BackgroundTo identify molecular alterations in skeletal muscle in rheumatoid arthritis (RA) that may contribute to ongoing disability in RA.MethodsPersons with seropositive or erosive RA (n = 51) and control subjects matched for age, gender, race, body mass index (BMI), and physical activity (n = 51) underwent assessment of disease activity, disability, pain, physical activity and thigh muscle biopsies. Muscle tissue was used for measurement of pro-inflammatory markers, transcriptomics, and comprehensive profiling of metabolic intermediates. Groups were compared using mixed models. Bivariate associations were assessed with Spearman correlation.ResultsCompared to controls, patients with RA had 75% greater muscle concentrations of IL-6 protein (p = 0.006). In patients with RA, muscle concentrations of inflammatory markers were positively associated (p < 0.05 for all) with disease activity (IL-1β, IL-8), disability (IL-1β, IL-6), pain (IL-1β, TNF-α, toll-like receptor (TLR)-4), and physical inactivity (IL-1β, IL-6). Muscle cytokines were not related to corresponding systemic cytokines. Prominent among the gene sets differentially expressed in muscles in RA versus controls were those involved in skeletal muscle repair processes and glycolytic metabolism. Metabolic profiling revealed 46% higher concentrations of pyruvate in muscle in RA (p < 0.05), and strong positive correlation between levels of amino acids involved in fibrosis (arginine, ornithine, proline, and glycine) and disability (p < 0.05).ConclusionRA is accompanied by broad-ranging molecular alterations in skeletal muscle. Analysis of inflammatory markers, gene expression, and metabolic intermediates linked disease-related disruptions in muscle inflammatory signaling, remodeling, and metabolic programming to physical inactivity and disability. Thus, skeletal muscle dysfunction might contribute to a viscous cycle of RA disease activity, physical inactivity, and disability.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1215-7) contains supplementary material, which is available to authorized users.
Objectives In prior reports, individuals with rheumatoid arthritis (RA) exhibited increased insulin resistance. However, these studies were limited by either suboptimal assessment methods for insulin sensitivity or a failure to account for important determinants, adiposity and physical activity. Our objectives were to carefully assess, compare and determine predictors of skeletal muscle insulin sensitivity (SI) in RA, accounting for adiposity and physical activity. Methods Thirty-nine individuals with established (seropositive or erosions) and treated RA and 39 age, gender, race, BMI, and physical activity-matched controls underwent a frequently-sampled intravenous glucose tolerance test to determine SI. Inflammation, body composition, and physical activity were assessed with systemic cytokine measurements, CT scans, and accelerometry, respectively. Exclusions were diabetes, cardiovascular disease, medication changes within three months, and prednisone use over 5 mg/d. This investigation was powered to detect a clinically significant, moderate effect size for SI difference. Results Despite elevated systemic inflammation (interleukin (IL)-6, IL-18, tumor necrosis factor-alpha; P<0.05 for all), persons with RA were not less insulin sensitive (SI geometric mean (SD): RA 4.0 (2.4) versus Control 4.9 (2.1)*10−5 min−1/[pmol/l]; P=0.39). Except for visceral adiposity being slightly greater in controls (P=0.03), there were no differences in body composition or physical activity. Lower SI was independently associated with increased abdominal and thigh adiposity, but not with cytokines, disease activity, duration, disability, or disease modifying medication use. Conclusions In established and treated RA, traditional risk factors, specifically excess adiposity, play more of a role in predicting skeletal muscle insulin sensitivity than systemic inflammation or other disease-related factors.
Purpose: Improvement in outcomes of LT for pediatric HB and HCC has been reported in small series. We analyzed national outcomes and changes in donor, recipient, and perioperative factors over time that may contribute to survival differences. Methods:The UNOS database was queried for patients age <21 years that underwent LT for a primary diagnosis of HB or HCC . Subjects were divided into historic (transplant before 2010) and contemporary (transplant after 2010) cohorts. Baseline characteristics were compiled and examined. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test. Results:In total, 599 children with HB received LT (320 historic vs 279 contemporary). Concurrently, 141 children with HCC received LT (92 historic vs 49 contemporary). For both tumors, waitlist time decreased (HB 56.2 days historic vs 33.2 days contemporary, P = 0.017; HCC 189.3 days historic vs 71.7 days contemporary, P = 0.012). In the historic cohorts, patients with HB had a 1-year and 5-year OS of 84.6% and 75.1%, respectively. Survival for HCC was 84.4% and 59.9%, respectively.Outcomes improved in the contemporary era to 89.1% and 82.6% for HB, and 94.7% and 80.8% for HCC, respectively (both log-rank test P < 0.0001). Conclusion:Outcomes of LT have improved significantly, with contemporary survival now equivalent between these tumors and exceeding 80% 5-year OS. Future studies are needed to explore whether offering LT in patients that are resectable is justifiable. K E Y W O R D Shepatoblastoma, hepatocellular carcinoma, liver transplantation, outcomes, pediatric
Background Renal medullary carcinoma (RMC) is an aggressive malignancy seen predominantly in young males with sickle cell trait. RMC is poorly understood, with fewer than 220 cases described in the medical literature to date. We used a large national registry to define the typical presentation, treatments, and outcomes of this rare tumor. Methods The National Cancer Database was queried for patients under 40 years of age diagnosed with RMC from 1998 to 2011. An analysis of patient and tumor characteristics, treatment details, and overall survival (OS) was undertaken, and factors associated with mortality were identified using multivariable regression analysis. Results In total, 159 patients with RMC were identified, of whom a majority were male (71%), African American (87%), and had metastatic disease (71%). Median tumor size was 6 cm and median survival was 7.7 months. Most patients underwent surgery (60%) and chemotherapy (65%). Few patients received radiation (12%). Patients with metastatic disease had a significantly worse median survival (4.7 vs. 17.8 months, P < 0.001) and were less likely to receive surgery (42% vs. 91%, P < 0.001). Age and tumor size did not appear to impact OS. Conclusion In the largest cohort to date of patients with RMC, we found a dismal median survival of less than 8 months. Age and tumor size were not associated with OS. Metastatic disease at presentation was the main negative prognostic indicator in RMC and was present in a majority of patients at the time of diagnosis.
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