Evaluation of Genetic and Nongenetic Risk Factors for Degenerative Cervical Myelopathy.

STUDY DESIGN: Cohort study. OBJECTIVE: We aimed to evaluate the associations of genetic and nongenetic factors with degenerative cervical myelopathy (DCM). SUMMARY OF BACKGROUND DATA: There is mounting evidence for an inherited predisposition for DCM, but uncertainty remains regarding specific genetic markers involved. Similarly, nongenetic factors are thought to play a role. MATERIALS AND METHODS: Using diagnosis codes from hospital records linked to the UK Biobank cohort, patients with cervical spondylosis were identified followed by the identification of a subset with DCM. Nongenetic variables evaluated included age, sex, race, Townsend deprivation index, body mass index, occupational demands, osteoporosis, and smoking. Genome-wide association analyses were conducted using logistic regression adjusted for age, sex, population principal components, and follow-up. RESULTS: A total of 851 DCM cases out of 2787 cervical spondylosis patients were identified. Several nongenetic factors were independently associated with DCM including age [odds ratio (OR)=1.11, 95% CI=1.01-1.21, P =0.024], male sex (OR=1.63, 95% CI=1.37-1.93, P <0.001), and relative socioeconomic deprivation (OR=1.03, 95% CI=1.00-1.06, P =0.030). Asian race was associated with lower DCM risk (OR=0.44, 95% CI=0.22-0.85, P =0.014). We did not identify genome-wide significant (≤5×10 -8 ) single-nucleotide polymorphisms (SNPs) associated with DCM. The strongest genome-wide signals were at SNP rs67256809 in the intergenic region of the genes LINC02582 and FBXO15 on chromosome 18 ( P =1.12×10 -7 ) and rs577081672 in the GTPBP1 gene on chromosome 22 ( P =2.9×10 -7 ). No SNPs reported in prior DCM studies were significant after adjusting for replication attempts. CONCLUSIONS: Increasing age, male sex, and relative socioeconomic deprivation were identified as independent risk factors for DCM, whereas Asian race was inversely associated. SNPs of potential interest were identified in GTPBP1 and an intergenic region on chromosome 18, but these associations did not reach genome-wide significance. Identification of genetic and nongenetic DCM susceptibility markers may guide understanding of DCM disease processes, inform risk, guide prevention and potentially inform surgical outcomes. LEVEL OF EVIDENCE: Prognostic level III.

Focal Periphyseal Edema: Are We Overtreating Physiologic Adolescent Knee Pain?

The goals of this study were to (1) introduce the MRI phenomenon of focal periphyseal edema (FOPE) to the orthopaedic community and (2) describe characteristic features and clinical outcomes of a small series of adolescents with FOPE lesions about the knee. The inclusion criterion was the presence of activity-related knee pain and periphyseal edema on T2-weighted MRI. Exclusion criteria were skeletal maturity, history of traumatic knee injury, and the presence of other knee abnormalities. Participants completed the Short Form 10 and Pediatric International Knee Documentation Committee (pedi-IKDC) outcome assessments. Four patients (average age, 13.7 years) with atraumatic activity-related knee pain and FOPE lesions were retrospectively identified. At follow-up (average, 15.8 months), all patients reported the ability to participate in physical activities at the desired level. The mean pedi-IKDC score was 71.2. With supportive treatment, patients with FOPE were able to return to sport, although they had lower-than-average outcome scores. Increased awareness and understanding of this clinical entity are necessary for provision of effective, cost-efficient care to patients with FOPE.

Subtypes of endothelial progenitor cells affect healing of segmental bone defects differently.

PURPOSE: Treating fracture nonunion with endothelial progenitor cells (EPCs) is a promising approach. Nevertheless, the effect of different EPC-related cell populations remains unclear. In this study, we compared the therapeutic potential of early (E-EPCs) and late EPCs (L-EPCs). METHODS: Male Fischer 344 rats were used for cell isolation and in vivo experiments. Bone marrow-derived E-EPCs and L-EPCs were kept in culture for seven to ten days and four weeks, respectively. For each treatment group, we seeded one million cells on a gelatin scaffold before implantation in a segmental defect created in a rat femur; control animals received a cell-free scaffold. Bone healing was monitored via radiographs for up to ten weeks after surgery. In vitro, secretion of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2 was quantified by ELISA for both cell populations. Tube formation assays were also performed. RESULTS: Final radiographs showed complete (four out of five rats) or partial (one out of five rats) union with E-EPC treatment. In contrast, complete healing was achieved in only one of five animals after L-EPC implantation, while control treatment resulted in nonunion in all animals. In vitro, E-EPCs released more VEGF, but less BMP-2 than L-EPCs. In addition, L-EPCs formed longer and more mature tubules on basement membrane matrix than E-EPCs. However, co-culture with primary osteoblasts stimulated tubulogenesis of E-EPCs while inhibiting that of L-EPCs. CONCLUSIONS: We demonstrated that bone marrow-derived E-EPCs are a better alternative than L-EPCs for treatment of nonunion. We hypothesize that the expression profile of E-EPCs and their adaptation to the local environment contribute to superior bone healing.

Apophyseal Avulsion of the Greater Trochanter in an Adolescent: Treatment with Abduction Bracing: A Case Report.

CASE: We describe a case of an adolescent athlete who sustained a greater trochanteric avulsion fracture. After conservative management with abduction bracing, the patient made a full recovery, with no signs of osteonecrosis at 12 months. We describe the presentation, the course of recovery, and the literature regarding treatment and outcomes. CONCLUSION: Isolated fracture of the greater trochanteric apophysis is a rare but possibly devastating injury to the adolescent hip when complicated by osteonecrosis. We describe the successful conservative treatment of this injury in what we believe to be the second such report in the English-language literature.

Osteogenesis and cytotoxicity of a new Carbon Fiber/Flax/Epoxy composite material for bone fracture plate applications.

This study is part of an ongoing program to develop a new CF/Flax/Epoxy bone fracture plate to be used in orthopedic trauma applications. The purpose was to determine this new plate's in-vitro effects on the level of bone formation genes, as well as cell viability in comparison with a medical grade metal (i.e. stainless steel) commonly employed for fabrication of bone plates (positive control). Cytotoxicity and osteogenesis induced by wear debris of the material were assessed using Methyl Tetrazolium (MTT) assay and reverse transcription polymerase chain reaction (RT-PCR) for 3 osteogenesis specific gene markers, including bone morphogenetic proteins (BMP2), runt-related transcription factor 2 (Runx2) and Osterix. Moreover, the Flax/Epoxy and CF/Epoxy composites were examined separately for their wettability properties by water absorption and contact angle (CA) tests using the sessile drop technique. The MTT results for indirect and direct assays indicated that the CF/Flax/Epoxy composite material showed comparable cell viability with no cytotoxicity at all incubation times to that of the metal group (p≥0.05). Osteogenesis test results showed that the expression level of Runx2 marker induced by CF/Flax/Epoxy were significantly higher than those induced by metal after 48 h (p=0.57). Also, the Flax/Epoxy composite revealed a hydrophilic character (CA=68.07°±2.05°) and absorbed more water up to 17.2% compared to CF/Epoxy, which reached 1.25% due to its hydrophobic character (CA=93.22°±1.95°) (p<0.001). Therefore, the new CF/Flax/Epoxy may be a potential candidate for medical applications as a bone fracture plate, as it showed similar cell viability with no negative effect on gene expression levels responsible for bone formation compared to medical grade stainless steel.

Increased risk of complications after anterior cervical discectomy and fusion in the elderly: an analysis of 6253 patients in the American College of Surgeons National Surgical Quality Improvement Program database.

STUDY DESIGN: Retrospective cohort analysis of anterior cervical discectomy and fusion (ACDF) surgical procedures using a prospectively collected database. OBJECTIVE: To characterize the 30-day postoperative outcomes in elderly patients undergoing ACDF after adjustment for comorbidities using a multi-institutional database. SUMMARY OF BACKGROUND DATA: Prior studies on the effect of age after ACDF have mostly focused on in-hospital complications, have come from single institutions, or have included ACDF in pooled analyses and have not distinctly analyzed the specific complications associated with age after ACDF. METHODS: Patients undergoing ACDF were selected in the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2012. Patients were stratified into 4 age-groups: 18 to 39 years, 40 to 64 years, 65 to 74 years, and 75 years or more (based on standard deviation cohorts). Patients in the different age categories were compared using the χ statistic, the Fisher exact test, and analysis of variance. Multivariate linear/logistic regression models were used to adjust for preoperative comorbidities. Significance was defined as P < 0.05. RESULTS: Data were available for 6253 patients who underwent ACDF. On multivariate logistic regression, both groups of elderly patients (65-74 and ≥75 yr) were more likely to have blood transfusions, reoperations, urinary complications, extended length of stays, and 1 or more complication, overall. Only patients 65 to 74 years were more likely to have a pulmonary embolism/deep vein thrombosis, whereas only patients aged 75 years or older were more likely to experience respiratory complications, central nervous system complications, or death. There were no differences in complication rates between the 18- to 39-year age-group and 40- to 64-year age-group. The 18- to 39-year age-group and 75-year age-group had shorter operating room times. CONCLUSION: Older age is an independent risk factor for greater morbidity and longer hospitalizations after ACDF, even after adjustment for comorbidities when compared with younger patients. Surgeons should be aware of the increased risk of multiple complications for patients of advanced age in their surgical decision making. LEVEL OF EVIDENCE: 3.

Heterotopic ossification in orthopaedic trauma.

Heterotopic ossification (HO) can be defined as the pathologic formation of bone in extraskeletal tissues. There has been a substantial amount of recent research on the pathophysiology, prophylaxis, and treatment of HO and traumatic conditions associated with the development of HO. This research has advanced our understanding of this disease and helped to clarify evidence-based approaches to both the prophylaxis and treatment of HO. This article reviews the literature on these topics with a focus on their application in orthopaedic trauma.

Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disorders.

Alcohol consumption during pregnancy can result in a myriad of health problems in the affected offspring ranging from growth deficiencies to central nervous system impairments that result in cognitive deficits. Adult hippocampal neurogenesis is thought to play a role in cognition (i.e. learning and memory) and can be modulated by extrinsic factors such as alcohol consumption and physical exercise. We examined the impact of voluntary physical exercise on adult hippocampal neurogenesis in a rat model of fetal alcohol spectrum disorders (FASD). Intragastric intubation was used to deliver ethanol to rats in a highly controlled fashion through all three trimester equivalents (i.e. throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed animals and their pair-fed and ad libitum controls were left undisturbed until they reached a young adult stage at which point they had free access to a running wheel for 12 days. Prenatal and early postnatal ethanol exposure altered cell proliferation in young adult female rats and increased early neuronal maturation without affecting cell survival in the dentate gyrus (DG) of the hippocampus. Voluntary wheel running increased cell proliferation, neuronal maturation and cell survival as well as levels of brain-derived neurotrophic factor in the DG of both ethanol-exposed female rats and their pair-fed and ad libitum controls. These results indicate that the capacity of the brain to respond to exercise is not impaired in this model of FASD, highlighting the potential therapeutic value of physical exercise for this developmental disorder.

Altered adult hippocampal neuronal maturation in a rat model of fetal alcohol syndrome.

Exposure to ethanol during pregnancy can be devastating to the developing nervous system, leading to significant central nervous system dysfunction. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of ethanol. In the present study, we tested a rat model of fetal alcohol syndrome (FAS) with ethanol administered via gavage throughout all three trimester equivalents. Subsequently, we assessed cell proliferation, as well as neuronal survival, and differentiation in the dentate gyrus of the hippocampus of adolescent (35 days old), young adult (60 days old) and adult (90 days old) Sprague-Dawley rats. Using both extrinsic (bromodeoxyuridine) and intrinsic (Ki-67) markers, we observed no significant alterations in cell proliferation and survival in ethanol-exposed animals when compared with their pair-fed and ad libitum controls. However, we detected a significant increase in the number of new immature neurons in animals that were exposed to ethanol throughout all three trimester equivalents. This result might reflect a compensatory mechanism to counteract the deleterious effects of prenatal ethanol exposure or an ethanol-induced arrest of the neurogenic process at the early neuronal maturation stages. Taken together these results indicate that exposure to ethanol during the period of brain development causes a long-lasting dysregulation of the neurogenic process, a mechanism that might contribute, at least in part, to the hippocampal deficits that have been reported in rodent models of FAS.