The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy2J/dy2J mouse model of merosin deficient congenital muscular dystrophy. The dy2J/dy2J mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy2J/dy2J mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy2J/dy2J mouse model of congenital muscular dystrophy

Virtual nonenhanced abdominal dual-energy MDCT: Analysis of image characteristics

AIM: To evaluate abdominal and pelvic image characteristics and artifacts on virtual nonenhanced (VNE) images generated from contrast-enhanced dual-energy multidetector computed tomography (MDCT) studies

Quantitative live cell imaging reveals a gradual shift between DNA repair mechanisms and a maximal use of HR in mid S phase.

DNA double-strand breaks are repaired by two main pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR). The choice between these pathways depends on cell-cycle phase; however the continuous effect of cell cycle on the balance between them is still unclear. We used live cell imaging and fluorescent reporters for 53BP1, Rad52, and cell cycle to quantify the relative contribution of NHEJ and HR at different points of the cell cycle in single cells. We found that NHEJ is the dominant repair pathway in G1 and G2 even when both repair pathways are functional. The shift from NHEJ to HR is gradual, with the highest proportion of breaks repaired by HR in mid S, where the amount of DNA replication is highest. Higher proportions of HR also strongly correlate with slower rates of repair. Our study shows that the choice of repair mechanism is continuously adjusted throughout the cell cycle and suggests that the extent of active replication, rather than the presence of a sister chromatid influences the balance between the two repair pathways in human cells

Surface stabilization treatment enhances initial cell viability and adhesion for biodegradable zinc alloys

Zinc-based alloys hold promise as next generation biodegradable implants. Although zinc implants exhibit excellent biocompatibility in vivo, they have been found to inhibit cell attachment and viability under in vitro conditions. In order to clarify the cell response disparity and improve the biocompatibility of zinc implant materials, Zn-1Mg and Zn-1Mg-0.5Ca alloys underwent surface stabilization treatment in cell culture medium. Surface processing resulted in a stable surface oxide film of ∼300 nm thickness. The stability of the oxide layer substantially increased the viability of cells in both direct and indirect contact assays. It is consequently believed that the surface film characteristics of zinc implants may be an important determinant of biocompatibility

Evaluation of biodegradable Zn-1%Mg and Zn-1%Mg-0.5%Ca alloys for biomedical applications

Increasing interest in biodegradable metals (Mg, Fe, and Zn) as structural materials for orthopedic and cardiovascular applications mainly relates to their promising biocompatibility, mechanical properties and ability to self-remove. However, Mg alloys suffer from excessive corrosion rates associated with premature loss of mechanical integrity and gas embolism risks. Fe based alloys produce voluminous corrosion products that have a detrimental effect on neighboring cells and extracellular matrix. In contrast, Zn does not appear to exhibit a harmful mode of corrosion. Unfortunately, pure zinc possesses insufficient mechanical strength for biomedical structural applications. The present study aimed at examining the potential of two new zinc based alloys, Zn-1%Mg and Zn-1%Mg-0.5%Ca to serve as structural materials for biodegradable implants. This examination was carried out under in vitro conditions, including immersion testing, potentiodynamic polarization analysis, electrochemical impedance spectroscopy (EIS), and stress corrosion cracking (SCC) assessments in terms of slow strain rate testing (SSRT). In order to assess the cytotoxicity of the tested alloys, cell viability was evaluated indirectly using Saos-2 cells. The results demonstrate that both zinc alloys can be considered as potential candidates for biodegradable implants, with a relative advantage to the Zn-1%Mg alloy in terms of its corrosion resistance and SCC performance

Bone marrow edema in traumatic vertebral compression fractures: Diagnostic accuracy of dual-layer detector CT using calcium suppressed images

Purpose: To evaluate calcium suppressed images (CaSupp) in dual-layer detector computed tomography (DLCT) for the detection of bone marrow edema (BME) in vertebral fractures. Materials and methods: The retrospective study was approved by the institutional review board. 34 patients with synchronous DLCT and MRI, who were diagnosed with one or more acute vertebral fractures, were included. MRI were systematically analyzed as reference standard. Two blinded and independent readers evaluated CaSupp for vertebral BME. Additionally, both readers determined the optimal calcium suppression indices (CaSupp-I) for visualization of BME in consensus and correlated the CaSupp-I with parallel measurement of trabecular density as surrogate parameter for bone mineral density. ROI-based measurements of the contrast-to-noise ratios (CNR) were also conducted. Interrater agreement was determined by kappa-statistics. CNR were analyzed using Wilcoxon signed rank test. Results: Fifty-seven acute fractured vertebrae out of 383 vertebrae (14.9%) were found. CaSupp yielded an average sensitivity of 87% and specificity of 99%, a positive predictive value of 95%, a negative predictive value of 98% and an accuracy of 97% for the detection of fracture-associated edema. Interrater agreement was excellent (kappa 0.91). Increase in CNR of BME correlated with increasing CaSupp-I. Edema adjacent to the cortical endplates was better visualized using CaSupp-I of 70 and 80, while extensive edema was better visualized using a CaSupp-I of 90 and 100 (chi2 0.2). Conclusion: CaSupp reconstructed from DLCT enable visualization and detection of BME in traumatic fractured vertebrae with high diagnostic accuracy using CaSupp-I of 70-100