Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism

Sector Expansion and Elliptical Modeling of Blue-Gray Ovoids for Basal Cell Carcinoma Discrimination in Dermoscopy Images

Background: Blue-gray ovoids (B-GOs), a critical dermoscopic structure for basal cell carcinoma (BCC), offer an opportunity for automatic detection of BCC. Due to variation in size and color, B-GOs can be easily mistaken for similar structures in benign lesions. Analysis of these structures could afford accurate characterization and automatic recognition of B-GOs, furthering the goal of automatic BCC detection. This study utilizes a novel segmentation method to discriminate B-GOs from their benign mimics. Methods: Contact dermoscopy images of 68 confirmed BCCs with B-GOs were obtained. Another set of 131 contact dermoscopic images of benign lesions possessing B-GO mimics provided a benign competitive set. A total of 22 B-GO features were analyzed for all structures: 21 color features and one size feature. Regarding segmentation, this study utilized a novel sector-based, non-recursive segmentation method to expand the masks applied to the B-GOs and mimicking structures. Results: Logistic regression analysis determined that blue chromaticity was the best feature for discriminating true B-GOs in BCC from benign, mimicking structures. Discrimination of malignant structures was optimal when the final B-GO border was approximated by a best-fit ellipse. Using this optimal configuration, logistic regression analysis discriminated the expanded and fitted malignant structures from similar benign structures with a classification rate as high as 96.5%. Conclusions: Experimental results show that color features allow accurate expansion and localization of structures from seed areas. Modeling these structures as ellipses allows high discrimination of B-GOs in BCCs from similar structures in benign images

The seeds of divergence: the economy of French North America, 1688 to 1760

Generally, Canada has been ignored in the literature on the colonial origins of divergence with most of the attention going to the United States. Late nineteenth century estimates of income per capita show that Canada was relatively poorer than the United States and that within Canada, the French and Catholic population of Quebec was considerably poorer. Was this gap long standing? Some evidence has been advanced for earlier periods, but it is quite limited and not well-suited for comparison with other societies. This thesis aims to contribute both to Canadian economic history and to comparative work on inequality across nations during the early modern period. With the use of novel prices and wages from Quebec—which was then the largest settlement in Canada and under French rule—a price index, a series of real wages and a measurement of Gross Domestic Product (GDP) are constructed. They are used to shed light both on the course of economic development until the French were defeated by the British in 1760 and on standards of living in that colony relative to the mother country, France, as well as the American colonies. The work is divided into three components. The first component relates to the construction of a price index. The absence of such an index has been a thorn in the side of Canadian historians as it has limited the ability of historians to obtain real values of wages, output and living standards. This index shows that prices did not follow any trend and remained at a stable level. However, there were episodes of wide swings—mostly due to wars and the monetary experiment of playing card money. The creation of this index lays the foundation of the next component. The second component constructs a standardized real wage series in the form of welfare ratios (a consumption basket divided by nominal wage rate multiplied by length of work year) to compare Canada with France, England and Colonial America. Two measures are derived. The first relies on a “bare bones” definition of consumption with a large share of land-intensive goods. This measure indicates that Canada was poorer than England and Colonial America and not appreciably richer than France. However, this measure overestimates the relative position of Canada to the Old World because of the strong presence of land-intensive goods. A second measure is created using a “respectable” definition of consumption in which the basket includes a larger share of manufactured goods and capital-intensive goods. This second basket better reflects differences in living standards since the abundance of land in Canada (and Colonial America) made it easy to achieve bare subsistence, but the scarcity of capital and skilled labor made the consumption of luxuries and manufactured goods (clothing, lighting, imported goods) highly expensive. With this measure, the advantage of New France over France evaporates and turns slightly negative. In comparison with Britain and Colonial America, the gap widens appreciably. This element is the most important for future research. By showing a reversal because of a shift to a different type of basket, it shows that Old World and New World comparisons are very sensitive to how we measure the cost of living. Furthermore, there are no sustained improvements in living standards over the period regardless of the measure used. Gaps in living standards observed later in the nineteenth century existed as far back as the seventeenth century. In a wider American perspective that includes the Spanish colonies, Canada fares better. The third component computes a new series for Gross Domestic Product (GDP). This is to avoid problems associated with using real wages in the form of welfare ratios which assume a constant labor supply. This assumption is hard to defend in the case of Colonial Canada as there were many signs of increasing industriousness during the eighteenth and nineteenth centuries. The GDP series suggest no long-run trend in living standards (from 1688 to circa 1765). The long peace era of 1713 to 1740 was marked by modest economic growth which offset a steady decline that had started in 1688, but by 1760 (as a result of constant warfare) living standards had sunk below their 1688 levels. These developments are accompanied by observations that suggest that other indicators of living standard declined. The flat-lining of incomes is accompanied by substantial increases in the amount of time worked, rising mortality and rising infant mortality. In addition, comparisons of incomes with the American colonies confirm the results obtained with wages— Canada was considerably poorer. At the end, a long conclusion is provides an exploratory discussion of why Canada would have diverged early on. In structural terms, it is argued that the French colony was plagued by the problem of a small population which prohibited the existence of scale effects. In combination with the fact that it was dispersed throughout the territory, the small population of New France limited the scope for specialization and economies of scale. However, this problem was in part created, and in part aggravated, by institutional factors like seigneurial tenure. The colonial origins of French America’s divergence from the rest of North America are thus partly institutional

China's turbulent quest

A dense but rather repetitive study of Chinese Communist foreign relations and internal policy conflicts by the author of a major ""standard"" work, Communist China in World Politics (1966). The prefatory discussion of the legacy of China's past includes a fine summary of twentieth-century political history. Much of the rest of the book reads rather like a compilation of high-level intelligence reports. Hinton emphasizes China's difficulties with the activist, ""irreconcilably anti-Chinese"" Khrushchev, whom it initially preferred over Malenkov. In dealing with domestic developments, Hinton is usually sound as far as he goes--e.g. when analyzing the Hundred Flowers period in relation to Mao's intra-party jockeying, or the 1969 reduction in the role of the provincial military; but the basic issue of bureaucratic shakeup in both campaigns lies outside his scope.xi, 352 p.; 20 c

China's turbulent quest

A dense but rather repetitive study of Chinese Communist foreign relations and internal policy conflicts by the author of a major ""standard"" work, Communist China in World Politics (1966). The prefatory discussion of the legacy of China's past includes a fine summary of twentieth-century political history. Much of the rest of the book reads rather like a compilation of high-level intelligence reports. Hinton emphasizes China's difficulties with the activist, ""irreconcilably anti-Chinese"" Khrushchev, whom it initially preferred over Malenkov. In dealing with domestic developments, Hinton is usually sound as far as he goes--e.g. when analyzing the Hundred Flowers period in relation to Mao's intra-party jockeying, or the 1969 reduction in the role of the provincial military; but the basic issue of bureaucratic shakeup in both campaigns lies outside his scope.xi, 352 p.; 20 c

China's turbulent quest

A dense but rather repetitive study of Chinese Communist foreign relations and internal policy conflicts by the author of a major ""standard"" work, Communist China in World Politics (1966). The prefatory discussion of the legacy of China's past includes a fine summary of twentieth-century political history. Much of the rest of the book reads rather like a compilation of high-level intelligence reports. Hinton emphasizes China's difficulties with the activist, ""irreconcilably anti-Chinese"" Khrushchev, whom it initially preferred over Malenkov. In dealing with domestic developments, Hinton is usually sound as far as he goes--e.g. when analyzing the Hundred Flowers period in relation to Mao's intra-party jockeying, or the 1969 reduction in the role of the provincial military; but the basic issue of bureaucratic shakeup in both campaigns lies outside his scope.xi, 352 p.; 20 c

Three and a Half Powers

The dramatic confrontations and shifting alliances of the two great superpowers, and their sometimes disastrous consequences for lesser nations, are set forth in this searching analysis of political developments in the Far East since the Second World War. Hinton skillfully presents the grand design of events in Asia; the period of American ascendancy giving way to an era of Soviet-American strategic parity, which has in turn been succeeded by a multilateral balance of "three and a half powers"—the Soviet Union, the People's Republic of China, the United States—and Japan. Part I (1945-1969) analyzes decolonization and nation-building in South Asia, Japan's re-emergence after the war, the influence of the Cold War upon Asia, and the American attempt to contain and isolate the People's Republic of China. Part II (1969-1974) discusses in greater detail the emerging Sino-Soviet confrontation, the United States' military disengagement from Asia, American detente with China and the Soviet Union, and the resultant new balance of power in Asia. The outcome of more than twenty years' research, this book is for general readers as well as students and scholars

China's turbulent quest

A dense but rather repetitive study of Chinese Communist foreign relations and internal policy conflicts by the author of a major ""standard"" work, Communist China in World Politics (1966). The prefatory discussion of the legacy of China's past includes a fine summary of twentieth-century political history. Much of the rest of the book reads rather like a compilation of high-level intelligence reports. Hinton emphasizes China's difficulties with the activist, ""irreconcilably anti-Chinese"" Khrushchev, whom it initially preferred over Malenkov. In dealing with domestic developments, Hinton is usually sound as far as he goes--e.g. when analyzing the Hundred Flowers period in relation to Mao's intra-party jockeying, or the 1969 reduction in the role of the provincial military; but the basic issue of bureaucratic shakeup in both campaigns lies outside his scope.xi, 352 p.; 20 c