Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults

The treatment of inflammatory arthritis has been revolutionised by the introduction of biologic treatments. Many biologic agents are currently licensed for use in both paediatric and adult patients with inflammatory arthritis and contribute to improved disease outcomes compared with the pre-biologic era. However, immunogenicity to biologic agents, characterised by an immune reaction leading to the production of anti-drug antibodies (ADAs), can negatively impact the therapeutic efficacy of biologic drugs and induce side effects to treatment. This review explores for the first time the impact of immunogenicity against all licensed biologic treatments currently used in inflammatory arthritis across age, and will examine any significant differences between ADA prevalence, titres and timing of development, as well as ADA impact on therapeutic drug levels, clinical efficacy and side effects between paediatric and adult patients. In addition, we will investigate factors associated with differences in immunogenicity across biologic agents used in inflammatory arthritis, and their potential therapeutic implications

Stops making sense: translational trade-offs and stop codon reassignment

Background Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature. Results In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences. Conclusions We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants

ICMSF Methods Studies. XV. Comparison of Four Media and Methods for Enumerating Staphylococcus aureus in Powdered Milk.

Four media were examined for their usefulness in enumerating Staphylococcus aureus inoculated (a) into milk that was then dried or (b) directly into dried milk powder. In all, seven strains of S. aureus were inoculated individually into each preparation and were enumerated after two periods of storage (18 to 19 d and 60 to 61 d). Fourteen laboratories from twelve countries participated in the comparison which found that direct plating on agar medium in 14-cm petri dishes may be as useful as enrichment followed by streaking. Plating on Baird-Parker medium or on Hauschild pork plasma fibrinogen medium and a MPN method using Giolitti and Cantoni's broth with Tween 80 were equally sensitive for enumerating S. aureus in dried milk powder. The use of Hauschild medium may eliminate the need for supplementary tests to confirm colonies as S. aureus , but in some cases was found to fail in some laboratories. Giolitti and Cantoni's broth without Tween 80 generally was less useful than the three other media for enumerating S. aureus . S. aureus inoculated into milk that was then dried survived longer than when inoculated into dried milk

Cognitive loading affects motor awareness and movement kinematics but not locomotor trajectories during goal-directed walking in a virtual reality environment.

The primary purpose of this study was to investigate the effects of cognitive loading on movement kinematics and trajectory formation during goal-directed walking in a virtual reality (VR) environment. The secondary objective was to measure how participants corrected their trajectories for perturbed feedback and how participants' awareness of such perturbations changed under cognitive loading. We asked 14 healthy young adults to walk towards four different target locations in a VR environment while their movements were tracked and played back in real-time on a large projection screen. In 75% of all trials we introduced angular deviations of ±5° to ±30° between the veridical walking trajectory and the visual feedback. Participants performed a second experimental block under cognitive load (serial-7 subtraction, counter-balanced across participants). We measured walking kinematics (joint-angles, velocity profiles) and motor performance (end-point-compensation, trajectory-deviations). Motor awareness was determined by asking participants to rate the veracity of the feedback after every trial. In-line with previous findings in natural settings, participants displayed stereotypical walking trajectories in a VR environment. Our results extend these findings as they demonstrate that taxing cognitive resources did not affect trajectory formation and deviations although it interfered with the participants' movement kinematics, in particular walking velocity. Additionally, we report that motor awareness was selectively impaired by the secondary task in trials with high perceptual uncertainty. Compared with data on eye and arm movements our findings lend support to the hypothesis that the central nervous system (CNS) uses common mechanisms to govern goal-directed movements, including locomotion. We discuss our results with respect to the use of VR methods in gait control and rehabilitation

Lateralization in escape behaviour at different hierarchical levels in a Gecko: Tarentola angustimentalis from eastern Canary Islands

At the individual level, to be behaviourally lateralized avoids costly duplication of neural circuitry and decreases possible contradictory order from the two brain hemispheres. However, being prey behaviour lateralized at higher hierarchical levels could generate different negative implications, especially if predators are able to make predictions after multiple encounters. These conflicting pressures, namely between the advantages for individuals and the disadvantages for populations could be concealed if higher-level lateralization would arise from the combination of lateralized behaviours of individuals which are mutually dependent. Here, we investigated the lateralization patterns in the escape behaviour of the gecko Tarentola angustimentalis undergoing a predatory attack simulation in a "T" maze experiment. Results showed that gecko populations displayed different degrees of lateralization, with an overall dominance of right-biased individuals. This trend is similar to that observed in the Podarcis wall lizards, which share predators with Tarentola. In addition, different morphological parameters plausible to affect refuge selection were explored in order to link directional asymmetries at morphological level with lateralization during refuge selection.Fieldwork was carried out with the support of the project PTDC/BIA-BEC/101256/2008 funded by Fundação para a Ciência e a Tecnologia (FCT, Portugal). E.G.-M. was supported by postdoc grant from FCT (SFRH/BPD/72806/2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Thanks are due to Herve Seligmann and an anonymous reviewer for comments and suggestions on an earlier draft of the manuscript.publishe

Amino Acid Metabolic Origin as an Evolutionary Influence on Protein Sequence in Yeast

The metabolic cycle of Saccharomyces cerevisiae consists of alternating oxidative (respiration) and reductive (glycolysis) energy-yielding reactions. The intracellular concentrations of amino acid precursors generated by these reactions oscillate accordingly, attaining maximal concentration during the middle of their respective yeast metabolic cycle phases. Typically, the amino acids themselves are most abundant at the end of their precursor’s phase. We show that this metabolic cycling has likely biased the amino acid composition of proteins across the S. cerevisiae genome. In particular, we observed that the metabolic source of amino acids is the single most important source of variation in the amino acid compositions of functionally related proteins and that this signal appears only in (facultative) organisms using both oxidative and reductive metabolism. Periodically expressed proteins are enriched for amino acids generated in the preceding phase of the metabolic cycle. Proteins expressed during the oxidative phase contain more glycolysis-derived amino acids, whereas proteins expressed during the reductive phase contain more respiration-derived amino acids. Rare amino acids (e.g., tryptophan) are greatly overrepresented or underrepresented, relative to the proteomic average, in periodically expressed proteins, whereas common amino acids vary by a few percent. Genome-wide, we infer that 20,000 to 60,000 residues have been modified by this previously unappreciated pressure. This trend is strongest in ancient proteins, suggesting that oscillating endogenous amino acid availability exerted genome-wide selective pressure on protein sequences across evolutionary time

The influence of visual flow and perceptual load on locomotion speed

Visual flow is used to perceive and regulate movement speed during locomotion. We assessed the extent to which variation in flow from the ground plane, arising from static visual textures, influences locomotion speed under conditions of concurrent perceptual load. In two experiments, participants walked over a 12-m projected walkway that consisted of stripes that were oriented orthogonal to the walking direction. In the critical conditions, the frequency of the stripes increased or decreased. We observed small, but consistent effects on walking speed, so that participants were walking slower when the frequency increased compared to when the frequency decreased. This basic effect suggests that participants interpreted the change in visual flow in these conditions as at least partly due to a change in their own movement speed, and counteracted such a change by speeding up or slowing down. Critically, these effects were magnified under conditions of low perceptual load and a locus of attention near the ground plane. Our findings suggest that the contribution of vision in the control of ongoing locomotion is relatively fluid and dependent on ongoing perceptual (and perhaps more generally cognitive) task demands

Gait stability and variability measures show effects of impaired cognition and dual tasking in frail people

<p>Abstract</p> <p>Background</p> <p>Falls in frail elderly are a common problem with a rising incidence. Gait and postural instability are major risk factors for falling, particularly in geriatric patients. As walking requires attention, cognitive impairments are likely to contribute to an increased fall risk. An objective quantification of gait and balance ability is required to identify persons with a high tendency to fall. Recent studies have shown that stride variability is increased in elderly and under dual task condition and might be more sensitive to detect fall risk than walking speed. In the present study we complemented stride related measures with measures that quantify trunk movement patterns as indicators of dynamic balance ability during walking. The aim of the study was to quantify the effect of impaired cognition and dual tasking on gait variability and stability in geriatric patients.</p> <p>Methods</p> <p>Thirteen elderly with dementia (mean age: 82.6 ± 4.3 years) and thirteen without dementia (79.4 ± 5.55) recruited from a geriatric day clinic, walked at self-selected speed with and without performing a verbal dual task. The Mini Mental State Examination and the Seven Minute Screen were administered. Trunk accelerations were measured with an accelerometer. In addition to walking speed, mean, and variability of stride times, gait stability was quantified using stochastic dynamical measures, namely regularity (sample entropy, long range correlations) and local stability exponents of trunk accelerations.</p> <p>Results</p> <p>Dual tasking significantly (p < 0.05) decreased walking speed, while stride time variability increased, and stability and regularity of lateral trunk accelerations decreased. Cognitively impaired elderly showed significantly (p < 0.05) more changes in gait variability than cognitive intact elderly. Differences in dynamic parameters between groups were more discerned under dual task conditions.</p> <p>Conclusions</p> <p>The observed trunk adaptations were a consistent instability factor. These results support the concept that changes in cognitive functions contribute to changes in the variability and stability of the gait pattern. Walking under dual task conditions and quantifying gait using dynamical parameters can improve detecting walking disorders and might help to identify those elderly who are able to adapt walking ability and those who are not and thus are at greater risk for falling.</p