The secondary injury cascade after spinal cord injury:an analysis of local cytokine/chemokine regulation

After spinal cord injury,there is an extensive infiltration of immune cells,which exacerbates the injury and leads to further neural degeneration.Therefore,a major aim of current research involves targeting the immune response as a treatment for spinal cord injury.Although much research has been performed analyzing the complex inflammatory process following spinal cord injury,there remain major discrepancies within previous literature regarding the timeline of local cytokine regulation.The objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury,identify sexual dimorphisms in terms of cytokine levels,and determine local cytokines that significantly change based on the severity of spinal cord injury.Rats were inflicted with either a mild contusion,moderate contusion,severe contusion,or complete transection,7 mm of spinal cord centered on the injury was harvested at varying times post-injury,and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex assay.Results demonstrated pro-inflammatory cytokines including tumor necrosis factorα,interleukin-1β,and interleukin-6 were all upregulated after spinal cord injury,but returned to uninjured levels within approximately 24 hours post-injury,while chemokines including monocyte chemoattractant protein-1 remained upregulated for days post-injury.In contrast,several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days post-injury.After spinal cord injury,tissue inhibitor of metalloproteinase-1,which specifically affects astrocytes involved in glial scar development,increased more than all other cytokines tested,reaching 26.9-fold higher than uninjured rats.After a mild injury,11 cytokines demonstrated sexual dimorphisms;however,after a severe contusion only leptin levels were different between female and male rats.In conclusion,pro-inflammatory cytokines initiate the inflammatory process and return to baseline within hours post-injury,chemokines continue to recruit immune cells for days post-injury,while anti-inflammatory cytokines are downregulated by a week post-injury,and sexual dimorphisms observed after mild injury subsided with more severe injuries.Results from this work define critical chemokines that influence immune cell infiltration and important cytokines involved in glial scar development after spinal cord injury,which are essential for researchers developing treatments targeting secondary damage after spinal cord injury.

Detailed description of Division I ice hockey concussions:Findings from the NCAA and Department of Defense CARE Consortium

Objective:Since concussion is the most common injury in ice hockey,the objective of the current study was to elucidate risk factors,specific mechanisms,and clinical presentations of concussion in men’s and women’s ice hockey.Methods:Ice hockey players from 5 institutions participating in the Concussion Assessment,Research,and Education Consortium were eligible for the current study.Participants who sustained a concussion outside of this sport were excluded.There were 332(250 males,82 females)athletes who participated in ice hockey,and 47(36 males,11 females)who sustained a concussion.Results:Previous concussion(odds ratio(OR)=2.00;95%confidence interval(95%CI):1.02‒3.91)was associated with increased incident concussion odds,while wearing a mouthguard was protective against incident concussion(OR=0.43;95%CI:0.22‒0.85).Overall,concussion mechanisms did not significantly differ between sexes.There were specific differences in how concussions presented clinically across male and female ice hockey players,however.Females(9.09%)were less likely than males(41.67%)to have a delayed symptom onset(p=0.045).Additionally,females took significantly longer to reach asymptomatic(p=0.015)and return-to-play clearance(p=0.005).Within the first 2 weeks post-concussion,86.11%of males reached asymptomatic,while only 45.50%of females reached the same phase of recovery.Most males(91.67%)were cleared for return to play within 3 weeks of their concussion,compared to less than half(45.50%)of females.Conclusion:The current study proposes possible risk factors,mechanisms,and clinical profiles to be validated in future concussions studies with larger female sample sizes.Understanding specific risk factors,concussion mechanisms,and clinical profiles of concussion in collegiate ice hockey may generate ideas for future concussion prevention or intervention studies.

Relationship of PDCD5 expression with apoptosis, inflammatory factors and MMPs/TIMPs expression in degenerated intervertebral disc tissue

Objective: To study the relationship of PDCD5 expression with apoptosis, inflammatory factors and MMPs/TIMPs expression in degenerated intervertebral disc tissue. Methods:Patients with lumbar disc herniation who were treated in the Seventh People's Hospital of Shanghai between March 2015 and February 2017 were selected as the LDH group and patients with violent thoracolumbar vertebral fracture were selected as the control group. The intervertebral disc tissue was collected to determine the mRNA expression of PDCD5 as well as the protein levels of apoptosis molecules, inflammatory factors and MMPs/TIMPs molecules. Results: PDCD5 mRNA expression in intervertebral disc tissue of LDH group was significantly higher than that of control group;Caspase-3, Caspase-8, Fas, Caspase-9, Bax, SDF-1, CXCR-4, TNF-α, PGE2, MMP1, MMP2, MMP8 and MMP9 protein levels in intervertebral disc tissue of LDH group were significantly higher than those of control group and positively correlated with PDCD5 mRNA expression while TIMP1 and TIMP2 protein levels were significantly lower than those of control group and negatively correlated with PDCD5 mRNA expression. Conclusion: The high expression of PDCD5 in degenerated intervertebral disc tissue can activate apoptosis and inflammatory response and cause MMPs/TIMPs imbalance.

β-catenin mRNA encapsulated in SM-102 lipid nanoparticles enhances bone formation in a murine tibia fracture repair model

Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture healing.In this study,we aimed to develop an osteoanabolic therapy which activates the Wnt/β-catenin pathway,a molecular driver of endochondral ossification.We hypothesize that using an mRNAbased therapeutic encodingβ-catenin could promote cartilage to bone transformation formation by activating the canonical Wnt signaling pathway in chondrocytes.To optimize a delivery platform built on recent advancements in liposomal technologies,two FDA-approved ionizable phospholipids,DLin-MC3-DMA(MC3)and SM-102,were used to fabricate unique ionizable lipid nanoparticle(LNP)formulations and then tested for transfection efficacy both in vitro and in a murine tibia fracture model.Using firefly luciferase mRNA as a reporter gene to track and quantify transfection,SM-102 LNPs showed enhanced transfection efficacy in vitro and prolonged transfection,minimal fracture interference and no localized inflammatory response in vivo over MC3 LNPs.The generatedβ-cateninGOF mRNA encapsulated in SM-102 LNPs(SM-102-β-cateninGOF mRNA)showed bioactivity in vitro through upregulation of downstream canonical Wnt genes,axin2 and runx2.When testing SM-102-β-cateninGOF mRNA therapeutic in a murine tibia fracture model,histomorphometric analysis showed increased bone and decreased cartilage composition with the 45μg concentration at 2 weeks post-fracture.μCT testing confirmed that SM-102-β-cateninGOF mRNA promoted bone formation in vivo,revealing significantly more bone volume over total volume in the 45μg group.Thus,we generated a novel mRNA-based therapeutic encoding aβ-catenin mRNA and optimized an SM-102-based LNP to maximize transfection efficacy with a localized delivery.

Lateral Intra-Articular Transposition of the Anterior Tibialis Tendon for the Treatment of Relapsed Clubfoot in Toddlers: A Previously Unreported Surgical Technique

Dynamic supination of the foot is a common residual deformity in children with clubfeet treated with the Ponseti method. Transfer of the anterior tibialis tendon (ATT) to the lateral cuneiform is an effective method for correcting this deformity when the cuneiform is ossified in children who are 3 to 5 years of age. We describe two cases of a previously unreported method of ATT transposition for correction of bilateral residual dynamic supination in a 26-month-old and a 19-month-old patient. Both patients presented shortly after birth with bilateral congenital idiopathic clubfoot and were initially treated with the Ponseti method. Both had residual deformity following initial treatment that included posterior contracture and metatarsus adductus with dynamic forefoot supination. This was surgically corrected with a posterior release and medial release of the 1st metatarsal/1st cuneiform joint. To correct dynamic supination, the ATT was transplanted laterally into the released midfoot joint. These two patients were followed post-operatively for 7.5 years and have correction of their residual deformity in both feet based on subjective functioning, appearance, range of motion, strength, and gait. Both have excellent lateral pull of their ATT, which functions as a strong foot dorsiflexor. No residual supination is present. This is the first report of lateral transposition of the ATT as an interposition graft at the released 1st metatarsal/1st cuneiform joint in patients with relapsed clubfoot. We suggest that this method should provide a high level of functioning in children with relapsed supination deformity and whose 3rd cuneiform has not yet ossified.

Different types of mechanical complications after surgical correction of adult spine deformity with osteotomy

AIM To determine the incidence and risk factors for mechanical complications （MC） after surgical correction of adult spinal deformity （ASD） with osteotomy.METHODSA retrospective study was performed. Inclusion criteria： Surgical correction of ASD using osteotomy; male or female; 〉 20 years old; follow-up ≥ 24 mo or revision. The MC of spine and spinal instrumentation were studied separately. Risk analysis included assessment of the association between more than 50 different characteristics （demographic, clinical, radiographic, and instrumentation） with different types of MC.RESULTSThe medical records of 94 operations in 88 subjects were analyzed： Female （68%）, mean age 58.6 （SD, 12.7） years. Cumulative incidence of MC at 2 year follow-up was 43.6%. Of these, 78% required revision （ P 〈 0.001）. The following characteristics had significant （ P ≤ 0.05） association with MC： （1） Preoperative： osteoporosis, smoking, previous spinal operation, sagittal vertical axis （SVA） 〉 100 mm, lumbar lordosis （LL） 〈 34°; （2） postoperative： SVA 〉 75 mm; operative correction： SVA 〉 75 mm, LL 〉 30°, thoracic kyphosis 〉 25°, and pelvic tilt 〉 9°; a fall; pseudarthrosis; and （3） device and surgical technique： use of previously implanted instrumentation; use of domino and/or parallel connectors; type of osteotomy （PSO vs SPO） if preoperative SVA 〈 100 mm; lumbar osteotomy location; in-situ rod contouring 〉 60°; and fxation to sacrum/pelvis.CONCLUSIONRisk of MC after surgical correction of ASD is substantial. To decrease this risk over- and/or insuffcient correction of the sagittal imbalance should be avoided.

Ultra-High Molecular Weight Polyethylene Tape Applied for Distal Humeral Condyle Fracture around Total Elbow Arthroplasty in Patients with Rheumatoid Arthritis: Report of Two Cases

Managing fractures of distal humerus in patients with rheumatoid arthritis (RA) is technically challenging. Total elbow arthroplasty (TEA) is one of the treatment options for these fractures. While elbow motion is largely regained by TEA, comminuted condyle fragments are often ignored. Although numerous approaches for repair of condylar fragments around TEA are described, any universal fixation strategy for these fractures has not been established. This report describes, for the first time, application of an ultra-high molecular weight polyethylene (UHMWPE) tape for the treatment of distal humerus fracture in 2 patients with rheumatic elbow arthropathy. The post-operative clinical courses were good. Radiographs showed bony union of the condylar fragments without loosening in two cases. Because of its flat configuration, softness, and flexibility, UHMWPE tape is a promising material for stabilizing fracture of the distal humerus associated with TEA.

Orthopaedic education in the era of surgical simulation: Still at the crawling stage

Surgical skills education is in the process of a crucial transformation from a master-apprenticeship model to simulation-based training. Orthopaedic surgery is one of the surgical specialties where simulation-based skills training needs to be integrated into the curriculum efficiently and urgently. The reason for this strong and pressing need is that orthopaedic surgery covers broad human anatomy and pathologies and requires learning enormously diverse surgical procedures including basic and advanced skills. Although the need for a simulationbased curriculum in orthopaedic surgery is clear, several obstacles need to be overcome for a smooth transformation. The main issues to be addressed can be summarized as defining the skills and procedures so that simulation-based training will be most effective; choosing the right time period during the course of orthopaedic training for exposure to simulators; the right amount of such exposure; using objective, valid and reliable metrics to measure the impact of simulation-based training on the development and progress of surgical skills; and standardization of the simulation-based curriculum nationwide and internationally. In the new era of surgical education, successful integration of simulation-based surgical skills training into the orthopaedic curriculum will depend on efficacious solutions to these obstacles in moving forward.

肌电生物反馈在陈旧性颈脊髓损伤中的应用

目的 :观察EMG生物反馈治疗是否能够恢复和增强陈旧性颈脊髓 (C1—C6)损伤患者上肢各肌的自主肌电信号和肌力。方法 :1 39例非完全性颈脊髓 (C1—C6)损伤患者 ,病程均在 6个月以上、伴有不同程度的上肢功能障碍和肌力缺陷 ,且经其它康复方法治疗而无进一步功能恢复者。全部患者均接受 1个疗程、1 5次、每次 50min的治疗。分别记录治疗前后的中三角肌、肱二头肌、肱三头肌、腕伸肌、腕屈肌、指伸肌和指屈肌肌电信号和肌力测定分级数据 ,进行统计学分析。结果 :治疗后患者自主肌电信号和肌力均较治疗前有明显提高 (P <0 .0 0 1 )。结论 :EMG生物反馈是治疗非完全性、陈旧性颈脊髓 (C1—C6)

操作性肌电生物反馈治疗陈旧性颈脊髓损伤多疗程疗效观察

目的观察操作性EMG生物反馈多疗程连续治疗是否能够在前一疗程疗效的基础上,进一步恢复和增强陈旧性颈脊髓(C1—C6)损伤患者上肢各肌的自主肌电信号和肌力。方法39例非完全性颈脊髓(C1—C6)损伤患者,病程均在6个月以上、均有不同程度上肢功能障碍和肌力缺陷,而且均经其它康复方法治疗而无进一步功能恢复者。全部患者均接受每年1疗程,每疗程15次,每次50min,连续4个疗程的治疗。记录中三角肌、肱二头肌、肱三头肌、腕伸肌、腕屈肌、指伸肌和指屈肌治疗前后的肌电信号和肌力测定分级数据,进行比较。结果每疗程治疗后患者的自主肌电信号和肌力均较前一疗程治疗后的自主肌电信号和肌力有明显提高(P<0.01)。结论多疗程操作性EMG生物反馈治疗能够在前一疗程疗效的基础上,进一步提高陈旧性颈脊髓损伤患者上肢各肌的自主肌电信号和肌力。

The principles and practice of open fracture care, 2018

The principles of open fracture management are to manage the overall injury and specifically prevent primary contamination becoming frank infection. The surgical management of these complex injuries includes debridement ＆ lavage of the open wound with combined bony and soft tissue reconstruction. Good results depend on early high quality definitive surgery usually with early stable internal fixation and associated soft tissue repair. While all elements of the surgical principles are very important and depend on each other for overall success the most critical element appears to be achieving very early healthy soft tissue cover. As the injuries become more complex this involves progressively more complex soft tissue reconstruction and may even requiring urgent free tissue transfer requiring close co-operative care between orthopaedic and plastic surgeons. Data suggests that the best results are obtained when the whole surgical reconstruction is completed within 48-72 h.

Functional recovery after peripheral nerve injury via sustained growth factor delivery from mineral-coated microparticles

The gold standard for treating peripheral nerve injuries that have large nerve gaps where the nerves cannot be directly sutured back together because it creates tension on the nerve,is to incorporate an autologous nerve graft.However,even with the incorporation of a nerve graft,generally patients only regain a small portion of function in limbs affected by the injury.Although,there has been some promising results using growth factors to induce more axon growth through the nerve graft,many of these previous therapies are limited in their ability to release growth factors in a sustained manner and tailor them to a desired time frame.The ideal drug delivery platform would deliver growth factors at therapeutic levels for enough time to grow axons the entire length of the nerve graft.We hypothesized that mineral coated microparticles(MCMs)would bind,stabilize and release biologically active glial cell-derived neurotrophic factor(GDNF)and nerve growth factor(NGF)in a sustained manner.Therefore,the objective of this study was to test the ability of MCMs releasing growth factors at the distal end of a 10 mm sciatic nerve graft,to induce axon growth through the nerve graft and restore hind limb function.After sciatic nerve grafting in Lewis rats,the hind limb function was tested weekly by measuring the angle of the ankle at toe lift-off while walking down a track.Twelve weeks after grafting,the grafts were harvested and myelinated axons were analyzed proximal to the graft,in the center of the graft,and distal to the graft.Under physiological conditions in vitro,the MCMs delivered a burst release of NGF and GDNF for 3 days followed by a sustained release for at least 22 days.In vivo,MCMs releasing NGF and GDNF at the distal end of sciatic nerve grafts resulted in significantly more myelinated axons extending distal to the graft when compared to rats that received nerve grafts without growth factor treatment.The rats with nerve grafts incorporated with MCMs releasing NGF and GDNF also showed significant improvement in hind limb function starting at 7 weeks postoperatively and continuing through 12 weeks postoperatively when compared to rats that received nerve grafts without growth factor treatment.In conclusion,MCMs released biologically active NGF and GDNF in a sustained manner,which significantly enhanced axon growth resulting in a significant improvement of hind limb function in rats.The animal experiments were approved by University of Wisconsin-Madison Animal Care and Use Committee(ACUC,protocol#M5958)on January 3,2018.

操作性肌电生物反馈治疗慢性颈脊髓损伤的疗效观察

目的 观察操作性肌电生物反馈治疗是否能够增强慢性颈脊髓 (C1～ 6)损伤患者上肢各肌的自主肌电信号和肌力。方法 慢性非完全性颈脊髓 (C1～ 6)损伤患者 13 9例 ,为美国迈阿嘧大学医学院附属Jackson医学中心骨、康复科门诊患者 ,病程 >6个月 ,均有不同程度上肢功能障碍和肌力减低 ,而且均为经其它康复方法治疗而无进一步功能恢复者。全部患者均接受 15次 (1个疗程 )、每次 5 0min的治疗。分别记录治疗前、后三角肌中部、肱二头肌、肱三头肌、腕伸肌、腕屈肌、指伸肌和指屈肌的肌电信号和肌力测定分级数据 ,并进行比较和统计学分析。结果 治疗后患者自主肌电信号和肌力均较治疗前有明显提高 ,差异有显著性 (P <0 .0 1)。结论 操作性肌电生物反馈是治疗非完全性、慢性颈脊髓 (C1～ 6)损伤的有效方法。