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Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin-1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes.

Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.

In this book, more than a dozen experts offer a broad and skeptical assessment of taxpayer financing of election campaigns.

The main purpose of this study was to determine whether the optic cups of tamoxifen users and anastrozole users differ in size, with the cups of the tamoxifen users being smaller. Optic nerve head (ONH) topography was measured using a commercially available, confocal scanning laser ophthalmoscope for three populations of amenorrheic women ages 40-69 years: subjects using (1) tamoxifen (20 mg/day) or (2) anastrozole (1 mg/day) for < or = 2 years as adjuvant therapy after successful primary treatment for breast cancer, and (3) control subjects with no breast cancer histories and not using any hormonal medication. All subjects had excellent visual acuity and healthy eyes, based on conventional photographic assessment. The cup volumes of the tamoxifen users were shown to be significantly smaller than the cup volumes of the anastrozole users, which were indistinguishable from normal. Because the cup volumes of the tamoxifen users decreased markedly with age at about 50 years and because anastrozole is indicated only for post-menopausal women, comparisons were reassessed for subjects older than 50 years. For these subjects, the cup volumes of the tamoxifen users averaged less than half of the volumes for each of the other two subject groups, and significant between-group differences existed in both the lateral (cup area) and axial (cup depth) directions. In contrast, any between-group differences at the ONH margin were small and not significant. The results of this study suggest that the ONH be assessed biomorphometrically for tamoxifen users reporting visual change that cannot be attributed to non-tamoxifen causes. The ability of modern intraocular imaging techniques to reveal anatomic change on the order of tens of microns may be useful for assessing tamoxifen-induced effects occurring simultaneously elsewhere in the brain, particularly since the presence of small cups is consistent with the possibility of tamoxifen-induced astrocytic swelling.

In 1980, Ronald Reagan said, It is time to check and reverse the growth of government, which shows signs of having grown beyond the consent of the governed. A little more than 25 years later, Barack Obama declared the Reagan Revolution over. This book surveys the highlights and low points of the nearly 30-year struggle to limit American government, set against the big-government world of the New Deal and the Great Society. The book assesses Reagan's successes and failures, and looks at the 1994 election as a mandate to resume Reagan's efforts. It explores George W. Bush's rejection of limited government in favor of high spending, a mixture of religion and government, and a floundering crusade to bring democracy to the Middle East. Finally, it asks whether the elections of 2006 and 2008 were a rejection of the limited government message or just a repudiation of the failed Bush presidency.

Since 1998, U.S. House incumbents have won a staggering 98 percent of their reelection races. Electoral competition has also declined in some state and primary elections.The Marketplace for Democracycombines the resources of two eminent research organizations -Brookings and the Cato Institute -to address several important questions about our democratic system. How pervasive is the lack of competition in arenas only previously speculated on, such as state legislative contests and congressional primaries? What have previous reform efforts, such as direct primaries and term limits, had on electoral competition? What are the effects of redistricting and campaign finance regulation? What role do third parties play? In sum, what does all this tell us about what might be done to increase electoral competition? The authors, including a number of today's most important scholars in American politics, consider the historical development, legal background, and political aspects of a system that is supposed to be responsive and accountable yet for many is becoming stagnant, self-perpetuating, and tone-deaf. How did we get to this point, and what -if anything -should be done about it? Elections are the vehicles through which Americans choose who governs them, and the power of the ballot is still the best lever ordinary citizens have in keeping public officials accountable. The Marketplace of Democracy considers different policy options for increasing the competition needed to keep American politics vibrant, responsive, and democratic. Contributors include Stephen Ansolabehere (MIT), William D. Berry (Florida State University), Bruce Cain (University of California-Berkeley), Thomas Carsey (Florida StateUniversity) James Gimpel (University of Maryland) John Hanley (UC-Berkeley), John Mark Hansen (University of Chicago), Paul S. Herrnson (University of Maryland) Gary Jacobson (University of California-San Diego) Thad Kousser (UC-San Diego), Frances Lee (University of Maryland), John Matsusaka (University of Southern California), Kenneth Mayer (University of Wisconsin-Madison), Michael P. McDonald (Brookings Institution and George Mason University), Jeffrey Milyo (University of Missouri-Columbia), Richard Niemi (University of Rochester) Nate Persily (University of Pennsylvania Law School), Lynda Powell (University of Rochester), David Primo (University of Rochester), John Samples (Cato Institute), and James Snyder Jr. (MIT).

At first glance, campaign finance reform looks like a good idea. McCain-Feingold, for instance, regulates campaigns by prohibiting national political parties from accepting soft money contributions from corporations, labor unions, and wealthy individuals. But are such measures, or any of the numerous and similarly restrictive proposals that have circulated through Washington in recent years, really good for our democracy? John Samples says no, and here he takes a penetrating look into the premises and consequences of the long crusade against big money in politics. How many Americans, he asks, know that there is little to no evidence that campaign contributions really influence members of Congress? Or that so-called negative political advertising actually improves the democratic process by increasing voter turnout and knowledge? Or that limits on campaign contributions make it harder to run for office, thereby protecting incumbent representatives from losing their seats of power? Posing tough questions such as these, Samples uncovers numerous fallacies beneath proposals for campaign finance reform. He argues that our most common concerns about money in politics are misplaced because the ideals implicit in our notion of corruption are incoherent or indefensible. The chance to regulate money in politics allows representatives to serve their own interests at a cost to their constituents. And, ironically, this long crusade against the corruption caused by campaign contributions allows public officials to reduce their vulnerability by suppressing electoral competition. Defying long-held ssumptions and conventional political wisdom, The Fallacy of Campaign Finance Reform is a provocative and decidedly nonpartisan work that will be essential for anyone concerned about the future of American government.

In 1995, Republicans took control of Congress for the first time in 40 years. Here, 18 experts - including Newt Gingrich and Dick Armey - reexamine the successes and failures of the Republican revolution.