanical tests of repaired tendons, no significant difference was found between oriented fibrous membrane and blank control in maximum tensile strength; both oriented fibrous membranes and random fibrous membranes showed lower work of flexion than blank control, which was consistent with gross assessment. CONCLUSION: It was practicable to promote tendon healing while preventing adhesion via bi-layer PLLA membranes with an inner-oriented-fiber fabricated structure.

A new pathologic classification for elbow stiffness based on our experience in 216 patients.

BACKGROUND: Elbow stiffness commonly causes functional impairment and upper-limb disability. This study aimed to develop a new pathologic classification to further understand and standardize elbow arthrolysis from a new perspective, as well as to determine clinical outcomes. METHODS: Extension-flexion dysfunction was classified into 4 types: EFI, tethers alone; EFII, tethers with blocks; EFIII, articular malformation; and EFIV, bony ankylosis. Forearm rotation dysfunction was classified into 3 types: FRI, contracture alone; FRII, radial head malunion or nonunion; and FRIII, proximal radioulnar bony ankylosis. A total of 216 patients with elbow stiffness were prospectively included and categorized preoperatively. All surgical procedures were performed by the same chief surgeon; different types underwent specific procedures. Patient data, elbow motion, and functional scores were analyzed. RESULTS: Mean range of motion (ROM) increased from 40° preoperatively to 118° at final follow-up; 88% of patients regained ROM of 100° or greater. The forearm rotation arc (FRA) with forearm rotation dysfunction increased from a preoperative mean of 76° to 128°; 82% of patients regained an FRA of 100° or greater. The mean Mayo Elbow Performance Index (MEPI) increased from 63 to 91 points; the proportion of patients with good or excellent results was 95%. EFI patients had the best ROM (129°) and MEPI (93 points) and EFIV patients achieved the most-changed ROM (116°), whereas EFIII patients had the worst ROM (104°) and MEPI (84 points) and the least-changed ROM (64°). The FRA was best in FRI patients (142°), followed by FRII patients (118°), and worst in FRIII patients (82°); in contrast, the changed FRA was greatest in FRIII patients (82°), followed by FRII patients (64°), and least in FRI patients (37°). CONCLUSION: This study suggests that the proposed pathologic classification provides a new perspective on the understanding and standardization of elbow arthrolysis, providing satisfactory clinical outcomes.

Bifocal osteosynthesis to treat radial shortening deformity with dislocation of the inferior radioulnar joint.

BACKGROUND: Several methods have been reported to correct deformity and shortening of the distal radius. However, the results are not entirely satisfactory. The results of bifocal osteosynthesis were retrospectively analyzed in this study. METHODS: Eight patients treated with bifocal osteosynthesis were evaluated retrospectively. Pre-operative and post-operative clinical and radiographic examinations were performed. Subjective symptoms and objective joint function were assessed. Radiographic data of the extent of radial lengthening and distal radial articular angle were collected. RESULTS: The mean follow-up period was 46 months (37-68 months). Satisfactory wrist appearance and radial lengthening was achieved in all patients. All patients were satisfied with the wrist appearance and willing to undergo the same treatment again. The range of motion (ROM) of the forearm and wrist was significantly improved. Pin-track infections occurred in two patients, for which they received wound care and oral antibiotics. Complications such as fixation device failure, tendon rupture, fracture of regenerated bone or nerve impairment did not occur. The duration of lengthening depended on the shortening of the radius. Delayed union in the docking site was observed in two patients and union was achieved after bone grafting. CONCLUSIONS: Bifocal osteosynthesis using the Ilizarov method provides a useful method for correction of radial shortening deformity with dislocation of the inferior radioulnar joint. Despite the fact that we did not validate pre-and post-operation functional outcome scores, all patients were satisfied with the wrist appearance and function.

Integrated analysis of long non-coding RNAs and mRNAs associated with peritendinous fibrosis.

The dysregulation of long non-coding RNAs (lncRNAs) is associated with the development of various diseases. However, little is known about the regulatory function of lncRNAs in peritendinous fibrosis. Therefore, the expression profiles of lncRNAs and mRNAs in normal tendon and fibrotic peritendinous tissues were analyzed in this study using RNA sequencing. In total, 219 lncRNAs and 3403 mRNAs were identified that were differentially expressed between the two sets of tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the dysregulated mRNAs were mainly associated with immune regulation, inflammation, extracellular matrix (ECM) production and remodeling, and cell cycle regulation. An lncRNA-mRNA co-expression network revealed 181 network pairs comprising eight dysregulated lncRNAs and 146 mRNAs. The results of the bioinformatics analysis indicated that the dysregulated lncRNAs play a role in fibrogenesis through regulation of the cell cycle, inflammation, and ECM production. Furthermore, silencing the lncRNA dnm3os prevented transforming growth factor (TGF)-ß1-induced tenocyte proliferation and expression of genes related to fibrogenesis. These findings provide a basis for investigations into the regulatory mechanisms underlying the development and progression of peritendinous fibrosis.

Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy.

Dysregulation of autophagy plays a pivotal role in fibrosis in multiple organs. However, the role of autophagy in peritendinous fibrosis is not well understood. Here, we hypothesize that autophagy plays a protective role in preventing adhesion formation. In a rat model of tendon injury, we observed dysregulated autophagy during excessive extracellular matrix deposition. Pharmacological induction of autophagy by rapamycin markedly alleviated the severity of peritendinous fibrosis in vivo. In NIH/3T3 fibroblasts and tenocytes, transforming growth factor ß1 (TGF-ß1) markedly activated myofibroblasts and increased collagen synthesis. Addition of rapamycin activated autophagy, reduced collagen synthesis, and suppressed myofibroblast activation. In vitro experiments also showed that rapamycin decreased cell proliferation and increased the number of cells arrested in G0/G1 phase. However, following pretreatment with the autophagy inhibitor 3-methyladenine (3-MA), rapamycin was unable to repress the fibrotic changes induced by TGF-ß1. Autophagy related protein 5 (Atg5) RNA interference in fibroblasts also abolished the protective effects of rapamycin in vitro. In conclusion, our results point to rapamycin as a potential treatment strategy in the prevention of peritendinous fibrosis after tendon injury.

Humeral lengthening and proximal deformity correction with monorail external fixator in young adults.

PURPOSE: Several humeral lengthening or simultaneous deformity corrections through one osteotomy using various external fixators were reported, while literature regarding correction of shortening and proximal varus deformity is scarce. This retrospective clinical study evaluated the results of preforming an acute correction and delayed lengthening in young adults through two osteotomies using monorail external fixator. METHODS: We report seven patients with various pathologies who underwent humeral proximal deformity correction and lengthening between 2009 and 2015. Pre-operative and post-operative clinical and radiographic data were collected. The mean follow-up time was 33.4 months (25-46 months). RESULTS: The humeral neck-shaft angle improved from 97.9° (85-110°) to 138.6° (135-145°). The magnitude of lengthening achieved was average 7.6 cm (range, 6-10 cm) at an average healing index of lengthening of 30.2 days/cm (range, 27.7-35.4 days/cm). There was a significant increase in range of shoulder abduction, and active abduction improved from pre-operative 136.4° (range, 95-160°) to post-operative 166.4° (range, 150-180°). The DASH score improved significance from 23.29 ± 8.36 to 6.57 ± 3.65 (t = 4.848; p < 0.001). CONCLUSION: Acute deformity correction and gradual lengthening with the monorail external fixator can be used for humeral shortening and proximal varus angular deformity. Functional improvement is expected after surgery and post-operative therapy.

Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor-ß signaling.

Injury-induced peritendinous adhesion is a critical clinical problem that leads to tendon function impairment. Therefore, it is very urgent to explore potential approaches to attenuate peritendinous adhesion formation. Recently, several studies have demonstrated the biological effect of metformin in inhibiting multiple tissue fibrosis. In this study, we performed in vitro and in vivo experiments to examine whether metformin prevents injury-induced peritendinous fibrosis. We found that tendon injury induced severe fibrosis formation in rats. However, orally administered metformin significantly alleviated the fibrosis based on macroscopic and histological evaluation. Peritendinous tissue from metformin-treated rats also showed decreased expression of fibrotic genes including col1a1, col3a1, and α-smooth muscle actin (α-SMA), and inhibition of transforming growth factor (TGF)-ß1 signaling. The cell counting kit (CCK)-8, flow cytometry, and 5-ethynyl-2'-deoxyuridine (EdU) staining analyses showed that treatment of NIH/3T3 fibroblasts with metformin significantly inhibited excessive cell proliferation and promoted cell apoptosis. Metformin treatment also inhibited the expression of fibrotic genes and decreased the phosphorylation of smad2/3 and extracellular signal-regulated kinase (ERK) 1/2. Furthermore, blocking AMP-activated protein kinase (AMPK) signaling abolished the inhibitory effect of metformin on fibrosis. Our findings indicate that metformin has a protective role against peritendinous tissue fibrosis and suggest its clinical use could be a promising therapeutic approach.

RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis.

Peritendinous tissue fibrosis which leads to poor tendon function is a worldwide clinical problem; however, its mechanism remains unclear. Transcription factor RelA/p65, an important subunit in the NF-κB complex, is known to have a critical role in many fibrotic diseases. Here, we show that RelA/p65 functions as a core fibrogenic regulator in tendon adhesion and that its inhibition exerts an anti-fibrogenic effect on peritendinous adhesion. We detected the upregulation of the NF-κB pathway in human tendon adhesion using a gene chip microarray assay and revealed the overexpression of p65 and extracellular matrix (ECM) proteins Collagen I, Collagen III, and α-smooth muscle actin (α-SMA) in human fibrotic tissues by immunohistochemistry and western blotting. We also found that in a rat model of tendon injury, p65 expression correlated with tendon adhesion, whereas its inhibition by small interfering (si)RNA prevented fibrous tissue formation and inflammatory reaction as evidenced by macroscopic, biomechanical, histological, immunohistochemical, and western blotting analyses. Furthermore, in cultured fibroblasts, p65-siRNA, p65-specific inhibitor, Helenalin and JSH23 suppressed cell proliferation and promoted apoptosis, whereas inhibiting the mRNA and protein expression of ECM components and cyclo-oxygenase-2, an inflammatory factor involved in tendon adhesion. Our findings indicate that p65 has a critical role in peritendinous tissue fibrosis and suggest that p65 knockdown may be a promising therapeutic approach to prevent tendon adhesion.