The disease-ameliorating function of autoregulatory CD8 T cells is mediated by targeting of encephalitogenic CD4 T cells in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS, and CD8 T cells are the predominant T cell population in MS lesions. Given that transfer of CNS-specific CD8 T cells results in an attenuated clinical demyelinating disease in C57BL/6 mice with immunization-induced experimental autoimmune encephalomyelitis (EAE), we investigated the cellular targets and mechanisms of autoreactive regulatory CD8 T cells. In this study we report that myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced CD8 T cells could also attenuate adoptively transferred, CD4 T cell-mediated EAE. Whereas CD8(-/-) mice exhibited more severe EAE associated with increased autoreactivity and inflammatory cytokine production by myelin-specific CD4 T cells, this was reversed by adoptive transfer of MOG-specific CD8 T cells. These autoregulatory CD8 T cells required in vivo MHC class Ia (K(b)D(b)) presentation. Interestingly, MOG-specific CD8 T cells could also suppress adoptively induced disease using wild-type MOG35-55-specific CD4 T cells transferred into K(b)D(b-/-) recipient mice, suggesting direct targeting of encephalitogenic CD4 T cells. In vivo trafficking analysis revealed that autoregulatory CD8 T cells are dependent on neuroinflammation for CNS infiltration, and their suppression/cytotoxicity of MOG-specific CD4 T cells is observed both in the periphery and in the CNS. These studies provide important insights into the mechanism of disease suppression mediated by autoreactive CD8 T cells in EAE.

Hands-free Femoral Traction Using the Bookwalter Retractor System During Anterior Approaches to the Acetabulum.

SUMMARY: Displaced acetabular fractures with medial and cranial displacement of the femoral head commonly require an anterior approach for reduction and stabilization. Restoration of the femoral head to its native position under the reduced acetabular dome is a primary goal of surgery. We present a surgical technique for applying traction to the proximal femur using the Bookwalter retractor system during the repair of acetabular fractures when using an anterior approach. By placing traction in line with the femoral neck, the femoral head is moved to a more anatomical position allowing acetabular fracture fragments to be reduced unimpeded and the femoral head may be used as a reconstructive template. We review a case series of 116 patients treated using this technique and report the short- and long-term radiographic and clinical results of treatment.

Local Infiltrative Analgesia of Murine Femur Fractures In Vivo Does Not Inhibit Fracture Healing.

The opioid epidemic in the United States has forced care providers to seek out alternatives to narcotic analgesics. Physicians involved in trauma care, including orthopaedic trauma surgeons, often have patients requiring significant amounts of these medications, especially in the perioperative period, given the acuity and severity of their injuries. Modalities such as local infiltration of fractures with anesthetic agents during operative treatment may provide some benefit to this population by decreasing postoperative pain and narcotic usage. However, prior data suggest that these agents are chondrotoxic, which may impede secondary fracture healing. The purpose of this study was to investigate the hypothesis that local anesthetics decrease secondary bone healing and callus formation in stabilized murine femur fractures through chondrocyte apoptosis. Male C57BL/6 mice underwent intramedullary stabilization and fracture of bilateral femurs followed by immediate infiltration of the fracture site with local anesthetic agents. Femurs were dissected at 10- and 20-days post-fracture and evaluated by [Formula: see text]CT and histological analysis. No significant differences were seen in callus size or mineralization between controls and fractures treated with a local anesthetic. When the callus was analyzed histologically, local anesthetic agents appeared to increase cartilage density. Therefore, infiltration of local anesthetics during operative treatment of fracture as part of a multimodal approach to pain control does not appear to significantly affect callus formation in a preclinical model, although subclinical molecular effects may be present. Local infiltrative analgesia with local anesthetics may be used as an adjunct for perioperative pain control during femur fracture surgery without a significant effect on secondary bone healing.

Extra-articular Unstable Iliac Fractures: Associated Injuries, Fixation Strategies, and Outcomes.

OBJECTIVE: To characterize the associated injuries, fixation constructs, and outcomes of extra-articular unstable iliac fractures. DESIGN: Retrospective cohort study. SETTING: Level I trauma center. PATIENTS: Thirty-three extra-articular unstable iliac fractures treated over a 20-year period. INTERVENTION: Percutaneous or open fixation of iliac fractures at the pelvic brim AND/OR iliac crest. MAIN OUTCOME MEASURES: Incidence of union, fixation failure, and angiography at the time of injury. RESULTS: Twenty-five patients were treated operatively with appropriate follow-up. Four patients had fixation failure with displacement, all in the group with only brim OR crest fixation (4/8 patients, 50% rate). In patients with both crest AND brim fixation (n = 17), there were no cases of implant failure or late displacement. In displaced fractures (n = 22), 4 patients (18%) required embolization by interventional radiology. In all 4 cases, the superior gluteal artery was embolized. In patients with both crest AND brim fixation, all went on to uneventful union with an average Visual Analog Scale (VAS) pain score of 0.9 (range, 0-5) at final follow-up. CONCLUSIONS: Extra-articular unstable iliac fractures are high-energy injuries that demonstrate a high rate of union when both pelvic brim AND iliac crest fixation is used. Approximately 1 in 5 patients with a displaced iliac fracture presented with a superior gluteal artery disruption requiring embolization. Pelvic brim OR iliac crest fixation used in isolation was associated with a fixation failure rate of 50%, supporting previous biomechanical work. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Preoperative and Intraoperative Considerations Using Intramedullary Nails for the Treatment of Tibial Shaft Fractures Below Total Knee Arthroplasty.

SUMMARY: Periprosthetic tibial shaft fractures below total knee arthroplasty (TKA) are relatively rare, with an incidence of approximately 1%. However, as the rates of arthroplasty increase, orthopaedic surgeons are likely to see a corresponding increase in these types of fractures. Native tibial shaft fractures are routinely treated with either nails or plates, and the success of intramedullary nailing of tibial shaft fractures has been well described in the literature. In this article, we seek to describe a case series of tibial shaft fractures in patients with ipsilateral TKA treated with infrapatellar intramedullary nailing. We will focus on preoperative considerations including templating and measurement of the anterior cortical implant distance on the lateral radiograph to ensure space for safe nail passage. We will also discuss intraoperative technical tricks, including Kirschner wire insertion for sounding the start point, utilization of the curved awl, use of hand reamers, and rotation of the nail to bypass the implant. Using meticulous preoperative planning and technical intraoperative tricks, patients with tibial shaft fractures below TKA may be successfully treated with intramedullary nailing.

Immune regulatory CNS-reactive CD8+T cells in experimental autoimmune encephalomyelitis.

Immune-based self-recognition and failure to modulate this response are believed to contribute to the debilitating autoimmune pathology observed in multiple sclerosis (MS). Studies from its murine model, experimental autoimmune encephalomyelitis (EAE), have shown that neuroantigen-specific CD4+T cells are capable of inducing disease, while their immune sibling, the CD8+T cells, have largely been ignored. To understand their role in autoimmune demyelination, we first confirmed that, similar to our observations in human MS, there is robust induction of neuroantigen-reactive CD8+T cells in several models, including MOG(35-55)/CFA-induced EAE. However, MOG(35-55)-specific CD8+T-cells, when purified, were unable to adoptively transfer disease into naïve mice (in contrast to CD4+T-cells). In fact, we observed that the transfer of these neuroantigen-specific CD8+T cells was able to suppress the induction of EAE and to inhibit ongoing EAE. These regulatory CD8+T cells produced IFN-gamma and perforin and were able to kill MOG loaded CD4+T-cells as well as CD4-depleted APC, suggesting a cytotoxic/suppressor mechanism. Inhibition of EAE was associated with both the modulation of APC function as well as decreased MOG-specific CD4+T cell responses. Our studies reveal a novel and unexpected immune regulatory function for neuroantigen-specific CD8+T cells and have interesting biologic and therapeutic implications.

Comparison of Spatiotemporal Gait Parameters Following Operative Treatment of Trimalleolar Ankle Fractures vs Healthy Controls.

BACKGROUND: Controversy continues regarding appropriate indications for posterior malleolus fracture fixation in unstable rotational trimalleolar ankle injuries, with limited data comparing gait in operatively treated trimalleolar ankle fractures vs control populations. The purpose of this study was to evaluate the effect of trimalleolar ankle fracture fixation on gait parameters in the early postoperative period as compared to a healthy control population. METHODS: Adult patients having undergone operative treatment of isolated trimalleolar ankle fractures were eligible for inclusion. A total of 10 patients met the inclusion criteria and participated in the analysis. Patients were evaluated using standard parameters of human gait 6 months after their index procedures, with gait values compared to a population of 17 non-age-matched healthy control subjects in addition to literature values of healthy populations of younger and older subjects. RESULTS: Significant differences were noted between the spatiotemporal gait parameters of healthy control subjects and patients who had undergone operative treatment of trimalleolar ankle fractures. However, within the fracture group itself, no differences were found between patients with or without posterior malleolar fixation for any of the tested gait parameters. When patients were compared to literature values of younger and older healthy control populations, they were found to have gait patterns more similar to older rather than younger individuals. CONCLUSION: Operative fixation of trimalleolar ankle fracture does not restore normal gait function in the early postoperative period. Fixation of the posterior malleolus in particular also does not appear to improve gait characteristics. Patients who undergo surgery for these injuries demonstrate gait patterns similar to those of healthy older adults. LEVEL OF EVIDENCE: Level II, Therapeutic (prospective cohort study).

CD8(+) T Cells Are Required For Glatiramer Acetate Therapy in Autoimmune Demyelinating Disease.

The exact mechanism of glatiramer acetate (GA, Copaxone®), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8(+) T cell responses that can potentially suppress pathogenic CD4(+) T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8(+) T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8(+) T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non-classical MHC class I, IFN-γ, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4(+) regulatory T cells in an antigen-independent manner, required CD8(+) T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8(+) T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent.