Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease.

Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.

Bias on the Bench: How Judges’ Legal Backgrounds Influence Their Decisions

The ideal conception of a judge is that of a neutral arbitrator. However, there exist good reasons to believe that personal characteristics, including professional experiences, bias judges. Such suspicions inspired two hypotheses: (1) judges that are former prosecutors are biased in favor of the government in criminal appeals; (2) judges that are former criminal defense attorneys are biased in favor of the criminal appellant. These hypotheses were tested by gathering professional information about state supreme court judges in the south during the years from 1995 until 1998. That was then matched to an existing database that recorded those judges’ demographics and decisions in criminal appeals during that time. Logistic regressions of that data revealed that despite when other characteristics, including gender, race, and legal experience, were accounted for, criminal defense remained a statistically significant predictor. Judges with a background in criminal defense were more likely to reverse criminal court decisions. In contrast, prosecutorial experience was not a good predictor of how a judge ruled. Judges that had backgrounds in prosecution did not rule much differently than those that did not have such a background.