Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

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)

The United States has long been a model for accessible, affordable education, as exemplified by the country's public universities. And yet less than 60 percent of the students entering American universities today are graduating. Why is this happening, and what can be done? Crossing the Finish Line provides the most detailed exploration ever of college completion at America's public universities. This groundbreaking book sheds light on such serious issues as dropout rates linked to race, gender, and socioeconomic status. Probing graduation (...) rates at twenty-one flagship public universities and four statewide systems of public higher education, the authors focus on the progress of students in the entering class of 1999--from entry to graduation, transfer, or withdrawal. They examine the effects of parental education, family income, race and gender, high school grades, test scores, financial aid, and characteristics of universities attended. The conclusions are compelling: minority students and students from poor families have markedly lower graduation rates--and take longer to earn degrees--even when other variables are taken into account. Noting the strong performance of transfer students and the effects of financial constraints on student retention, the authors call for improved transfer and financial aid policies, and suggest ways of improving the sorting processes that match students to institutions. An outstanding combination of evidence and analysis, Crossing the Finish Line should be read by everyone who cares about the nation's higher education system. (shrink)

Playing with correct intonation is one of the major challenges for a string player. A player must learn how to physically reproduce a target pitch, but before that, the player must learn what correct intonation is. This requires audiation- the aural equivalent of visualization- of every note along with self-assessment whether the pitch played matches the target, and if not, what action should be taken to correct it. A challenge for successful learning is that much of it occurs during practice, (...) typically without outside supervision. A student who has not yet learned to hear correct intonation may repeatedly practice out of tune, blithely normalising bad habits and bad intonation. The real-time reflective nature of intonation and its consistent demand on attention make it a ripe target for technological intervention. Using a violin augmented to combine fingerboard sensors with audio analysis for real-time pitch detection, we examine the efficacy of three methods of real-time feedback for improving intonation and pitch learning. The first, aural feedback in the form of an in-tune guide pitch following the student in real-time, is inspired by the tradition of students playing along with teachers. The second is visual feedback on intonation correctness using an algorithm optimised for use throughout normal practice. The third is a combination of the two methods, simultaneously providing aural and visual feedback. Twelve beginning violinists, including children and adults, were given four in-situ 20-30 minute lessons. Each lesson used one of the intonation feedback methods, along with a control lesson using no feedback. We collected data on intonation accuracy and conducted interviews on student experience and preference. The results varied by player, with evidence of some players being helped by the feedback methods but also cases where the feedback was distracting and intonation suffered. However interviews suggested a high level of interest and potential in having such tools to help during practice, and results also suggested that it takes time to learn to use the real-time aural and visual feedback. Both methods of feedback demonstrate potential for assisting self-reflection during individual practice. (shrink)

Objective: To explore the experiences of people with a “terminal illness”, focusing on the patients’ perspective of euthanasia and assisted suicide.Method: A qualitative study using narrative interviews was conducted throughout the UK. The views of the 18 people who discussed euthanasia and assisted suicide were explored. These were drawn from a maximum variation sample, who said that they had a “terminal” illness, malignant or non-malignant.Results: That UK law should be changed to allow assisted suicide or voluntary euthanasia was felt strongly (...) by most people. Those who had seen others die were particularly convinced that this should be a right. Some had multiple reasons, including pain and anticipated pain, fear of indignity, loss of control and cognitive impairment. Those who did not want to be a burden also had other reasons for wanting euthanasia. Suicide was contemplated by a few, who would have preferred a change in the law to allow them to end their lives with medical help and in the company of family or friends. The few who opposed a change in UK law, or who felt ambivalent, focused on involuntary euthanasia, cited religious reasons or worried that new legislation might be open to abuse.Conclusion: Qualitative research conducted on people who know they are nearing death is an important addition to the international debate on euthanasia and assisted suicide. Those who had seen others die were particularly convinced that the law should be changed to allow assisted death. (shrink)

The massive disparity between the relative wealth of most citizens in affluent countries and the profound poverty of billions of people struggling elsewhere for survival is morally jolting. But why exactly is this disparity so outrageous and how should the citizens of affluent countries respond? Political philosopher, Thomas Pogge, has emerged as one of the world’s most ardent critics of global injustice which, he argues, is caused directly by the operation of a global institutional order that not only systematically disadvantages (...) poor countries but is imposed on them by precisely those wealthy, powerful countries that benefit the most from the order’s injustice. In allowing their governments to perpetrate this injustice, Pogge contends that citizens of the wealthy countries collude in a monumental crime against humanity. In this book Pogge’s challenging and controversial ideas are debated by leading political philosophers from a range of philosophical viewpoints. With a clear and informative introduction by Alison Jaggar, and original contributions from Neera Chandhoke, Jiwei Ci, Joshua Cohen, Erin Kelly, Lionel McPherson, Charles W. Mills, Kok-Chor Tan, and Leif Wenar, this volume deepens and expands the debate over global justice and moral responsibility in the world today. (shrink)

The purpose of the article is to reveal philosophical ideas in the mythology and folklore of the indigenous peoples of North America. An important question: "Can we assume that the spiritual culture of the American Indians contained philosophical knowledge?" remains relevant today. For example, European philosophy is defined by appeals to philosophers of the past, their texts. The philosophical tradition is characterized by rational argumentation and formulation of philosophical questions that differ from the questions of ordinary language. However, the problem (...) lies in the term "philosophy", which belongs to the so-called "philosophical untranslatability" and has many definitions. The question of whether philosophy is exclusively a phenomenon of European culture is still controversial. In the article, the concept of philosophy is used in a broad sense, which allows the analysis of the intellectual heritage of the culture of the indigenous people of North America for philosophical ideas. Theoretical basis of the study consists of primary sources, which are limited due to the "documentary horizon". It contains myths about the Twins, ritual rhetoric, examples of dream interpretation practices and the practical wisdom of tribal chiefs. The Chronicle of "Vallamolum", or "the Red List", testifies to the special idea of the Indians about history and their own historicity. Analysis of cosmogonical and cosmological ideas reveals the special features of the anthropological ideas of the North American Indians. Combined with the philosophical ideas of the Puritan philosophy of the settlers of New England, this analysis allows us to explore in more detail the processes of acculturation. The study uses critical literature from scholars and leading researchers of the wisdom and philosophy of Native Americans, such as Michael Yellow Bird, J. Baird Callicott, Henry Wadsworth Longfellow, Dennis H. McPherson, Lewis Henri Morgan, Thomas M. Norton-Smith, J. Douglas Rabb, Paul Radin, Jon Ewbank Manchip White. The views of early American philosophers: R. Williams, W. Penn, R. W. Emerson, on the problem of the relationship between the culture of settlers and the indigenous people of North America are noteworthy. Originality lies in the application of historical and philosophical methodology, identifying the features of philosophizing in the spiritual culture and worldview of the indigenous people of North America. Conclusions. In the conclusions, the obtained results complement the history of the origin and development of philosophical thought of the early American philosophy. (shrink)

Consider orthodox motivational judgment internalism: necessarily, A’s sincere moral judgment that he or she ought to φ motivates A to φ. Such principles fail because they cannot accommodate the amoralist, or one who renders moral judgments without any corresponding motivation. The orthodox alternative, externalism, posits only contingent relations between moral judgment and motivation. In response I first revive conceptual internalism by offering some modifications on the amoralist case to show that certain community-wide motivational failures are not conceptually possible. Second, I (...) introduce a theory of moral motivation that supplements the intuitive responses to different amoralist cases. According to moral judgment purposivism (MJP), in rough approximation, a purpose of moral judgments is to motivate corresponding behaviors such that a mental state without this purpose is not a moral judgment. MJP is consistent with conceptual desiderata, provides an illuminating analysis of amoralist cases, and offers a step forward in the internalist-externalist debates. (shrink)

Today's complex and decentralized organization gives rise to organizational needs for both loyalty and institutionalized whistle blowing. However, ethicists see a contradiction between both needs. This paper argues there is no such contradiction. It shows why earlier attempts to go beyond the dilemma are not satisfying. The solution proposed in this paper starts from an organizational perspective instead of an individual one. It does so by reframing the concept of loyalty into rational loyalty. This means that the object of loyalty (...) is not the physicality of an organization, but its corpus of explicit mission statement, goals, value statement and code of conduct. An implication is that organizations are – as their side of the duty of loyalty – obliged to institutionalize whistle blowing. (shrink)

Among Plato's works, the Statesman is usually seen as transitional between the Republic and the Laws. This book argues that the dialogue deserves a special place of its own. Whereas Plato is usually thought of as defending unchanging knowledge, Dr Lane demonstrates how, by placing change at the heart of political affairs, Plato reconceives the link between knowledge and authority. The statesman is shown to master the timing of affairs of state, and to use this expertise in managing the conflict (...) of opposed civic factions. To this political argument corresponds a methodological approach which is seen to rely not only on the familiar method of 'division', but equally on the unfamiliar centrality of the use of 'example'. The demonstration that method and politics are interrelated transforms our understanding of the Statesman and its fellow dialogues. (shrink)

The study ascertained (1) whether an observer's scope of justice with reference to either the moral agent or the target person of a moral act, would affect his/her judgements of the ethicality of the act, and (2) whether observer judgements of ethicality parallel the moral agent's decision processes in systematically evaluating the intensity of the moral issue. A scenario approach was used. Results affirmed both research questions. Discussions covered the implications of the findings for the underlying cognitive processes of moral (...) judgements, for the link between judgements of fairness and ethicality, as well as for the debate of ethical absolutism versus relativism. (shrink)

This introduction to the Journal of Business Research special issue on anti-consumption briefly defines and highlights the importance of anticonsumption research, provides an overview of the latest studies in the area, and suggests an agenda for future research on anti-consumption.

Since 1994, when the first fetal imaging boutique appeared in Texas, many sites have been established around the country for parents to receive nonmedical fetal imaging using three- and four-dimensional ultrasound machines. These businesses boast the benefits they offer to parental-fetal bonding, but the medical community objects to the use of ultrasound machines for nonmedical purposes. In this article, I present the statements released by the medical community, highlighting the alarmist strategies used to paint boutique ultrasounds as bad science and (...) elevate the medical use of ultrasounds. Through a close reading of the statements, it is shown that the medical community's primary concern is not the health of the fetus or the woman but rather their place as the sole users of fetal ultrasounds. This detailed analysis reveals a medical community fearful that its authority is being usurped and is therefore responding with statements meant to denigrate boutique fetal ultrasounds. (shrink)

In ‘Naming and Necessity,’ Saul Kripke defends a number of essentialist claims. One of them is that having a certain origin is a necessary property of a material thing. Used in connection with a human being or, presumably, a living thing of another kind whose members sexually reproduce, ‘necessity of origin’ means that the organism must have been born of those individuals who are its parents, i.e., whose body tissues are sources of the sperm and egg from which it issued, (...) in the actual world. To say that the origin of an inanimate material thing is necessary is to say that having its origin in the hunk of matter from which it came is essential to it. (shrink)

This book offers a major reinterpretation of the `secularization' of medieval ideas by examining scholastic discussions on the nature of the common good. It challenges the view that the rediscovery of Aristotle was the primary catalyst for the emergence of a secular theory of the state. A detailed exposition of the content and the context of late scholastic political and ethical thought reveals that the roots of medieval 'secularization' were profoundly theological.

All illness represents a state of diminished autonomy and therefore the doctor-patient relationship necessarily and justifiably involves a degree of medical paternalism argues the author, an American medical student. In a broad-ranging paper he discusses the concepts of autonomy and paternalism in the context of the doctor-patient relationship. Given the necessary diminution of autonomy which illness inflicts, a limited form of medical paternalism, aimed at restoring or maximising the patient's autonomy is entirely acceptable, and indeed fundamental to the relationship he (...) argues. However, the exercise of this paternalism should be flexible and related to the current 'level of autonomy' of the patient himself. An editorial in this issue comments briefly on this paper. (shrink)

The community representative plays a very important role in an institutional review board but there is sparse data about their understanding of their role in an IRB. This study was conducted to assess perceptions of community members serving on IRBs of one region in India. A validated questionnaire was administered to community members of IRBs in a prospective cross-sectional study. The questions related to demography, perceptions of their role in the IRB, experiences while serving on the IRBs, difficulties faced by (...) them, and suggestions to improve their contributions. Of the 56 IRBs contacted, all 15 of the public institutions shared details of their community members, while only 26 of the 41 IRBs of private institutions responded. When questioned about why they joined the IRB, one third of the respondents said either that there was “no specific reason” for joining or that they accepted the invitation to serve on the insistence of other members of the IRBs or the head of their institution. All except one felt that community members were needed for optimal functioning. Six participants said that they did not review informed consent documents, and 10 were unaware that their presence was vital for quorum to be met. Twenty-eight said they participated actively in meetings and did not feel intimidated by the presence of clinicians. Twelve reported difficulties in understanding medical terminologies in ICDs. Although the majority of participants were aware about their role in an IRB, some did not review important documents such as ICDs. Restricted participation by private hospital IRBs was a striking observation in our study. There is a need to define eligibility criteria and develop targeted training modules for community members to ensure their effective contribution to effective oversight of clinical research. (shrink)

Miranda Fricker appeals to the idea of moral-epistemic disappointment in order to show how our practices of moral appraisal can be sensitive to cultural and historical contingency. In particular, she thinks that moral-epistemic disappointment allows us to avoid the extremes of crude moralism and a relativism of distance. In my response I want to investigate what disappointment is, and whether it can constitute a form of focused moral appraisal in the way that Fricker imagines. I will argue that Fricker is (...) unable to appeal to disappointment as standardly understood, but that there is a more plausible way of understanding the notion that she can employ. There are, nevertheless, significant worries about the capacity of disappointment in this sense to function as a form of moral appraisal. I will argue, finally, that even if Fricker can address these worries, her position might end up closer to moralism than she would like. (shrink)

The attention schema theory explains how a biological, information processing machine can claim to have consciousness, and how, by introspection (by assessing its internal data), it cannot determine that it is a machine whose claims are based on computations. The theory directly addresses Chalmers' meta-problem of consciousness, the problem of why we think we have a difficult-to-explain consciousness in the first place.

‘It is supposed’, declared the poet Wordsworth in 1802, ‘that by the act of writing in verse an author makes a formal engagement that he will gratify certain known habits of association; that he not only thus apprizes the reader that certain classes of ideas and expressions will be found in his book, but that others will be carefully excluded. This exponent or symbol held forth by metrical language must in different eras of literature have excited very different expectations.’ For (...) his own era of literature Wordsworth proposed a language derived from the ‘simple and unelaborated expressions’ of the ‘language really spoken by men’, at the expense of ‘devices to elevate the style’ and ‘what is usually called poetic diction’. (shrink)

This is the first comprehensive study of Nietzsche's earliest (and extraordinary) book, The Birth of Tragedy (1872). When he wrote it, Nietzsche was a Greek scholar, a friend and champion of Wagner, and a philosopher in the making. His book has been very influential and widely read, but has always posed great difficulties for readers because of the particular way Nietzsche brings his ancient and modern interests together. The proper appreciation of such a work requires access to ideas that cross (...) the boundaries of conventional specialisms. This is now provided by M. S. Silk and J. P. Stern in their joint study of Nietzsche's book. They examine in detail its content, style and form; its strange genesis and hybrid status; its biographical background and the controversy engendered by its publication; its value as an account of ancient Greek culture and as a theory of tragedy and music; its relation to other theories of tragedy; and its place in the history of German ideas and in Nietzsche's own philosophical career. (shrink)

In the First Antinomy of The Critique of Pure Reason, Kant drew two conclusions from the argument he gives. First, Kant took his argument to show that the referent of the concept of ‘world’ does not exist as a thing in itself. For at B532 he says.

In the First Antinomy of The Critique of Pure Reason, Kant drew two conclusions from the argument he gives. First, Kant took his argument to show that the referent of the concept of ‘world’ does not exist as a thing in itself. For at B532 he says.