Angiotensin receptor blockers may provide a safe, clinically available treatment for improving healing after skeletal muscle injury.

Recovery from skeletal muscle injury is often incomplete because of the formation of fibrosis and inadequate myofiber regeneration; therefore, injured muscle could benefit significantly from therapies that both stimulate muscle regeneration and inhibit fibrosis. To this end, we focused on blocking myostatin, a member of the transforming growth factor-β superfamily and a negative regulator of muscle regeneration, with the myostatin antagonist follistatin. In vivo, follistatin-overexpressing transgenic mice underwent significantly greater myofiber regeneration and had less fibrosis formation compared with wild-type mice after skeletal muscle injury. Follistatin's mode of action is likely due to its ability to block myostatin and enhance neovacularization. Furthermore, muscle progenitor cells isolated from follistatin-overexpressing mice were significantly superior to muscle progenitors isolated from wild-type mice at regenerating dystrophin-positive myofibers when transplanted into the skeletal muscle of dystrophic mdx/severe combined immunodeficiency mice. In vitro, follistatin stimulated myoblasts to express MyoD, Myf5, and myogenin, which are myogenic transcription factors that promote myogenic differentiation. Moreover, follistatin's ability to enhance muscle differentiation is at least partially due to its ability to block myostatin, activin A, and transforming growth factor-β1, all of which are negative regulators of muscle cell differentiation. The findings of this study suggest that follistatin is a promising agent for improving skeletal muscle healing after injury and muscle diseases, such as the muscular dystrophies.

BackgroundAtrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.Methods and ResultsIn the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P<0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677).ConclusionsIn a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

Skeletal muscle injuries are extremely common, accounting for up to 35-55% of all sports injuries and quite possibly impacting all musculoskeletal traumas. These injuries result in the formation of fibrosis that may lead to development of painful contractures, increases their risk for repeat injuries, and limits their ability to return to a baseline or pre-injury level of function. The development of successful therapies for these injuries must consider the pathophysiology of these musculoskeletal conditions. We discuss the direct use of muscle-derived stem cells and some key cell population dynamics, as well as the use of clinically applicable modalities which may enhance the local supply of stem cells to the zone of injury by promoting angiogenesis.

The results support the hypothesis that, within the department studied, there was a significant association between similarities in personality type and the rankings that individual faculty interviewers assigned to applicants at the completion of each interview session. The authors believe that it is important for the faculty member to recognize that this tendency exists. Finally, promoting diversity within the admission committee may foster a diverse resident body and orthopaedic workforce.

Signal transducer and activator of transcription 3 (STAT3) is an oncogene and a critical regulator of multiple cell-fate decisions, including myeloid cell differentiation. Two isoforms of STAT3 have been identified: ␣ (p92) and ␤ (p83). These differ structurally in their C-terminal transactivation domains, resulting in distinct functional activities. The cis genetic elements that regulate the ratio of ␣ to ␤ messenger RNA (mRNA) are unknown. In this study, cloning, sequencing, and splicing analysis of the human and murine STAT3 genes revealed a highly conserved 5 donor site for generation of both ␣ and ␤ mRNA and distinct branch-point sequences, polypyrimidine tracts, and 3 acceptor sites (ASs) for each. The ␤ 3 AS was found to be located 50 nucleotides downstream of the ␣ 3 AS in exon 23. IntroductionAlthough there is only one signal transducer and activator of transcription 3 (STAT3) gene in mice and humans, 2 protein isoforms have been identified in both species: STAT3␣ (p92) 1,2 and STAT3␤ (p83). [3][4][5] The messenger RNA (mRNA) encoding STAT3␤ has a 50-nucleotide deletion at the 3Ј end that is presumably due to alternative mRNA splicing and results in a protein's missing the C-terminal 55 amino acid residues of STAT3␣. In contrast to other STAT protein ␤ isoforms, in which the C-terminal transactivation domain is simply deleted, in STAT3␤, the 55 amino acid residues of STAT3␣ are replaced by 7 unique amino acid residues at its C-terminal. These residues are encoded by 21 nucleotides spliced in the ϩ2 reading frame downstream of the deletion. The Cterminal 55 amino acid residues comprise the transactivation domain of STAT3␣ and contain serine 727, whose phosphorylation results in enhanced transcriptional activity. 6 This same region of STAT3␣ also influences STAT3␣ dimerization, since the DNAbinding activity of STAT3␣ was shown to be reduced by 15 to 25 fold compared with that of STAT3␤. 7,8 The reduced DNA-binding activity of STAT3␣ was attributed to a reduced stability of STAT3␣ homodimers compared with STAT3␤ homodimers.The ratio of STAT3␣ to STAT3␤ varies in cells and tissues, ranging from 3:1 to 10:1 at the mRNA level and 1:3 to 10:1 at the protein level. 5,9 This variation may have important biologic consequences because the functions of the 2 isoforms do not overlap. When STAT3␤ and STAT3␣ were overexpressed in Cos cells, STAT3␤, but not STAT3␣, was constitutively able to cooperate with c-Jun to activate a reporter construct containing ␣ 2 -macroglobulin. 3 In contrast, STAT3␤ activated downstream of the interleukin 5 receptor inhibited the ability of STAT3␣ to activate a reporter construct containing an intercellular adhesion molecule 1 promoter. 4 In studies examining the distinct biologic functions of the STAT3 isoforms, STAT3␣ enhanced whereas STAT3␤ inhibited v-Src-mediated fibroblast transformation. 10 More relevant for myeloid development, we and others found that overexpression of STAT3␣ inhibited myeloid differentiation mediated by gp130 and granulocyte colony-stimulating factor receptor 1...

This report describes technical tricks for using the reamer irrigator aspirator to harvest autologous bone graft from the femur. This device is a focus of interest in orthopaedics because it can be used to harvest bone graft from the femoral canal and medial condyle in voluminous quantities. Moreover, according to some authors, the osteogenic potential of this graft is at least as effective as that of autogenous bone obtained from the iliac crest. The reamer irrigator aspirator device has substantially different design characteristics and technicalities compared with those of a standard reamer. First, a guidewire must be redirected into multiple areas, including the center of the distal femur and into both condyles, to harvest ample bone graft. This is accomplished by prebending the guidewire in a stronger fashion than required for regular reaming in the case of femoral nailing procedures. This bend can increase the risk for eccentric reaming as well as lodging of the suctioning device within the femoral canal. Second, the front and lateral drilling surfaces of this device are very sharp and further cleaned and maintained sharp by the irrigation process to permit the surgeon to obtain significant volumes of graft with a single passage of this device. At the same time, however, this sharp front-end cutting design can increase the risk of iatrogenic fracture if reaming is performed without caution. Third, a powerful suctioning device is connected to the reamer such that the blood loss that can occur during continuous reaming, irrigation, and aspiration must be considered with this technique. We hereby discuss these potential dangers and describe the correct use of this device with technical tricks to minimize the risk of unexpected intraoperative events.

Background: Over a hundred years ago, Wolff originally observed that bone growth and remodeling are exquisitely sensitive to mechanical forces acting on the skeleton. Clinical studies have noted that the size and the strength of bone increase with weight bearing and muscular activity and decrease with bed rest and disuse. Although the processes of mechanotransduction and functional response of bone to mechanical strain have been extensively studied, the molecular signaling mechanisms that mediate the response of bone cells to mechanical stimulation remain unclear.