This work is a volume in the series Ancient Commentators on Aristotle, edited by Richard Sorabji. The aim of the series is to make the Greek commentaries available in English. Konstan does an admirable job of this. The translation is extremely careful, clear, and readable. Konstan succeeds in staying close to the text without sacrificing intelligibility. Whenever necessary, he inserts words or phrases in brackets to complete the sense of an accurately translated passage. Konstan also makes use of brackets to (...) give precise citations to fill out Simplicius' references. The footnotes, too, are excellent. There the reader finds information about deviations from Diels's text, about alternative readings, and explanations of renderings into English that might be controversial. In the introduction, Sorabji gives a thumbnail sketch of the philosophical issues raised by Physics 6. Several useful documents are appended to the commentary, namely, a list of all departures from Diels's text, an appendix written by the editor providing a brief survey of the ancient Greek commentators, and a list of the philosophers cited by Simplicius with a onesentence description of each. (shrink)

This book is a carefully crafted introduction to ancient Greek thought and philosophy. Irwin begins with Homer and ends with Augustine and along the way looks at all save one of the significant Greek philosophical traditions.

This book is a carefully crafted introduction to ancient Greek thought and philosophy. Irwin begins with Homer and ends with Augustine and along the way looks at all save one of the significant Greek philosophical traditions.

This edited volume illustrates the central importance of diversity of human values throughout healthcare. The readings are organised around the main stages of the clinical encounter from the patient's perspective. This introductory chapter opens up crucial issues of methodology and of practical application in this highly innovative approach to the role of ethics in healthcare.

This volume of articles, literature and case studies illustrates the central importance of human values throughout healthcare. The readings are structured around the main stages of the clinical encounter from the patient's perspective.

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Intuitively, vagueness involves some sort of indeterminacy: if Plato is a borderline case of baldness, then there is no fact of the matter about whether or not he’s bald—he’s neither bald nor not bald. The leading formal treatments of such indeterminacy—three valued logic, supervaluationism, etc.—either fail to validate the classical theorems, or require that various classically valid inference rules be restricted. Here we show how a fully classical, yet indeterminist account of vagueness can be given within natural semantics, an alternative (...) semantics for classical proof theory. The key features of the account are: there is a single notion of truth—definite truth—and a single notion of validity; sentences can be true, false, or undetermined; all classical theorems and all classical inference rule are valid; the sorites argument is unsound; ‘definitely’ is treated as a meta-language predicate; higher-order vagueness is handled via semantic ascent. (shrink)

Background In Switzerland, right-to-die organisations assist their members with suicide by lethal drugs, usually barbiturates. One organisation, Dignitas, has experimented with oxygen deprivation as an alternative to sodium pentobarbital. Objective To analyse the process of assisted suicide by oxygen deprivation with helium and a common face mask and reservoir bag. Method This study examined four cases of assisted suicide by oxygen deprivation using helium delivered via a face mask. Videos of the deaths were provided by the Zurich police. Dignitas provided (...) protocol and consent information. Results One man and three women were assisted to death by oxygen deprivation. There was wide variation in the time to unconsciousness and the time to death, probably due to the poor mask fit. Swiss law prevented attendants from effectively managing the face mask apparatus. Purposeless movements of the extremities were disconcerting for Dignitas attendants, who are accustomed to assisting suicide with barbiturates. None of the dying individuals attempted self-rescue. Conclusions The dying process of oxygen deprivation with helium is potentially quick and appears painless. It also bypasses the prescribing role of physicians, effectively demedicalising assisted suicide. Oxygen deprivation with a face mask is not acceptable because leaks are difficult to control and it may not eliminate rebreathing. These factors will extend time to unconsciousness and time to death. A hood method could reduce the problem of mask fit. With a hood, a flow rate of helium sufficient to provide continuous washout of expired gases would remedy problems observed with the mask. (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated (...) region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Electronic communication and commerce facilitate the collection of information about individual use of the Internet. Focusing on the case of Comet Systems Inc. and its data gathering practices, this paper explores the technical details of gathering personal information in databases in general and the special character of the privacy issue raised by 'anonymous' information about individual behavior on the Internet. The case analysis suggests new insights for our understanding of privacy and frames a discussion of policy alternatives with respect to (...) the privacy of Internet communication. (shrink)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated Abeta1-40 (...) localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

Sensation elicited by a skin stimulus was subjectively reported to feel stronger when followed by a stimulus to somatosensory cerebral cortex , even when C was delayed by up to 400 ms or more. This expands the potentiality for retroactive effects beyond that previously known as backward masking. It also demonstrates that the content of a sensory experience can be altered by another cerebral input introduced after the sensory signal arrives at the cortex. The long effective S-C intervals support the (...) thesis that a duration of cortical activity of up to 0.5 s is required before awareness of a sensory stimulus is developed. (shrink)

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)