Disease activity flares and pain flares in an early rheumatoid arthritis inception cohort; characteristics, antecedents and sequelae

© 2019 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: RA flares are common and disabling. They are described in terms of worsening inflammation but pain and inflammation are often discordant. To inform treatment decisions, we investigated whether inflammatory and pain flares are discrete entities. Methods: People from the Early RA Network (ERAN) cohort were assessed annually up to 11 years after presentation (n = 719, 3703 person-years of follow up). Flare events were defined in 2 different ways that were analysed in parallel; DAS28 or Pain Flares. DAS28 Flares satisfied OMERACT flare criteria of increases in DAS28 since the previous assessment (≥1.2 points if active RA or ≥ 0.6 points if inactive RA). A ≥ 4.8-point worsening of SF36-Bodily Pain score defined Pain Flares. The first documented episode of each of DAS28 and Pain Flare in each person was analysed. Subgroups within DAS28 and Pain Flares were determined using Latent Class Analysis. Clinical course was compared between flare subgroups. Results: DAS28 (45%) and Pain Flares (52%) were each common but usually discordant, with 60% of participants in DAS28 Flare not concurrently in Pain Flare, and 64% of those in Pain Flare not concurrently in DAS28 Flare. Three discrete DAS28 Flare subgroups were identified. One was characterised by increases in tender/swollen joint counts (14.4%), a second by increases in symptoms (13.1%), and a third displayed lower flare severity (72.5%). Two discrete Pain Flare subgroups were identified. One occurred following low disease activity and symptoms (88.6%), and the other occurred on the background of ongoing active disease and pain (11.4%). Despite the observed differences between DAS28 and Pain Flares, each was associated with increased disability which persisted beyond the flare episode. Conclusion: Flares are both common and heterogeneous in people with RA. Furthermore our findings indicate that for some patients there is a discordance between inflammation and pain in flare events. This discrete flare subgroups might reflect different underlying inflammation and pain mechanisms. Treatments addressing different mechanisms might be required to reduce persistent disability after DAS28 and Pain Flares.Peer reviewedFinal Published versio

AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity

RegenBase: a knowledge base of spinal cord injury biology for translational research.

Spinal cord injury (SCI) research is a data-rich field that aims to identify the biological mechanisms resulting in loss of function and mobility after SCI, as well as develop therapies that promote recovery after injury. SCI experimental methods, data and domain knowledge are locked in the largely unstructured text of scientific publications, making large scale integration with existing bioinformatics resources and subsequent analysis infeasible. The lack of standard reporting for experiment variables and results also makes experiment replicability a significant challenge. To address these challenges, we have developed RegenBase, a knowledge base of SCI biology. RegenBase integrates curated literature-sourced facts and experimental details, raw assay data profiling the effect of compounds on enzyme activity and cell growth, and structured SCI domain knowledge in the form of the first ontology for SCI, using Semantic Web representation languages and frameworks. RegenBase uses consistent identifier schemes and data representations that enable automated linking among RegenBase statements and also to other biological databases and electronic resources. By querying RegenBase, we have identified novel biological hypotheses linking the effects of perturbagens to observed behavioral outcomes after SCI. RegenBase is publicly available for browsing, querying and download.Database URL:http://regenbase.org

Therapeutic Improvement of Scarring: Mechanisms of Scarless and Scar-Forming Healing and Approaches to the Discovery of New Treatments

Scarring in the skin after trauma, surgery, burn or sports injury is a major medical problem, often resulting in loss of function, restriction of tissue movement and adverse psychological effects. Whilst various studies have utilised a range of model systems that have increased our understanding of the pathways and processes underlying scar formation, they have typically not translated to the development of effective therapeutic approaches for scar management. Existing treatments are unreliable and unpredictable and there are no prescription drugs for the prevention or treatment of dermal scarring. As a consequence, scar improvement still remains an area of clear medical need. Here we describe the basic science of scar-free and scar-forming healing, the utility of pre-clinical model systems, their translation to humans, and our pioneering approach to the discovery and development of therapeutic approaches for the prophylactic improvement of scarring in ma

Central nociceptive sensitization vs. spinal cord training: opposing forms of plasticity that dictate function after complete spinal cord injury

The spinal cord demonstrates several forms of plasticity that resemble brain-dependent learning and memory. Among the most studied form of spinal plasticity is spinal memory for noxious (nociceptive) stimulation. Numerous papers have described central pain as a spinally-stored memory that enhances future responses to cutaneous stimulation. This phenomenon, known as central sensitization, has broad relevance to a range of pathological conditions. Work from the spinal cord injury (SCI) field indicates that the lumbar spinal cord demonstrates several other forms of plasticity, including formal learning and memory. After complete thoracic SCI, the lumbar spinal cord can be trained by delivering stimulation to the hindleg when the leg is extended. In the presence of this response-contingent stimulation the spinal cord rapidly learns to hold the leg in a flexed position, a centrally mediated effect that meets the formal criteria for instrumental (response-outcome) learning. Instrumental flexion training produces a central change in spinal plasticity that enables future spinal learning on both the ipsilateral and contralateral leg. However, if stimulation is given in a response-independent manner, the spinal cord develops central maladaptive plasticity that undermines future spinal learning on both legs. The present paper tests for interactions between spinal cord training and central nociceptive sensitization after complete spinal cord transection. We found that spinal training alters future central sensitization by intradermal formalin (24 h post-training). Conversely intradermal formalin impaired future spinal learning (24 h post-injection). Because formalin-induced central sensitization has been shown to involve NMDA receptor activation, we tested whether pre-treatment with NMDA would also affect spinal learning in manner similar to formalin. We found intrathecal NMDA impaired learning in a dose-dependent fashion, and that this effect endures for at least 24 h. These data provide strong evidence for an opposing relationship between nociceptive plasticity and use-dependent learning in the spinal cord. The present work has clinical implications given recent findings that adaptive spinal training improves recovery in humans with SCI. Nociception below the SCI may undermine this rehabilitation potential

Smoke gets in your eyes:what is sociological about cigarettes?

Contemporary public health approaches increasingly draw attention to the unequal social distribution of cigarette smoking. In contrast, critical accounts emphasize the importance of smokers’ situated agency, the relevance of embodiment and how public health measures against smoking potentially play upon and exacerbate social divisions and inequality. Nevertheless, if the social context of cigarettes is worthy of such attention, and sociology lays a distinct claim to understanding the social, we need to articulate a distinct, positive and systematic claim for smoking as an object of sociological enquiry. This article attempts to address this by situating smoking across three main dimensions of sociological thinking: history and social change; individual agency and experience; and social structures and power. It locates the emergence and development of cigarettes in everyday life within the project of modernity of the nineteenth and twentieth centuries. It goes on to assess the habituated, temporal and experiential aspects of individual smoking practices in everyday lifeworlds. Finally, it argues that smoking, while distributed in important ways by social class, also works relationally to render and inscribe it

Conservation Status of the Plains Spotted Skunk, Spilogale putorius interrupta, in Texas, with an Assessment of Genetic Variability in the Species

Robert C. Dowler, Department of Biology at Angelo State University is the corresponding author, robert dot dowler at angelo dot eduIn this report, we present results of research on the conservation status of the plains spotted skunk (Spilogale putorius interrupta) in Texas and an assessment of the genetic variability in populations throughout the range of the species. The conservation status portion of the study included (1) mapping the species’ potential habitat in Texas using maximum entropy modeling (Maxent) with historic museum specimen records, (2) field-based surveying of locations in 10 counties to determine occurrence of the plains spotted skunk, (3) seeking additional occurrence records in Texas through crowd sourcing and citizen scientist approaches (4) using all current (2001 – 2017) occurrences to produce a model of probable geographic distribution in Texas and (5) assessing anthropogenic changes in land use, which may threaten the species’ habitats, by mapping current and forecasted oil and gas development and urbanization within the species’ modeled range. The species distribution model, combined with the land-change assessment, was used to select sites in 10 representative counties for field-based surveys in the hopes of revealing patterns of current distribution. Field surveys were carried out using live traps, enclosed track plates, and camera traps. These methods documented detections of plains spotted skunks (n = 12) in 4 of the 10 sites sampled. All methods of detection were successful, but cameras and live traps out-performed track plates. Crowd-sourced approaches and citizen scientist camera trapping revealed an additional 82 occurrences in the state, 79 of which were since 2009. These recent records were used to produce a species distribution model that provides relative probability of occurrence for the plains spotted skunk in the state. Our land-change mapping revealed potential anthropogenic threats to habitats at 2 of the sites (Katy Prairie and Fort Hood), which also had robust populations of plains spotted skunks based on 25 and 51detections, respectively). For our genetic assessment, samples of tissue from three sources (i.e., field surveys, state agencies throughout the distribution of the eastern spotted skunk, and museum tissue collections) allowed a detailed assessment of the genetic variability in the species (S. putorius) using both microsatellite markers and cytochrome b gene sequence. Our analysis of 119 specimens was able to establish that genetic patterns were consistent with currently accepted taxonomy of the 3 recognized subspecies of S. putorius (S. p. putorius, S. p. ambarvalis, and S. p. interrupta). We also determined that there was no evidence for hybridization with the congener, S. gracilis (western spotted skunk), a species co-occurring with the eastern spotted skunk in parts of Texas. The differentiation between S. p. putorius and S. p. ambarvalis was less pronounced (FST = 0.178; cytochrome b sequence divergence = 1.2%) than between these subspecies and the plains spotted skunk (average FST = 0.278; cytochrome b sequence divergence = 2.9%). Overall, genetic variability (observed heterozygosity = 0.474) in the plains spotted skunk was lower than that seen in common carnivores (striped skunks, raccoons), but slightly higher than some endangered carnivores (black-footed ferret). The heterozygosity levels more closely resemble the levels found within the island spotted skunk (S. gracilis amphiala) from the Channel Islands of California and other vertebrates that have a “threatened” conservation status. Key findings of the study include: 1) the current geographic distribution of the plains spotted skunk in Texas is reduced relative to historic records; 2) the species distribution model based on recorded occurrences since 2001 suggests areas of the state that are in need of further survey efforts; 3) genetic variability of plains spotted skunks is lower than more common carnivores, but higher than some recognized endangered species; 4) the subspecies, S. p. interrupta is a distinct genetic subunit of the eastern spotted skunk; and 5) continued energy development and especially future urbanization in some parts of Texas may affect populations of the plains spotted skunk.Texas Comptroller of Public AccountsBureau of Economic Geolog

The Sloan Lens ACS Survey. XI. Beyond Hubble resolution: size, luminosity and stellar mass of compact lensed galaxies at intermediate redshift

We exploit the strong lensing effect to explore the properties of intrinsically faint and compact galaxies at intermediate redshift, at the highest possible resolution at optical wavelengths. Our sample consists of 46 strongly-lensed emission line galaxies discovered by the Sloan Lens ACS (SLACS) Survey. The galaxies have been imaged at high resolution with HST in three bands (V_HST, I_814 and H_160), allowing us to infer their size, luminosity, and stellar mass using stellar population synthesis models. Lens modeling is performed using a new fast and robust code, klens, which we test extensively on real and synthetic non-lensed galaxies, and also on simulated galaxies multiply-imaged by SLACS- like galaxy-scale lenses. Our tests show that our measurements of galaxy size, flux, and Sersic index are robust and accurate, even for objects intrinsically smaller than the HST point spread function. The median magnification is 8.8, with a long tail that extends to magnifications above 40. Modeling the SLACS sources reveals a population of galaxies with colors and Sersic indices (median n ~ 1) consistent with the objects detected in the field with HST in the GEMS survey, but that are (typically) ~ 2 magnitudes fainter and ~ 5 times smaller in apparent size. The closest analog are ultracompact emission line galaxies identified by HST grism surveys. The lowest mass galaxies in our sample are comparable to the brightest Milky Way satellites in stellar mass (10^7 solar masses) and have well-determined half light radii of 0."05 (~0.3 kpc).Comment: 19 pages, 12 figures, 6 tables, accepted for publication in Ap