True infliximab resistance in rheumatoid arthritis: a role for lymphotoxin α?

Background: The combination of methotrexate and the anti-tumour necrosis factor (TNF) antibody infliximab is a very effective treatment for rheumatoid arthritis (RA). However, a proportion of patients are not responsive to this treatment. Inefficacy may represent a TNF independent disease or insufficient drug at the site of action. Case report: A patient with RA resistant to repeated high dose infliximab infusions and intra-articular infliximab into an inflamed knee is described. No beneficial clinical effect was observed. Pre-injection arthroscopic biopsy of the study knee demonstrated TNF staining but also confirmed the presence of lymphotoxin (LT or TNFß) on immunohistochemistry. Subsequent treatment with etanercept (which blocks LT as well as TNF) resulted in clinical remission of disease. Conclusion: This case suggests that resistance to TNF blockade may occur when TNF is not the dominant inflammatory cytokine and suggests that LT may have a pathogenic role in RA

Development of the PsAQoL: a quality of life instrument specific to psoriatic arthritis

Background: Patient reported outcome measures used in studies of psoriatic arthritis (PsA) have been found to be inadequate for determining the impact of the disease from the patient’s perspective. Objective: To produce the PsAQoL, a PsA-specific quality of life (QoL) instrument, employing the needs based model of QoL that would be relevant and acceptable to respondents, valid, and reliable. Methods: Content was derived from qualitative interviews conducted with patients with PsA. Face and content validity were assessed by field test interviews with a new sample of patients with PsA. A postal survey was conducted to improve the scaling properties of the new measure. Finally, a test-retest postal survey was used to identify the final measure and to test its scaling properties, reliability, internal consistency, and validity. Results: Analysis of the qualitative interview transcripts identified a 51 item questionnaire. Field test interviews confirmed the acceptability and relevance of the measure. Analysis of data from the first postal survey (n = 94) reduced the questionnaire to 35 items. Rasch analysis of data from the test-retest survey (n = 286) identified a 20 item version of the PsAQoL with good item fit. This version had excellent internal consistency (a = 0.91), test-retest reliability (0.89), and validity. Conclusions: The PsAQoL is a valuable tool for assessing the impact of interventions for PsA in clinical studies and trials. It is well accepted by patients, taking about three minutes to complete, is easy to administer, and has excellent scaling and psychometric properties

The MASSIVE Survey - VIII. Stellar Velocity Dispersion Profiles and Environmental Dependence of Early-Type Galaxies

We measure the radial profiles of the stellar velocity dispersions, $\sigma(R)$, for 90 early-type galaxies (ETGs) in the MASSIVE survey, a volume-limited integral-field spectroscopic (IFS) galaxy survey targeting all northern-sky ETGs with absolute $K$-band magnitude $M_K < -25.3$ mag, or stellar mass $M_* > 4 \times 10^{11} M_\odot$, within 108 Mpc. Our wide-field 107" $\times$ 107" IFS data cover radii as large as 40 kpc, for which we quantify separately the inner (2 kpc) and outer (20 kpc) logarithmic slopes $\gamma_{\rm inner}$ and $\gamma_{\rm outer}$ of $\sigma(R)$. While $\gamma_{\rm inner}$ is mostly negative, of the 56 galaxies with sufficient radial coverage to determine $\gamma_{\rm outer}$ we find 36% to have rising outer dispersion profiles, 30% to be flat within the uncertainties, and 34% to be falling. The fraction of galaxies with rising outer profiles increases with $M_*$ and in denser galaxy environment, with 10 of the 11 most massive galaxies in our sample having flat or rising dispersion profiles. The strongest environmental correlations are with local density and halo mass, but a weaker correlation with large-scale density also exists. The average $\gamma_{\rm outer}$ is similar for brightest group galaxies, satellites, and isolated galaxies in our sample. We find a clear positive correlation between the gradients of the outer dispersion profile and the gradients of the velocity kurtosis $h_4$. Altogether, our kinematic results suggest that the increasing fraction of rising dispersion profiles in the most massive ETGs are caused (at least in part) by variations in the total mass profiles rather than in the velocity anisotropy alone.Comment: Accepted/in press, MNRA

Player movement patterns in an elite junior Australian Rules Football team : an exploratory study

This study explored the physical movement patterns associated with an elite Under 18 Australian Football (AF) team. Five field positions were selected with observations recording the number and relative per cent of &quot;working&quot; efforts (jogging, running, and sprinting), &quot;resting&quot; efforts (walking) and the total distances associated with &quot;working&quot; or &quot;resting&quot; efforts. Intra-observer reliability, using test- retest method, showed correlations were r = 0.98 or greater. The Wing position covered 11,877 m, the greatest total distance during an entire game, whilst the HBF and Centre positions both recorded 11,545 m and 11,537 m respectively and the Ruck position covered 9,203 m. The HBF recorded the greatest frequency of \u27working\u27 and \u27resting\u27 efforts (180 and 182 respectively), whilst the Wing (166 and 158), Centre (162 and 149) and Ruck (161 and 166) showed similarities in their results. The Wing position recorded the longest average distance per \u27working\u27 effort (58 m) whilst the Centre position recorded the longest average distance per \u27resting\u27 effort (17 m). Results also show the completion of less total efforts and smaller total distances, in Under 18 players, recorded compared to professional senior AF data. The results from this study suggest that further in-depth research is required into movement patterns and game activity demands in this AF playing group. <br /

Reliability and validity of a reactive agility test for Australian football

Purpose: The aim of this study was to test the reliability and construct validity of a reactive agility test (RAT), designed for Australian Football (AF). Methods: Study I tested the reliability of the RAT, with 20 elite junior AF players (17.44 &plusmn; 0.55 y) completing the test on two occasions separated by 1 wk. Study II tested its construct validity by comparing the performance of 60 participants (16.60 &plusmn; 0.50 y) spread over three aged-matched population groups: 20 athletes participating in a State Under-18 AF league who had represented their state at national competitions (elite), 20 athletes participating in the same league who had not represented their state (subelite), and 20 healthy males who did not play AF (controls). Results: Test-retest reliability reported a strong correlation (0.91), with no significant difference (P = .22) between the mean results (1.74 &plusmn; 0.07 s and 1.76 &plusmn; 0.07 s) obtained (split 2+3). Nonparametric tests (Kruskal-Wallis and Mann-Whitney) revealed both AF groups performed significantly faster on all measures than the control group (ranging from P = .001 to .005), with significant differences also reported between the two AF groups (ranging from P = .001 to .046). Stepwise discriminant analyses found total time discriminated between the groups, correctly classifying 75% of the participants. Conclusions: The RAT used within this study demonstrates evidence of reliability and construct validity. It further suggests the ability of a reactive component within agility test designs to discriminate among athletes of different competition levels, highlighting its importance within training activities. <br /

The MASSIVE Survey - VII. The Relationship of Angular Momentum, Stellar Mass and Environment of Early-Type Galaxies

We analyse the environmental properties of 370 local early-type galaxies (ETGs) in the MASSIVE and ATLAS3D surveys, two complementary volume-limited integral-field spectroscopic (IFS) galaxy surveys spanning absolute $K$-band magnitude $-21.5 > M_K > -26.6$, or stellar mass $8 \times 10^{9} < M_* < 2 \times 10^{12} M_\odot$. We find these galaxies to reside in a diverse range of environments measured by four methods: group membership (whether a galaxy is a brightest group/cluster galaxy, satellite, or isolated), halo mass, large-scale mass density (measured over a few Mpc), and local mass density (measured within the $N$th neighbour). The spatially resolved IFS stellar kinematics provide robust measurements of the spin parameter $\lambda_e$ and enable us to examine the relationship among $\lambda_e$, $M_*$, and galaxy environment. We find a strong correlation between $\lambda_e$ and $M_*$, where the average $\lambda_e$ decreases from $\sim 0.4$ to below 0.1 with increasing mass, and the fraction of slow rotators $f_{\rm slow}$ increases from $\sim 10$% to 90%. We show for the first time that at fixed $M_*$, there are almost no trends between galaxy spin and environment; the apparent kinematic morphology-density relation for ETGs is therefore primarily driven by $M_*$ and is accounted for by the joint correlations between $M_*$ and spin, and between $M_*$ and environment. A possible exception is that the increased $f_{\rm slow}$ at high local density is slightly more than expected based only on these joint correlations. Our results suggest that the physical processes responsible for building up the present-day stellar masses of massive galaxies are also very efficient at reducing their spin, in any environment.Comment: Accepted to MNRA

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

Aims The mode of action by which doxapram acts as a respiratory stimulant in humans is controversial. Studies in rodent models, have shown that doxapram is a more potent and selective inhibitor of TASK-1 and TASK-1/TASK-3 heterodimer channels, than TASK-3. Here we investigate the direct effect of doxapram and chirally separated, individual positive and negative enantiomers of the compound, on both human and mouse, homodimeric and heterodimeric variants of TASK-1 and TASK-3. Methods Whole-cell patch clamp electrophysiology on tsA201 cells was used to assess the potency of doxapram on cloned human or mouse TASK-1, TASK-3 and TASK-2 channels. Mutations of amino acids in the pore-lining region of TASK-3 channels were introduced using site-directed mutagenesis. Results Doxapram was an equipotent inhibitor of human TASK-1 and TASK-3 channels, compared with mouse channel variants, where it was more selective for TASK-1 and heterodimers of TASK-1 and TASK-3. The effect of doxapram could be attenuated by either the removal of the C-terminus of human TASK-3 channels or mutations of particular hydrophobic residues in the pore-lining region. These mutations, however, did not alter the effect of a known extracellular inhibitor of TASK-3, zinc. The positive enantiomer of doxapram, GAL-054, was a more potent antagonist of TASK channels, than doxapram, whereas the negative enantiomer, GAL-053, had little inhibitory effect. Conclusion These data show that in contrast to rodent channels, doxapram is a potent inhibitor of both TASK-1 and TASK-3 human channels, providing further understanding of the pharmacological profile of doxapram in humans and informing the development of new therapeutic agents

No safety without emotional safety

This Personal View highlights how emotional safety is required for a person to keep themselves physically safe. We explain how trying to control behaviour to increase physical safety in the short term can carry the unintended consequence of reducing emotional safety, which might in turn result in higher levels of stress and hopelessness. We use examples from institutions with psychiatric inpatients to describe these processes. We argue that emotional and physical safety cannot be separated, and therefore that the absence of emotional safety compromises basic care either in an acute crisis or in the long term. Staff who fear being criticised, and so feel driven to take autonomy and responsibility away from patients, unwittingly undermine patients' experience of being empathically understood and supported, adding to patients' sense of emotional turmoil and lack of safety. We suggest that a change in culture and regulatory reform is required to bring psychiatric care more in line with the psychological needs of patients to achieve both physical and emotional safety

Long term clinical results following Salto Talaris total ankle arthroplasty

INTRODUCTION: Total ankle arthroplasty is a surgery that is being performed at an increasing rate. As this is a fairly new procedure in the realm of orthopedics, there is limited data on the survival ship of modern fixed-bearing total ankle replacements. With increased prevalence around the country, more long-term data is required to determine the expected survival of the implant, as well as common complications over the long-term. This study seeks to follow-up on our previous mean 5.2-year study to determine implant survival of a modern fixed-bearing total ankle arthroplasty performed by a single surgeon. The specific model in question is the Salto Talaris TAA system. It is hypothesized that the survival of the metallic component of the implant will decrease dramatically compared to the previous follow-up, as the implant reaches its lifespan. METHODS: We reviewed the charts of 78 consecutive patients (81 ankles) that were involved in a previous mean 5.2-year study. Of these 78 patients, 63 were still living of which we were able to follow-up with 45 (87.2%) of them (47 ankles). From the 45 patients we followed up with 31 of these patients (33 ankles) completed self-reported questionnaires, including the visual analog scale (VAS) for pain, the Short Form (SF)-36v2, and the Foot and Ankle Disability Index (FADI). At each follow-up visit patients underwent range-of-motion examination and radiographic evaluation of the implant. Updated radiographs were obtained on 34 of the patients. RESULTS: Implant survival of the metallic components of the cohort was 87.5% at a mean follow-up time of 10.1 years. There were a total of six revisions, one of which was complicated by a deep infection and explant after revision surgery. 17 ankles required subsequent surgery after the index total ankle replacement, with gutter debridement being the most common (n = 10). Outcome scores at a mean of 10.1 years revealed promising and stable scores from the 5.2-year study with a mean VAS pain of 18.5 and FADI of 77.7. Mean total range of motion was 35.7º. CONCLUSION: Salto Talaris fixed-bearing total ankle arthroplasty had excellent implant survival, maintained range of motion, and good functional outcomes at a mean follow-up of 10.1 years. This study provided evidence that total ankle arthroplasty is a viable long-term alternative to ankle arthrodesis for the treatment of end-stage arthritis, but more prospective research is needed to justify this claim