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)

We have begun work on two separate but related ontologies for the study of neurological diseases. The first, the Neurological Disease Ontology (ND), is intended to provide a set of controlled, logically connected classes to describe the range of neurological diseases and their associated signs and symptoms, assessments, diagnoses, and interventions that are encountered in the course of clinical practice. ND is built as an extension of the Ontology for General Medical Sciences — a high-level candidate OBO Foundry ontology that (...) provides a set of general classes that can be used to describe general aspects of medical science. ND is being built with classes utilizing both textual and axiomatized definitions that describe and formalize the relations between instances of other classes within the ontology itself as well as to external ontologies such as the Gene Ontology, Cell Ontology, Protein Ontology, and Chemical Entities of Biological Interest. In addition, references to similar or associated terms in external ontologies, vocabularies and terminologies are included when possible. Initial work on ND is focused on the areas of Alzheimer’s and other diseases associated with dementia, multiple sclerosis, and stroke and cerebrovascular disease. Extensions to additional groups of neurological diseases are planned. The second ontology, the Neuro-Psychological Testing Ontology (NPT), is intended to provide a set of classes for the annotation of neuropsychological testing data. The intention of this ontology is to allow for the integration of results from a variety of neuropsychological tests that assay similar measures of cognitive functioning. Neuro-psychological testing is an important component in developing the clinical picture used in the diagnosis of patients with a range of neurological diseases, such as Alzheimer’s disease and multiple sclerosis, and following stroke or traumatic brain injury. NPT is being developed as an extension to the Ontology for Biomedical Investigations. (shrink)

We are developing the Neurological Disease Ontology (ND) to provide a framework to enable representation of aspects of neurological diseases that are relevant to their treatment and study. ND is a representational tool that addresses the need for unambiguous annotation, storage, and retrieval of data associated with the treatment and study of neurological diseases. ND is being developed in compliance with the Open Biomedical Ontology Foundry principles and builds upon the paradigm established by the Ontology for General Medical Science (OGMS) (...) for the representation of entities in the domain of disease and medical practice. Initial applications of ND will include the annotation and analysis of large data sets and patient records for Alzheimer’s disease, multiple sclerosis, and stroke. (shrink)

The rapid rise of international collaborative science has enabled access to genomic data. In this article, it is argued that to move beyond mapping genomic variation to understanding its role in complex disease aetiology and treatment will require extending data sharing for the purposes of clinical research translation and implementation.

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Hamlet’s PerfectionJohn D. CoxHamlet’s Perfection, by William Kerrigan; xviii & 179pp. Baltimore: Johns Hopkins University Press, 1994, $29.95.While acknowledging that his reading of Hamlet is “idiosyncratic and unfashionable” (p. x), Kerrigan offers no apologies for it, asserting, instead, that tradition is worth vindicating, because “those who have been trained in a tradition may discard it, but those who come after, students of the discarders, will be simply oblivious” (...) (pp. 2–3). Putting all his cards on the table, Kerrigan acknowledges four influences in the tradition he defends: literary formalism, historical scholarship, intellectual history, and psychoanalysis (pp. xii–xiii).Hamlet criticism thus “begins with the Romantic Germans” (p. 1), and they eventually give rise to Freud, who “influences most of the criticism of our century” (p. 14), even when critics (like Eliot) disagree with him. Kerrigan’s reading of the tradition is illuminating, subtle, informed, and informative, and he uses it to establish his reading of the play, working within the tradition but extending it in hitherto unseen and insightful ways. Of course Hamlet delays for Kerrigan, but no one has ever explained his delay so carefully or with so many other factors taken into account. “This seems to me much the best reading yet of the delay,” Kerrigan asserts (p. 76), and one is inclined to assent, given the assumptions.But why make these assumptions? Kerrigan dismisses postmodern criticism: it is a symptom of “our current decadence” (p. 31) and has contributed “little to the elucidation of Hamlet” (p. xi). Since the elucidation of texts and characters is not the aim of postmodern critics, they unsurprisingly fail at what they do not attempt. Yet they follow a tradition established, for the most part, by Marx and Nietzsche, and Kerrigan does not explain why he venerates one of Paul Ricoeur’s “masters of suspicion,” namely Freud, and not the other two.In fact, many readers may feel that Kerrigan fails to avoid decadence himself. He relates his Oedipal explanation of Hamlet’s delay to the observation that Shakespeare never has anything good to say about cosmetics, even though he was a man of the theater. Kerrigan relates this “split,” in turn, to early traumas in Shakespeare’s life. The fact that Mary Shakespeare had lost two daughters before William’s birth means that she must have been overattentive to him as an infant, yet she must have weaned him nine months before birth of younger brother Gilbert, thus splitting William’s attitude toward her between resentment of her overattention and resentment of being displaced at the breast. Kerrigan finds evidence of the latter in Timon 4.3.114–20, where Timon inveighs against “milk-paps” as “horrible traitors” (p. 78). Never mind that these are virgin’s paps and that Timon’s emphasis is sexual, not maternal: breasts are traitors to Timon as sex objects, not as sources of nutrition. The critic’s confusion between virgin and maternal breasts perhaps explains why Kerrigan places Thaisa in a brothel in Pericles, rather than Marina (p. 80), but I am not sure what psychological explanation to offer for this particular split. [End Page 381]Kerrigan would do well to heed the postmodern insight that we all speak out of a specific tradition, with the attendant lesson that tolerance and mutual respect across traditions is imperative, since “ridiculous” and “mockable” are relative to context, as Corin points out to Touchstone.In privileging Freud, Kerrigan not only dismisses the heritage of Marx and Nietzsche but underestimates the importance of what lies behind all three. For the Romantic/Freudian tradition cannot claim to have originated either character analysis or individuality, which Kerrigan purports to value. “A man’s character is his fate,” Heraclitus says, perhaps generalizing from Homer, but the insight would eventually inform Aristotle’s notion of an ethics based on virtuous character, which in turn was Christianized by Thomas (where it complements the moral sense of individual worth that Hamlet acknowledges in the providential oversight of sparrows), and came to influence the Reformers in various ways. Kerrigan has good things to say about Stoicism in Hamlet, but to assert that “It all begins with the Romantic Germans... (shrink)

While some may argue that universities are in a state of crisis, others claim that we are living in a post-university era; a time after universities. If there was a battle for the survival of the institution, it is over and done with. The buildings still stand. Students enrol and may attend lectures, though let’s be clear—most do not. But virtually nothing real remains. What some mistakenly take to be a university is, in actuality, an ‘uncanny’ spectral presence; ‘the nagging (...) presence of an absence … a “spectralized amnesiac modernity with its delusional totalizing systems”’. It is the remains and remnants of the university.[1]Overstatement? Perhaps. We think many if not most administrators, at all levels, will likely dissent. So too will many if not most teachers and students. Trying to determine whether this is correct, or to what extent, by consulting polls and reading opinion pieces in various education journals and professional papers is likely to be of little help. In any case, it is the hypothesis, along with closely related ones, and concerns about what can be done in the circumstances, that have generated this special issue.This special issue highlights and illustrates that most of the contested issues regarding educational theory and practice central to how universities and schools should be, and how they should be run, are first and foremost questions of value rather than fact. They are questions regarding what we want, but more importantly what we should want, from our universities and schools; about what they should be and what students, teachers and administrators should be doing to facilitate this.[1] See Cox and Levine and Boaks, Cox and Levine. (shrink)

There has been little previous research regarding the effectiveness of ethics education interventions for residential care‐givers. The Researching Interventions to Promote Ethics in social care project responded to the question: Which is the most effective ethics education intervention for care‐givers in residential social care? A pragmatic cluster trial explored the impact of three ethics education interventions for: (a) interactive face‐to‐face ethics teaching; (b) reflective ethics discussion groups; and (c) an immersive simulation experience. There was also a control arm (d). 144 (...) trial participants were recruited from 39 residential care homes for older people in southern England. Change scores compared across intervention arms showed a significant reduction in work‐related moral stress in the teaching arm compared with control group (p =.03); there were no significant differences between control and intervention arms in change scores for moral sensitivity, interpersonal reactivity (empathy) or ethical leadership. Qualitative data themes were as follows: ethical care; care challenges; and ethical care inhibitors. Overall findings stimulate reflection on the value of three different ethics education interventions and the most appropriate means to evaluate their impact. Findings suggest the complexity and diverse nature of ethical competence in care. We suggest a way forward for research evaluating ethics education. (shrink)

Extract: Clearly, academic life takes place at the intersection of many social practices. If MacIntyre is right, the role-specific virtues of academic life should be understood in terms of these practices.2 Academic virtues are those excellences required to obtain the internal goods of the social practices constituting academic life. And the social practices of academic life are sustained, competitive and cooperative attempts to achieve a set of academic goals and realize academic forms of excellence. They are also sustained attempts to (...) expand and improve conceptions of these goals and forms of excellence. They emerge out of traditions—for instance the tradition of scientific argument— and must be understood in terms of these traditions. MacIntyre argues that this preliminary account of virtues in relation to social practices needs to be deepened in two ways: connecting it to the unity of an individual’s life on the one hand and to a coherent historical tradition on the other. Virtues are not just any set of traits delivering the internal goods of social practices, but those that serve to make coherent a person’s life and her place in an on-going tradition. They are crucial to lending meaning to one’s life and its struggles. (shrink)

Recent studies in semantics of modal and superintuitionistic predicate logics provided many examples of incompleteness, especially for Kripke semantics. So there is a problem: to find an appropriate possible- world semantics which is equivalent to Kripke semantics at the propositional level and which is strong enough to prove general completeness results. The present paper introduces a new semantics of Kripke metaframes' generalizing some earlier notions. The main innovation is in considering "n"-tuples of individuals as abstract "n"-dimensional vectors', together with some (...) transformations of these vectors. Soundness of the semantics is proved to be equivalent to some non- logical properties of metaframes; and thus we describe the maximal semantics of Kripke- type. (shrink)

A laboratory-testable, solid-state Maxwell demon is proposed that utilizes the electric field energy of an open-gap p-n junction. Numerical results from a commercial semiconductor device simulator (Silvaco International–Atlas) verify primary results from a 1-D analytic model. Present day fabrication techniques appear adequate for laboratory tests of principle.

Folie à deux is the transference of delusional ideas from one 'primary' individual to one or more 'secondary' individuals (Lasègue & Falret, 1877). However, it is difficult to investigate experimentally because often only one patient is identified as delusional. We investigated whether hypnosis could model the experiences of the secondary in this delusion. Our primary was a confederate, who displayed two delusional beliefs and attempted to transmit them to hypnotised subjects. We manipulated the status of the confederate so that they (...) were portrayed as either "credible" or merely "interesting". Many high hypnotisable individuals adopted the confederate's beliefs and confabulated evidence in support of them. Also, subjects who interacted with a credible confederate extended their delusions beyond those displayed by the confederate. We discuss the strengths and limitations of this approach and suggest ways to improve the validity of this model. (shrink)

Many medical ethicists accept the thesis that there is no moral difference between withholding and withdrawing life-sustaining therapy. In this paper, we offer an interesting counterexample which shows that this thesis is not always true. Withholding is distinguished from withdrawing by the simple fact that therapy must have already been initiated in order to speak coherently about withdrawal. Provided that there is a genuine need and that therapy is biomedically effective, the historical fact that therapy has been initiated entails a (...) claim to continue therapy that cannot be attributed to patients who have not yet received therapy. This intrinsic difference between withholding and withdrawing therapy is of moral importance. In many instances, patients will waive this claim. But when one considers withdrawing therapy from one patient to help another in a setting of scarce resources, this intrinsic moral difference comes into sharp focus. In an era of shrinking medical resources, this difference cannot be ignored. (shrink)

Computer-based logic proofs are a form of unnatural language in which the process and structure of proof generation can be observed in considerable detail. We have been studying how students respond to multimodal logic teaching, and performance measures have already indicated that students' pre-existing cognitive styles have a significant impact on teaching outcome. Furthermore, a large corpus of proofs has been gathered via automatic logging of proof development. This paper applies a series of techniques, including corpus statistical methods, to the (...) proof logs. The results indicate that students' cognitive styles influence the structure of their logical discourse, via their differing methods of handling abstract information in diagrams, and transferring information between modalities. (shrink)

OBJECTIVE: To examine the long-term effects of an innovative curriculum on medical house officers' (HOs') knowledge, confidence, and attitudes regarding medical ethics. DESIGN: Long term cohort study. The two-year curriculum, implemented by a single physician ethicist with assistance from other faculty, was fully integrated into the programme. It consisted of monthly sessions: ethics morning report alternating with didactic conferences. The content included topics such as ethics vocabulary and principles, withdrawing life support, informed consent, and justice. Identical content was offered simultaneously (...) at the largest affiliated community hospital. SETTING: A multi-hospital university training programme from July, 1992 to June, 1994. PARTICIPANTS: Thirty-nine HOs responded in 92. Thirty HOs from the same cohort responded in 94 (response rates = 83% v 71%; P = 0.19). RESULTS: The curriculum was well received, with 96% of HOs finding the sessions stimulating. Previously validated scales of knowledge and confidence were administered at baseline and at follow-up. The average knowledge score improved 14% (P < 0.001). Confidence also improved, rising from 3.3 to 3.8 on a 5-point Likert scale (P < 0.001). These findings were independent of age, gender, religion, and prior education. The only attitudinal change was an increase in the proportion of residents who thought that ethics should be a required part of residency training (57% v 80%, P = 0.05). CONCLUSION: This curriculum appears practical, popular, and effective. It should be readily transferable to other institutions. (shrink)

In 1885, during initial discussions of J. C. Maxwell's celebrated thermodynamic demon, Whiting (1) observed that the demon-like velocity selection of molecules can occur in a gravitationally bound gas. Recently, a gravitational Maxwell demon has been proposed which makes use of this observation [D. P. Sheehan, J. Glick, and J. D. Means, Found. Phys. 30, 1227 (2000)]. Here we report on numerical simulations that detail its microscopic phase space structure. Results verify the previously hypothesized mechanism of its paradoxical behavior. This (...) system appears to be the only example of a fully classical mechanical Maxwell demon that has not been resolved in favor of the second law of thermodynamics. (shrink)

We report the results of a randomized trial to assess the impact of an innovative ethics curriculum on the knowledge and confidence of 85 medical house officers in a university hospital programme, as well as their responses to a simulated clinical case. Twenty-five per cent of the house officers received a lecture series, 25 per cent received lectures and case conferences, with an ethicist in attendance, and 50 per cent served as controls. A post-intervention questionnaire was administered. Knowledge scores did (...) not differ among the groups. Confidence regarding ethical issues was significantly greater in the aggregate intervention group compared to the control group. Confidence regarding procedural issues related to ethics was significantly higher for the EI group than for the controls. Responses to a simulated case showed that significantly fewer house officers in the EI group would intubate a patient for whom such therapy would be futile. We conclude that ethics education can have an impact on house officers' confidence and their responses to a simulated case, and that the EI was more effective than the LI. Such results have implications regarding the implementation of ethics education during residency. (shrink)

In a recent article in this journal our unit was accused of a number of errors of judgment in applying covert video surveillance (CVS) to infants and children suspected of life-threatening abuse. The article implied, that on moving from the Royal Brompton Hospital in London to North Staffordshire Hospital, we failed to present our work to the Research Ethics Committee (REC). We did send our protocol to the REC though we did not consider that, after a total of 16 patients (...) had been documented as being the subject of life-threatening abuse, this was research. The REC in Staffordshire agreed with us. We were also accused of undertaking work that should be pursued by the Police. We agree with this. However, unlike the Metropolitan Police the Staffordshire Police would not undertake CVS. We fail to agree that 'working together' with parents is necessarily practical or safe when trying to protect children from life-threatening abuse of this kind. (shrink)

First published in 1966. Professor Dryer has furnished a highly illuminating account of Kant’s _Critique of Pure Reason _by unfolding its central argument. _Kant’s Solution for Verification in Metaphysics _brings out the light which Kant has to throw on central topics of philosophy. It takes its place as an indispensable guide to every student of the _Critique of Pure Reason. _.

Little is known about distance processing in patients with posterior brain damage. Although many investigators have claimed that distance estimates are normal or abnormal in some of these patients, many of these observations were made informally and the examiners often asked for relative, and not absolute, distance estimates. The present investigation served two purposes. First, we wanted to contrast the use of distance information in peripersonal space for perceptual report as opposed to visuomotor control in our visual form agnosic patient, (...) DF. Second, we wanted to see to what extent her abilities to process distance cues were dependent on binocular vision, in light of Milner et al.'s (1991) observations of preserved stereopsis in DF, and Dijkerman et al.'s (1996) and Marotta et al.'s (1997) observations that her visual guidance of grasping may be particularly dependent on binocular vision of the target. We hypothesized that DF's visuomotor responses would show normal sensitivity to target distance, while her perceptual estimates would not. In the first experiment, we required DF and two age- and sex-matched control subjects to reach out and grasp black cubes placed at varying distances, or to estimate the distance of the cubes from the hand starting position without making a reaching movement. In the second experiment, we required DF and two age-matched control subjects to point as rapidly and accurately as possible to small LED targets which differed in spatial location, under binocular and monocular conditions. The results showed that, relative to the control subjects, DF's grasping movements produced normal peak velocity-distance scaling-when she reached for blocks which varied in depth or pointed to LED targets which were presented at different distances in depth. In contrast, in the cube experiment, her verbal estimates of object distance were poorly scaled, although they improved slightly under the binocular conditions. The results are discussed in terms of current theories of processing streams in extrastriate visual cortex and the distinction between categorical and coordinate spatial processing. (shrink)

In any competition for monuments of wasted labour the collection of accidental acrostics in Latin poets published by I. Hilberg would stand a good chance of a prize. But amongst his examples of ‘neckische Spiele des Zufalls’ is one I am gullible enough to believe may be more significant. In Aeneid 7. 601–15 Vergil describes the custom of opening the gates of war in a long anacoluthic sentence, the first four lines of which run: Mos erat Hesperio in Latio, quern (...) protinus urbes Albanae coluere sacrum, nunc maxima rerum Roma colit, cum prima movent in proelia Mortem, Sive Getis inferre manu lacrimabile bellum…. (shrink)

In 2000, a simple, foundational thermodynamic paradox was proposed: a sealed blackbody cavity contains a diatomic gas and a radiometer whose apposing vane surfaces dissociate and recombine the gas to different degrees (A $_{2} \rightleftharpoons $ 2A). As a result of differing desorption rates for A and A $_{2}$ , there arise between the vane faces permanent pressure and temperature differences, either of which can be harnessed to perform work, in apparent conflict with the second law of thermodynamics. Here we (...) report on the first experimental realization of this paradox, involving the dissociation of low-pressure hydrogen gas on high-temperature refractory metals (tungsten and rhenium) under blackbody cavity conditions. The results, corroborated by other laboratory studies and supported by theory, confirm the paradoxical temperature difference and point to physics beyond the traditional understanding of the second law. (shrink)