Methylphenidate transdermal system: clinical applications for attention-deficit/hyperactivity disorder.

The methylphenidate transdermal system (MTS) provides a novel method of delivery for methylphenidate, a well-studied and effective medication for attention-deficit/hyperactivity disorder. The MTS achieves two major goals. First, the delivery system allows for administration throughout the day with a single patch, thus improving adherence. Second, it is the first approved attention-deficit/hyperactivity disorder medication that is not administered orally, thus bypassing gastrointestinal absorption and first-pass metabolism through the enteric circulation. In this article, we review the current data on MTS, including preclinical, clinical and post-marketing studies, and compare efficacy and tolerability to currently available treatments.

Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice.

Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc+/- mice. Our data show that postnatal Ptc+/- mouse granule cell precursor growth is not globally altered. However, many older Ptc+/- mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc+/- mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc+/- mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the neurotrophin-3 receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression.

Magnetic resonance imaging of patched heterozygous and xenografted mouse brain tumors.

Experimental mouse models are emerging as useful systems for the study of human brain tumors. Nuclear magnetic resonance imaging (MRI) methods can noninvasively provide images of complex heterogeneous tissues such as experimental brain tumors. The current report demonstrates the feasibility of longitudinal high-resolution MRI in two mouse brain tumor models: patched heterozygous (ptc +/-) mice with spontaneously arising posterior fossa tumors that resemble human medulloblastoma, and homozygous nude mice implanted with intracerebral xenografts of human medulloblastoma cell lines. Methods were optimized to achieve favorable volumetric comparison with histologic methods and sub-millimeter resolution, improved by contrast enhancement with intravenous administration of a gadolinium-based agent. Results also show that experimental mice, even symptomatic mice, tolerate repeated serial imaging studies over weeks to months to follow tumor progression and to visualize placement of an intracerebral drug delivery system.