Citations

Chronic Lisfranc injury is a subtle and severe injury in high-level athletes, including dancers. This patient population is generally intolerant of intra-articular screw fixation and can develop significant post-traumatic arthritis with potentially career ending complications. Flexible fixation with suture-button devices provides potential restoration of physiologic motion at the joint, with appropriate support for healing that may facilitate return to en pointe activities for dancers. We hypothesized that the suture-button device would restore motion at the Lisfranc joint and allow for return to activities in this particular population without the limitations and complications of rigid fixation. We operated on seven dancers and high-level athletes with diagnosed Lisfranc injuries by installing a suture-button device. All patients had failed conservative management after late presentation. They were allowed to return to sport in 6 months, preoperative and postoperative American Orthopaedic Foot and Ankle Score (AOFAS) foot scores were obtained, and patients were followed for a minimum of 15 months. All seven returned to full activities in 6 months, with radiographic evidence of fixation and no complications to date. AOFAS foot scores improved from an average of 65 preoperatively to an average of 97 postoperatively at latest follow-up. It is concluded that flexible fixation with suture-button type device represents a viable alternative to screw fixation or fusion that may allow dancers and athletes to return to previous levels of activity after Lisfranc injury. This case series represents to our knowledge the first application of this device to a unique population that requires flexibility at the Lisfranc joint for performance.

OBJECT There is currently no consensus on the safety of sports participation for patients with Chiari I malformation (CM-I). The authors' goal was to define the risk of sports participation for children with the imaging finding of CM-I. METHODS A prospective survey was administered to 503 CM-I patients at 2 sites over a 46-month period. Data were gathered on imaging characteristics, treatment, sports participation, and any sport-related injuries. Additionally, 81 patients completed at least 1 subsequent survey following their initial entry into the registry and were included in a prospective group, with a mean prospective follow-up period of 11 months. RESULTS Of the 503 CM-I patients, 328 participated in sports for a cumulative duration of 4641 seasons; 205 of these patients participated in contact sports. There were no serious or catastrophic neurological injuries. One patient had temporary extremity paresthesias that resolved within hours, and this was not definitely considered to be related to the CM-I. In the prospective cohort, there were no permanent neurological injuries. CONCLUSIONS No permanent or catastrophic neurological injuries were observed in CM-I patients participating in athletic activities. The authors believe that the risk of such injuries is low and that, in most cases, sports participation by children with CM-I is safe.

We tested hypothesis that activation of the prostacyclin (PGI 2 ) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI 2 , iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPα (sAPPα). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor δ (PPARδ) in human brain microvascular endothelial cells. PPARδ-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARδ) upregulated ADAM10 and increased production of sAPPα. Genetic deletion of endothelial PPARδ (ePPARδ −/− ) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPα. In vivo treatment with GW501516 increased sAPPα content in hippocampus of wild type mice but not in hippocampus of ePPARδ −/− mice. Our findings identified previously unrecognized role of IP-PPARδ signal transduction pathway in the production of sAPPα in cerebral microvasculature.

Diabetes-induced cognitive decline has been recognized in human patients of type 2 diabetes mellitus and mouse model of obesity, but the underlying mechanisms or therapeutic targets are not clearly identified. We investigated the effect of caloric restriction on diabetes-induced memory deficits and searched a molecular mechanism of caloric restriction-mediated neuroprotection. C57BL/6 mice were fed a high-fat diet for 40 weeks and RNA-seq analysis was performed in the hippocampus of high-fat diet-fed mice. To investigate caloric restriction effect on differential expression of genes, mice were fed high-fat diet for 20 weeks and continued on high-fat diet or subjected to caloric restriction (2 g/day) for 12 weeks. High-fat diet-fed mice exhibited insulin resistance, glial activation, blood–brain barrier leakage, and memory deficits, in that we identified neurogranin, a down-regulated gene in high-fat diet-fed mice using RNA-seq analysis; neurogranin regulates Ca 2+ /calmodulin-dependent synaptic function. Caloric restriction increased insulin sensitivity, reduced high-fat diet-induced blood–brain barrier leakage and glial activation, and improved memory deficit. Furthermore, caloric restriction reversed high-fat diet-induced expression of neurogranin and the activation of Ca 2+ /calmodulin-dependent protein kinase II and calpain as well as the downstream effectors. Our results suggest that neurogranin is an important factor of high-fat diet-induced memory deficits on which caloric restriction has a therapeutic effect by regulating neurogranin-associated calcium signaling.

The accurate reconstruction of hip anatomy and biomechanics is thought to be important in achieveing good clinical outcomes following total hip arthroplasty (THA). To this end some newer hip designs have introduced further modularity into the design of the femoral component such that neck­shaft angle and anteversion, which can be adjusted intra-operatively. The clinical effect of this increased modularity is unknown. We have investigated the changes in these anatomical parameters following conventional THA with a prosthesis of predetermined neck–shaft angle and assessed the effect of changes in the hip anatomy on clinical outcomes.In total, 44 patients (mean age 65.3 years (standard deviation (sd) 7); 17 male/27 female; mean body mass index 26.9 (kg/m²) (sd 3.1)) underwent a pre- and post-operative three-dimensional CT scanning of the hip. The pre- and post-operative neck–shaft angle, offset, hip centre of rotation, femoral anteversion, and stem alignment were measured. Additionally, a functional assessment and pain score were evaluated before surgery and at one year post-operatively and related to the post-operative anatomical changes.The mean pre-operative neck–shaft angle was significantly increased by 2.8° from 128° (sd 6.2; 119° to 147°) to 131° (sd 2.1; 127° to 136°) (p = 0.009). The mean pre-operative anteversion was 24.9° (sd 8; 7.9 to 39.1) and reduced to 7.4° (sd 7.3; -11.6° to 25.9°) post-operatively (p < 0.001). The post-operative changes had no influence on function and pain. Using a standard uncemented femoral component, high pre- and post-operative variability of femoral anteversion and neck–shaft angles was found with a significant decrease of the post-operative anteversion and slight increase of the neck–shaft angles, but without any impact on clinical outcome.Cite this article: Bone Joint J 2015;97-B:1615–22.

Background— Quadricuspid aortic valve (QAV) is a rare congenital cardiac defect. This study sought to determine QAV frequency in a large echocardiography database, to characterize associated cardiovascular abnormalities, and to describe long-term outcomes. Methods and Results— Fifty patients (mean±SD age, 43.5±21.8 years at the time of the index diagnosis; female sex, 52%) received a diagnosis of QAV between January 1, 1975, and March 14, 2014 (frequency, 0.006%). The QAV was type A in 32% and type B in 32% (Hurwitz and Roberts classification). Aortic dilatation was present in 29% of the patients, and 26% had moderate or severe aortic valve regurgitation at the index diagnosis. Stenosis affected only 8% of the valves and was mild. Other findings, including abnormalities of other cardiac valves, septal defects, persistent left superior vena cava, and patent ductus arteriosus, were present in 32% of patients. During a mean±SD follow-up of 4.8±5.6 years, 8 patients underwent aortic valve surgery, with severe aortic valve regurgitation being the surgical indication in 7 patients. One patient with mild to moderate aortic valve regurgitation underwent aortic valve repair for obstruction of the left coronary ostium by the accessory cusp of QAV. No infective endocarditis or aortic dissection was found. Overall survival was 91.5% and 87.7% at 5 and 10 years. Conclusions— Aortic dilatation and other structural cardiac abnormalities were relatively common among patients with QAV. Aortic valve regurgitation was the predominant hemodynamic abnormality and the indication for aortic valve surgery in most patients who received surgery. Long-term survival was excellent.

Speech recognition software can increase the frequency of errors in radiology reports, which may affect patient care. We retrieved 213,977 speech recognition software–generated reports from 147 different radiologists and proofread them for errors. Errors were classified as “material” if they were believed to alter interpretation of the report. “Immaterial” errors were subclassified as intrusion/omission or spelling errors. The proportion of errors and error type were compared among individual radiologists, imaging subspecialty, and time periods. In all, 20,759 reports (9.7%) contained errors, of which 3992 (1.9%) were material errors. Among immaterial errors, spelling errors were more common than intrusion/omission errors ( p < .001). Proportion of errors and fraction of material errors varied significantly among radiologists and between imaging subspecialties ( p < .001). Errors were more common in cross-sectional reports, reports reinterpreting results of outside examinations, and procedural studies (all p < .001). Error rate decreased over time ( p < .001), which suggests that a quality control program with regular feedback may reduce errors.

Abstract Purpose: There is a clear need to improve risk stratification and to identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets. Experimental Design: We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4 years). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score. Results: Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell-cycle progression signature, and CAPRA-S). Conclusions: To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes. Clin Cancer Res; 22(7); 1777–86. ©2015 AACR.

Recent applications of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system have greatly improved the efficiency of genome editing in pigs. However, in some cases, genetically modified pig models need an additional modification to improve their application. The objective of this experiment was to determine whether a combination of somatic cell NT (SCNT) by using a previously modified donor cell line and subsequent zygote injection with CRISPR/Cas9 guide RNA to target a second gene would result in embryos and offspring successfully containing both modifications. Fibroblast cell lines were collected from fumarylacetoacetate hydrolase deficient (FAH–/–) fetuses and used as the donor cell line. Somatic cell NT was performed by standard technique. A CRISPR guide RNA specific for recombination activating gene 2 (RAG2) was designed and in vitro transcribed from a synthesised gBlock (IDT) containing a T7 promoter sequence, the CRISPR Guide RNA (20 bp), and 85 bp of tracer RNA. The gBlock was PCR amplified with Q5 polymerase (NEB, Ipswich, MA, USA) and in vitro transcribed with the MEGAshortscript™ T7 Transcription Kit (Life Technologies, Grand Island, NY, USA). Guide RNA (20 ng µL–1) and polyadenylated Cas9 (20 ng µL–1, Sigma, St. Louis, MO, USA) were co-injected into the cytoplasm of SCNT zygotes at 14 to 16 h after fusion and activation. Injected SCNT were then cultured in vitro in PZM3 + 1.69 mM arginine medium (MU1) to Day 5. Three embryo transfers were performed surgically into recipient gilts on Day 4 or 5 of oestrus (50, 62, or 70 embryos per pig) to evaluate in vivo development. The remaining embryos were cultured in MU1 to Day 7 and analysed for the presence of modifications to the RAG2 gene. Embryos were classified as modified if they contained an INDEL as measured by both gel electrophoresis and DNA sequencing of PCR amplicons spanning the targeted exon. The RAG2 modification rate was 83.3% (n = 6), of which 50% (n = 3) of the embryos contained biallelic modifications. All control embryos contained a wild-type RAG2 gene (n = 5). Embryo transfer resulted in a 33.3% pregnancy rate (1/3). The combination of SCNT and CRISPR/Cas9 zygote injection can be a highly efficient tool to successfully create pig embryos with an additional modification. This additional technique further improves the usefulness of already created genetically modified pig models. This study was funded by the National Institutes of Health via U42 OD011140.