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

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

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

Category: Tumor Introduction/Purpose: Soft tissue sarcomas (STS) of the foot and ankle are common, accounting for 10% of sarcomas; however, there exists little published data on the outcome of treatment. Because of the unique anatomy of the foot and ankle, and the fact that benign lesions in this area are 200-fold more common than malignant lesions, these tumors can be frequently misdiagnosed, leading to unplanned excision and poor outcomes. The purpose of this study was to describe outcomes of the surgical treatment of STS of the foot and ankle at our institution, with an analysis on risk factors for local and distant recurrence, as well as overall survival. Methods: 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. Age, gender, anatomic location, tumor size, subtype, stage, neoadjuvant and adjuvant treatments, previous surgery, surgical procedure, and disease status at latest follow-up was recorded. Results: 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. Post treatment 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. Conclusion: The results of our study highlight the aggressive nature of soft tissue sarcomas of the foot and ankle, with smaller tumors than previously reported (<5 cm) behaving like high-grade advanced disease