Cytosolic Sequestration of Prep1 Influences Early Stages of T Cell Development

Objective: Prep1 and Pbx2 are the main homeodomain DNA-binding proteins of the TALE (three amino acid loop extension) family expressed in the thymus. We previously reported reduced Pbx2 expression and defective thymocyte maturation in Prep1 hypomorphic mice. To further investigate the role of this homeodomain DNA-binding protein in T cell development, we generated transgenic mice expressing the N-terminal fragment of Pbx1 (Pbx1NT) under the control of the Lck proximal promoter. Principal Findings: Pbx1NT causes Prep1 cytosolic sequestration, abolishes Prep1-dependent DNA-binding activity and results in reduced Pbx2 expression in developing thymocytes. Transgenic thymi reveal increased numbers of CD4 2 CD8 2 CD44 2 (DN3 and DN4) thymocytes, due to a higher frequency of DN2 and DN4 Pbx1NT thymocytes in the S phase. Transgenic thymocytes however do not accumulate at later stages, as revealed by a normal representation of CD4/CD8 double positive and single positive thymocytes, due to a higher rate of apoptotic cell death of DN4 Pbx1NT thymocytes. Conclusion: The results obtained by genetic (Prep1 hypomorphic) and functional (Pbx1NT transgenic) inactivation of Prep

Strange Attractors in Dissipative Nambu Mechanics : Classical and Quantum Aspects

We extend the framework of Nambu-Hamiltonian Mechanics to include dissipation in $R^{3}$ phase space. We demonstrate that it accommodates the phase space dynamics of low dimensional dissipative systems such as the much studied Lorenz and R\"{o}ssler Strange attractors, as well as the more recent constructions of Chen and Leipnik-Newton. The rotational, volume preserving part of the flow preserves in time a family of two intersecting surfaces, the so called {\em Nambu Hamiltonians}. They foliate the entire phase space and are, in turn, deformed in time by Dissipation which represents their irrotational part of the flow. It is given by the gradient of a scalar function and is responsible for the emergence of the Strange Attractors. Based on our recent work on Quantum Nambu Mechanics, we provide an explicit quantization of the Lorenz attractor through the introduction of Non-commutative phase space coordinates as Hermitian $N \times N$ matrices in $R^{3}$. They satisfy the commutation relations induced by one of the two Nambu Hamiltonians, the second one generating a unique time evolution. Dissipation is incorporated quantum mechanically in a self-consistent way having the correct classical limit without the introduction of external degrees of freedom. Due to its volume phase space contraction it violates the quantum commutation relations. We demonstrate that the Heisenberg-Nambu evolution equations for the Quantum Lorenz system give rise to an attracting ellipsoid in the $3 N^{2}$ dimensional phase space.Comment: 35 pages, 4 figures, LaTe

Consumer perceptions of co-branding alliances: Organizational dissimilarity signals and brand fit

This study explores how consumers evaluate co-branding alliances between dissimilar partner firms. Customers are well aware that different firms are behind a co-branded product and observe the partner firms’ characteristics. Drawing on signaling theory, we assert that consumers use organizational characteristics as signals in their assessment of brand fit and for their purchasing decisions. Some organizational signals are beyond the control of the co-branding partners or at least they cannot alter them on short notice. We use a quasi-experimental design and test how co-branding partner dissimilarity affects brand fit perception. The results show that co-branding partner dissimilarity in terms of firm size, industry scope, and country-of-origin image negatively affects brand fit perception. Firm age dissimilarity does not exert significant influence. Because brand fit generally fosters a benevolent consumer attitude towards a co-branding alliance, the findings suggest that high partner dissimilarity may reduce overall co-branding alliance performance

Engineered spatial inversion symmetry breaking in an oxide heterostructure built from isosymmetric room-temperature magnetically ordered components

The oxide heterostructure [(YFeO3)5(LaFeO3)5]40, which is magnetically ordered and piezoelectric at room temperature, has been constructed from two weak ferromagnetic AFeO3 perovskites with different A cations using RHEED-monitored pulsed laser deposition. The polarisation arises through the removal of inversion centres present within the individual AFeO3 components. This symmetry reduction is a result of combining ordering on the A site, imposed by the periodicity of the grown structure, with appropriate orientations of the octahedral tilting characteristic of the perovskite units themselves, according to simple symmetry-controlled rules. The polarisation is robust against A site interdiffusion between the two layers which produces a sinusoidally modulated occupancy that retains the coupling of translational and point symmetries required to produce a polar structure. Magnetization and magneto-optical Kerr rotation measurements show that the heterostructure's magnetic structure is similar to that of the individual components. Evidence of the polarity was obtained from second harmonic generation and piezoelectric force microscopy measurements. Modeling of the piezoresponse allows extraction of d33 (approximately 10 pC N�1) of the heterostructure, which is in agreement with DFT calculations

Two Decades of Research on Euthanasia from the Netherlands. What Have We Learnt and What Questions Remain?

Two decades of research on euthanasia in the Netherlands have resulted into clear insights in the frequency and characteristics of euthanasia and other medical end-of-life decisions in the Netherlands. These empirical studies have contributed to the quality of the public debate, and to the regulating and public control of euthanasia and physician-assisted suicide. No slippery slope seems to have occurred. Physicians seem to adhere to the criteria for due care in the large majority of cases. Further, it has been shown that the majority of physicians think that the euthanasia Act has improved their legal certainty and contributes to the carefulness of life-terminating acts. In 2005, eighty percent of the euthanasia cases were reported to the review committees. Thus, the transparency envisaged by the Act still does not extend to all cases. Unreported cases almost all involve the use of opioids, and are not considered to be euthanasia by physicians. More education and debate is needed to disentangle in these situations which acts should be regarded as euthanasia and which should not. Medical end-of-life decision-making is a crucial part of end-of-life care. It should therefore be given continuous attention in health care policy and medical training. Systematic periodic research is crucial for enhancing our understanding of end-of-life care in modern medicine, in which the pursuit of a good quality of dying is nowadays widely recognized as an important goal, in addition to the traditional goals such as curing diseases and prolonging life

Multilevel psychometric properties of the AHRQ hospital survey on patient safety culture

<p>Abstract</p> <p>Background</p> <p>The Agency for Healthcare Research and Quality (AHRQ) <it>Hospital Survey on Patient Safety Culture </it>was designed to assess staff views on patient safety culture in hospital settings. The purpose of this study was to examine the multilevel psychometric properties of the survey.</p> <p>Methods</p> <p>Survey data from 331 U.S. hospitals with 2,267 hospital units and 50,513 respondents were analyzed to examine the psychometric properties of the survey's items and composites. Item factor loadings, intraclass correlations (ICCs), design effects, internal consistency reliabilities, and multilevel confirmatory factor analyses (MCFA) were examined as well as intercorrelations among the survey's composites.</p> <p>Results</p> <p>Psychometric analyses confirmed the multilevel nature of the data at the individual, unit and hospital levels of analysis. Results provided overall evidence supporting the 12 dimensions and 42 items included in the AHRQ <it>Hospital Survey on Patient Safety Culture </it>as having acceptable psychometric properties at all levels of analysis, with a few exceptions. The Staffing composite fell slightly below cutoffs in a number of areas, but is conceptually important given its impact on patient safety. In addition, one hospital-level model fit indicator for the Supervisor/Manager Expectations & Actions Promoting Patient Safety composite was low (CFI = .82), but all other psychometrics for this scale were good. Average dimension intercorrelations were moderate at .42 at the individual level, .50 at the unit level, and .56 at the hospital level.</p> <p>Conclusions</p> <p>Psychometric analyses conducted on a very large database of hospitals provided overall support for the patient safety culture dimensions and items included in the AHRQ <it>Hospital Survey on Patient Safety Culture</it>. The survey's items and dimensions overall are psychometrically sound at the individual, unit, and hospital levels of analysis and can be used by researchers and hospitals interested in assessing patient safety culture. Further research is needed to study the criterion-related validity of the survey by analysing the relationship between patient safety culture and patient outcomes and studying how to improve patient safety culture.</p

Differences in Nutrient Requirements Imply a Non-Linear Emergence of Leaders in Animal Groups

Collective decision making and especially leadership in groups are among the most studied topics in natural, social, and political sciences. Previous studies have shown that some individuals are more likely to be leaders because of their social power or the pertinent information they possess. One challenge for all group members, however, is to satisfy their needs. In many situations, we do not yet know how individuals within groups distribute leadership decisions between themselves in order to satisfy time-varying individual requirements. To gain insight into this problem, we build a dynamic model where group members have to satisfy different needs but are not aware of each other's needs. Data about needs of animals come from real data observed in macaques. Several studies showed that a collective movement may be initiated by a single individual. This individual may be the dominant one, the oldest one, but also the one having the highest physiological needs. In our model, the individual with the lowest reserve initiates movements and decides for all its conspecifics. This simple rule leads to a viable decision-making system where all individuals may lead the group at one moment and thus suit their requirements. However, a single individual becomes the leader in 38% to 95% of cases and the leadership is unequally (according to an exponential law) distributed according to the heterogeneity of needs in the group. The results showed that this non-linearity emerges when one group member reaches physiological requirements, mainly the nutrient ones – protein, energy and water depending on weight - superior to those of its conspecifics. This amplification may explain why some leaders could appear in animal groups without any despotism, complex signalling, or developed cognitive ability

Survey of the general public's attitudes toward advance directives in Japan: How to respect patients' preferences

BACKGROUND: Japanese people have become increasingly interested in the expression and enhancement of their individual autonomy in medical decisions made regarding medical treatment at and toward the end of life. However, while many Western countries have implemented legislation that deals with patient autonomy in the case of terminal illness, no such legislation exists in Japan. The rationale for this research is based on the need to investigate patient's preferences regarding treatment at the end of life in order to re-evaluate advance directives policy and practice. METHODS: We conducted a cross-sectional survey with 418 members of the general middle-aged and senior adults (aged between 40 and 65) in Tokyo, Japan. Respondents were asked about their attitudes toward advance directives, and preferences toward treatment options. RESULTS: Over 60% of respondents agreed that it is better to express their wishes regarding advance directives (treatment preferences in writing, appointment of proxy for care decision making, appointment of legal administrator of property, stating preferences regarding disposal of one's property and funeral arrangements) but less than 10% of them had already done so. About 60% of respondents in this study preferred to indicate treatment preferences in broad rather than concrete terms. Over 80% would like to decide treatment preferences in consultation with others (22.2% with their proxy, 11.0% with the doctor, and 47.8% with both their proxy and the doctor). CONCLUSION: This study revealed that many Japanese people indicate an interest in undertaking advance directives. This study found that there is a range of preferences regarding how advance directives are undertaken, thus it is important to recognize that any processes put into place should allow flexibility in order to best respect patients' wishes and autonomy

Relationship between alcohol-attributable disease and socioeconomic status, and the role of alcohol consumption in this relationship: a systematic review and meta-analysis

Background: Studies show that alcohol consumption appears to have a disproportionate impact on people of low socioeconomic status. Further exploration of the relationship between alcohol consumption, socioeconomic status and the development of chronic alcohol-attributable diseases is therefore important to inform the development of effective public health programmes. Methods: We used systematic review methodology to identify published studies of the association between socioeconomic factors and mortality and morbidity for alcohol-attributable conditions. To attempt to quantify differences in the impact of alcohol consumption for each condition, stratified by SES, we (i) investigated the relationship between SES and risk of mortality or morbidity for each alcohol-attributable condition, and (ii) where, feasible explored alcohol consumption as a mediating or interacting variable in this relationship. Results: We identified differing relationships between a range of alcohol-attributable conditions and socioeconomic indicators. Pooled analyses showed that low, relative to high socioeconomic status, was associated with an increased risk of head and neck cancer and stroke, and in individual studies, with hypertension and liver disease. Conversely, risk of female breast cancer tended to be associated with higher socioeconomic status. These findings were attenuated but held when adjusted for a number of known risk factors and other potential confounding factors. A key finding was the lack of studies that have explored the interaction between alcohol-attributable disease, socioeconomic status and alcohol use. Conclusions: Despite some limitations to our review, we have described relationships between socioeconomic status and a range of alcohol-attributable conditions, and explored the mediating and interacting effects of alcohol consumption where feasible. However, further research is needed to better characterise the relationship between socioeconomic status alcohol consumption and alcohol-attributable disease risk so as to gain a greater understanding of the mechanisms and pathways that influence the differential risk in harm between people of low and high socioeconomic status

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies