An investigation of the pharmacological modulation of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis

Osteoarthritis (OA) is a disabling disease of the synovial joints. Structurally, OA involves the degenerative breakdown of articular cartilage, inflammation of the synovium and sclerosis of the subchondral bone, which ultimately results in a loss of function and integrity of the synovial joints. Clinically, it is the chronic pain associated with OA that causes patients to seek medical attention. Traditional analgesics used to relieve the chronic pain associated with OA aim to alleviate peripheral nociception at the level of the diseased joint. However, OA patients often develop referred pain and suffer with chronic pain even after total joint replacement surgery, which indicates that the chronic pain associated with OA is not always driven by purely peripheral mechanisms. Therefore, a better understanding of the central mechanisms involved in the development of OA associated chronic pain may aid the development of effective analgesics that tackle the centrally driven element. Diffuse Noxious Inhibitory Controls (DNIC) describes the phenomenon where one pain inhibits another; this system utilizes endogenous descending inhibitory controls, which mediate an inhibitory effect at the level of the spinal cord. In order to characterize this system in rats, in vivo electrophysiological recordings were made from single unit dorsal horn convergent neurons. The dorsal horn neurons were activated by mechanical and thermal stimulation of the hind paw and DNIC was induced by a concurrent noxious conditioning pinch. This thesis aimed to investigate the pharmacology of DNIC. OA of the knee was modeled in this thesis with a 2mg monoiodoacetate (MIA) intrarticular injection in the rat. This thesis investigated central neuronal plasticity with spinal electrophysiology, assessed the functionality of descending controls through measuring DNIC responses, and characterized the joint histopathology and pain-like behaviour associated with this model. Studies presented in this thesis confirmed that DNIC are mediated via noradrenergic inhibitory descending controls, but that serotonergic descending controls can also influence the expression of DNIC. Early phase MIA animals (2-6 days post injection) displayed significant mechanical hypersensitivity, yet showed little articular cartilage degradation and had a functional DNIC system. DNIC expression was abolished in early phase animals through blocking the actions of spinal α2-adrenoceptors with the antagonist atipamezole, while blocking the actions of spinal 5-HT7 receptors reduced DNIC expression. Late phase MIA animals (14-20 days post injection) demonstrated significant articular cartilage degradation, mechanical hypersensitivity, and an abolished DNIC system. DNIC expression was restored in late phase MIA animals by enhancing noradrenergic modulation with the NRI and μ-opioid receptor agonist tapentadol, and by activating spinal 5-HT7 receptors with the selective 5-HT7 receptor agonist AS-19. In addition, pregbalin significantly reduced spinal neuronal responses in late phase MIA animals yet had no effect in early phase animals. Overall, these results suggest there is a decreased noradrenergic inhibitory descending drive acting at spinal α2-adrenoceptors, and modulation of serotonergic descending controls acting at spinal 5-HT7 receptors in late phase MIA animals. The studies presented in this thesis demonstrate the applications of assessing DNIC in this experimental model of OA, that the DNIC system becomes abolished as the model progresses, and that DNIC can be restored through pharmacologically manipulating monoaminergic descending controls. Overall, this may represent a strategy for relieving centrally driven OA associated chronic pain

A combination pharmacotherapy of tapentadol and pregabalin to tackle centrally driven Osteoarthritis pain

BACKGROUND: Many Osteoarthritis (OA) patients report with clinical features to their pain that cannot be explained by purely peripheral mechanisms. Yet, the analgesic agents available that tackle centrally driven chronic pain often provide only partial pain relief, or have dose-limiting side effects. We explored a combination therapy of the centrally acting analgesic agents tapentadol and pregabalin, to investigate if they could be used in combination to provide superior analgesia. METHODS: Using electrophysiological single-unit recordings taken from spinal wide dynamic range (WDR) neurons, Diffuse Noxious Inhibitory Controls (DNIC) were assessed as a marker of potential changes in descending controls in a monoiodoacetate (MIA) model of OA. We investigated if a subcutaneous injection of tapentadol or pregabalin, both alone and in combination, inhibited neuronal responses and restored the expression of DNIC, quantified as a reduction in neuronal firing in the presence of a conditioning noxious stimulus. RESULTS: Tapentadol restored DNIC induced neuronal inhibition in MIA animals, while pregabalin inhibited pre-conditioned mechanically evoked neuronal responses but did not restore DNIC. Given in combination, tapentadol and pregabalin restored DNIC expression and also inhibited spinal neuronal responses. CONCLUSIONS: We propose that there is both central sensitisation and an imbalance in inhibitory and facilitatory descending controls in MIA animals. The combination therapy of tapentadol and pregabalin restored descending noradrenergic inhibitory tone, and also inhibited nociceptive transmission at the level of the spinal cord. This article is protected by copyright. All rights reserved

Spatial distribution of metabolites in the retina and its relevance to studies of metabolic retinal disorders

Introduction: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. Objectives: To better understand the properties of different retinal areas we studied the differential distribution of metabolites across the retina. Methods: We conducted an untargeted metabolomics analysis on full-thickness punches from three different regions (macula, temporal peri-macula and periphery) of healthy primate retina. Results: Nearly half of all metabolites identified showed differential abundance in at least one comparison between the three regions. Furthermore, mapping metabolomics results from macula-specific eye diseases onto our region-specific metabolite distributions revealed differential abundance defining systemic metabolic dysregulations that were region specific. Conclusions: The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Our results may help to better understand the pathobiology of retinal diseases with region specificity

Characterisation of peripheral and central components of the rat monoiodoacetate model of Osteoarthritis

OBJECTIVE: Pain is the main reason patients report Osteoarthritis (OA), yet current analgesics remain relatively ineffective. This study investigated both peripheral and central mechanisms that lead to the development of OA associated chronic pain. DESIGN: The monoiodoacetate (MIA) model of OA was investigated at early (2-6 days post injection) and late (>14 days post injection) time points. Pain-like behaviour and knee histology were assessed to understand the extent of pain due to cartilage degradation. Electrophysiological single-unit recordings were taken from spinal wide dynamic range (WDR) neurons to investigate Diffuse Noxious Inhibitory Controls (DNIC) as a marker of potential changes in descending controls. Immunohistochemistry was performed on dorsal root ganglion (DRG) neurons to assess any MIA induced neuronal damage. Furthermore, qPCR was used to measure levels of glia cells and cytokines in the dorsal horn. RESULTS: Both MIA groups develop pain-like behaviour but only late phase animals display extensive cartilage degradation. Early phase animals have a normally functioning DNIC system but there is a loss of DNIC in late phase animals. We found no evidence for neuronal damage caused by MIA in either group, yet an increase in IL-1β mRNA in the dorsal horn of late phase animals. CONCLUSION: The loss of DNIC in late phase MIA animals suggests an imbalance in inhibitory and facilitatory descending controls, and a rise in the mRNA expression of IL-1β mRNA suggest the development of central sensitisation. Therefore, the pain associated with OA in late phase animals may not be attributed to purely peripheral mechanisms

An evaluation of strategies used by the Landscapes and Policy Hub to achieve interdisciplinary and transdisciplinary research

The report presents an evaluation of the Landscapes and Policy Hub's approach to interdisciplinary and transdisciplinary research. The hub was a national, four year, $15 million collaborative research program. The focus of the evaluation was for researchers to reflect on the effectiveness of strategies used by the hub to facilitate interdisciplinarity (where researchers from different disciplines work together to solve problems) and transdisciplinarity (where researchers from different disciplines work in partnership with research users to solve problems). The evaluation was commissioned in the final phase of the hub’s life in the interests of improving performance of future interdisciplinary and transdisciplinary research. It was based on a number of strategies that had been implemented by the hub to encourage and facilitate interdisciplinary research occurring in partnership with research users. The aim of the evaluation was to improve performance of future interdisciplinary and transdisciplinary research. Six recommendations are presented

Possible impacts of a future grand solar minimum on climate: Stratospheric and global circulation changes.

This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/2014JD022022A future decline in solar activity would not offset projected global warmingA future decline in solar activity could have larger regional effects in winterTop-down mechanism contributes to Northern Hemisphere regional response.LJG and ACM were supported by the National Centre for Atmospheric Science's Climate Directorate. ACM also acknowledges support from the ERC ACCI project no. 267760 and an AXA Postdoctoral Fellowship. SI and AAS were supported by the Joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101). LJG and JAA were supported by a grant from the National Environmental Research Council

Determining solar effects in Neptune’s atmosphere

Long-duration observations of Neptune’s brightness in two visible wavelengths provide a disk-averaged estimate of its atmospheric aerosol. Brightness variations were previously associated with the 11-year solar cycle, through solar-modulated mechanisms linked with either ultra-violet (UV) or galactic cosmic ray (GCR) effects on atmospheric particles. Here we use a recently extended brightness dataset (1972-2014), with physically realistic modelling to show that rather than alternatives, UV and GCR are likely to be modulating Neptune’s atmosphere in combination. The importance of GCR is further supported by the response of Neptune's atmosphere to an intermittent 1.5 to 1.9 year periodicity, which occurred preferentially in GCR (not UV) during the mid-1980s. This periodicity was detected both at Earth, and in GCR measured by Voyager 2, then near Neptune. A similar coincident variability in Neptune’s brightness suggests nucleation onto GCR ions. Both GCR and UV mechanisms may occur more rapidly than the subsequent atmospheric particle transport

Long-term cycles in the history of life: Periodic biodiversity in the Paleobiology Database

Time series analysis of fossil biodiversity of marine invertebrates in the Paleobiology Database (PBDB) shows a significant periodicity at approximately 63 My, in agreement with previous analyses based on the Sepkoski database. I discuss how this result did not appear in a previous analysis of the PBDB. The existence of the 63 My periodicity, despite very different treatment of systematic error in both PBDB and Sepkoski databases strongly argues for consideration of its reality in the fossil record. Cross-spectral analysis of the two datasets finds that a 62 My periodicity coincides in phase by 1.6 My, equivalent to better than the errors in either measurement. Consequently, the two data sets not only contain the same strong periodicity, but its peaks and valleys closely correspond in time. Two other spectral peaks appear in the PBDB analysis, but appear to be artifacts associated with detrending and with the increased interval length. Sampling-standardization procedures implemented by the PBDB collaboration suggest that the signal is not an artifact of sampling bias. Further work should focus on finding the cause of the 62 My periodicity.Comment: Published in PLoS ONE. 5 pages, 3 figures. Version with live links, discussion available at http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004044#to

Standardization as emerging content in technology education at all levels of education

Integration of standardization into different levels of technology education has surfaced as a critical issue for educational practitioners and policy makers at national and regional (APEC, EU) level. In this paper, we describe and analyze empirical data collected from 118 educational experiences and practices about technology standards and standardization in 21 countries of a regional variety. Specifically, this research examines standardization education programs these countries have implemented, and explores suggestive indications for the design and development of an educational policy for standardization. Online surveys, offline interviews, face-to-face meetings and case studies have been used to determine the way these standardization education programs are segmented and implemented in different contexts. The findings are consolidated into a framework for standardization education. The framework presents an applicable combination of target groups (who), appropriate learning objectives (why), probable program operators (where), prospective contents modules (what), and preferred teaching methods (how). This framework may contribute to planning and implementing more inclusive standardization education programs