Argument and Medicine: A model of reasoning for clinical practice

In a doctor-linguist collaboration, a framework of reasoning in clinical contexts is presented. Arguments used for inquiry, justification and persuasion are sketched in diagnosis, counselling, and management settings integral to everyday clinical practice thereby extending the diagnostic function typically associated with clinical reasoning per se. A system of logic, a method of persuasive orientation, and a synthesis of negotiation in dialogue are then elaborated to illustrate the complexity of argument practice in medical culture

A critical role for suppressor of cytokine signalling 3 in promoting M1 macrophage activation and function in vitro and in vivo

Funded by Medical Research Council. Grant Number: 74804 NHS Grampian Endowments Research Trust. Grant Number: 12/16 Kidney Research UK. Grant Number: RP1/2012 Cunningham Trust. Grant Number: ACC/KWF/CT08/03Peer reviewedPublisher PD

An immunodominant La/SSB autoantibody proteome derives from public clonotypes

This item is under embargo for a period of 12 months from the date of publication, in accordance with the publisher's policy.The La/SSB autoantigen is a major target of long-term humoral autoimmunity in primary Sjögren’s Syndrome (SS) and systemic lupus erythematosus. A majority of patients with linked anti-Ro60/Ro52/La responses target an NH2-terminal epitope designated LaA that is expressed on Ro/La ribonucleoprotein complexes and the surface membrane of apoptotic cells. In this study, we used high-resolution Orbitrap mass spectrometry to determine the clonality, isotype and V-region sequences of LaA-specific autoantibodies in seven patients with primary SS. Anti-LaA immunoglobulin (Ig)Gs purified from polyclonal sera by epitope-specific affinity chromatography were analysed by combined database and de-novo mass spectrometric sequencing. Autoantibody responses comprised two heavily mutated IgG1 kappa-restricted monoclonal species that were shared (public) across unrelated patients; one clonotype was specified by an IGHV3-30 heavy chain paired with IGKV3-15 light chain and the second by an IGHV3- 43/IGKV3-20 pairing. Shared amino acid replacement mutations were also seen within heavy and light chain complementarity-determining regions, consistent with a common breach of B cell tolerance followed by antigendriven clonal selection. The discovery of public clonotypic autoantibodies directed against an immunodominant epitope on La, taken together with recent findings for the linked Ro52 and Ro60 autoantigens, supports a model of systemic autoimmunity in which humoral responses against protein–RNA complexes are mediated by public sets of autoreactive B cell clonotypes.This work was supported by an Australian National Health and Medical Research Council grant 1041900 to T. P. Gordon and T. K. Chataway

Impact of rural-to-urban migration on family and gender values in China

Drawing on data from the 2006 China General Social Survey, propensity score matching was used to investigate the impact of rural-to-urban migration on family and gender values in China at distinct stages of the migratory process. Little evidence of ideational difference is found between rural natives who intend to migrate to urban areas and those who intend to stay in rural China. However, rural-to-urban migration has significant, diverse and gendered impacts on various domains of family and gender values at distinct migratory stages. The results also cast light on the important roles played by hukou status and various forms of socioeconomic and cultural status, such as education and occupation, in mediating the impact of rural-to-urban migration on family and gender values. The ideational impact of migration is shown to be shaped by China’s distinctive institutional features

Wireless aquatic navigator for detection and analysis (WANDA)

The cost of monitoring and detecting pollutants in natural waters is of major concern. Current and forthcoming bodies of legislation will continue to drive demand for spatial and selective monitoring of our environment, as the focus increasingly moves towards effective enforcement of legislation through detection of events, and unambiguous identification of perpetrators. However, these monitoring demands are not being met due to the infrastructure and maintenance costs of conventional sensing models. Advanced autonomous platforms capable of performing complex analytical measurements at remote locations still require individual power, wireless communication, processor and electronic transducer units, along with regular maintenance visits. Hence the cost base for these systems is prohibitively high, and the spatial density and frequency of measurements are insufficient to meet requirements. In this paper we present a more cost effective approach for water quality monitoring using a low cost mobile sensing/communications platform together with very low cost stand-alone ‘satellite’ indicator stations that have an integrated colorimetric sensing material. The mobile platform is equipped with a wireless video camera that is used to interrogate each station to harvest information about the water quality. In simulation experiments, the first cycle of measurements is carried out to identify a ‘normal’ condition followed by a second cycle during which the platform successfully detected and communicated the presence of a chemical contaminant that had been localised at one of the satellite stations

Assessing the safety of cosmetic chemicals: Consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of Toxicological Concern)

AbstractThreshold of Toxicological Concern (TTC) aids assessment of human health risks from exposure to low levels of chemicals when toxicity data are limited. The objective here was to explore the potential refinement of exposure for applying the oral TTC to chemicals found in cosmetic products, for which there are limited dermal absorption data. A decision tree was constructed to estimate the dermally absorbed amount of chemical, based on typical skin exposure scenarios. Dermal absorption was calculated using an established predictive algorithm to derive the maximum skin flux adjusted to the actual ‘dose’ applied. The predicted systemic availability (assuming no local metabolism), can then be ranked against the oral TTC for the relevant structural class. The predictive approach has been evaluated by deriving the experimental/prediction ratio for systemic availability for 22 cosmetic chemical exposure scenarios. These emphasise that estimation of skin penetration may be challenging for penetration enhancing formulations, short application times with incomplete rinse-off, or significant metabolism. While there were a few exceptions, the experiment-to-prediction ratios mostly fell within a factor of 10 of the ideal value of 1. It can be concluded therefore, that the approach is fit-for-purpose when used as a screening and prioritisation tool

Phosphorylation regulates targeting of cytoplasmic dynein to kinetochores during mitosis

Cytoplasmic dynein functions at several sites during mitosis; however, the basis of targeting to each site remains unclear. Tandem mass spectrometry analysis of mitotic dynein revealed a phosphorylation site in the dynein intermediate chains (ICs) that mediates binding to kinetochores. IC phosphorylation directs binding to zw10 rather than dynactin, and this interaction is needed for kinetochore dynein localization. Phosphodynein associates with kinetochores from nuclear envelope breakdown to metaphase, but bioriented microtubule (MT) attachment and chromosome alignment induce IC dephosphorylation. IC dephosphorylation stimulates binding to dynactin and poleward streaming. MT depolymerization, release of kinetochore tension, and a PP1-γ mutant each inhibited IC dephosphorylation, leading to the retention of phosphodynein at kinetochores and reduced poleward streaming. The depletion of kinetochore dynactin by moderate levels of p50(dynamitin) expression disrupted the ability of dynein to remove checkpoint proteins by streaming at metaphase but not other aspects of kinetochore dynein activity. Together, these results suggest a new model for localization of kinetochore dynein and the contribution of kinetochore dynactin

"Cult of equity": actuaries and the transformation of pension fund investing, 1948–1960

This article examines the mid-twentieth-century transformation of U.K. pension fund investment policy known as the “cult of equity.” It focuses on the influence exercised by the Association of Superannuation and Pension Funds over actuarial and corporate governance standards, through actuaries who were members of its council. This intervention led to increasingly permissive actuarial valuations that reduced contributions for sponsors of pension funds investing in equities. Increased demand for equities required pension funds to adopt a more permissive approach to corporate governance than insurance companies and investment trusts, and contributed to declining standards of corporate governance

Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression

Lytic replication of the human gamma herpes virus Epstein-Barr virus (EBV) is an essential prerequisite for the spread of the virus. Differential regulation of a limited number of cellular genes has been reported in B-cells during the viral lytic replication cycle. We asked whether a viral bZIP transcription factor, Zta (BZLF1, ZEBRA, EB1), drives some of these changes. Using genome-wide chromatin immunoprecipitation coupled to next-generation DNA sequencing (ChIP-seq) we established a map of Zta interactions across the human genome. Using sensitive transcriptome analyses we identified 2263 cellular genes whose expression is significantly changed during the EBV lytic replication cycle. Zta binds 278 of the regulated genes and the distribution of binding sites shows that Zta binds mostly to sites that are distal to transcription start sites. This differs from the prevailing view that Zta activates viral genes by binding exclusively at promoter elements. We show that a synthetic Zta binding element confers Zta regulation at a distance and that distal Zta binding sites from cellular genes can confer Zta-mediated regulation on a heterologous promoter. This leads us to propose that Zta directly reprograms the expression of cellular genes through distal elements