FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses.

An essential pathogenic element of acute limb ischemia/reperfusion (I/R) injury is microvascular dysfunction. The majority of studies indicates that fibroblast growth factor 2 (FGF2) exhibits protective properties in cases of acute I/R injury. Albeit its specific role in the context of acute limb I/R injury is yet unknown. An impressive post-reperfusion increase in FGF2 expression was seen in a mouse model of hind limb I/R, followed by a decline to baseline levels, suggesting a key role for FGF2 in limb survivability. FGF2 appeared to reduce I/R-induced hypoperfusion, tissue edema, skeletal muscle fiber injury, as well as microvascular endothelial cells (ECs) damage within the limb, according to assessments of limb vitality, Western blotting, and immunofluorescence results. The bioinformatics analysis of RNA-sequencing revealed that ferroptosis played a key role in FGF2-facilitated limb preservation. Pharmacological inhibition of NFE2L2 prevented ECs from being affected by FGF2's anti-oxidative and anti-ferroptosis activities. Additionally, silencing of kruppel-like factor 2 (KLF2) by interfering RNA eliminated the antioxidant and anti-ferroptosis effects of FGF2 on ECs. Further research revealed that the AMPK-HDAC5 signal pathway is the mechanism via which FGF2 regulates KLF2 activity. Data from luciferase assays demonstrated that overexpression of HDAC5 prevented KLF2 from becoming activated by FGF2. Collectively, FGF2 protects microvascular ECs from I/R injury by KLF2-mediated ferroptosis inhibition and antioxidant responses.

Sulforaphane protects microvascular endothelial cells in lower limb ischemia/reperfusion injury mice.

Background: Microvascular damage is a key pathological factor in acute lower limb ischemia/reperfusion (I/R) injury. Current evidence suggests that sulforaphane (SFN) protects tissue from I/R injury. However, the role of SFN in acute lower limb I/R injury remains elusive. This study aimed to investigate the role and potential mechanism of SFN in I/R-related microvascular damage in the limb. Methods: Limb viability was evaluated by laser Doppler imaging, tissue edema analysis and histological analysis. Western blotting and immunofluorescence were applied to analyze the levels of apoptosis, oxidative stress, autophagy, transcription factor EB (TFEB) activity and mucolipin 1 (MCOLN1)-calcineurin signaling pathway. Results: SFN administration significantly ameliorated I/R-induced hypoperfusion, tissue edema, skeletal muscle fiber injury and endothelial cell (EC) damage in the limb. Pharmacological inhibition of NFE2L2 (nuclear factor, erythroid 2 like 2) reversed the anti-oxidation and anti-apoptosis effects of SFN on ECs. Additionally, silencing of TFEB by interfering RNA abolished the SFN-induced autophagy restoration, anti-oxidant response and anti-apoptosis effects on ECs. Furthermore, silencing of MCOLN1 by interfering RNA and pharmacological inhibition of calcineurin inhibited the activity of TFEB induced by SFN, demonstrating that SFN regulates the activity of TFEB through the MCOLN1-calcineurin signaling pathway. Conclusion: SFN protects microvascular ECs against I/R injury by TFEB-mediated autophagy restoration and anti-oxidant response.

Comparison of "complications" and functional outcome of anterolateral thigh flap and sural neurofasciocutaneus flap for foot and ankle reconstruction: A single center cohort study.

BACKGROUND: Skin and soft-tissue defects around the foot and ankle remain a challenge for orthopedic and plastic surgeons. Anterolateral thigh (ALT) flap and sural neurofasciocutaneous (NFC) flap are both used to reconstruct lower-extremity soft-tissue defects. The purpose of this study was to compare outcomes of the two flaps and attempt to provide an optimal strategy. METHODS: A retrospective study was conducted, reviewing data from 93 patients who underwent reconstruction of wounds around the foot and ankle with ALT flap (42 cases) or NFC flap (51 cases) from January 2014 to January 2020. Patients' demographics, characteristics of the defect, complications, cosmetic appearance, and functional outcome were analyzed, and statistical analysis was performed. RESULT: There was no difference in gender and etiology; however, NFC flaps were more frequently used in elderly patients. Mean size of the flap in the ALT group was significantly larger in comparison with the NFC group. The ALT group had longer operation and hospitalization time than the NFC group (P < 0.05). The incidence of partial necrosis in ALT group was significantly lower than that in NFC group, while its general complications rate was higher. In long-term follow-up, esthetic appearance of the reconstructed site was comparable in both groups, the ALT group had a higher ratio of revision surgery. Moreover, the ALT group showed better overall esthetic outcomes in the donor site. CONCLUSIONS: The study showed that anterolateral thigh flaps in wound coverage of foot and ankle achieved better outcomes than neurofasciocutaneous flaps in terms of recipient benefits and donor-site compromise with a special indication for larger and more distally located defects.

Foot and ankle reconstruction using the lateral supramalleolar flap versus the anterolateral thigh flap in the elderly: A comparative study.

The purpose of this study was to compare the reconstructive outcomes of soft-tissue defects around the foot and ankle with anterolateral thigh (ALT) flap or lateral supramalleolar (LSM) flap and attempt to provide an optimal strategy for elderly patients. A retrospective review of all continuous patients with foot and ankle reconstruction using different flaps from October of 2010 and October of 2020 was performed. Based on the flap types, the patients were divided into two groups: ALT flap group (n = 50) and LSM flap group (n = 46). Outcomes were assessed according to the flap survival rate, early complications, general complications, late complications, cosmetic appearance, functional outcomes and Vancouver Scar Scale (VSS). We found that there was no difference in average age, gender, aetiology, size of the defect, debridement times between the two groups; however, a significant difference in operation time, hospitalisation time and cost were noted between them. What's more, the early flap complications between them were not significantly different. The LSM flap group showed less general complications, less flap bulky and lower cosmetic appearance. Moreover, the functional evaluation and VSS seem similar (P > .05). Thus, The ALT flap and LSM flap are both flaps available for foot and ankle reconstruction in elderly patients. However, the LSM flap offers short operation time, short hospitalisation time, and less cost with a lower frequency of postoperative complications. Thus, we advocate the LSM flap for the reconstruction of moderate-size defects of the foot and ankle region in elderly patients.

Olfactory ensheathing cells seeded decellularized scaffold promotes axonal regeneration in spinal cord injury rats.

Spinal cord decellularized (DC) scaffolds can promote axonal regeneration and restore hindlimb motor function of spinal cord defect rats. However, scarring caused by damage to the astrocytes at the margin of injury can hinder axon regeneration. Olfactory ensheathing cells (OECs) integrate and migrate with astrocytes at the site of spinal cord injury, providing a bridge for axons to penetrate the scars and grow into lesion cores. The purpose of this study was to evaluate whether DC scaffolds carrying OECs could better promote axon growth. For these studies, DC scaffolds were cocultured with primary extracted and purified OECs. Immunofluorescence and electron microscopy were used for verification of cells adhere and growth on the scaffold. Scaffolds with OECs were transplanted into rat spinal cord defects to evaluate axon regeneration and functional recovery of hind limbs. Basso, Beattie, and Bresnahan (BBB) scoring was used to assess motor function recovery, and glial fibrillary acidic protein (GFAP) and NF200-stained tissue sections were used to evaluate axonal regeneration and astrological scar distribution. Our results indicated that spinal cord DC scaffolds have good histocompatibility and spatial structure, and can promote the proliferation of adherent OECs. In animal experiments, scaffolds carrying OECs have better axon regeneration promoting protein expression than the SCI model, and improve the proliferation and distribution of astrocytes at the site of injury. These results proved that the spinal cord DC scaffold with OECs can promote axon regeneration at the site of injury, providing a new basis for clinical application.

Fibroblast growth factor 21 facilitates peripheral nerve regeneration through suppressing oxidative damage and autophagic cell death.

Seeking for effective drugs which are beneficial to facilitating axonal regrowth and elongation after peripheral nerve injury (PNI) has gained extensive attention. Fibroblast growth factor 21 (FGF21) is a metabolic factor that regulates blood glucose and lipid homeostasis. However, there is little concern for the potential protective effect of FGF21 on nerve regeneration after PNI and revealing related molecular mechanisms. Here, we firstly found that exogenous FGF21 administration remarkably promoted functional and morphologic recovery in a rat model of sciatic crush injury, manifesting as persistently improved motor and sensory function, enhanced axonal remyelination and regrowth and accelerated Schwann cells (SCs) proliferation. Furthermore, local FGF21 application attenuated the excessive activation of oxidative stress, which was accompanied with the activation of nuclear factor erythroid-2-related factor 2 (Nrf-2) transcription and extracellular regulated protein kinases (ERK) phosphorylation. We detected FGF21 also suppressed autophagic cell death in SCs. Additionally, treatment with the ERK inhibitor U0126 or autophagy inhibitor 3-MA partially abolishes anti-oxidant effect and reduces SCs death. Taken together, these results indicated that the role of FGF21 in remyelination and nerve regeneration after PNI was probably related to inhibit the excessive activation of ERK/Nrf-2 signalling-regulated oxidative stress and autophagy-induced cell death. Overall, our work suggests that FGF21 administration may provide a new therapy for PNI.

Comparison of Hybrid Fixation to Dual Plating for Both-Bone Forearm Fractures in Older Children.

When operative stabilization of forearm fractures in older children is necessary, the optimal method of fixation is controversial. This study compared the radiographic and functional outcomes of dual plating to a hybrid fixation construct with elastic intramedullary nailing of the radius and plate fixation of the ulna of forearm fractures in children aged between 10 and 16 years. Nineteen patients were treated using a hybrid fixation construct and 13 patients were treated with dual plating fixation. The 2 groups were compared retrospectively according to perioperative data and patient outcome measures. The hybrid fixation construct group had 19, with a mean age of 13.3 years (range, 10-16 years) and the dual plate group had 13 patients, with a mean age of 12.9 years (range, 10-16 years). Groups were similar for sex, arm injured, and fracture location. Duration of surgery and tourniquet use was significantly shorter in the hybrid fixation construct group. There was no significant difference in either time to union or Price scores for function evaluation between the 2 groups. Complication rates were also similar between groups, with 1 ulna delayed unions, 1 superficial infection at entry of nail in hybrid fixation construct group, and 1 ulna delayed unions in the dual plating group. Hybrid fixation, using open reduction and internal fixation with a plate-and-screw construct on the ulna and closed reduction and elastic intramedullary fixation of the ulna, is an acceptable method for treating both-bone diaphyseal forearm fractures in skeletally immature patients aged 10-16 years.

Comparison of Pediatric Forearm Fracture Fixation Between Single- and Double-Elastic Stable Intramedullary Nailing.

The purpose of this study was to evaluate and compare the outcome of single- and double-elastic stable intramedullary nailing (ESIN) for the treatment of pediatric both-bone forearm fractures. We retrospectively analyzed 49 children with both-bone forearm fractures treated with ESIN. Twenty-four patients were treated with single-ESIN (S-ESIN) to fixate the radius only, and the other 25 patients were treated with double-ESIN (D-ESIN) to fixate the radius and ulna. The duration of surgery, times of fluoroscopy, cost of hospitalization, period of castoff, union time, radiographic outcomes, clinical results, and postoperative complications were compared. The duration of surgery, times of fluoroscopy, and cost of hospitalization were significantly lower in the S-ESIN group; however, the average period of castoff was longer in the S-ESIN group. The incidence of delayed union of the ulna was significantly higher in the D-ESIN than in the S-ESIN group. Although the mean angulation deformity of the ulna in the S-ESIN group was significantly larger than in the D-ESIN group, both of them were acceptable (<10 degrees). Despite this, there was no difference in the loss of forearm motion and complication rates between the 2 groups. In conclusion, our data suggest that S-ESIN to fixate the radius alone remains an equally effective fixation method in the pediatric population compared with both-bone fixation and is our treatment of choice.

[Delayed union or nonunion of the ulna after intramedullary nailing for pediatric forearm fractures].

OBJECTIVE: To analyze the causes of delayed union or nonunion of the ulna after intramedullary nailing in pediatric forearm fractures. METHODS: From February 2005 to February 2010,5 patients with forearm fractures who were treated with titanium elastic nailing (TEN) were identified to fulfill the criteria of having developed a delayed union or nonunion of the ulna. The causes of delayed union or nonunion were investigated according to mechanism of injury, fracture location, treatments methods and postoperative management. All patients were male and the age was 3 to 14 years old with an average of 9.4 years. All fractures were located on the mid-third part of forearm. Two cases had a re-fracture. Among them, 3 cases caused by high-energy injury and 2 cases by falling down. Open reduction were performed in 4 cases while the other one was treated with closed reduction. Four patients were immobilized in an above-elbow cast, postoperatively. RESULTS: All patients were followed up from 7 to 19 months with an average of 11.4 months. There were 4 delayed union and 1 nonunion. Three patients healed after the removal of the nail and avoidance of weight-bearing. Two patients healed by replacing another fixation. No patients had soft-tissue irritation or nail-entry-site infections.. The clinical effect was evaluated according to Daruwalla and Price scores with 3 excellent and 2 good of the results. CONCLUSIONS: Using titanium elastic nailing for the treatment of pediatric both-bone forearm fractures is a good method. However,strict indication selection should be followed to avoid delayed union or nonunion.