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)

In current dairy farming it is possible to run a profitable farm without having to adapt the system to the needs of dairy cows. In such systems the interests of the farmer and animals often diverge. Consequently, specific animal welfare problems occur. Foot disorders in dairy cattle are an illustrative example resulting from the specific methods of housing and management in current dairy farming. Foot disorders and the resulting lameness are considered the most important welfare problem in dairy farming. However, (...) these foot disorders not only typify welfare problems related to certain housing systems, but they also lead to the premature culling of cows. The assessment of the impact of foot disorders on the welfare of dairy cows raised the question of whether premature culling affects animal welfare since it affects the longevity of a cow. We argue that this aspect of longevity is morally relevant as an animal welfare issue. In this paper we aim to explore whether longevity is both (a) a morally relevant aspect in the discussion on killing animals and (b) a constitutive element of animal welfare. In other words, we aim to explore whether longevity is an independent moral argument in an animal welfare discussion. We claim that longevity is not merely important as an indicator of animal welfare, but is also a constitutive element of animal welfare. We argue that we need a more integrated approach to animal welfare and that an assessment that includes the aspect of time is necessary. This view involves a shift from views on animal welfare in terms of functioning or feeling well to a view on animal welfare that includes the aspect of natural living in which species-specific development is important. To show the impact of these points of view, we look at the practical implications for choices concerning the management of foot disorders in dairy cattle. (shrink)

Theoretical and empirical research in bioethics frequently focuses on ethical dilemmas or problems. This paper draws on anthropological and phenomenological sources to develop an alternative framework for bioethical enquiry that allows examination of a broader range of how the moral is experienced in the everyday lives of individuals and groups. Our account of moral experience is subjective and hermeneutic. We define moral experience as “Encompassing a person's sense that values that he or she deem important are being realised or thwarted (...) in everyday life. This includes a person's interpretations of a lived encounter, or a set of lived encounters, that fall on spectrums of right-wrong, good-bad or just-unjust”. In our conceptualisation, moral experience is not limited to situations that are heavily freighted with ethically-troubling ramifications or are sources of debate and disagreement. Important aspects of moral experience are played out in mundane and everyday settings. Moral experience provides a research framework, the scope of which extends beyond the evaluation of ethical dilemmas, processes of moral justification and decision-making, and moral distress. This broad research focus is consistent with views expressed by commentators within and beyond bioethics who have called for deeper and more sustained attention in bioethics scholarship to a wider set of concerns, experiences and issues that better captures what is ethically at stake for individuals and communities. In this paper we present our conceptualisation of moral experience, articulate its epistemological and ontological foundations and discuss opportunities for empirical bioethics research using this framework. (shrink)

The US neutrino community gathered at the Workshop on the Intermediate Neutrino Program at Brookhaven National Laboratory February 4-6, 2015 to explore opportunities in neutrino physics over the next five to ten years. Scientists from particle, astroparticle and nuclear physics participated in the workshop. The workshop examined promising opportunities for neutrino physics in the intermediate term, including possible new small to mid-scale experiments, US contributions to large experiments, upgrades to existing experiments, R&D plans and theory. The workshop was organized into (...) two sets of parallel working group sessions, divided by physics topics and technology. Physics working groups covered topics on Sterile Neutrinos, Neutrino Mixing, Neutrino Interactions, Neutrino Properties and Astrophysical Neutrinos. Technology sessions were organized into Theory, Short-Baseline Accelerator Neutrinos, Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Rest sessions.This report summarizes discussion and conclusions from the workshop. (shrink)

The second edition of this book on the problem of truth and the idea of semantics is an unchanged reprint of a volume originally published in 1957. While it is formally organized into twelve chapters, it effectively falls into three parts of which the first two primarily deal with the theories of A. Tarski and R. Carnap. Aside from a brief chapter on "Semantics, Quantification Theory and Metamathematics," the final part consists of a chapter, which the author entitles "Epistemological-Theoretical Discussion (...) of Semantic Concepts." In this the longest, and for anybody acquainted with the theories of Tarski and Carnap, probably most valuable chapter of the book, Stegmüller deals with a dozen objections to the semantic conception of truth, the importance of semantic concepts for various disciplines, including logic, mathematics, epistemology, and the empirical sciences, with the interrelation between semantic linguistic analysis and Wittgensteinian ideas, and finally with Quine's criticism of the analytic--synthetic distinction and certain aspects of the ensuing discussion up to the time of the book's original publication. To ascertain the author's current ideas about many of the topics with which he deals, it is obviously necessary to turn to his more recent writings. This book stands as an example of its author's incomparable clarity of critical exposition.--R. F. M. (shrink)

Overdenkingen in proza en poëzie over filosofische vraagstukken door de in ongenade gevallen Romeinse ex-consul (480-524).

With the publication of this volume from the prolific pen of one of Germany's outstanding younger philosophers, the German-speaking scholarly world has a more extensive survey of key issues in the philosophy of science than the English-speaking world. The book is the first of a comprehensive work whose title is "Problems and Results in the Philosophy of Science and Analytic Philosophy." While the title of the book under consideration shows that it is primarily concerned with scientific explanation and justification, Stegmüller (...) not merely undertakes to acquaint his readers with the most important Anglo-American developments concerning these topics, but also independently develops his own ideas with respect to them and an important, if brief, feature of the volume is an appendix in which he sets forth over thirty "problems that are either unsolved or the solution of which is controversial." Without going into substantival detail, perhaps the quickest way to indicate Stegmüller's main concerns and general orientation is to note the extent of the page references in the index of names where, in descending order, one finds the names of Carl G. Hempel, to whom the volume is dedicated, R. Carnap, N. Goodman, N. Rescher, W. V. Quine, P. Oppenheim, E. Nagel, W. Dray and K. Popper. Curiously, Stegmüller indicates that, aside from Hempel, the man who has exercised the greatest influence on him has been Sir Karl Popper, but then he limits his consideration of him mainly to Popper's early exposition of explanation by reference to the breaking of a thread, while ignoring what he has to say about such topics as falsification, induction, and the problem of demarcation. Under these circumstances it is not surprising that there are no references to P. Duhem, J. Agassi, and P. Feyerabend, but there are also none to G. Bergmann, M. Bunge, P. Frank, N. R. Hanson, A. Koyré, V. Kraft, G. Radnitzky, and J. J. C. Smart, to mention just a few.--R. F. M. (shrink)

Background: Informed consent is regarded as a contract between autonomous and equal parties and requires the elements of information disclosure, understanding, voluntariness and consent. The validity of informed consent for critically ill patients has been questioned. Little is known about how these patients experience the process of consent.Objective: The aim of this study was to explore critically ill patients’ experience with the principle of informed consent in a clinical trial and their ability to give valid informed consent.Design: 11 stroke patients (...) who had been informed about thrombolytic treatment and had been through the process of deciding whether or not to participate in a thrombolysis trial went through repeated qualitative semistructured interviews.Results: None of the patients had any clear understanding of the purpose of the trial. Neither did they understand the principles of randomisation and voluntariness. Reasons for giving or not giving consent were trust, conceptions of benefits and risks and altruism. Several patients found it immoral to involve patients in the consent procedure and argued that this was the doctors’ responsibility. Others argued that it is a duty to question patients and perceived it as a sign of being treated with respect and dignity. A majority of the patients found the consent process vague and ambiguous.Conclusions: The results indicate that the principle of informed consent from critically ill patients cannot be seen as a contract between equal and autonomous parties. Further studies are needed to explore critically ill patients’ experiences with the process of informed consent. (shrink)

The second edition of this book on the problem of truth and the idea of semantics is an unchanged reprint of a volume originally published in 1957. While it is formally organized into twelve chapters, it effectively falls into three parts of which the first two primarily deal with the theories of A. Tarski and R. Carnap. Aside from a brief chapter on "Semantics, Quantification Theory and Metamathematics," the final part consists of a chapter, which the author entitles "Epistemological-Theoretical Discussion (...) of Semantic Concepts." In this the longest, and for anybody acquainted with the theories of Tarski and Carnap, probably most valuable chapter of the book, Stegmüller deals with a dozen objections to the semantic conception of truth, the importance of semantic concepts for various disciplines, including logic, mathematics, epistemology, and the empirical sciences, with the interrelation between semantic linguistic analysis and Wittgensteinian ideas, and finally with Quine's criticism of the analytic--synthetic distinction and certain aspects of the ensuing discussion up to the time of the book's original publication. To ascertain the author's current ideas about many of the topics with which he deals, it is obviously necessary to turn to his more recent writings. This book stands as an example of its author's incomparable clarity of critical exposition.--R. F. M. (shrink)

With the publication of this volume from the prolific pen of one of Germany's outstanding younger philosophers, the German-speaking scholarly world has a more extensive survey of key issues in the philosophy of science than the English-speaking world. The book is the first of a comprehensive work whose title is "Problems and Results in the Philosophy of Science and Analytic Philosophy." While the title of the book under consideration shows that it is primarily concerned with scientific explanation and justification, Stegmüller (...) not merely undertakes to acquaint his readers with the most important Anglo-American developments concerning these topics, but also independently develops his own ideas with respect to them and an important, if brief, feature of the volume is an appendix in which he sets forth over thirty "problems that are either unsolved or the solution of which is controversial." Without going into substantival detail, perhaps the quickest way to indicate Stegmüller's main concerns and general orientation is to note the extent of the page references in the index of names where, in descending order, one finds the names of Carl G. Hempel, to whom the volume is dedicated, R. Carnap, N. Goodman, N. Rescher, W. V. Quine, P. Oppenheim, E. Nagel, W. Dray and K. Popper. Curiously, Stegmüller indicates that, aside from Hempel, the man who has exercised the greatest influence on him has been Sir Karl Popper, but then he limits his consideration of him mainly to Popper's early exposition of explanation by reference to the breaking of a thread, while ignoring what he has to say about such topics as falsification, induction, and the problem of demarcation. Under these circumstances it is not surprising that there are no references to P. Duhem, J. Agassi, and P. Feyerabend, but there are also none to G. Bergmann, M. Bunge, P. Frank, N. R. Hanson, A. Koyré, V. Kraft, G. Radnitzky, and J. J. C. Smart, to mention just a few.--R. F. M. (shrink)

In his writings, Edmund Pellegrino analyzes four deficiencies in the humanity of those who fall ill: the loss of (1) freedom of action, (2) freedom to make rational choices, (3) freedom from the power of others, and (4) a sense of the integrity of the self. Since Pellegrino's analysis and commitment to virtuebased ethics preceded much of the attention later given by philosophers to the importance of the moral principle of autonomy (in contrast to beneficence) in patient care, it is (...) helpful to trace the source of his commitment to virtue-based ethics and his account of freedom to Aristotle's analysis of the human soul, as an entelechy of an intact and healthy living organism that, unimpeded by illness, moves itself to act, to actualize its intellectual potential in the form of making rational choices, and to free itself from the power of others by remaining independent and without need of continuous assistance, while at the same time retaining the integrity of a unified self that can act, think, and choose for itself autonomously. (shrink)

Cognition or higher brain activity is sometimes seen as a phenomenon greater than the sum of its parts. This viewpoint however is largely dependent on the state of the art of experimental techniques that endeavor to characterize morphology and its association to function. Retinal ganglion cells are readily accessible for this work and we discuss recent advances in computational techniques in identifying novel parameters that describe structural attributes possibly associated with specific function. These parameters are based on calculating wavelet gradients (...) from cell images followed by the extraction of meaningful measures including 2nd wavelet moment, entropy of orientation, and curvature. For the three cell types analyzed, the mean 2nd wavelet moment, which relates to the field of influence of the dendritic-tree segments was significantly different. cells had the highest mean 2nd wavelet moment, followed by the and cells (134 ± 22, 93 ± 19 and 63 ± 12, respectively). There was no significant difference between cells for entropy of orientation, indicating no class with a preferential orientation of their dendritic tree. Curvature provided similar results to the 2nd wavelet moment with cells having the highest curvature followed by and the cells (mean ± SD: 161 ± 15; 134 ± 22; 121 ± 15). Our feature space analysis also indicated a difference between these cell types. No difference was found between the and cell types and their physiological counterparts the Y and X cells based on wavelet analysis. Both the X and Y cells can be divided into two subtypes, the ON- and OFF-center cells based on the stratification level of the dendritic tree within the retina. Using 2nd wavelet moment, a difference in their morphological attributes, not reported previously, was noted for these subtypes. The 2nd wavelet moment and curvature are further discussed with respect to explaining regularity of spacing and coverage associated with retinal ganglion cell mosaics. (shrink)

In this new and third edition, the additional fragments contained in the appendix of the second edition have been incorporated in the main text. Some further discoveries have been included, and reference has been made to the results of recent research on the relative placing of certain papyrus fragments. The index of names has been brought up to date.

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged (...) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)