Although many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal acid alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease. We have addressed the issue of reversibility of the disease in the Gaa(-/-) mouse model. We have made transgenic lines expressing human GAA in skeletal and cardiac muscle of Gaa(-/-) mice, and we turned the transgene on at different stages of disease progression by using a tetracycline-controllable system. We have demonstrated that levels of 20-30% of normal activity are indeed sufficient to clear glycogen in the heart of young Gaa(-/-) mice, but not in older mice with a considerably higher glycogen load. However, in skeletal muscle-a major organ affected in infantile and in milder, late-onset variants in humans-induction of GAA expression in young Gaa(-/-) mice to levels greatly exceeding wildtype values did not result in full phenotypic correction, and some muscle fibers showed little or no glycogen clearance. The results demonstrate that complete reversal of pathology in skeletal muscle or long-affected heart muscle will require much more enzyme than previously expected or a different approach.

tracking analysis of the left ventricular anterior wall shows significantly decreased relative radial strain patterns in dystrophin deficient mice after 9 months of age. PLOS Currents Muscular Dystrophy. 2011 Oct 24 . Edition 1. doi: 10.1371/currents.RRN1273. AbstractBackground: Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder with an incidence of 1 in 3,500 male births. Early treatment of DMD cardiomyopathy is under investigation and echocardiographic analysis of strain patterns may provide measures to better quantify early treatment outcomes.

Hepatitis B virus (HBV) continues to be a significant cause for post-transfusion hepatitis in India, in spite of the introduction of compulsory hepatitis B surface antigen (HBsAg) screening. To understand the true HBV-infective pool in the blood donor population, HBV DNA was detected by a 32P-labelled dot blot hybridisation assay in 605 donor units that were negative for HBsAg by a third-generation Elisa. Serum alanine aminotransferase (ALT) was estimated in all these samples and correlated with DNA positivity. The frequency of HBV DNA positivity in HBsAg-negative units was very high (9.91%) and correlated well with the elevation in ALT (p < 0.00005). However, the frequency of elevated ALT was high (11.9%), using the locally determined upper limit of normal, and half of the DNA-positive samples had a normal ALT. Thus, ALT is a poor surrogate marker for HBV infectivity and efforts should be made to apply DNA detection systems in blood banks.

Dystrophin deficiency causes contraction-induced injury and damage to the muscle fiber, resulting in sustained increase in intracellular calcium levels, activation of calcium-dependent proteases and cell death. It is known that the Ryanodine receptor (RyR1) on the sarcoplasmic reticular (SR) membrane controls calcium release. Dantrolene, an FDA approved skeletal muscle relaxant, inhibits the release of calcium from the SR during excitation-contraction and suppresses uncontrolled calcium release by directly acting on the RyR complex to limit its activation. This study examines whether Dantrolene can reduce the disease phenotype in the mdx mouse model of muscular dystrophy. We treated mdx mice (4 weeks old) with daily intraperitoneal injections of 40mg/kg of Dantrolene for 6 weeks and measured functional (grip strength, in vitro force contractions), behavioral (open field digiscan), imagining (optical imaging for inflammation), histological (H&E), and molecular (protein and RNA) endpoints in a blinded fashion. We found that treatment with Dantrolene resulted in decreased grip strength and open field behavioral activity in mdx mice. There was no significant difference in inflammation either by optical imaging analysis of cathepsin activity or histological (H&E) analysis. In vitro force contraction measures showed no changes in EDL muscle-specific force, lengthening-contraction force deficit, or fatigue resistance. We found Dantrolene treatment significantly reduces serum CK levels. Further, Dantrolene-treated mice showed decreased SERCA1 but not RyR1 expression in skeletal muscle. These results suggest that Dantrolene treatment alone has no significant beneficial effects at the tested doses in young mdx mice.