Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (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)

Aristotle and the sea battle, by G. E. M. Anscombe.--Aristotle's different possibilities, by K. J. J. Hintikka.--On Aristotle's square of opposition, by M. Thompson.--Categories in Aristotle and in Kant, by J. C. Wilson.--Aristotle's Categories, chapters I-V: translation and notes, by J. L. Ackrill--Aristotle's theory of categories, by J. M. E. Moravcsik.--Essence and accident, by I. M. Copi.--Tithenai ta phainomena, by G. E. L. Owen.--Matter and predication in Aristotle, by J. Owens.--Problems in Metaphysics Z, chapter 13, by M. J. Woods.--The meaning (...) of agathon in the Ethics of Aristotle, by H. A. Prichard.--Agathon and eudaimonia in the Ethics of Aristotle, by J. L. Austin.--The final good in Aristotle's Ethics, by W. F. R. Hardie.--Aristotle on pleasure, by J. O. Urmson.--Bibliography (p. 335-41). (shrink)

Aristotle and the sea battle, by G. E. M. Anscombe.--Aristotle's different possibilities, by K. J. J. Hintikka.--On Aristotle's square of opposition, by M. Thompson.--Categories in Aristotle and in Kant, by J. C. Wilson.--Aristotle's Categories, chapters I-V: translation and notes, by J. L. Ackrill.--Aristotle's theory of categories, by J. M. E. Moravcsik.--Essence and accident, by I. M. Copi.--Tithenai ta phainomena, by G. E. L. Owen.--Matter and predication in Aristotle, by J. Owens.--Problems in Metaphysics Z, chapter 13, by M. J. Woods.--The meaning (...) of agathon in the Ethics of Aristotle, by H. A. Prichard.--Agathon and eudaimonia in the Ethics of Aristotle, by J. L. Austin.--The final good in Aristotle's Ethics, by W. F. R. Hardie.--Aristotle on pleasure, by J. O. Urmson.--Bibliography (p. 335-341). (shrink)

This new edition of Law and Medical Ethics continues to chart the ever-widening field that the topics cover. The interplay between the health caring professions and the public during the period intervening since the last edition has, perhaps, been mainly dominated by wide-ranging changes in the administration of the National Health Service and of the professions themselves but these have been paralleled by important developments in medical jurisprudence.

This article revisits long-standing questions about consent, membership and emigration in Locke’s thought. Commentators such as A John Simmons have argued that Locke opens political membership to both express consenters and some kind of tacit consenters, and not just to the former, as some have suggested. Simmons’s reading seems to render Locke more sensible in that it does not exclude large numbers of people from membership or burden the few members with all the civic duties, and also in that it (...) allows at least tacit-consenting members the right to relocate, while this right is denied to express-consenting members. Against this reading, the article shows, by resolving seemingly conflicting claims in the text, that people become members only by express consent. It also responds to the criticism that the express-consent-only reading would limit membership to a few and so would render Locke’s account implausible from a practical point of view. The article then addresses the purported restriction Locke imposes on express consenters’ right to emigrate, arguing that the restriction concerns the change of membership and not the right to relocate. (shrink)

Mason and McCall Smith's classic textbook discusses the relationship of medical practice and ethics with the operation of the law. The subjects covered include natural and assisted reproduction, the impact of modern genetics on medicine, medical confidentiality, consent to medical treatment, the use of resources and problems surrounding death in the new medical era. It is of significance to anyone with an interest in the ethical and legal practice of medicine.

Background and objectives: Physicians are exposed to matters of existential character at work, but little is known about the personal impact of such issues. Methods: To explore how physicians experience and cope with existential aspects of their clinical work and how such experiences affect their professional identities, a qualitative study using individual semistructured interviews has analysed accounts of their experiences related to coping with such challenges. Analysis was by systematic text condensation. The purposeful sample comprised 10 physicians (including three women), (...) aged 33–66 years, residents or specialists in cardiology or cardiothoracic surgery, working in a university hospital with 24-hour emergency service and one general practitioner. Results: Participants described a process by which they were able to develop a capacity for coping with the existential challenges at work. After episodes perceived as shocking or horrible earlier in their career, they at present said that they could deal with death and mostly keep it at a distance. Vulnerability was closely linked to professional responsibility and identity, perceived as a burden to be handled. These demands were balanced by an experience of meaning related to their job, connected to making a difference in their patients’ lives. Belonging to a community of their fellows was a presupposition for coping with the loneliness and powerlessness related to their vulnerable professional position. Conclusions: Physicians’ vulnerability facing life and death has been underestimated. Belonging to caring communities may assist growth and coping on exposure to existential aspects of clinical work and developing a professional identity. (shrink)

Background and objectives: Physicians are exposed to matters of existential character at work, but little is known about the personal impact of such issues.Methods: To explore how physicians experience and cope with existential aspects of their clinical work and how such experiences affect their professional identities, a qualitative study using individual semistructured interviews has analysed accounts of their experiences related to coping with such challenges. Analysis was by systematic text condensation. The purposeful sample comprised 10 physicians , aged 33–66 years, (...) residents or specialists in cardiology or cardiothoracic surgery, working in a university hospital with 24-hour emergency service and one general practitioner.Results: Participants described a process by which they were able to develop a capacity for coping with the existential challenges at work. After episodes perceived as shocking or horrible earlier in their career, they at present said that they could deal with death and mostly keep it at a distance. Vulnerability was closely linked to professional responsibility and identity, perceived as a burden to be handled. These demands were balanced by an experience of meaning related to their job, connected to making a difference in their patients’ lives. Belonging to a community of their fellows was a presupposition for coping with the loneliness and powerlessness related to their vulnerable professional position.Conclusions: Physicians’ vulnerability facing life and death has been underestimated. Belonging to caring communities may assist growth and coping on exposure to existential aspects of clinical work and developing a professional identity. (shrink)

This breakthrough volume integrates European, British, and American scholarship in advanced areas of philosophy and decision theory. Contributions cover a broad area of economics--from criticism of institutional economics to examination of the role of induction in economic forecasting.

In lieu of an abstract, here is a brief excerpt of the content:MACINTYRE'S REPUBLIC J. K. SWINDLER Westminster College Fulton, Missouri CONTRARY TO HIS own evident intentions and perceptions, in After Virtue A'lasdair Macinty!l.·e is much more of a Ptlatonist 1than the A1 ristotelian he aims to be. I hase this judgment both on the positive evidence that Macintyre and Plato (in the Republic) m1gue for and against the same crucial theses and on the negative evidence that Plato has read (...) answers to the very issues which Macintyre finds 1 intractable from an AristoteHan point of viiew. My thesis can be made out in terms of a half dozen issues which Maclntyire takes as crucial to his case: (1) Can there he a science of government? (2) Is there an answer to the sophist's chaillenge to morality? (3) How oan the fragmentation of the modern self he theoretically overcome? (4) What are the hi1stocical and social determinants of morality? (5) Is there a unity of virtue in addition to individual virtues? (6) Can we reconcile ourselves to teleofogy, the absence of the polis, and the tragedy of human 1:ife? I will consider each of these in turn. I. Wisdom Plato defines wisdom as knowledge of how to rule, and Aristotle (in the Nichomachean Ethics) distinguishes between theoretical and practical wisdom, 1suggesting thereby an interesting ambiguity in Plato's view, an ambiguity of which Macintyre makes a great deal. One may rule eithecr hy law or by judgment. In his attack on the Enlightenment, MacIntyre showis quite clearly tha;t the idea of a social science that would p11ovide laws of human behavior, which could in 343 344 J. K. SWINDLER turn be used by il"ulers and managers to predict and therefore manipulate!human action, was an invention of the eighteenth century. He offers an extensive 1oritique o.f this conception of socirul science, grounded primarily in the claim that human.behavior is essentially unlawful, at least if we judge it by the standards of the physical sciences. There is in human affairs a farge 1and uneliminwble element of fortiuna which makes it impossrible rto.formulate laws of human nature or behavior that would he exceptionless and therefore underwrite predictions of behavior. For there is nothing to be done about the unpredictability of innovations or, from one's own point of view, of one's own future actions; nor can the uncertainties of gametheoretie decisions and 1 the general contingency of the outcomes of ruction,be remedied. There is therefore no possibility of a social science in the sense in which Hume tried to imitate Newton. So much for Marx and Weber and the horde of modern.social scientists. This is not to say that life is completely uncertain; on the contrary, there are genuine and general regularities in society, some natural, some social, ·some statistical, some causal, wihich make life bearable. But these provide a,ground for the Aristotelian idea, endorsed by MacIntyre, that the principles of conduct, such as they might be, hold only for the most part and not universa1ly. There is therefore in Maclntyre's view no justification for 1a mora;l oode in the modern sense, nor ev;en of moral principles of the kind we are used to from Kant ·and Mill, Rawls and Nozick, which purport to istand as a sufficient criterion of right in all cases. But, importantly, we do not find any such rules or codes in Pla.to either. For Plato, too, insists on the mixed reign of chaos and logos in the materia;l world and in our Jives and concludes that judgment is essential to· determining right conduct. He tellrs us that wise rule comes only &om good oharructer and good institutions, that legislating in such detaii1 as to eliminate judgment is "cut:ting off the heads of a hy:dra." One cannot help hut think that tMs (essentially Hemclitean) point is something Aristotle ~earned at his MACINTYRE'S REPUBLIC 345 master's knee. And both aspects of Plato's :point ~e ipresent in Aristotle, viz., that s~nce the:ve is chance in nature, there is luck (good 'and had) in life, and since no rule can capture the particularity of conorete situations right... (shrink)

Recent scholarship on technology-induced ‘conceptual disruption’ has spotlighted the notion of a conceptual gap. Conceptual gaps have also been discussed in scholarship on epistemic injustice, yet up until now these bodies of work have remained disconnected. This article shows that ‘gaps’ of interest to both bodies of literature are closely related, and argues that a joint examination of conceptual disruption and epistemic injustice is fruitful for both fields. I argue that hermeneutical marginalization—a skewed division of hermeneutical resources, which serves to (...) diminish the experiences of marginalized folk—does not only transpire because of conceptual gaps, but also because of two other kinds of conceptual disruption: conceptual overlaps and conceptual misalignments. Hence, there are multiple kinds of conceptual disruption that can be usefully studied through the normative lens of epistemic injustice. Technology can play different roles vis-a-vis epistemic injustices, both as a causal trigger of conceptual disruption, but also as a mediator of hermeneutical resources. Its role is normatively significant, in particular because socially disruptive technologies can have different epistemic implications for different groups: they may amplify the epistemic resources of some groups, while diminishing those of others. (shrink)

Originally published in 1926, this book attempts to state 'what has been believed with regard to God's incapacity for suffering'. Mozley charts the development of the doctrine from the Apostolic Fathers through the Reformation to the modern influence of metaphysical philosophy and concludes with six questions intended to prompt further theological discussion on this point. This book will be of value to anyone with an interest in the history of Christian theology.

Medical ethics and medical practice -- Public health and the state-patient relationship -- Health rights and obligations in the European Union -- Consent to treatment -- Liability for medical injury -- Medical confidentiality -- Genetic information and the law -- The management of infertility and childlessness -- The control of fertility -- Civil and criminal liability in reproductive medicine -- Health resources and dilemmas in treatment -- Treatment of the aged -- Mental health and human rights -- The body as (...) property -- Medical futility -- The diagnosis of death -- The donation of organs and transplantation -- Euthanasia and assistance in dying -- Biomedical human research and experimentation -- Research on children, fetuses and embryos. (shrink)

In the present research, two studies test the efficacy of an innovative procedure designed to reduce distortion and enhance communication of accurate childhood memories. One hundred two 7-year-olds participated in a staged activity and were randomly assigned to one of two treatment conditions . Two weeks later, half of the children participated in the innovative procedure designed to increase resistance to misleading questions by addressing sociolinguistic and socioemotional factors thought to promote acquiescence to misinformation. The other half of the children (...) participated in control sessions and were given motivating instructions to do their best. Then, memory for the staged activity was tested in an interview with an unfamiliar authority figure. The results of both studies suggest that the children who participated in the innovative procedure made significantly fewer errors in response to misleading questions than children in the control groups, hence diminishing acquiescence. This was accomplished without generating additional errors on the other question types. These findings are interpreted as a promising first step toward reducing the potential for distortion in the recall of childhood memories. Implications for adult recall of childhood trauma are discussed. (shrink)

A set is said to be amorphous if it is infinite, but is not the disjoint union of two infinite subsets. Thus amorphous sets can exist only if the axiom of choice is false. We give a general study of the structure which an amorphous set can carry, with the object of eventually obtaining a complete classification. The principal types of amorphous set we distinguish are the following: amorphous sets not of projective type, either bounded or unbounded size of members (...) of partitions of the set into finite pieces), and amorphous sets of projective type, meaning that the set admits a non-degenerate pregeometry, over finite fields either of bounded cardinality or of unbounded cardinality. The hope is that all amorphous sets will be of one of these types. Examples of each sort are constructed, and a reconstruction result for bounded amorphous sets is presented, indicating that the amorphous sets of this kind constructed in the paper are the only possible ones. The final section examines some questions concerned with the resulting cardinal arithmetic. (shrink)

In two important articles, Thomas Hurka applies his recursive account of value to virtue. Hurka’s contention is that being virtuous is merely a matter of having the proper pro-attitude toward what is objectively good. Hurka argues that the recursive framework honors much of our traditional conception of virtue, and even if it does not capture everything involved in virtue, it “describes at least part of what virtue involves.” I argue that the recursive account of virtue is not a partial description (...) of traditional virtue, however, but a reconception of virtue. Accepting the recursive account would require abandoning the most distinctive elements of traditional virtue ethics. (shrink)

Two firm points in the chronology of Antiphon's speeches are VI περ το χορευτο in 419/81 and the Defence in 411/02. Speech V περ τσ 'Hρδου is now generally dated between these two; only the vaguest attempts have been made to date I κατ τσ μητρυασ; there is no general agreement on either the date or the authorship of the Tetralogies. The main purpose of this paper is to adduce linguistic as well as external evidence for the dating of V (...) in the neighbourhood of 414 and to show grounds for dating I between VI and V. Its secondary purpose is to apply some of the results gained in this inquiry to the fragments and the Tetralogies. (shrink)