Briefly, DVD-deficient neonates had larger lateral ventricles, increased cellular proliferation and reduced apoptosis, altered neurogenesis, reduced density of neurotrophin receptor, and reduced levels of nerve growth factor and glial cell line-derived growth factor compared to controls. Extracellular adenosine binds adenosine receptors to affect a reduction in inflammation. AICA is also cytotoxic to T lymphocytes, potentiates the cytotoxicity of methotrexate added to cultured T lymphocytes and activates AMP-activated kinase. Funk et al. recently demonstrated AICAR increased 115-fold following exposure of an erythroblastoid cell line to 10 nM methotrexate, but decreased with increasing methotrexate concentrations, declining to baseline with 1000 nM methotrexate. In contrast, the substrate for thymidylate synthase, 29deoxyuridine 59-monophosphate, displayed concentration-dependent accumulation over the same range of methotrexate concentration. It was suggested that if clinical response is dependent on the accumulation of AICAR, that these in vitro findings might predict a clinical therapeutic response paradoxically related to dose. Initial trials of methotrexate in AD simply adopted the dose and regimen commonly used to treat psoriasis and rheumatoid arthritis. However, given the different underlying pathologic mechanisms between AD and these other autoimmune diseases, it is not clear that the same dosing strategy would be equally applicable. In fact, no study has examined how dose and regimen affect antifolate efficacy in AD, and thus how to best administer antifolate therapy in AD remains a significant unresolved question. Although mouse models of AD have many practical benefits in the laboratory, they also have significant limitations in how clinically similar their disease is to human AD. Owners were not required to take any special handling precautions of study drug. A pre-planned interim efficacy checkpoint at day 56 was instituted based on pilot trial data that indicated responsive subjects achieved the majority of benefit by 4�C8 weeks, whereas unresponsive subjects failed to improve with further treatment. Subjects achieving at least 25% GS improvement passed the checkpoint and continued to receive treatment up to day 84.