Citations

ABSTRACTTrauma, surgery, and other inflammatory conditions can lead to debilitating joint contractures. Adjunct pharmacologic modalities may permit clinical prevention and treatment of recalcitrant joint contractures. We investigated the therapeutic potential of rosiglitazone by intra‐articular delivery via oligo[poly(ethylene glycol)fumarate] (OPF) hydrogels in an established rabbit model of arthrofibrosis. OPF hydrogels loaded with rosiglitazone were characterized for drug elution properties upon soaking in minimum essential media (MEM) with 10% fetal bovine serum and measurements of drug concentrations via High Performance Liquid Chromatography (HPLC). Drug‐loaded scaffolds were surgically implanted into 24 skeletally mature female New Zealand White rabbits that were divided into equal groups receiving OPF hydrogels loaded with rosiglitazone (1.67 mg), or vehicle control (10 µl DMSO). After 8 weeks of joint immobilization, rabbits were allowed unrestricted cage activity for 16 weeks. Contracture angles of rabbit limbs treated with rosiglitazone showed statistically significant improvements in flexion compared to control animals (mean angles, respectively, 64.4° vs. 53.3°, p < 0.03). At time of sacrifice (week 24), animals in the rosiglitazone group continued to exhibit less joint contracture than controls (119.0° vs. 99.5°, p = 0.014). The intra‐articular delivery of rosiglitazone using implanted OPF hydrogels decreases flexion contractures in a rabbit model of arthrofibrosis without causing adverse effects (e.g., gross inflammation or arthritis). Statement of Clinical Significance: Post‐traumatic joint contractures are common and debilitating, with limited available treatment options. Pharmacologic interventions can potentially prevent and treat such contractures. This study is translational in that a commercially approved medication has been repurposed through a novel delivery device. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2949–2955, 2018.

Background: The dynamin 1-like gene ( DNM1L) encodes a GTPase that mediates mitochondrial and peroxisomal fission and fusion. We report a new clinical presentation associated with a DNM1L pathogenic variant and review the literature. Results: A 13-year-old boy with mild developmental delays and paroxysmal dystonia presented acutely with multifocal myoclonic super-refractory status epilepticus. Despite sustained and aggressive treatment, seizures persisted and care was ultimately withdrawn in the context of extensive global cortical atrophy. Rapid trio-whole exome sequencing revealed a de novo heterozygous c.1207C>T (p.R403C) pathogenic variant in DNM1L. Immunofluorescence staining of fibroblast mitochondria revealed abnormally elongated and tubular morphology. Conclusions: This case highlights the diagnostic importance of rapid whole exome sequencing within a critical care setting and reveals the expanding phenotypic spectrum associated with DNM1L variants. This now includes progressive paroxysmal dystonia and adolescent-onset super-refractory myoclonic status epilepticus contributing to strikingly rapid and progressive cortical atrophy and death.

Background and Aims: The benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) patients remains unclear, emphasizing the need for improved prognostic biomarkers to identify patients at risk of metastatic recurrence. To address this unmet clinical need, we examined the expression and phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP) in CRC tumor progression. VASP, a processive actin polymerase, promotes the formation of invasive membrane structures leading to extracellular matrix remodeling and tumor invasion. Phosphorylation of VASP serine (Ser) residues 157 and 239 regulate VASP function, directing subcellular localization and inhibiting actin polymerization, respectively. Methods: The expression levels of VASP protein, pSer157-VASP, and pSer239-VASP were determined by immunohistochemistry in tumors and matched normal adjacent tissue from 141 CRC patients, divided into 2 cohorts, and the association of VASP biomarker expression with clinicopathologic features and disease recurrence was examined. Results: We report that changes in VASP expression and phosphorylation were significantly associated with tumor invasion and disease recurrence. Furthermore, we disclose a novel 2-tiered methodology to maximize VASP positive and negative predictive value performance for prognostication. Conclusion: VASP biomarkers may serve as prognostic biomarkers in CRC and should be evaluated in a larger clinical study.

Background: Microbleeds in the brain have been shown to occur in Alzheimer’s disease (AD), affecting approximately a third of subjects that present with typical dementia of the Alzheimer’s type (DAT). However, little is known about the frequency or distribution of microbleeds in subjects with AD that present with atypical clinical presentations. Objective: To determine whether the frequency and regional distribution of microbleeds in atypical AD differs from that observed in subjects with DAT, and to determine whether microbleeds in atypical AD are associated with age, demographics, or cognitive impairment. Methods: Fifty-five subjects with amyloid-β deposition on Pittsburgh compound B (PiB) PET who presented with predominant language (n = 37) or visuospatial/perceptual (n = 18) deficits underwent T2*weighted MRI. These subjects were compared to 41 PiB-positive subjects with DAT. Microbleeds were identified and assigned a lobar location. Results: The proportion of subjects with microbleeds did not differ between atypical AD (42%) and DAT (32%). However, atypical AD had larger numbers of microbleeds than DAT. In addition, the topographic distribution of microbleeds differed between atypical AD and DAT, with atypical AD showing the highest density of microbleeds in the frontal lobes. Among atypical AD, number of microbleeds was associated with age, but not gender or cognition. Microbleeds were more common in subjects with language (51%) versus visuospatial/perceptual deficits (22%). Conclusions: Microbleeds are relatively common in both DAT and atypical AD, although atypical AD subjects appear to be at particular risk for developing large numbers of microbleeds and for developing microbleeds in the frontal lobe.

Dialysis associated steal syndrome (DASS) is a relatively rare but debilitating complication of arteriovenous fistulas. While mild symptoms can be observed, if severe symptoms are left untreated, DASS can result in ulcerations and limb threatening ischemia. High-flow with resultant heart failure is another documented complication following dialysis access procedures. Historically, open surgical procedures have been the mainstay of therapy for both DASS as well as high-flow. These procedures included ligation, open surgical banding, distal revascularization-interval ligation, revascularization using distal inflow, and proximal invasion of arterial inflow. While effective, open surgical procedures and general anesthesia are preferably avoided in this high-risk population. Minimally invasive limited ligation endoluminal-assisted revision (MILLER) offers both a precise as well as a minimally invasive approach to treating both dialysis associated steal syndrome as well as high-flow with resultant heart failure. MILLER is not ideal for all DASS patients, particularly those with low-flow fistulas. We aim to briefly describe the open surgical therapies as well as review both the technical aspects of the MILLER procedure and the available literature.

Purpose To evaluate the validity of scores from three instruments measuring achievement goal motivation-related constructs: a shortened version of Dweck’s Implicit Theories of Intelligence Scale (ITIS-S), measuring incremental and entity mindsets; Elliot’s Achievement Goal Questionnaire–Revised (AGQ-R), measuring mastery-approach, mastery-avoidance, performance-approach, and performance-avoidance achievement goals; and Midgley’s Patterns of Adaptive Learning Scales (PALS), measuring mastery, performance-approach, and performance-avoidance achievement goals. Method High school students participating in a medical simulation training activity in May 2017 completed each instrument. The authors evaluated internal structure using reliability and factor analysis and relations with other variables using the multitrait–multimethod matrix. Results There were 178 participants. Internal consistency reliability (Cronbach alpha) was > 0.70 for all subscores. Confirmatory factor analysis of ITIS-S scores demonstrated good model fit. Confirmatory factor analysis of AGQ-R scores demonstrated borderline fit; exploratory factor analysis suggested a three-domain model (approach, mastery-avoidance, performance-avoidance). Confirmatory factor analysis of PALS scores also demonstrated borderline fit; exploratory factor analyses suggested consistent distinction between mastery and performance goals but inconsistent distinction between performance-approach and performance-avoidance goals. Correlations among AGQ-R and PALS scores were large for mastery ( r = 0.72) and moderate for performance (≥ 0.45) domains; correlations among incremental and mastery scores were moderate (≥ 0.34). Contrary to expectations, correlations between entity and performance scores were negligible. Correlations between conceptually unrelated domains were small or negligible. Conclusions All instrument scores had good internal consistency and generally appropriate relations with other variables, but empirically determined domain structures did not consistently match theory.

Background Medial epicondylitis (ME), or “golfer's elbow,” is often treated initially by conservative means. Up to 15% of recalcitrant cases require surgical intervention, according to small sample populations, but no national study has determined the incidence of the diagnosis or corroborated the rate of surgical intervention. Purpose/Question We sought to review the annual incidence of ME, surgical rates, and health care costs in a population setting. Methods A national database was queried for ME from 2007 to 2014. Annual rates and the percentage of diagnosed cases subjected to surgical intervention were recorded. Epidemiologic data was reported with descriptive statistics, and the significant trends over time were analyzed using linear regression. Results We identified 19, 856 cases of ME in the study period. There was a significant increase in the annual incidence and overall incidence per 10, 000 patients. The proportion of diagnoses in patients under 65 years of age decreased significantly, while the proportion in those 65 years of age or older significantly increased. The annual number of surgical interventions significantly increased over the study period, although the annual proportion of diagnosed cases proceeding to surgery remained constant. The proportion of patients 65 years of age or older undergoing surgery significantly increased. Total reimbursement for the management of ME during the study period was $1, 877,189. While there was a significant increase in the total annual reimbursement, annual per-patient reimbursement did not change significantly. Conclusions While the annual incidence of ME and surgical treatment of ME increased significantly from 2007 to 2014, the proportion of cases treated surgically did not. Notably, the proportion of patients 65 years of age or older diagnosed with and being surgically treated for ME has increased in recent years. Total reimbursement for ME has steadily risen, although per-patient reimbursement rates have not significantly changed.

AimsRhabdomyosarcomas of bone are extremely rare, with fewer than 10 reported cases. A very rare subtype of spindle cell/sclerosing rhabdomyosarcoma harbouring a FUS–TFCP2 fusion and involving both soft tissue and bone locations has been reported very recently. We report only the fourth case of this unusual, clinically aggressive rhabdomyosarcoma.Material and resultsA previously well 72‐year‐old male presented with a destructive lesion of the mandible. Morphological and immunohistochemical study of a needle biopsy and the subsequent resection showed a spindle cell rhabdomyosarcoma. RNA‐seq, RT–PCR and FISH confirmed the presence of the FUS–TFCP2 fusion.ConclusionsSpindle cell rhabdomyosarcomas carrying the FUS–TFCP2 fusion are very rare rhabdomyosarcoma variants with osseous predilection. The classification and differential diagnosis of this unusual molecular variant of spindle cell/sclerosing rhabdomyosarcoma are discussed.