Letter Reply: Distribution of TNFA haplotypes in healthy Caucasians: Comment on the articles by Newton et al and Zeggini et al

We thank Ploski and colleagues for their interest in our study. The explanation for the difference in our findings is a typographic error in Table 2 of our article, whereby the alleles for marker TNF ⫺1031 were labeled incorrectly...

Investigation of the role of ANKH in ankylosing spondylitis

Objective The ank/ank mouse develops a phenotype similar to ankylosing spondylitis (AS) in humans. ANKH, the human homolog of the mutated gene in the ank/ank mouse, has been implicated in familial autosomal-dominant chondrocalcinosis and autosomal-dominant craniometaphyseal dysplasia. This study was undertaken to investigate the role of ANKH in susceptibility to and clinical manifestations of AS. Methods Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls. Linkage to the ANKH locus was assessed in 185 affected-sibling-pair families. Results Five single-nucleotide polymorphisms were identified within the coding region and flanking splice sites. No association between either susceptibility to AS or its clinical manifestations and these novel polymorphisms, or between disease susceptibility and 3 known promoter variants, was seen. No linkage between the ANKH locus and AS was observed. Multipoint exclusion mapping rejected the hypothesis of a locus of a magnitude λ≥1.4 (logarithm of odds score <-2) (equivalent to a genetic contribution of >10% to the AS sibling recurrence risk ratio) within this area contributing to AS. Conclusion These findings indicate that ANKH is not significantly involved in susceptibility to or clinical manifestations of AS.

Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5′-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate

Objective Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. Methods ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. Results Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5′-untranslated region (5′-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. Conclusion A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5′-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.

Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice

Objective Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin-23 (IL-23) receptor signaling in the development of SpA and IBD, and IL-23 overexpression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However, in genetically prone individuals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP-70W163C-mutant (SKG) mice injected intraperitoneally with β-1,3-glucan (curdlan). Methods Eight weeks after curdlan injection in wild-type or IL-17A-/- SKG or BALB/c mice, pathology was scored in tissue sections. Mice were treated with anti-IL-23 or anti-IL-22. Cytokine production and endoplasmic reticulum (ER) stress were determined in affected organs. Results In curdlan-treated SKG mice, arthritis, enthesitis, and ileitis were IL-23 dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it amplified ER stress, goblet cell dysfunction, and proinflammatory cytokine production. IL-17A was pathogenic, while IL-22 was protective against ileitis. IL-22+CD3- innate-like cells were increased in lamina propria mononuclear cells of ileitis-resistant BALB/c mice, which developed ileitis after curdlan injection and anti-IL-22. Conclusion In response to systemic β-1,3-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/IL-22-dependent enthesitis. Innate IL-22 production promotes ileal tolerance.

Antibody treatments of inflammatory arthritis

Inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis are extremely common in the community, with a prevalence of up to 5%, and they cause substantial morbidity. The development of anti-TNF agents for use initially in rheumatoid arthritis, and subsequently more broadly in inflammatory arthritis, represents the biggest advance in management of these conditions since the introduction of corticosteroid agents, and is a major vindication of public funded arthritis research. However, there are limitations of even these highly effective agents. A significant minority of patients with inflammatory arthritis do not respond to these anti-TNF agents, they are associated with substantial risk of toxicity, require parenteral administration, and are extremely expensive. New antibody treatments in development can be divided into anti-cytokine agents, cell-targeted therapies, co-stimulation inhibitors, and treatments aimed at preventing joint erosion consequent on inflammation. This review discusses the state of the art in the development of these agents for management of this common group of diseases.

Is one-parameter scaling theory of localisation consistent? Comment on Schuh's comment

It is maintained that the one-parameter scaling theory is inconsistent with the physics of Anderson localisation.

At the Limits of Presentation : Coming-into-Presence and its Aesthetic Relevance in Jean-Luc Nancy's Philosophy

This study investigates the significance of art in Jean-Luc Nancy s philosophy. I argue that the notion of art contributes to some of Nancy s central ontological ideas. Therefore, I consider art s importance in its own right whether art does have ontological significance, and if so, how one should describe this with respect to the theme of presentation. According to my central argument, with his thinking on art Nancy attempts to give one viewpoint to what is called the metaphysics of presence and to its deconstruction. On which grounds, as I propose, may one say that art is not reducible to philosophy? The thesis is divided into two main parts. The first part, Presentation as a Philosophical Theme, is a historical genesis of the central concepts associated with the birth of presentation in Nancy s philosophy. I examine this from the viewpoint of the differentiation between the ontological notions of presentation and representation by concentrating on the influence of Martin Heidegger and Jacques Derrida, as well as of Hegel and Kant. I give an overview of the way in which being or sense for Nancy is to be described as a coming-into-presence or presentation . Therefore, being takes place in its singular plurality. I argue that Nancy redevelops Heidegger s account of being in two principal ways: first, in rethinking the ontico-ontological difference, and secondly, by striving to radicalize the Heideggerian concept of Mitsein, being-with . I equally wish to show the importance of Derrida s notion of différance and its inherence in Nancy s questioning of being that rests on the unfoundedness of existence. The second part, From Ontology to Art, draws on the importance of art and the aesthetic. If, in Nancy, the question of art touches upon its own limit as the limit of nothingness, how is art able to open its own strangeness and our exposure to this strangeness? My aim is to investigate how Nancy s thinking on art finds its place within the conceptual realm of its inherent difference and interval. My central concern is the thought of originary ungroundedness and the plurality of art and of the arts. As for the question of the difference between art and philosophy, I wish to show that what differentiates art from thought is the fact that art exposes what is obvious but not apparent, if apparent is understood in the sense of givenness. As for art s ability to deconstruct Nancy s ontological notions, I suggest that in question in art is its original heterogeneity and diversity. Art is a matter of differing art occurs singularly, as a local difference. With this in mind, I point out that in reflecting on art in terms of spacing and interval, as a thinker of difference Nancy comes closer to Derrida and his idea of différance than to the structure of Heidegger s ontological difference.

Genetic association analysis of miRNA SNPs implicates MIR145 in breast cancer susceptibility

Background MicroRNAs (miRNAs) are important small non-coding RNA molecules that regulate gene expression in cellular processes related to the pathogenesis of cancer. Genetic variation in miRNA genes could impact their synthesis and cellular effects and single nucleotide polymorphisms (SNPs) are one example of genetic variants studied in relation to breast cancer. Studies aimed at identifying miRNA SNPs (miR-SNPs) associated with breast malignancies could lead towards further understanding of the disease and to develop clinical applications for early diagnosis and treatment. Methods We genotyped a panel of 24 miR-SNPs using multiplex PCR and chip-based matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) analysis in two Caucasian breast cancer case control populations (Primary population: 173 cases and 187 controls and secondary population: 679 cases and 301 controls). Association to breast cancer susceptibility was determined using chi-square (X 2 ) and odds ratio (OR) analysis. Results Statistical analysis showed six miR-SNPs to be non-polymorphic and twelve of our selected miR-SNPs to have no association with breast cancer risk. However, we were able to show association between rs353291 (located in MIR145) and the risk of developing breast cancer in two independent case control cohorts (p = 0.041 and p = 0.023). Conclusions Our study is the first to report an association between a miR-SNP in MIR145 and breast cancer risk in individuals of Caucasian background. This finding requires further validation through genotyping of larger cohorts or in individuals of different ethnicities to determine the potential significance of this finding as well as studies aimed to determine functional significance. Keywords: Association analysis; Breast cancer; microRNA; miR-SNPs; MIR145

Focus on Form : J. J. Tikkanen, Giotto and Art Research in the 19th Century

My doctoral dissertation is on Johan Jakob Tikkanen (1857 1930), the first professor of art history in Finland, and his significance and methods in the context of late 19th and early 20th-century European art history. Tikkanen was one of the pioneering scholars in the field of medieval art research, and, along with Anton Springer, Heinrich Wölfflin, Aloïs Riegl, Adolfo Venturi, Franz Wickhoff, Julius von Schlosser, Aby Warburg, Emile Mâle and others, one of the scholars who defined art history as an independent academic discipline. Tikkanen s scholarly interests and his methods resemble those of many formalistically oriented German and Austrian art historians of his time. He became well known throughout Europe, mainly for his studies on illustrated medieval manuscripts. Tikkanen s dissertation, Der Malerische Styl Giotto s Versuch zu einer Characteristik Desselben, from 1884 was regarded in its day as the best form-analytical study on the painter. It has a central position in the present thesis, as it already included nearly all the methods that Tikkanen used and elaborated upon throughout his career. Giotto also gives a good perspective for comparing Tikkanen s ideas with a long art-historical tradition. Tikkanen was profoundly interested in artistic creativity. In his own words, he wanted to study das künstlerische Können , artistic ability, instead of das künstlerische Wollen or artistic will, which was an important theoretical issue in art history in the late 19th century. This starting point led him to the history of style and iconographical research. Along with the Danish art historian, Julius Lange, he was one of the first scholars who began to study the meaning of gestures and postures in art. In my dissertation I have emphasized the importance of Tikkanen s personal art education. I regard it as having influenced both his scholarly argumentation and his working methods. I have also written a short overview of the situation of art history in Finland and in Northern Countries before Tikkanen s time in order to give an idea of his scientific background. My thesis is a critical and historiographical study on J. J. Tikkanen s role in the development of art history and its methodology.

Lionhearts of the Playworld : An ethnographic case study of the development of agency in play pedagogy

This is an ethnographic case study of the creation and emergence of a playworld – a pedagogical approach aimed at promoting children’s development and learning in early education settings through the use of play and drama. The data was collected in a Finnish experimental mixed-age elementary school classroom in the school year 2003-2004. In the playworld students and teachers explore different social and cultural phenomena through taking on the roles of characters from a story or a piece of literature and acting inside the frames of an improvised plot. The thesis takes under scrutiny the notion of agency in education. It produces theoretically grounded empirical knowledge of the ways in which children struggle to become recognized and agentive actors in early education settings and how their agency develops in their interaction with adults. The study builds on the activity theoretical and sociocultural tradition and develops a methodological framework called video-based narrative interaction analysis for studying student agency as developing over time but manifesting through the situational material and discursive local interactions. The research questions are: 1. What are the children’s ways of enacting their agency in the playworld? 2. How do the children’s agentive actions change and develop over the spring? 3. What are the potentials and challenges of the playworld for promoting student agency? 4. How do the teachers and the children deal with the contradiction between control and agency in the playworld? The study consists of a summary part and four empirical articles which each have a particular viewpoint. Articles I and II deal with individual students’ paths to agency. In Article I the focus is on the role of resistance and questioning in enabling important spaces for agency. Article II takes a critical gender perspective and analyzes how two girls struggled towards recognition in the playworld. It also illuminates the role of imagination in developing a sense of agency. Article III examines how the open-ended and improvisational nature of the playworld interaction provided experiences and a sense of ‘shared agency’ for the students and teachers in the class. Article IV turns the focus on the teachers and analyzes how their role actions in the playworld helped the children to enact agency. It also discusses the challenges that the teachers faced in this work and asks what makes the playworld activity sustainable in the class. The summary part provides a critical literature review on the concept of agency and argues that the inherently contradictory nature of the phenomenon of agency has not been sufficiently theorized. The summary part also locates the playworld intervention in a historical frame by discussing the changing conceptions of adulthood and childhood in the West. By focusing on the changing role of play and art in both adults’ and children’s contemporary lives, the thesis opens up an important but often neglected perspective on the problem of promoting student agency in education. The results illustrate how engaging in a collectively imagined and dramatized pretend play space together with the children enabled the teachers to momentarily put aside their “knower” positions in the classroom. The fictive roles and the narrative plot helped them to create a necessary incompleteness and open-endedness in the activity that stimulated the children’s initiatives. This meant that the children too could momentarily step out of their traditional classroom positions as pupils and initiate action to further the collective play. Engaging in this kind of unconventional activity and taking up and enacting agency was, however, very challenging for the participating children and teachers. It often contradicted the need to sustain control and order in the classroom. The study concludes that play- and drama-based pedagogies offer a unique but undeveloped potential for developing educational spaces that help teachers and children deal with the often contradictory requirements of schooling.

Inconsistency of surrogate measures of alcohol-related accidents in South Australia

Three major changes in drink driving enforcement have occurred in South Australia since 1981. The effect of these changes on a number of surrogate measures of alcohol involvement in accidents were investigated. The surrogates included alcohol involvement of driver fatalities, and combinations of casualty, serious casualty, single vehicle and nighttime accidents. Data from previous studies were also cited. It was found that relationships between surrogate measures were inconsistent, and incompatible with assumptions about drink driving levels and related accidents. It was concluded that until these effects are understood the use of surrogate measures should be treated with caution.

Multi-species sequence comparison reveals conservation of ghrelin gene-derived splice variants encoding a truncated ghrelin peptide

The peptide hormone ghrelin is a potent orexigen produced predominantly in the stomach. It has a number of other biological actions, including roles in appetite stimulation, energy balance, the stimulation of growth hormone release and the regulation of cell proliferation. Recently, several ghrelin gene splice variants have been described. Here, we attempted to identify conserved alternative splicing of the ghrelin gene by cross-species sequence comparisons. We identified a novel human exon 2-deleted variant and provide preliminary evidence that this splice variant and in1-ghrelin encode a C-terminally truncated form of the ghrelin peptide, termed minighrelin. These variants are expressed in humans and mice, demonstrating conservation of alternative splicing spanning 90 million years. Minighrelin appears to have similar actions to full-length ghrelin, as treatment with exogenous minighrelin peptide stimulates appetite and feeding in mice. Forced expression of the exon 2-deleted preproghrelin variant mirrors the effect of the canonical preproghrelin, stimulating cell proliferation and migration in the PC3 prostate cancer cell line. This is the first study to characterise an exon 2-deleted preproghrelin variant and to demonstrate sequence conservation of ghrelin gene-derived splice variants that encode a truncated ghrelin peptide. This adds further impetus for studies into the alternative splicing of the ghrelin gene and the function of novel ghrelin peptides in vertebrates.

Estimation of cosmological parameters using adaptive importance sampling

We present a Bayesian sampling algorithm called adaptive importance sampling or population Monte Carlo (PMC), whose computational workload is easily parallelizable and thus has the potential to considerably reduce the wall-clock time required for sampling, along with providing other benefits. To assess the performance of the approach for cosmological problems, we use simulated and actual data consisting of CMB anisotropies, supernovae of type Ia, and weak cosmological lensing, and provide a comparison of results to those obtained using state-of-the-art Markov chain Monte Carlo (MCMC). For both types of data sets, we find comparable parameter estimates for PMC and MCMC, with the advantage of a significantly lower wall-clock time for PMC. In the case of WMAP5 data, for example, the wall-clock time scale reduces from days for MCMC to hours using PMC on a cluster of processors. Other benefits of the PMC approach, along with potential difficulties in using the approach, are analyzed and discussed.

Frequency of dressing changes for central venous access devices on catheter-related infections

Background People admitted to intensive care units and those with chronic health care problems often require long-term vascular access. Central venous access devices (CVADs) are used for administering intravenous medications and blood sampling. CVADs are covered with a dressing and secured with an adhesive or adhesive tape to protect them from infection and reduce movement. Dressings are changed when they become soiled with blood or start to come away from the skin. Repeated removal and application of dressings can cause damage to the skin. The skin is an important barrier that protects the body against infection. Less frequent dressing changes may reduce skin damage, but it is unclear whether this practice affects the frequency of catheter-related infections. Objectives To assess the effect of the frequency of CVAD dressing changes on the incidence of catheter-related infections and other outcomes including pain and skin damage. Search methods In June 2015 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. We also searched clinical trials registries for registered trials. There were no restrictions with respect to language, date of publication or study setting. Selection criteria All randomised controlled trials (RCTs) evaluating the effect of the frequency of CVAD dressing changes on the incidence of catheter-related infections on all patients in any healthcare setting. Data collection and analysis We used standard Cochrane review methodology. Two review authors independently assessed studies for inclusion, performed risk of bias assessment and data extraction. We undertook meta-analysis where appropriate or otherwise synthesised data descriptively when heterogeneous. Main results We included five RCTs (2277 participants) that compared different frequencies of CVAD dressing changes. The studies were all conducted in Europe and published between 1995 and 2009. Participants were recruited from the intensive care and cancer care departments of one children's and four adult hospitals. The studies used a variety of transparent dressings and compared a longer interval between dressing changes (5 to15 days; intervention) with a shorter interval between changes (2 to 5 days; control). In each study participants were followed up until the CVAD was removed or until discharge from ICU or hospital. - Confirmed catheter-related bloodstream infection (CRBSI) One trial randomised 995 people receiving central venous catheters to a longer or shorter interval between dressing changes and measured CRBSI. It is unclear whether there is a difference in the risk of CRBSI between people having long or short intervals between dressing changes (RR 1.42, 95% confidence interval (CI) 0.40 to 4.98) (low quality evidence). - Suspected catheter-related bloodstream infection Two trials randomised a total of 151 participants to longer or shorter dressing intervals and measured suspected CRBSI. It is unclear whether there is a difference in the risk of suspected CRBSI between people having long or short intervals between dressing changes (RR 0.70, 95% CI 0.23 to 2.10) (low quality evidence). - All cause mortality Three trials randomised a total of 896 participants to longer or shorter dressing intervals and measured all cause mortality. It is unclear whether there is a difference in the risk of death from any cause between people having long or short intervals between dressing changes (RR 1.06, 95% CI 0.90 to 1.25) (low quality evidence). - Catheter-site infection Two trials randomised a total of 371 participants to longer or shorter dressing intervals and measured catheter-site infection. It is unclear whether there is a difference in risk of catheter-site infection between people having long or short intervals between dressing changes (RR 1.07, 95% CI 0.71 to 1.63) (low quality evidence). - Skin damage One small trial (112 children) and three trials (1475 adults) measured skin damage. There was very low quality evidence for the effect of long intervals between dressing changes on skin damage compared with short intervals (children: RR of scoring ≥ 2 on the skin damage scale 0.33, 95% CI 0.16 to 0.68; data for adults not pooled). - Pain Two studies involving 193 participants measured pain. It is unclear if there is a difference between long and short interval dressing changes on pain during dressing removal (RR 0.80, 95% CI 0.46 to 1.38) (low quality evidence). Authors' conclusions The best available evidence is currently inconclusive regarding whether longer intervals between CVAD dressing changes are associated with more or less catheter-related infection, mortality or pain than shorter intervals.