Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 and X-linked CLDN2 through a two-stage genome-wide study. The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is (...) associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men. © 2012 Nature America, Inc. All rights reserved. (shrink)

Progressive supranuclear palsy is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP and 3,247 controls followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the (...) stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. © 2011 Nature America, Inc. All rights reserved. (shrink)

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical (...) features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. (shrink)

This work has been selected by scholars as being culturally important and is part of the knowledge base of civilization as we know it. This work is in the public domain in the United States of America, and possibly other nations. Within the United States, you may freely copy and distribute this work, as no entity (individual or corporate) has a copyright on the body of the work. Scholars believe, and we concur, that this work is important enough to be (...) preserved, reproduced, and made generally available to the public. To ensure a quality reading experience, this work has been proofread and republished using a format that seamlessly blends the original graphical elements with text in an easy-to-read typeface. We appreciate your support of the preservation process, and thank you for being an important part of keeping this knowledge alive and relevant. (shrink)

A collection of fourteen essays, three of them previously unpublished, which manages to be both indispensable and unsatisfying. Wellek surveys methods of criticism in Europe and America, then outlines the conceptual ideals that ought to be followed. Wellek's belief in literature as a structure of norms, as imaginative writing concerned with values, will be familiar from his earlier Theory of Literature. Theoretically speaking, literary study has been muddled; the hope for it lies in applying period concepts, by approaching literature as (...) a structure of norms, and by following the guidelines set down by the New Critics. But the polemics go side by side with the erudition, in such a way that one finds judgment without argument. Contains a bibliography of Wellek's writings.—C. L. B. (shrink)

Over the last 20+ years, multinational corporations (MNCs) have been confronted with accusations of abuse of market power and unfair and unethical business conduct especially as it relates to their overseas operations and supply chain management. These accusations include, among others, worker exploitation in terms of unfairly low wages, excessive work hours, and unsafe work environment; pollution and contamination of air, ground water and land resources; and, undermining the ability of natural government to protect the well-being of their citizens. MNCs (...) have responded to these accusations by creating voluntary codes of conduct which commit them to specific standards for addressing these issues. These codes are created at both the industry-wide and the individual company level. Unfortunately, these codes have generated little credibility and public trust because their compliance claims cannot be independently verified, and they lack transparency and full public disclosure. In this article, we present a case study of the voluntary code of conduct by Mattel, Inc., the world's largest toy company. The code, called the Global Manufacturing Principles (GMP), confronts the general criticism leveled against voluntary codes of conduct by (a) creating detailed standards of compliance, (b) independent external monitoring of the company's compliance with its code of conduct, and (c) making full, and uncensored public disclosure of the audit findings and company's response in terms of remedial action. We present a detailed account of how Mattel's voluntary code of conduct was created, implemented, and ultimately abandoned over 9 years. We provide an evaluative analysis of the company's GMP compliance throughout its life span, which suggests a bellshaped curve, where early top management commitments were met with pockets of resistance from operational groups, who were concerned about balancing GMP compliance efforts with traditional performance criteria. The early stage response from Mattel's top management was quick and supported with the requisite resources. As a result, the compliance process accelerated, becoming increasingly more robust and effective. The success of code compliance and increased transparency in public disclosure energized field managers with a sense of professional satisfaction and publicly recognized accomplishments.The decline in GMP compliance was equally steep. When all the easily attainable targets had been reached at the company-operated plants, addressing vendor plants' compliance presented a new set of challenges, which taxed corporate resources and management commitment. It would seem that value-based and ethicsoriented considerations, i. e., doing the right thing for the right reason, were no longer the driving force for Mattel's management. Mattel did not see any economic benefit from its proactive stance, when competitors did not seem to suffer adverse consequences for not following suit. The final contributing factor to the code's abandonment was a widely publicized series of product recalls which absorbed top management's attention. (shrink)

The distinguished Dutch cultural historian, Johan Huizinga, once observed that the 17th was the most complex and least understood of the modern European centuries. Professor Loemker, one of America’s foremost Leibniz scholars has written a learned and searching study in the intellectual history of the "baroque" century in an effort to illuminate the background of Leibniz’ synthesis of order of freedom, his system of universal harmony. The cacophonous period within which Leibniz philosophized presented an overriding geistige Aufgabe and the very (...) essence of his thought can be interpreted as a response to that task. The peculiar burden or problematic of his age required the defining of those ideals and conditions which could lead to the foundation of an adequate and more comprehensive form of order. It is the author’s conviction that the systematic thinkers of the time accomplished this "on the basis of an enlarged version of Neoplatonism, particularly the Christian Neoplatonism of St. Augustine, though they differed greatly on details.". (shrink)

Critically analyzes and revitalizes agrarian philosophy by tracing its evolution. Today, most historians, philosophers, political theorists, and scholars of rural America take a dim view of the agrarian ideal that farmers and farming occupy a special moral and political status in society. Agrarian rhetoric is generally seen as special pleading on the part of farmers seeking protection from labor reform and environmental regulation while continuing to receive direct payments and subsidies from the public till. Agrarianism should not be viewed as (...) a set of immutable claims about farming and political order, but as a tradition of moral and political philosophy that has evolved and deepened over the centuries. Agrarian naturalism--the belief that culture and conduct are conditioned by nature because they are of a piece with nature--becomes pragmatic naturalism, giving way to a new set of puzzles about how we are to understand the rural landscape and our responsibilities for its use. The agrarian idea that personality and sociability are integrated with the material transformation of the landscape can serve as the basis for a new, pragmatically grounded ethic of natural resources and rural development. The essays in this volume critically analyze and revitalize agrarian philosophy by tracing its evolution in the classical American philosophy of key figures such as Franklin, Jefferson, Emerson, Thoreau, Dewey, and Royce. Three chapters address the belief that farming peoples develop moral virtue and a taste for democracy as it evolved in the American context, and four examine how a reconstitution of agrarian themes might invigorate our nation's thinking on environment, food, and rural development policy. The Agrarian Roots of Pragmatism will be of broad interest to scholars of American philosophy, rural history, history of ideas, geography, and agricultural or natural resource policy. (shrink)

Background: Although nurses worldwide are confronted with euthanasia requests from patients, the views of palliative care nurses on their involvement in euthanasia remain unclear.Objectives: In depth exploration of the views of palliative care nurses on their involvement in the entire care process surrounding euthanasia.Design: A qualitative Grounded Theory strategy was used.Setting and participants: In anticipation of new Belgian legislation on euthanasia, we conducted semistructured interviews with 12 nurses working in a palliative care setting in the province of Vlaams-Brabant.Results: Palliative (...) care nurses believed unanimously that they have an important role in the process of caring for a patient who requests euthanasia, a role that is not limited to assisting the physician when he is administering life terminating drugs. Nurses’ involvement starts when the patient requests euthanasia and ends with supporting the patient’s relatives and healthcare colleagues after the potential life terminating act. Nurses stressed the importance of having an open mind and of using palliative techniques, also offering a contextual understanding of the patient’s request in the decision making process. Concerning the actual act of performing euthanasia, palliative care nurses saw their role primarily as assisting the patient, the patient’s family, and the physician by being present, even if they could not reconcile themselves with actually performing euthanasia.Conclusions: Based on their professional nursing expertise and unique relationship with the patient, nurses participating as full members of the interdisciplinary expert team are in a key position to provide valuable care to patients requesting euthanasia. (shrink)

In both the literal and metaphorical senses, it seemed as if 1970s America was running out of gas.

Previous research in North America has supported the view that male involvement in committed, romantic relationships is associated with lower testosterone (T) levels. Here, we test the prediction that undergraduate men involved in committed, romantic relationships (paired) will have lower T levels than men not involved in such relationships (unpaired). Further, we also test whether these differences are more apparent in samples collected later, rather than earlier, in the day. For this study, 107 undergraduate men filled out a questionnaire and (...) collected one saliva sample (from which a subject’s T level was measured) at various times across the day. As in previous studies, men involved in committed, romantic relationships had lower salivary T levels, though only during later times of the day. Furthermore, additional analysis of the variation among unpaired subjects indicated that men without prior relationship experience had lower T levels than experienced men. Finally, while paired men as a group had lower T levels than unpaired men, those men at the earliest stage (less than six months) of a current relationship had higher T levels than unpaired men as well as men in longer-term relationships. These results suggest that variation in male testosterone levels may reflect differential behavioral allocation to mating effort. (shrink)

© 2015 Elsevier Inc.Postnatal organogenesis occurs in an immune competent environment and is tightly controlled by interplay between positive and negative regulators. Innate immune cells have beneficial roles in postnatal tissue remodeling, but roles for the adaptive immune system are currently unexplored. Here we show that adaptive immune responses participate in the normal postnatal development of a non-lymphoid epithelial tissue. Since the mammary gland is the only organ developing predominantly after birth, we utilized it as a powerful system to study (...) adaptive immune regulation of organogenesis. We found that antigen-mediated interactions between mammary antigen-presenting cells and interferon-γ -producing CD4+ T helper 1 cells participate in MG postnatal organogenesis as negative regulators, locally orchestrating epithelial rearrangement. IFNγ then affects luminal lineage differentiation. This function of adaptive immune responses, regulating normal development, changes the paradigm for studying players of postnatal organogenesis and provides insights into immune surveillance and cancer transformation. Plaks et al. (shrink)

I examine Mach's influence on American philosophy from 1890-1910, on Carus, James, Peirce, the American Realists and J.B. Stallo. I also consider the question of whether Mach was a pragmatist in the sense of Peirce and James. I conclude that early pragmatism was a method-centric theory whereas Mach's empiricism prized agreement with experience and downplayed the significance of inductive-scientific methods in general as a guide to discovery.

In 1943 Dr J.C.B. Grant, of the University of Toronto, published the first anatomical atlas ever fully produced in North America, An Atlas of Anatomy. Within the history of biomedical teaching, the publication of this textbook is remarkable for at least two reasons, both connected to the themes of animation and automation. The visual narrative of the anatomical body found in Grant’s Atlas encapsulated a paradigmatic shift in gross anatomy from a systemic approach to a regional anatomy. The contextually contingent (...) reasons for this shift in medical training are represented in the production of this textbook. What is crucial is that anatomy is thus conceived as directly applicable to surgical practice, which intervenes on the bodies of the living, rather than the dead. The second important dimension of Grant’s Atlas was his rigorous, yet invisible, incorporation of photography into the practice of medical illustration. Grant’s Atlas systematically deployed hand-drawn tracings of photographic images in the production of his bestselling textbook to affirm an indexical connection to a ‘real body’. At the same time, this use of photography is erased within the visuals, which rely instead on hand-drawn illustrations to produce this particular pedagogy of the anatomical body. The production of ‘textbook anatomy’ is thus articulated to changes in technical modes of representation and to the new techniques in print-technologies from the late 19th until the mid 20th century. (shrink)

This book is a collection of secondary essays on America's most important philosophic thinkers—statesmen, judges, writers, educators, and activists—from the colonial period to the present. Each essay is a comprehensive introduction to the thought of a noted American on the fundamental meaning of the American regime.

Taking Parenting Public makes a compelling case that parenting has become dangerously undervalued in America today. It calls for a new investment—both personal and public—into the work of raising children and argues that we are all "stockholders" in the next generation. With a foreword by Sylvia Ann Hewlett and Cornel West, Taking Parenting Public crosses boundaries to bring together thinkers from diverse fields spanning the political spectrum. It features contributions from distinguished experts in economics, political science, public policy, child development, (...) public health, history, and the media. While recent books have focused on working mothers or absent fathers, Taking Parenting Public is the first volume to take a comprehensive look at the common struggles of parents. These essays go beyond the usual chest-beating about busy parents torn between work and family demands to suggest bold solutions. Instead of the typical call for "parent replacement"—more child care, more after school programs and more mentors—the contributors offer fresh strategies for "parent replenishment," ways to put mothers and fathers back into the lives of their children not only as economic providers, but also as emotional and moral providers. (shrink)

Background: Pulsed dye laser is the gold standard for treatment of port-wine stain birthmarks but multiple treatments are required and complete resolution is often not achieved. Posttreatment vessel recurrence is thought to be a factor that limits efficacy of PDL treatment of PWS. Imiquimod 5% cream is an immunomodulator with antiangiogenic effects. Objective: We sought to determine if application of imiquimod 5% cream after PDL improves treatment outcome. Methods: Healthy individuals with PWS were treated with PDL and then randomized to (...) apply posttreatment placebo or imiquimod 5% cream for 8 weeks. Chromameter measurements for 57 PWS sites were taken at baseline and compared with measurements taken 8 weeks posttreatment. The Δa and ΔE were measured to quantify treatment outcome. Results: Two patients developed minor skin irritation. Other adverse effects were not noted. Average a was 0.43 for PDL + placebo sites and 1.27 for PDL + imiquimod sites indicating a greater reduction in erythema with imiquimod. Average E was 2.59 for PDL + placebo and 4.08 for PDL + imiquimod, again indicating a greater color improvement with imiquimod. Limitations: Effects were evaluated after a single treatment and duration of effect is unknown. Conclusion: Combined selective photothermolysis and antiangiogenic therapy may enhance PWS treatment efficacy. © 2011 by the American Academy of Dermatology, Inc. (shrink)