Human antibodies induce arthritis in mice deficient in the low-affinity inhibitory IgG receptor FcγRIIB

Rheumatoid arthritis (RA) is a complex autoimmune disease with a poorly understood pathogenesis. The disease is associated with polyclonal B cell activation and the production of autoantibodies (autoAbs), but there is a longstanding controversy as to whether such Abs contribute to, or are secondary to, the pathogenesis of RA. To address the potential pathogenicity of human RA–associated Abs, we developed a passive transfer model involving mice deficient in the low-affinity inhibitory Fc receptor, FcγRIIB. We report that plasma or serum from patients with active RA can induce inflammation and histological lesions in FcγRIIB−/− mice consistent with arthritis, and that this pathogenic activity is caused by the immunoglobulin G–rich fraction. Our results suggest that humoral autoimmunity can contribute directly to autoimmune arthritis, and that FcγRIIB−/− mice are a promising model to evaluate the arthritogenic potential of human autoAbs

A re-appraisal of the reliability of the 20 m multi-stage shuttle run test

This is the author's PDF version of an article published in European journal of applied physiology in 2007. The original publication is available at www.springerlink.co

The microstructure of coaching practice:Behaviours and activities of an elite rugby union head coach during preparation and competition

The activities and behaviours of a female head coach of a national rugby union team were recorded in both training and competition, across a whole rugby season, using the newly developed Rugby Coach Activities and Behaviours Instrument (RCABI). The instrument incorporates 24 categories of behaviour, embedded within three forms of activity (training form, playing form and competitive match) and seven sub-activity types. In contrast to traditional drill-based coaching, 58.5% of training time was found to have been spent in playing form activities. Moreover, the proportion of playing form activities increased to a peak average of 83.8% in proximity to the team’s annual international championship. Uniquely, one of the coach’s most prolific behaviours was conferring with associates (23.3%), highlighting the importance of interactions with assistant coaches, medical staff and others in shaping the coaching process. Additionally, the frequencies of key behaviours such as questioning and praise were found to vary between the different activity forms and types, raising questions about previous conceptions of effective coaching practice. The findings are discussed in the light of the Game Sense philosophy and the role of the head coach

The polygenic nature of telomere length and the anti-ageing properties of lithium

Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%, with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10-5). Gene-enrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat gene, LRRC34 (p = 3.69 × 10-18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p  0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual's inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium's anti-ageing efficacy

Disguised Propaganda from Digital to Social Media

Disguised propaganda and political deception in digital media have been studied since the early days of the World Wide Web. At the intersection of internet research and propaganda studies, this chapter explores disguised propaganda on websites and social media platforms. Based on a discussion of key concepts and terminology, this chapter outlines how new modes of deception and source obfuscation emerge in digital and social media environments, and how this development complicates existing conceptual and epistemological frameworks in propaganda studies. The chapter concludes by arguing that contemporary challenges of detecting and countering disguised propaganda can only be resolved, if social media companies are held accountable and provide the necessary support for user contestation

SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA

Utility of Survival Motor Neuron ELISA for Spinal Muscular Atrophy Clinical and Preclinical Analyses

Genetic defects leading to the reduction of the survival motor neuron protein (SMN) are a causal factor for Spinal Muscular Atrophy (SMA). While there are a number of therapies under evaluation as potential treatments for SMA, there is a critical lack of a biomarker method for assessing efficacy of therapeutic interventions, particularly those targeting upregulation of SMN protein levels. Towards this end we have engaged in developing an immunoassay capable of accurately measuring SMN protein levels in blood, specifically in peripheral blood mononuclear cells (PBMCs), as a tool for validating SMN protein as a biomarker in SMA.A sandwich enzyme-linked immunosorbent assay (ELISA) was developed and validated for measuring SMN protein in human PBMCs and other cell lysates. Protocols for detection and extraction of SMN from transgenic SMA mouse tissues were also developed.The assay sensitivity for human SMN is 50 pg/mL. Initial analysis reveals that PBMCs yield enough SMN to analyze from blood volumes of less than 1 mL, and SMA Type I patients' PBMCs show ∼90% reduction of SMN protein compared to normal adults. The ELISA can reliably quantify SMN protein in human and mouse PBMCs and muscle, as well as brain, and spinal cord from a mouse model of severe SMA.This SMN ELISA assay enables the reliable, quantitative and rapid measurement of SMN in healthy human and SMA patient PBMCs, muscle and fibroblasts. SMN was also detected in several tissues in a mouse model of SMA, as well as in wildtype mouse tissues. This SMN ELISA has general translational applicability to both preclinical and clinical research efforts

On sequential fixed-width confidence intervals for the mean and second-order expansions of the associated coverage probabilities

In order to construct fixed-width (2d) confidence intervals for the mean of an unknown distribution function F , a new purely sequential sampling strategy is proposed first. The approach is quite different from the more traditional methodology of Chow and Robbins (1965, Ann. Math. Statist. , 36 , 457–462). However, for this new procedure, the coverage probability is shown (Theorem 2.1) to be at least (1-α)+ Ad 2 + o (d 2 ) as d →0 where (1-α) is the preassigned level of confidence and A is an appropriate functional of F , under some regularity conditions on F . The rates of convergence of the coverage probability to (1-α) obtained by Csenki (1980, Scand. Actuar. J. , 107–111) and Mukhopadhyay (1981, Comm. Statist. Theory Methods , 10 , 2231–2244) were merely O (d 1/2-q ), with 0< q <1/2, under the Chow-Robbins stopping time τ * . It is to be noted that such considerable sharpening of the rate of convergence of the coverage probability is achieved even though the new stopping variable is O p (τ * ). An accelerated version of the stopping rule is also provided together with the analogous second-order characteristics. In the end, an example is given for the mean estimation problem of an exponential distribution.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47956/1/10463_2004_Article_BF00050850.pd