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)

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)

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead has been shown to elevate the Alzheimer's disease related beta-amyloid peptide , which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life , but was later elevated 20 months after exposure to Pb (...) had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase , manganese-SOD , and reduced-form glutathion . These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances. (shrink)

Alzheimer's disease is characterized by amyloid-beta peptide -loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 , which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization (...) of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene. (shrink)

Contributed articles on Buddhist doctrines and philosophy; festschrift in honor of Narayan Hemandas Samtani, Buddhist scholar.

In recent years the writings of Ludwig Wittgenstein have received much attention from philosophers in general and especially from philosophers interested in religion; and there is no doubt that Wittgenstein's legacy of thought is both highly suggestive and highly problematical. It seems likely, however, that the vogue which Wittgenstein now enjoys owes not a little to his peculiar place in the development of modern philosophy and, in particular, of that empiricist tradition in philosophy which stems from what has been called (...) the revolution in philosophy in the early decades of the present century. (shrink)

In his book on Karl Barth Professor T. F. Torrance spoke at one point of ‘the great watershed of modern theology’. ‘There are,’ he wrote, 1 ‘two basic issues here. On the one hand, it is the very substance of the Christian faith that is at stake, and on the other hand, it is the fundamental nature of scientific method, in its critical and methodological renunciation of prior understanding, that is at stake. This is the great watershed of modern theology: (...) either we take the one way or the other – there is no third alter native… one must go either in the direction taken by Barth or in the direction taken by Bultmann.’. (shrink)

This article aims to discuss the history of medical history in the British medical undergraduate curriculum and it reviews the main characters and organisations that have attempted to earn it a place in the curriculum. It also reviews the arguments for and against the study of the subject that have been used over the last 160 years.

Do people morally deserve what they earn in the market? More specifically, can people legitimately claim to deserve what they earn in the market in a way that counts against redistributing those earnings? As most liberal political philosophers do, I argue that the answer is no. Unlike many of these philosophers, however, I do not focus on whether or not people can be deserving. Instead, I focus on the relationship between social institutions and moral desert, and advance two claims. First, (...) in the market, desert claims are undermined by the very nature of the market even if people can be deserving in general. Second, part of the intuition that motivates accounts of moral desert may be explained instead with reference to a principle of fairness that demands the fulfillment of people's legitimate expectations as to what they will receive, and this principle places much weaker restrictions on redistributive policies than do claims of moral desert. (shrink)

The period between 1945 and 1952 marked the development of Professor Ryle's conception of the principles of inference as performance rules. This development has paralleled that of his now well-known distinction between knowing-how and knowing-that. Indeed, the former is a corollary to the latter. Beginning with the inaugural address to the Aristotelian Society in 1945 and reaching full fruition in The Concept of Mind in 1949, it finds its most detailed and illuminating expression in “‘If’, ‘So’, and ‘Because’,” which appeared (...) in 1950. The present essay will attempt to explore this conception of rules in some detail, in the hope of clarifying the nature of Professor Ryle's views on classical logic and on certain problems within the philosophy of logic. Professor Ryle belongs, if his views may be so labeled, to the school of informal language analysts. On the other hand, we incline more toward formalism. We tend to agree with those philosophers who consider certain schemata indispensable tools for the solution of philosophical problems. Logic and the philosophy of logic are, as everyone knows, the areas in which the formalists’ technique originated. In these areas it is accepted by virtually everybody. The only recent exception is a group of English writers, many of whom take their inspiration from Ryle. One may hope, then, that the present criticism of Ryle's view from the other standpoint will throw some light on both positions. What follows falls naturally into two parts. The first deals mainly with Ryle's objections to current logical theory, the second with his own philosophy of logic. (shrink)

Anthropologists have long explained social behaviour as if people always do what they think is best. But what if most of these explanations only work because they are premised upon ignoring what philosophers call 'akrasia' - that is, the possibility that people might act against their better judgment? The contributors to this volume turn an ethnographic lens upon situations in which people seem to act out of line with what they judge, desire and intend. The result is a robust examination (...) of how people around the world experience weaknesses of will, which speaks to debates in both the anthropology of ethics and moral philosophy. (shrink)

Educational theory; knowledge; sufism, an analytical treatise.

It is a curious fact that the much maligned ontological argument to prove the existence of God has in recent times enjoyed a revival of interest to which even Karl Barth, the arch-enemy of natural theology has contributed; but since the revival of interest has appared in a wide diversity of intellectual contexts, both philosophical and theological, the revival is itself almost as problematic as the argument itself.

In his article ‘Professor Bartley's Theory of Rationality and Religious Belief’ Mr W. D. Hudson has brought considerable clarification to the rather confused situation occasioned by Professor W. W. Bartley's book The Retreat to Commitment and its subsequent discussion; but the process can, I think, be carried still further.

Dewey's 1896 paper, "The Reflex Arc Concept in Psychology," was acclaimed 50 years later as the most important paper published in The Psychological Review in its first half-century of history. Today, Dewey's paper appears to be headed toward oblivion. Considering it worthy of resurrection, we use it as a starting point for tracing out the gradual evolution of Dewey and Bentley's formulation of their transactional viewpoint to its culmination in their book, Knowing and the Known. An exposition of the transactional (...) paradigm is developed via competing, contemporary self-actional and interactional theoretical systems. Then, the space-time postulates of self-actional, interactional, and transactional approaches are spelled out as they enter into philosophical, biological and psychological inquiry. Among prevailing theories, most of which fall into the self-actional/interactional categories, Kantor's interbehavioral viewpoint stands apart from the rest. And while it shares a certain similarity with the transactional approach, the historical record should document it as an independent and parallel development, dating back to Kantor's first publications almost seven decades ago. Furthermore, Kantor's system goes far beyond Dewey and Bentley's "unfractured observation," by providing highly refined analytic procedures in his theoretical constructs. (shrink)

In this article the phenomenon of religious imagination is taken as a test case for discussing the relevance of cognitive science to philosophy of religion and theology. With Lakoff and Johnson’s Philosophy in the Flesh, it is argued that all human cognitive faculties are both propelled and constrained by metaphors originating from the movements of self-aware bodies in space; accordingly, religious concepts and images are to be treated on par with all other concepts and images. Pascal Boyer’s Religion Explained is (...) then critically discussed. It is argued that Boyer’s claim of having ‘explained’ religious imagination as counterintuitive blendings of evolutionarily inherited templates is highly problematic. Evolutionary psychology has not yet given any evidence of an evolutionary hard-wiring of religious concepts, and Boyer’s reference to the mind-set of hunterers and gatherers does not catch the complexity of later developments in religious thought. For all, the internal systematization of religious imageries, and the possibility of a religious self-criticism in terms of philosophy is not reflected in Boyer’s theory. Religious imagination may indeed be natural; but its naturalness neither counts for nor against the truth-claims involved in religious images. (shrink)

Objectives To investigate risk perception relating to living kidney donation, to compare the risk donors would accept with current practice and identify influential factors. Design An observational study consisting of questionnaires completed by previous living donors and the general public. Participants selected the risk they would accept from a list of options, in various scenarios. Risk communication was investigated by randomly dividing the sample and presenting risk differently. Setting Primary care (two centres) and secondary care (one centre), London. Participants 175 (...) questionnaires were sent to patients who had previously undergone living-donor nephrectomy and to members of the public consulting a general practitioner. The living-donor sample comprised 77 consecutive donors at Guy's Hospital from May 2003 to January 2005. The general-public sample was recruited from two London healthcare centres. Of the eventual 151 participants, 61 were living donors and 90 were from the general public. Main outcome measure The amount of risk a participant would accept to donate a kidney. Results 74% of participants were willing to accept a risk of death higher than 1/3000. The most commonly accepted risk was 1/2 (29%). Those presented with a ‘chance of survival’ accepted higher risks than those presented with a ‘risk of death’ (p<0.01). Greater risks were accepted when the recipient was closely related and, for some, when the recipient's prognosis was worse. No difference was observed between the living-donor and general-public groups. Conclusions Kidney donors will accept a higher risk of death than is currently quoted, especially if risks are presented in terms of chance of survival. (shrink)