Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases.

BACKGROUND: The identification of the HLA class II, insulin (INS), CTLA-4 and PTPN22 genes as determinants of type 1 diabetes (T1D) susceptibility indicates that fine tuning of the immune system is centrally involved in disease development. Some genes have been shown to affect several immune-mediated diseases. Therefore, we tested the hypothesis that alleles of susceptibility genes previously associated with other immune-mediated diseases might perturb immune homeostasis, and hence also associate with predisposition to T1D. METHODS: We resequenced and genotyped tag single nucleotide polymorphisms (SNPs) from two genes, CRP and FCER1B, and genotyped 27 disease-associated polymorphisms from thirteen gene regions, namely FCRL3, CFH, SLC9A3R1, PADI4, RUNX1, SPINK5, IL1RN, IL1RA, CARD15, IBD5-locus (including SLC22A4), LAG3, ADAM33 and NFKB1. These genes have been associated previously with susceptibility to a range of immune-mediated diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease (GD), psoriasis, psoriatic arthritis (PA), atopy, asthma, Crohn disease and multiple sclerosis (MS). Our T1D collections are divided into three sample subsets, consisting of set 1 families (up to 754 families), set 2 families (up to 743 families), and a case-control collection (ranging from 1,500 to 4,400 cases and 1,500 to 4,600 controls). Each SNP was genotyped in one or more of these subsets. Our study typically had approximately 80% statistical power for a minor allele frequency (MAF) >5% and odds ratios (OR) of 1.5 with the type 1 error rate, alpha = 0.05. RESULTS: We found no evidence of association with T1D at most of the loci studied 0.02 <P < 1.0. Only a SNP in ADAM33, rs2787094, was any evidence of association obtained, P = 0.0004 in set 1 families (relative risk (RR) = 0.78), but further support was not observed in the 4,326 cases and 4,610 controls, P = 0.57 (OR = 1.02). CONCLUSION: Polymorphisms in a variety of genes previously associated with immune-mediated disease susceptibility and/or having effects on gene function and the immune system, are unlikely to be affecting T1D susceptibility in a major way, even though some of the genes tested encode proteins of immune pathways that are believed to be central to the development of T1D. We cannot, however, rule out effect sizes smaller than OR 1.5

Verbal short-term memory deficits in Down syndrome: phonological, semantic, or both?

The current study examined the phonological and semantic contributions to the verbal short-term memory (VSTM) deficit in Down syndrome (DS) by experimentally manipulating the phonological and semantic demands of VSTM tasks. The performance of 18 individuals with DS (ages 11–25) and 18 typically developing children (ages 3–10) matched pairwise on receptive vocabulary and gender was compared on four VSTM tasks, two tapping phonological VSTM (phonological similarity, nonword discrimination) and two tapping semantic VSTM (semantic category, semantic proactive interference). Group by condition interactions were found on the two phonological VSTM tasks (suggesting less sensitivity to the phonological qualities of words in DS), but not on the two semantic VSTM tasks. These findings suggest that a phonological weakness contributes to the VSTM deficit in DS. These results are discussed in relation to the DS neuropsychological and neuroanatomical phenotype

Prioritising surveillance for alien organisms transported as stowaways on ships travelling to South Africa

The global shipping network facilitates the transportation and introduction of marine and terrestrial organisms to regions where they are not native, and some of these organisms become invasive. South Africa was used as a case study to evaluate the potential for shipping to contribute to the introduction and establishment of marine and terrestrial alien species (i.e. establishment debt) and to assess how this varies across shipping routes and seasons. As a proxy for the number of species introduced (i.e. 'colonisation pressure') shipping movement data were used to determine, for each season, the number of ships that visited South African ports from foreign ports and the number of days travelled between ports. Seasonal marine and terrestrial environmental similarity between South African and foreign ports was then used to estimate the likelihood that introduced species would establish. These data were used to determine the seasonal relative contribution of shipping routes to South Africa's marine and terrestrial establishment debt. Additionally, distribution data were used to identify marine and terrestrial species that are known to be invasive elsewhere and which might be introduced to each South African port through shipping routes that have a high relative contribution to establishment debt. Shipping routes from Asian ports, especially Singapore, have a particularly high relative contribution to South Africa's establishment debt, while among South African ports, Durban has the highest risk of being invaded. There was seasonal variation in the shipping routes that have a high relative contribution to the establishment debt of the South African ports. The presented method provides a simple way to prioritise surveillance effort and our results indicate that, for South Africa, port-specific prevention strategies should be developed, a large portion of the available resources should be allocated to Durban, and seasonal variations and their consequences for prevention strategies should be explored further. (Résumé d'auteur

A grounded theory of Internet and social media use by young people who use augmentative and alternative communication (AAC).

PURPOSE: This paper presents a conceptual grounded theory for how young people with a diagnosis of cerebral palsy who use augmentative and alternative communication (AAC), perceive using the Internet and social media. The aims of the research were to understand and contextualise their perceptions of access and use and explore implications for self-representation and social participation; to date literature on this topic is limited. METHOD: A constructivist grounded theory research approach concurrently collected and analysed interview data from 25 participants (aged 14-24 years) who use AAC and additional sources. RESULTS: A conceptual grounded theory was developed around an emergent core category that showed young people who use AAC have a clear desire to use the Internet and social media. This was underpinned by eight supporting categories: reported use, described support, online challenges, access technology, speech generating device (SGD) issues, self-determination, self-representation and online social ties. CONCLUSION: The conceptual grounded theory supports understanding of facilitators and challenges to use of the Internet and social media by young people with a diagnosis of cerebral palsy who use AAC. The grounded theory illustrates how the desire to use the Internet and social media is based upon perceived benefits for enriching social relationships and enhancing opportunities for self-representation and self-determination that are synonymous with identified antecedents for community-based social inclusion. Some of the participants are engaging with the Internet and social media through collaborative practice and the implications for how this phenomenon may impact on orthographic literacy and the personal care workforce are raised

Vertebral body stenting: a new method for vertebral augmentation versus kyphoplasty

Vertebroplasty and kyphoplasty are well-established minimally invasive treatment options for compression fractures of osteoporotic vertebral bodies. Possible procedural disadvantages, however, include incomplete fracture reduction or a significant loss of reduction after balloon tamp deflation, prior to cement injection. A new procedure called “vertebral body stenting” (VBS) was tested in vitro and compared to kyphoplasty. VBS uses a specially designed catheter-mounted stent which can be implanted and expanded inside the vertebral body. As much as 24 fresh frozen human cadaveric vertebral bodies (T11-L5) were utilized. After creating typical compression fractures, the vertebral bodies were reduced by kyphoplasty (n = 12) or by VBS (n = 12) and then stabilized with PMMA bone cement. Each step of the procedure was performed under fluoroscopic control and analysed quantitatively. Finally, static and dynamic biomechanical tests were performed. A complete initial reduction of the fractured vertebral body height was achieved by both systems. There was a significant loss of reduction after balloon deflation in kyphoplasty compared to VBS, and a significant total height gain by VBS (mean ± SD in %, p < 0.05, demonstrated by: anterior height loss after deflation in relation to preoperative height [kyphoplasty: 11.7 ± 6.2; VBS: 3.7 ± 3.8], and total anterior height gain [kyphoplasty: 8.0 ± 9.4; VBS: 13.3 ± 7.6]). Biomechanical tests showed no significant stiffness and failure load differences between systems. VBS is an innovative technique which allows for the possibly complete reduction of vertebral compression fractures and helps maintain the restored height by means of a stent. The height loss after balloon deflation is significantly decreased by using VBS compared to kyphoplasty, thus offering a new promising option for vertebral augmentation

Visual Working Memory Capacity and Proactive Interference

Background: Visual working memory capacity is extremely limited and appears to be relatively immune to practice effects or the use of explicit strategies. The recent discovery that visual working memory tasks, like verbal working memory tasks, are subject to proactive interference, coupled with the fact that typical visual working memory tasks are particularly conducive to proactive interference, suggests that visual working memory capacity may be systematically under-estimated. Methodology/Principal Findings: Working memory capacity was probed behaviorally in adult humans both in laboratory settings and via the Internet. Several experiments show that although the effect of proactive interference on visual working memory is significant and can last over several trials, it only changes the capacity estimate by about 15%. Conclusions/Significance: This study further confirms the sharp limitations on visual working memory capacity, both in absolute terms and relative to verbal working memory. It is suggested that future research take these limitations into account in understanding differences across a variety of tasks between human adults, prelinguistic infants and nonlinguistic animals

Two independent proteomic approaches provide a comprehensive analysis of the synovial fluid proteome response to Autologous Chondrocyte Implantation

Background: Autologous chondrocyte implantation (ACI) has a failure rate of approximately 20%, but it is yet to be fully understood why. Biomarkers are needed that can pre-operatively predict in which patients it is likely to fail, so that alternative or individualised therapies can be offered. We previously used label-free quantitation (LF) with a dynamic range compression proteomic approach to assess the synovial fluid (SF) of ACI responders and non-responders. However, we were able to identify only a few differentially abundant proteins at baseline. In the present study, we built upon these previous findings by assessing higher-abundance proteins within this SF, providing a more global proteomic analysis on the basis of which more of the biology underlying ACI success or failure can be understood. Methods: Isobaric tagging for relative and absolute quantitation (iTRAQ) proteomic analysis was used to assess SF from ACI responders (mean Lysholm improvement of 33; n = 14) and non-responders (mean Lysholm decrease of 14; n = 13) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Differentially abundant proteins in iTRAQ and combined iTRAQ and LF datasets were investigated using pathway and network analyses. Results: iTRAQ proteomic analysis confirmed our previous finding that there is a marked proteomic shift in response to cartilage harvest (70 and 54 proteins demonstrating ≥ 2.0-fold change and p < 0.05 between stages I and II in responders and non-responders, respectively). Further, it highlighted 28 proteins that were differentially abundant between responders and non-responders to ACI, which were not found in the LF study, 16 of which were altered at baseline. The differential expression of two proteins (complement C1s subcomponent and matrix metalloproteinase 3) was confirmed biochemically. Combination of the iTRAQ and LF proteomic datasets generated in-depth SF proteome information that was used to generate interactome networks representing ACI success or failure. Functional pathways that are dysregulated in ACI non-responders were identified, including acute-phase response signalling. Conclusions: Several candidate biomarkers for baseline prediction of ACI outcome were identified. A holistic overview of the SF proteome in responders and non-responders to ACI  has been profiled, providing a better understanding of the biological pathways underlying clinical outcome, particularly the differential response to cartilage harvest in non-responders

Long-term associative learning predicts verbal short-term memory performance

Studies using tests such as digit span and nonword repetition have implicated short-term memory across a range of developmental domains. Such tests ostensibly assess specialized processes for the short-term manipulation and maintenance of information that are often argued to enable long-term learning. However, there is considerable evidence for an influence of long-term linguistic learning on performance in short-term memory tasks that brings into question the role of a specialized short-term memory system separate from long-term knowledge. Using natural language corpora, we show experimentally and computationally that performance on three widely used measures of short-term memory (digit span, nonword repetition, and sentence recall) can be predicted from simple associative learning operating on the linguistic environment to which a typical child may have been exposed. The findings support the broad view that short-term verbal memory performance reflects the application of long-term language knowledge to the experimental setting

Pharmacological Evaluation of the Long-Term Effects of Xanomeline on the M1 Muscarinic Acetylcholine Receptor

Xanomeline is a unique agonist of muscarinic receptors that possesses functional selectivity at the M1 and M4 receptor subtypes. It also exhibits wash-resistant binding to and activation of the receptor. In the present work we investigated the consequences of this type of binding of xanomeline on the binding characteristics and function of the M1 muscarinic receptor. Pretreatment of CHO cells that stably express the M1 receptor for 1 hr with increasing concentrations of xanomeline followed by washing and waiting for an additional 23 hr in control culture media transformed xanomeline-induced inhibition of [3H]NMS binding from monophasic to biphasic. The high-affinity xanomeline binding site exhibited three orders of magnitude higher affinity than in the case of xanomeline added directly to the binding assay medium containing control cells. These effects were associated with a marked decrease in maximal radioligand binding and attenuation of agonist-induced increase in PI hydrolysis and were qualitatively similar to those caused by continuous incubation of cells with xanomeline for 24 hr. Attenuation of agonist-induced PI hydrolysis by persistently-bound xanomeline developed with a time course that parallels the return of receptor activation by prebound xanomeline towards basal levels. Additional data indicated that blockade of the receptor orthosteric site or the use of a non-functional receptor mutant reversed the long-term effects of xanomeline, but not its persistent binding at an allosteric site. Furthermore, the long-term effects of xanomeline on the receptor are mainly due to receptor down-regulation rather than internalization

Adaptation and risk management

Many of the existing tensions about the application of risk management are between simplicity and complexity, and between predictability and uncertainty. Users undertaking adaptation assessments want access to simple and clear methods. However, simple methods are criticized as being unable to manage the range of situations in which they may be used. On the other hand, risk management guidance that tries to be flexible and comprehensive can become too complex. This is because the adaptation assessments themselves can range from being simple to encompassing the general class of wicked problems, 70 characterized by multiple drivers of stress, significant uncertainties and contested values that cannot easily be resolved