CD4+ T cell-mediated neuroprotection is independent of T cell-derived BDNF in a mouse facial nerve axotomy model.

BACKGROUND: The production of neurotrophic factors, such as BDNF, has generally been considered an important mechanism of immune-mediated neuroprotection. However, the ability of T cells to produce BDNF remains controversial. METHODS: In the present study, we examined mRNA and protein of BDNF using RT-PCR and western blot, respectively, in purified and reactivated CD4(+) T cells. In addition, to determine the role of BDNF derived from CD4(+) T cells, the BDNF gene was specifically deleted in T cells using the Cre-lox mouse model system. RESULTS: Our results indicate that while both mRNA expression and protein secretion of BDNF in reactivated T cells were detected at 24 h, only protein could be detected at 72 h after reactivation. The results suggest a transient up-regulation of BDNF mRNA in reactivated T cells. Furthermore, in contrast to our hypothesis that the BDNF expression is necessary for CD4(+) T cells to mediate neuroprotection, mice with CD4(+) T cells lacking BDNF expression demonstrated a similar level of facial motoneuron survival compared to their littermates that expressed BDNF, and both levels were comparable to wild-type. The results suggest that the deletion of BDNF did not impair CD4(+) T cell-mediated neuroprotection. CONCLUSION: Collectively, while CD4(+) T cells are a potential source of BDNF after nerve injury, production of BDNF is not necessary for CD4(+) T cells to mediate their neuroprotective effects.

Smoking Effects in Foot and Ankle Surgery: An Evidence-Based Review.

BACKGROUND: The purpose of this article was to review the basic science pertaining to the harmful effects of cigarette smoke, summarize recent clinical outcome studies, and examine the benefits of smoking cessation and the efficacy of current smoking cessation strategies. METHODS: The literature concerning basic science, clinical outcomes, and smoking cessation was reviewed; over half (56%) of the 52 articles reviewed were published in the last 5 years. RESULTS: Smoking is associated with low bone mineral density, delayed fracture union, peri-implant bone loss, and implant failure. Orthopedic surgical patients who smoke have increased pain and lower overall patient satisfaction, along with significantly increased rates of wound healing complications. DISCUSSION/CONCLUSION: Active smoking is a significant modifiable risk factor and should be discontinued before foot and ankle surgery whenever possible. Orthopedic surgeons play an important role in educating patients on the effects of smoking and facilitating access to smoking cessation resources. LEVEL OF EVIDENCE: Level V, expert opinion.

Identification of a resilient mouse facial motoneuron population following target disconnection by injury or disease.

BACKGROUND: When nerve transection is performed on adult rodents, a substantial population of neurons survives short-term disconnection from target, and the immune system supports this neuronal survival, however long-term survival remains unknown. Understanding the effects of permanent axotomy on cell body survival is important as target disconnection is the first pathological occurrence in fatal motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). OBJECTIVE: The goal of this study was to determine if facial motoneurons (FMN) could survive permanent target disconnection up to 26 weeks post-operation (wpo) after facial nerve axotomy (FNA). In addition, the potentially additive effects of immunodeficiency and motoneuron disease on post-axotomy FMN survival were examined. METHODS: This study included three wild type (WT) mouse strains (C57BL/6J, B6SJL, and FVB/NJ) and three experimental models (RAG-2-/-: immunodeficiency; mSOD1: ALS; Smn-/-/SMN2+/+: SMA). All animals received a unilateral FNA, and FMN survival was quantified at early and extended post-operative timepoints. RESULTS: In the C57BL/6J WT group, FMN survival significantly decreased at 10 wpo (55±6%), and then remained stable out to 26 wpo (47±6%). In the RAG-2-/- and mSOD1 groups, FMN death occurred much earlier at 4 wpo, and survival plateaued at approximately 50% at 10 wpo. The SMA model and other WT strains also exhibited approximately 50% FMN survival after FNA. CONCLUSION: These results indicate that immunodeficiency and motoneuron disease accelerate axotomy-induced neuron death, but do not increase total neuron death in the context of permanent target disconnection. This consistent finding of a target disconnection-resilient motoneuron population is prevalent in other peripheral nerve injury models and in neurodegenerative disease models as well. Characterization of the distinct populations of vulnerable and resilient motoneurons may reveal new therapeutic approaches for injury and disease.

What Factors Are Predictive of Outcome in the Treatment of Soft Tissue Sarcomas of the Foot and Ankle?

Soft tissue sarcomas of the foot and ankle are common. Currently, there exist limited data on prognostic variables. The aim of this study was to review our institution's experience with soft tissue sarcomas of the foot and ankle to identify factors affecting outcomes and survivorship. We reviewed the records of 62 foot and ankle soft tissue sarcomas treated with definitive surgery at our institution between 1992 and 2013. The cohort consisted of 35 males and 27 females with a mean age at diagnosis of 45 years and a mean follow-up of 7 years. The most common tumor subtype was synovial sarcoma (n = 16). The overall limb salvage rate was 53%. Local recurrence was observed in 9 patients and distant metastases in 15 patients. Tumor size ≥3 cm in maximal dimension was the greatest risk factor in mortality. Posttreatment complications occurred in 15 patients. Local recurrence and development of distant disease was relatively common following wide excision of a soft tissue sarcoma of the foot and ankle. Tumors that were ≥3 cm in maximal dimension were associated with a worse overall survival and patients with neoadjuvant radiation were at increased risk of complications. LEVELS OF EVIDENCE: Level IV: Retrospective Case Series.

Complex Primary Total Knee Arthroplasty: Long-Term Outcomes.

BACKGROUND: Total knee arthroplasty in patients with severe preoperative deformity, ligamentous instability, and/or marked bone loss occasionally requires a varus and valgus constrained or rotating-hinge design prosthesis. The purpose of this study was to compare patient populations that underwent primary total knee arthroplasty with constrained or unconstrained total knee arthroplasty implants to determine patient demographic characteristics, long-term survival, and reasons for reoperation and revision for each group. METHODS: We identified 28,667 primary total knee arthroplasties performed from 1979 to 2013 at our institution. A total of 427 knees had a varus and valgus constrained design and 246 knees underwent rotating-hinge total knee arthroplasties. Patient demographic information and preoperative diagnoses were analyzed by implant type. A multivariate analysis was performed to account for age, sex, and body mass index (BMI). Kaplan-Meier survival rates for each complication leading to reoperation or component revision were determined at 10 and 20 years. Adjusted hazard ratios were determined for the most common causes for reoperation and revision compared with a routine total knee arthroplasty control group. RESULTS: Patient demographic characteristics were significantly different (p < 0.05) between all groups for age, sex, and BMI. The varus and valgus constrained and rotating-hinge groups had decreased survival free of all-cause reoperation at 10 and 20 years compared with the unconstrained total knee arthroplasty group, with a hazard ratio of 1.74 (95% confidence interval [95% CI], 1.36 to 2.23) for the valgus and varus constrained group and 2.07 (95% CI, 1.58 to 2.70) for the rotating-hinge group. The adjusted hazard ratio for all-cause revision was significantly higher for the varus and valgus constrained group at 1.65 (p = 0.007) but not for the rotating-hinge group at 1.48 (p = 0.054) compared with the unconstrained total knee arthroplasty group. Wear and osteolysis, infection, and fracture were the most common reasons for component revision in both groups. CONCLUSIONS: We found increased reoperation and revision rates associated with the use of constrained implants at the time of index total knee arthroplasty. The rate of component revision for any reason at 10 years was >2 times higher in the constrained total knee arthroplasty groups compared with the unconstrained total knee arthroplasty group. At 20 years postoperatively, the component revision rate was >3 times higher. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Rotating platform versus fixed bearing total knee arthroplasty at mid-term follow-up.

BACKGROUND: Rotating platform posterior stabilized (RP) total knee arthroplasty (TKA) was initially developed in part to decrease polyethylene wear and to improve patellar tracking. There have been limited studies evaluating the longevity and causes of reoperation or revision for this implant. The following study compares mid-term survival rates and causes for reoperation between fixed bearing (FB) TKAs. METHODS: We identified 11,416 patients who underwent a primary posterior stabilized TKA between 2001 and 2013. This group was stratified to include patients with a RP (n=926) and FB (n=10,490) TKA design. Kaplan-Meier survival rates for each complication that led to reoperation were determined at five- and 10-years. Univariate hazard ratios were determined for the most common causes for reoperation and overall implant survival rates. A multivariate analysis was performed to account for the age, gender and preoperative diagnosis discrepancy between groups. RESULTS: The reoperation data demonstrated statistically increased all-cause reoperation rate (p=<0.001) and reoperation rate for stiffness in the RP group (p=0.001). After adjusting for demographic variables we noted no statistically significant differences in reoperation rate and reoperation for stiffness. Additionally, a statistically significant decrease was noted in all-cause revision (p=0.024) and revision for aseptic loosening or osteolysis in the RP group (p=0.029). CONCLUSION: After adjusting for patient demographic differences, we noted a statistically significant decrease in the overall revision and revision for aseptic loosening or osteolysis rates in the RP group.

Functional recovery and facial motoneuron survival are influenced by immunodeficiency in crush-axotomized mice.

Facial nerve axotomy is a well-described injury paradigm for peripheral nerve regeneration and facial motoneuron (FMN) survival. We have previously shown that CD4(+) T helper (Th) 1 and 2 effector subsets develop in the draining cervical lymph node, and that the IL-4/STAT-6 pathway of Th2 development is critical for FMN survival after transection axotomy. In addition, delayed behavioral recovery time in immunodeficient mice may be due to the absence of T and B cells. This study utilized a crush axotomy paradigm to evaluate FMN survival and functional recovery in WT, STAT-6 KO (impaired Th2 response), T-Bet KO (impaired Th1 response), and RAG-2 KO (lacking mature T and B cells) mice to elucidate the contributions of specific CD4(+) T cell subsets in motoneuron survival and recovery mechanisms. STAT-6 KO and RAG-2 KO mice exhibited decreased FMN survival after crush axotomy compared to WT, supporting a critical role for the Th2 effector cell in motoneuron survival before target reconnection. Long term FMN survival was sustained through 10 wpo after crush axotomy in both WT and RAG-2 KO mice, indicating that target derived neurotrophic support maintains FMN survival after target reconnection. In addition, RAG-2 KO mice exhibited delayed functional recovery compared to WT mice. Both STAT-6 and T-Bet KO mice exhibited partially delayed functional recovery compared to WT, though not to the extent of RAG-2 KO mice. Collectively, our findings indicate that both pro- and anti-inflammatory CD4(+) T cell responses contribute to optimal functional recovery from axotomy-induced facial paralysis, while FMN survival is supported by the anti-inflammatory Th2 response alone.

Exacerbation of facial motoneuron loss after facial nerve axotomy in CCR3-deficient mice.

We have previously demonstrated a neuroprotective mechanism of FMN (facial motoneuron) survival after facial nerve axotomy that is dependent on CD4(+) Th2 cell interaction with peripheral antigen-presenting cells, as well as CNS (central nervous system)-resident microglia. PACAP (pituitary adenylate cyclase-activating polypeptide) is expressed by injured FMN and increases Th2-associated chemokine expression in cultured murine microglia. Collectively, these results suggest a model involving CD4(+) Th2 cell migration to the facial motor nucleus after injury via microglial expression of Th2-associated chemokines. However, to respond to Th2-associated chemokines, Th2 cells must express the appropriate Th2-associated chemokine receptors. In the present study, we tested the hypothesis that Th2-associated chemokine receptors increase in the facial motor nucleus after facial nerve axotomy at timepoints consistent with significant T-cell infiltration. Microarray analysis of Th2-associated chemokine receptors was followed up with real-time PCR for CCR3, which indicated that facial nerve injury increases CCR3 mRNA levels in mouse facial motor nucleus. Unexpectedly, quantitative- and co-immunofluorescence revealed increased CCR3 expression localizing to FMN in the facial motor nucleus after facial nerve axotomy. Compared with WT (wild-type), a significant decrease in FMN survival 4 weeks after axotomy was observed in CCR3(-/-) mice. Additionally, compared with WT, a significant decrease in FMN survival 4 weeks after axotomy was observed in Rag2(-/-) (recombination activating gene-2-deficient) mice adoptively transferred CD4(+) T-cells isolated from CCR3(-/-) mice, but not in CCR3(-/-) mice adoptively transferred CD4(+) T-cells derived from WT mice. These results provide a basis for further investigation into the co-operation between CD4(+) T-cell- and CCR3-mediated neuroprotection after FMN injury.