Glucocorticoid-Treated Mice Are an Inappropriate Positive Control for Long-Term Preclinical Studies in the mdx Mouse

Dmd(mdx) (mdx) mice are used as a genetic and biochemical model of dystrophin deficiency. The long-term consequences of glucocorticoid (GC) treatment on dystrophin-deficient skeletal and heart muscle are not yet known. Here we used systematic phenotyping to assess the long-term consequences of GC treatment in mdx mice. Our investigation addressed not only the effects of GC on the disease phenotype but also the question of whether GCs can be used as a positive control for preclinical drug evaluations.We performed nine pre-clinical efficacy trials (treated N = 129, untreated N = 106) of different durations in 9-to-50-week-old dystrophic mdx mice over a 3-year time period using standardized methods. In all these trials, we used either 1 mg/kg body weight of prednisone or 5 mg/kg body weight of prednisolone as positive controls to compare the efficacy of various test drugs. Data from untreated controls and GC-treated mice in the various trials have been pooled and analyzed to assess the effects of GCs on dystrophin-deficient skeletal and cardiac muscles of mdx mice. Our results indicate that continuous GC treatment results in early (e.g., at 50 days) improvements in normalized parameters such as grip strength, motor coordination and maximal in vitro force contractions on isolated EDL muscle, but these initial benefits are followed by a progressive loss of muscle strength after 100 days. We also found a significant increase in heart fibrosis that is reflected in a significant deterioration in cardiac systolic function after 100 days of treatment.Continuous administration of prednisone to mdx mice initially improves skeletal muscle strength, but further therapy result in deterioration of muscle strength and cardiac function associated with enhanced cardiac fibrosis. These results suggest that GCs may not serve as an appropriate positive control for long-term mdx mouse preclinical trials

Robotic Living Donor Right Hepatectomy: A Systematic Review and Meta-Analysis

The introduction of robotics in living donor liver transplantation has been revolutionary. We aimed to examine the safety of robotic living donor right hepatectomy (RLDRH) compared to open (ODRH) and laparoscopic (LADRH) approaches. A systematic review was carried out in Medline and six additional databases following PRISMA guidelines. Data on morbidity, postoperative liver function, and pain in donors and recipients were extracted from studies comparing RLDRH, ODRH, and LADRH published up to September 2020; PROSPERO (CRD42020214313). Dichotomous variables were pooled as risk ratios and continuous variables as weighted mean differences. Four studies with a total of 517 patients were included. In living donors, the postoperative total bilirubin level (MD: −0.7 95%CI −1.0, −0.4), length of hospital stay (MD: −0.8 95%CI −1.4, −0.3), Clavien–Dindo complications I–II (RR: 0.5 95%CI 0.2, 0.9), and pain score at day > 3 (MD: −0.6 95%CI −1.6, 0.4) were lower following RLDRH compared to ODRH. Furthermore, the pain score at day > 3 (MD: −0.4 95%CI −0.8, −0.09) was lower after RLDRH when compared to LADRH. In recipients, the postoperative AST level was lower (MD: −0.5 95%CI −0.9, −0.1) following RLDRH compared to ODRH. Moreover, the length of stay (MD: −6.4 95%CI −11.3, −1.5) was lower after RLDRH when compared to LADRH. In summary, we identified low- to unclear-quality evidence that RLDRH seems to be safe and feasible for adult living donor liver transplantation compared to the conventional approaches. No postoperative deaths were reported

Whole Body Periodic Acceleration Is an Effective Therapy to Ameliorate Muscular Dystrophy in mdx Mice

Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the absence of dystrophin in both skeletal and cardiac muscles. This leads to severe muscle degeneration, and dilated cardiomyopathy that produces patient death, which in most cases occurs before the end of the second decade. Several lines of evidence have shown that modulators of nitric oxide (NO) pathway can improve skeletal muscle and cardiac function in the mdx mouse, a mouse model for DMD. Whole body periodic acceleration (pGz) is produced by applying sinusoidal motion to supine humans and in standing conscious rodents in a headward-footward direction using a motion platform. It adds small pulses as a function of movement frequency to the circulation thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of NO. In this study, we examined the potential therapeutic properties of pGz for the treatment of skeletal muscle pathology observed in the mdx mouse. We found that pGz (480 cpm, 8 days, 1 hr per day) decreased intracellular Ca2+ and Na+ overload, diminished serum levels of creatine kinase (CK) and reduced intracellular accumulation of Evans Blue. Furthermore, pGz increased muscle force generation and expression of both utrophin and the carboxy-terminal PDZ ligand of nNOS (CAPON). Likewise, pGz (120 cpm, 12 h) applied in vitro to skeletal muscle myotubes reduced Ca2+ and Na+ overload, diminished abnormal sarcolemmal Ca2+ entry and increased phosphorylation of endothelial NOS. Overall, this study provides new insights into the potential therapeutic efficacy of pGz as a non-invasive and non-pharmacological approach for the treatment of DMD patients through activation of the NO pathway