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)

Objectives: To study the attitudes of both medical and non-medical students towards the do-not-resuscitate decision in a university in Hong Kong, and the factors affecting their attitudes.Methods: A questionnaire-based survey conducted in the campus of a university in Hong Kong. Preferences and priorities of participants on cardiopulmonary resuscitation in various situations and case scenarios, experience of death and dying, prior knowledge of DNR and basic demographic data were evaluated.Results: A total of 766 students participated in the study. There were statistically (...) significant differences in their DNR decisions in various situations between medical and non-medical students, clinical and preclinical students, and between students who had previously experienced death and dying and those who had not. A prior knowledge of DNR significantly affected DNR decision, although 66.4% of non-medical students and 18.7% of medical students had never heard of DNR. 74% of participants from both medical and non-medical fields considered the patient’s own wish as the most important factor that the healthcare team should consider when making DNR decisions. Family wishes might not be decisive on the choice of DNR.Conclusions: Students in medical and non-medical fields held different views on DNR. A majority of participants considered the patient’s own wish as most important in DNR decisions. Family wishes were considered less important than the patient’s own wishes. (shrink)

The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment containing the (...) 5'-flanking region of the human APOE gene . Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

We acknowledge the limitations in measures of moral reasoning and pursue an alternative technique by investigating past behaviors as they relate to present behavioral intentions. Our purpose is to evaluate the merits of patterned normative behavior for predicting present and future, morally relevant outcomes. Participants completed a policy capturing experimental design responding to questions that orthogonally varied the situational nature of the decision context. Results indicate that past normative behaviors are significantly and directly related to ethical behavioral intentions. Moreover, they (...) moderate the relationships between situational factors and intended outcomes as well as moral reasoning and intended outcomes. (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)

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)

Medical paternalism has long been a common medical practice. However, patient autonomy in healthcare has been recently adopted by doctors and patients alike. This study explored whether doctors and patients in a tertiary care hospital in Saudi Arabia preferred autonomy or paternalism in shared decision‐making. A total of 118 participants (51 patients requiring total knee replacement, owing to stages 3–4 of osteoarthritis, and 67 doctors) from the Eastern province, Saudi Arabia. responded to a 17‐question category‐based questionnaire involving four scales of (...) autonomy. Descriptive statistics and chi‐square test results revealed that in this hospital, patients preferred a paternalistic approach toward their medical care along with a full disclosure of the risks related to surgical procedures. We recommend health education regarding the specific autonomy subscales (doctor knows best, patient should decide, right to non‐participation, and obligatory risk information), and the implementation of protocols that protect patients' rights and enhance personal autonomy. (shrink)

Objectives The objectives of the study are to understand the current practice of informed consent in medical research in public hospitals in Shanghai, and to share our views with other countries, especially developing countries. Methods In the study, 145 consent forms (CFs) of the selected research projects in eight public hospitals with ethics committees in Shanghai were audited, and the principle investigators (PIs) of these research projects and 40 student subjects who had participated in clinical drug tests were surveyed by (...) questionnaires. Results The CFs of medical researches in public hospitals with ethics committees in Shanghai were generally acceptable. However, there were some defects in the CFs. Although most of the surveyed PIs had correct recognition of informed consent, some processes of informed consent were not in accordance with generally accepted requirements. A large number of the PIs considered the greatest difficulty with informal consent was lack of correct recognition of subjects or legally authorised representatives on medical research. Discussion Informed consent in medical research should consider the research ethics, the background of potential subjects, the local resources and culture of medical research. In addition, special protection is needed for student subjects in informed consent as well as efforts for building and restoring the public's trust in biomedical research. Conclusion The informed consent in Shanghai's public hospitals with ethics committees was generally acceptable and the achievement of adequate informed consent is influenced by many factors. (shrink)

Although informed consent is important in clinical research, questions persist regarding when it is necessary, what it requires, and how it should be obtained. The standard view in research ethics is that the function of informed consent is to respect individual autonomy. However, consent processes are multidimensional and serve other ethical functions as well. These functions deserve particular attention when barriers to consent exist. We argue that consent serves seven ethically important and conceptually distinct functions. The first four functions pertain (...) principally to individual participants: (1) providing transparency; (2) allowing control and authorization; (3) promoting concordance with participants' values; and (4) protecting and promoting welfare interests. Three other functions are systemic or policy focused: (5) promoting trust; (6) satisfying regulatory requirements; and (7) promoting integrity in research. Reframing consent around these functions can guide approaches to consent that are context sensitive and that maximize achievable goals. (shrink)

Let ≤r and ≤sbe two binary relations on 2ℕ which are meant as reducibilities. Let both relations be closed under finite variation and consider the uniform distribution on 2ℕ, which is obtained by choosing elements of 2ℕ by independent tosses of a fair coin.Then we might ask for the probability that the lower ≤r-cone of a randomly chosen set X, that is, the class of all sets A with A ≤rX, differs from the lower ≤s-cone of X. By c osure (...) under finite variation, the Kolmogorov 0-1 aw yields immediately that this probability is either 0 or 1; in case it is 1, the relations are said to be separable by random oracles.Again by closure under finite variation, for every given set A, the probability that a randomly chosen set X is in the upper ≤r-cone of A is either 0 or 1; let Almostr be the class of sets for which the upper ≤r-cone has measure 1. In the following, results about separations by random oracles and about Almost classes are obtained in the context of generalized reducibilities, that is, for binary relations on 2ℕ which can be defined by a countable set of total continuous functionals on 2ℕ in the same way as the usual resource-bounded reducibilities are defined by an enumeration of appropriate oracle Turing machines. The concept of generalized reducibility comprises a natura resource-bounded reducibilities, but is more general; in particular, it does not involve any kind of specific machine model or even effectivity. The results on generalized reducibilities yield corollaries about specific resource-bounded reducibilities, including several results which have been shown previously in the setting of time or space bounded Turing machine computations. (shrink)

ABSTRACTThe rapid expansion of primary education in Ethiopia has enabled most children to attend primary education—or at least to start schooling. This expansion, however, is largely “symbolic” rat...

A new approach to policy analysis is formulated within the framework of the graph model for conflict resolution. A policy is defined as a plan of action for a decision maker (DM) that specifies the DM’s intended action starting at every possible state in a graph model of a conflict. Given a profile of policies, a Policy Stable State (PSS) is a state that no DM moves away from (according to its policy), and such that no DM would prefer to (...) change its policy given the policies of the other DMs. The profile of policies associated to a PSS is called a Policy Equilibrium. Properties of PSSs are developed, and a refinement is suggested that restricts DMs to policies that are credible in that they are in the DM’s immediate interest. Relationships with existing stability definitions in the graph model for conflict resolution are then explored. (shrink)