Faculty Bibliography

Background: Radiocarpal dislocations represent a high-energy wrist injury that can occur with or without concomitant fractures about the wrist. Poor outcomes are often due to radiocarpal instability and secondary ulnar translation. The purpose of this cadaveric study is to determine if there is any difference in the radiographic parameters in a wrist dislocation model given the different location of distal fixation. Methods: Ten paired fresh cadaver upper extremities were fluoroscopically evaluated with posterior-anterior (PA) and lateral views. We created a radiocarpal dislocation model and applied a dorsal bridge plate to either the second or third metacarpal. Repeat PA and lateral fluoroscopic views were obtained for evaluation of radial inclination, radial height, volar tilt, ulnar variance, radiolunate angle, radioscaphoid angle, scapholunate angle, radial rotation index, and four indices for ulnar translation (Taleisnik, Gilula, McMurtry, and Chamay). Results: Bridge plate application to the second metacarpal resulted in a significantly greater incidence of ulnar translation compared to the third metacarpal. Application to either metacarpal resulted in extension of the carpus relative to the radius. Conclusions: A more anatomic radiocarpal relationship was restored more often when distal fixation of the dorsal wrist-spanning bridge plate was applied to the third metacarpal. Further investigation is warranted to determine clinical relevance of these findings in conjunction with clinical and radiographic outcomes.

Background  The purpose of this study is to assess the epidemiology, population-specific treatment trends, and complications of distal radius fractures in the United States. Methods  The PearlDiver database (Humana [2007-2014], Medicare [2005-2014]) was used to access US inpatient and outpatient data for all patients who had undergone operative and nonoperative treatment for a distal radius fracture in the United States. Epidemiologic analysis was performed followed by age-based stratification, to assess prevalence, treatment trends, and rates of complications. Results  A total of 1,124,060 distal radius treatment claims were captured. The incidence of distal radius fractures follows a bimodal distribution with distinct peaks in the pediatric and elderly population. Fractures in the pediatric population occurred predominately in males, whereas fractures in the elderly population occurred more frequently in females. The most commonly used modality of treatment was nonoperative; however, the use of internal fixation increased significantly during the study period, from 8.75 to 20.02%, with a corresponding decrease in percutaneous fixation. The overall complication rate was 8.3%, with mechanical symptoms most frequently reported. Conclusions  The last decade has seen a significant increase in the use of internal fixation as treatment modality for distal radius fractures. The impetus for this change is likely multifactorial and partly related to recent innovations including volar locking plates and an increasingly active elderly population. The implicated financial cost must be weighed against the productivity cost of maintaining independent living to determine the true burden to the healthcare system.

Background  Dorsal bridge plate fixation is an effective technique for stabilization of highly comminuted, complex distal radius fractures. However, it is unknown whether fixation to the second or third metacarpal is optimal. Given dorsal bridge plating spans the radiocarpal joint, it is unclear if the dorsal spanning plate affects carpal position. This study investigates differences in carpal translocation resulting from bridge plate distal fixation to either the second or third metacarpal. Methods  Ten paired cadaveric upper extremities without evidence of gross deformity or prior surgery distal to the elbow were evaluated with three-view wrist fluoroscopic images for baseline radiographic measurements. An unstable distal radius fracture model was created via a volar approach using a 1-cm osteotomy. Following fracture creation, a dorsal bridge plate was applied with random to the second metacarpal on one limb, and the third metacarpal on the contralateral limb. Laterality for distal fixation was chosen randomly. Fluoroscopic images were repeated and radial inclination, radial height, radiocarpal angle, volar tilt, ulnar variance, radiolunate angle, radioscaphoid angle, radial rotation index, and carpal translocation were measured. Results  Radial inclination, radial height, radiocarpal angle, volar tilt, ulnar variance, radiolunate angle, and radioscaphoid angle were not statistically different before and after fixation, or when comparing the second or third metacarpal fixation. Additionally, there was no difference in Taleisnik's ulnar translocation index, Chamay's ulnar translation index, or McMurtry's carpal translation index based on which metacarpal was used for distal fixation. Conclusions  Dorsal bridge plate fixation of distal radius fractures restores preoperative physiologic measures of the radius, ulna, and carpus. Carpal translocation was similar when comparing distal fixation to the second or third metacarpal in distal radius fractures stabilized with a bridge plate. Level of Evidence  This is a Level V, therapeutic study.

Background  No consensus exists regarding postoperative splinting position following volar plate fixation of distal radius fractures. Purpose  The purpose of this study was to determine whether immobilization in supination would result in superior outcomes compared with no restriction of forearm range of motion. Patients and Methods  All patients >18 years of age with distal radius fractures indicated for volar plate fixation were eligible. Exclusion criteria were open fracture and concomitant injury to, or functional deficit of, either upper extremity. Patients were randomized to immobilization in (1) maximal supination with a sugar-tong splint or (2) no restriction of supination with a volar splint. Patient-Rated Wrist Evaluation (PRWE), Disabilities of the Arm, Shoulder, and Hand (DASH) score, and visual analog scale (VAS) score; wrist range of motion; and grip strength were recorded at 2 and 6 weeks postoperatively. A Student's t -test was used to compare mean values of all outcome measures at each time point. Results  A total of 46 patients enrolled in the study; 28 were immobilized with a volar splint and 18 were immobilized with a sugar-tong splint. Six-week follow-up data were obtained for 32 patients. There was no significant difference in PRWE, DASH, and VAS scores; or range of motion; or grip strength between the two groups postoperatively. Conclusion  Range of motion, grip strength, and patient-rated outcome measures were similar regardless of postoperative immobilization technique in patients with a distal radius fractures stabilized with a volar plate. Surgeons can elect to use the standard-of-care postoperative immobilization modality of their preference following volar plate fixation without compromising short-term return to function. Level of Evidence  This is a Level II, therapeutic study.

AIMS/HYPOTHESIS/OBJECTIVE:Ketogenic diets (KDs) have increasingly gained attention as effective means for weight loss and potential adjunctive treatment of cancer. The metabolic benefits of KDs are regularly ascribed to enhanced hepatic secretion of fibroblast growth factor 21 (FGF21) and its systemic effects on fatty-acid oxidation, energy expenditure (EE) and body weight. Ambiguous data from Fgf21-knockout animal strains and low FGF21 concentrations reported in humans with ketosis have nevertheless cast doubt regarding the endogenous function of FGF21. We here aimed to elucidate the causal role of FGF21 in mediating the therapeutic benefits of KDs on metabolism and cancer. METHODS:We established a dietary model of increased vs decreased FGF21 by feeding C57BL/6J mice with KDs, either depleted of protein or enriched with protein. We furthermore used wild-type and Fgf21-knockout mice that were subjected to the respective diets, and monitored energy and glucose homeostasis as well as tumour growth after transplantation of Lewis lung carcinoma cells. RESULTS:Hepatic and circulating, but not adipose tissue, FGF21 levels were profoundly increased by protein starvation, independent of the state of ketosis. We demonstrate that endogenous FGF21 is not essential for the maintenance of normoglycaemia upon protein and carbohydrate starvation and is therefore not needed for the effects of KDs on EE. Furthermore, the tumour-suppressing effects of KDs were independent of FGF21 and, rather, driven by concomitant protein and carbohydrate starvation. CONCLUSIONS/INTERPRETATION/CONCLUSIONS:Our data indicate that the multiple systemic effects of KD exposure in mice, previously ascribed to increased FGF21 secretion, are rather a consequence of protein malnutrition.

AIMS/OBJECTIVE:In the ischaemia-reperfused heart, transforming growth factor beta (TGFbeta) proteins trigger the differentiation of cardiac fibroblasts (CFs) contributing to fibrosis. Reoxygenation of the heart, in addition to being a trigger for reperfusion injury, induces tissue remodelling by hyperoxia-sensitive signalling processes involving TGFbeta. Here, we sought to characterize the molecular mechanisms responsible for the O(2)-sensitive transcriptional induction of TGFbeta in murine CF and to test the significance of such findings in the infarcted myocardium in vivo using laser capture microdissection. METHODS AND RESULTS/RESULTS:All three isoforms of TGFbeta were induced in the CF-rich peri-infarct tissue as well as in CF exposed to hyperoxic challenge. Reporter studies demonstrated that TGFbeta transcription is hyperoxia inducible. Deletion of any one or both of the activating protein-1 (AP-1) binding sites in the TGFbeta reporter construct resulted in loss of O(2) sensitivity, demonstrating that AP-1 confers O(2) sensitivity to TGFbeta transcription. Fos-related AP-1 transcription factor (Fra-2) and Ask-1 (apoptosis signal-regulating kinase-1) were identified as key mediators of AP-1-dependent O(2)-sensitive TGFbeta transcription. Knockdown of Fra-2 significantly blunted O(2)-induced expression of TGFbeta1 as well as TGFbeta3 in CF. Knockdown of Ask-1 blunted hyperoxia-induced Fra-2 gene expression and nuclear localization in CF. Collectively, these observations point towards a central role of Ask-1 and Fra-2 in O(2)-inducible AP-1 activation and induction of TGFbeta. CONCLUSION/CONCLUSIONS:Taken together with the observation that Fra-2-regulated genes are implicated in fibrosis, identification of Fra-2 as an O(2)-sensitive transcriptional regulator of inducible TGFbeta expression positions Fra-2 as an important player in reoxygenation-induced fibrosis.

BACKGROUND:Chronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing. METHODOLOGY/PRINCIPAL FINDINGS/RESULTS:Macrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocytosis switched wound macrophages from pro-inflammatory to an anti-inflammatory mode. CONCLUSIONS/SIGNIFICANCE/CONCLUSIONS:Taken together, this study presents first evidence demonstrating that diabetic wounds suffer from dysfunctional macrophage efferocytosis resulting in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates wound healing.

AIMS/OBJECTIVE:MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level by either degradation or translational repression of a target mRNA. Encoded in the genome of most eukaryotes, miRNAs have been proposed to regulate specifically up to 90% of human genes through a process known as miRNA-guided RNA silencing. For the first time, we sought to test how myocardial ischaemia-reperfusion (IR) changes miR expression. METHODS AND RESULTS/RESULTS:Following 2 and 7 h of IR or sham operation, myocardial tissue was collected and subjected to miRNA expression profiling and quantification using a Bioarray system that screens for human-, mice-, rat-, and Ambi-miR. Data mining and differential analyses resulted in 13 miRs that were up-regulated on day 2, 9 miRs that were up-regulated on day 7, and 6 miRs that were down-regulated on day 7 post-IR. Results randomly selected from expression profiling were validated using real-time PCR. Tissue elements laser-captured from the infarct site showed marked induction of miR-21. In situ hybridization studies using locked nucleic acid miR-21-specific probe identified that IR-inducible miR-21 was specifically localized in the infarct region of the IR heart. Immunohistochemistry data show that cardiac fibroblasts (CFs) are the major cell type in the infarct zone. Studies with isolated CFs demonstrated that phosphatase and tensin homologue (PTEN) is a direct target of miR-21. Modulation of miR-21 regulated expression of matrix metalloprotease-2 (MMP-2) via a PTEN pathway. Finally, we noted a marked decrease in PTEN expression in the infarct zone. This decrease was associated with increased MMP-2 expression in the infarct area. CONCLUSION/CONCLUSIONS:This work constitutes the first report describing changes in miR expression in response to IR in the mouse heart, showing that miR-21 regulates MMP-2 expression in CFs of the infarct zone via a PTEN pathway.