Tuberous sclerosis complex (TSC) is a familial tumor disorder for which there is no effective medical therapy. Disease-causing mutations in the TSC1 or TSC2 gene lead to increased mammalian target of rapamycin (mTOR) kinase activity in the conserved mTOR signaling pathway, which regulates nutrient uptake, cell growth, and protein translation. The normal function of TSC1 and TSC2 gene products is to form a complex that reduces mTOR kinase activity. Thus, mTOR kinase inhibition may be a useful targeted therapeutic approach. Elevated interferon-gamma (IFN-gamma) expression is associated with decreased severity of kidney tumors in TSC patients and mouse models; therefore, IFN-gamma also has therapeutic potential. We studied cohorts of Tsc2+/- mice and a novel mouse model of Tsc2-null tumors in order to evaluate the efficacy of targeted therapy for TSC. We found that treatment with either an mTOR kinase inhibitor (CCI-779, a rapamycin analog) or with IFN-gamma reduced the severity of TSC-related disease without significant toxicity. These results constitute definitive preclinical data that justify proceeding with clinical trials using these agents in selected patients with TSC and related disorders.

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Ronald Dworkin's Freedom's Law offers a solution to a thorny problem in American constitutional law. He argues that the authority of the American Supreme Court to make the final determination on constitutional questions is consistent with democratic principles. In this paper, I try to show that his solution is unsatisfactory because it permits the possibility of a judicial usurpation of authority that is inconsistent with his characterization of democratic principles. Freedom's Law is also a bold attempt to offer prescriptions for constitutional democracies generally. By drawing a distinction between two concepts of authority, I object to this effort. I argue that Dworkin's analysis assumes the operation of a conception of authority that I label the pyramid model. I also introduce a bipolar model of authority and try to show its application to the Canadian constitutional scheme. On this basis, I conclude that his prescriptions are relevant only for a portion of the spectrum of constitutional democracies.

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