Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis.

Contains fulltext : 69611.pdf (publisher's version ) (Closed access)Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity

Introduction : the rule of law in an era of multi-level governance and global legal pluralism

Reinold and Heupel's introductory chapter articulates the volume's overarching research question, surveys relevant International Relations and International Law scholarship, proposes a conceptual framework for answering the volume's question, and presents the structure of the book. The guiding question is whether the coexistence of (partially) overlapping and sometimes competing layers of authority, which characterizes today's global order, undermines or rather strengthens efforts to promote the rule of law on a global scale. Summarizing the volume's findings, Reinold and Heupel argue that whether multi-level governance and global legal pluralism have beneficial or detrimental effects on the international rule of law depend on specific scope conditions. Among these are the mobilization of powerful states and courts, and the fit between soft law and hard arrangements