Here we report that a 1-week exposure to oligonucleotide homologous to the telomere 3 -overhang sequence TTAGGG (T-oligo) similarly specifically induces a senescent phenotype in cultured human fibroblasts, mimicking serial passage or ectopic expression of a dominant negative form of the telomeric repeat binding factor, TRF2 DN . We propose that exposure of the 3 overhang due to telomere loop disruption may occur with critical telomere shortening or extensive acute DNA damage and that the exposed TTAGGG tandem repeat sequence then triggers DNA-damage responses. We further demonstrate that these responses can be induced by treatment with oligonucleotides homologous to the overhang in the absence of telomere disruption, a phenomenon of potential therapeutic importance.DNA damage ͉ aging

Telomere shortening induces a nonproliferative senescent phenotype, believed to reduce cancer risk, and telomeres are involved in a poorly understood manner in responses to DNA damage. Although telomere disruption induces p53 and triggers apoptosis or cell cycle arrest, the features of the disrupted telomere that trigger this response and the precise mechanism involved are poorly understood. Using human cells, we show that DNA oligonucleotides homologous to the telomere 3' overhang sequence specifically induce and activate p53 and activate an S phase checkpoint by modifying the Nijmegen breakage syndrome protein, known to mediate the S phase checkpoint after DNA damage. These responses are mediated, at least in part, by the ATM kinase and are not attributable to disruption of cellular telomeres. Based on these and earlier data, we propose that these oligonucleotides mimic a physiological signal, exposure of the telomere 3' overhang due to opening of the normal telomere loop structure, and hence evoke these protective antiproliferative responses in the absence of DNA damage or telomere disruption.

Conservative treatment of humeral shaft fractures has a higher rate of nonunion, while operative treatment is associated with a low incidence of iatrogenic nerve palsy but higher rates of infection.

Background: Several classification systems exist for sacral fractures; however, these systems are primarily descriptive, are not uniformly used, have not been validated, and have not been associated with a treatment algorithm or prognosis. The goal of the present study was to demonstrate the reliability of the AOSpine Sacral Classification System among a group of international spine and trauma surgeons. Methods: A total of 38 sacral fractures were reviewed independently by 18 surgeons selected from an expert panel of AOSpine and AOTrauma members. Each case was graded by each surgeon on 2 separate occasions, 4 weeks apart. Intrarater reproducibility and interrater agreement were analyzed with use of the kappa statistic (κ) for fracture severity (i.e., A, B, and C) and fracture subtype (e.g., A1, A2, and A3). Results: Seventeen reviewers were included in the final analysis, and a total of 1,292 assessments were performed (646 assessments performed twice). Overall intrarater reproducibility was excellent (κ = 0.83) for fracture severity and substantial (κ = 0.71) for all fracture subtypes. When comparing fracture severity, overall interrater agreement was substantial (κ = 0.75), with the highest agreement for type-A fractures (κ = 0.95) and the lowest for type-C fractures (κ = 0.70). Overall interrater agreement was moderate (κ = 0.58) when comparing fracture subtype, with the highest agreement seen for A2 subtypes (κ = 0.81) and the lowest for A1 subtypes (κ = 0.20). Conclusions: To our knowledge, the present study is the first to describe the reliability of the AOSpine Sacral Classification System among a worldwide group of expert spine and trauma surgeons, with substantial to excellent intrarater reproducibility and moderate to substantial interrater agreement for the majority of fracture subtypes. These results suggest that this classification system can be reliably applied to sacral injuries, providing an important step toward standardization of treatment.

Background Heterotopic ossification (HO) is a common complication of the operative treatment of acetabular fractures. Although the surgical approach has been shown to correlate with the development of ectopic bone, specific risk factors have not been elucidated. Questions/purposes The purposes of this study were to determine specific risk factors associated with the development of severe HO and the frequency with which patients develop severe HO after acetabular fracture fixation through an isolated Kocher-Langenbeck approach. Methods Using an institutional orthopaedic trauma database at a regional Level I trauma center, patients undergoing open treatment of acetabular fractures during the study period (January 2000 to January 2010) were identified. A review of medical records and imaging studies was performed on 508 patients who were treated by the senior author (MR) through an isolated Kocher-Langenbeck approach. During the study period, the senior author used indomethacin for HO prophylaxis in patients who had ipsilateral femur fracture treated with antegrade reamed medullary nailing or severe local soft tissue injury; 49 (10%) of the patients he treated with the Kocher-Langenbeck approach received prophylaxis, and they were excluded from this study, leaving a total of 459 patients who met inclusion criteria. Of those, 147 (29%) were lost to followup or did not have radiographs both before and at a minimum of 6 weeks (median, 1 week; range, 0-3 weeks), leaving 312 (61% of the patients treated with the Kocher-Langenbeck approach during this time) available for this analysis. Demographic data as well as information related to cause of injury, associated periacetabular findings, other system injuries, and treatment were gathered. Final followup radiographs were assessed for the presence of ectopic bone by two of the authors (TJO, AS) using the modified Brooker classification. Logistic regression was performed to identify possible predictors of development of severe ectopic bone. Results The only predictor we identified for the development of severe HO was the need for prolonged mechanical ventilation (odds ratio, 7

Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Background Femoral head fractures are uncommon injuries. Small series constitute the majority of the available literature. Surgical approach and fracture management is variable. The purpose of this study was to evaluate the incidence, method of treatment, and outcomes of consecutive femoral head fractures at a regional academic Level I trauma center.Materials and methodsA retrospective review of a prospective database was performed over a 13-year period. All AO/OTA 31C femoral head fractures were identified. A surgical approach and fixation method was recorded. Clinical and radiographic evaluation was performed for patients with 6 months or greater follow-up. Radiographs were evaluated for fixation failure, heterotopic ossification (HO), avascular necrosis (AVN) and post-traumatic arthritis.ResultsWe identified 164 fractures in 163 patients; 147 fractures were available for review. Treatment was operative reduction and internal fixation (ORIF) in 78 (53.1%), fragment excision in 37 (25.1%) and non-operative in 28 (19%). An anterior approach and mini-fragment screws were used in the majority of patients treated with fixation. Sixty-nine fractures had follow-up greater than 6 months. Sixty-two fractures (89.9%) proceeded to uneventful union. All Pipkin III fractures failed operative fixation. Six patients developed AVN, seven patients had a known conversion to hip arthroplasty; HO developed in 28 (40.6%) patients and rarely required excision.ConclusionsFractures of the femoral head are rare. An anterior approach can be used for fragment excision or fixation using mini-fragment screws. Pipkin III fractures represent catastrophic injuries. Non-bridging, asymptomatic HO is common. AVN and posttraumatic degenerative disease of the hip occur but are uncommon.Level of evidenceIV—prognostic.

Heterotopic ossification (HO) is a common complication of the surgical treatment of acetabular fractures. HO is the formation of trabecular bone in soft tissues where bone does not usually occur. Over the last decade, many risk factors have been identified for HO after surgical fixation of acetabular fractures; however, prophylaxis and treatment of this condition are controversial. Potential preventive measures range from NSAIDs to external beam irradiation, but recent studies have questioned the utility of these measures. The Brooker classification system, which has been correlated with patient function and outcomes, is most commonly used to describe HO severity. Advances will assist in the diagnosis, prevention, and management of HO as well as the assessment of risk factors that could affect outcomes.