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Search Results: 1 - 10 of 737 matches for " Gareth Hathway "
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Overcoming the Barriers to Greater Public Engagement
Ian M. Devonshire,Gareth J. Hathway
PLOS Biology , 2014, DOI: 10.1371/journal.pbio.1001761
The emergence of adolescent onset pain hypersensitivity following neonatal nerve injury
David Vega-Avelaira, Rebecca McKelvey, Gareth Hathway, Maria Fitzgerald
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-30
Abstract: Spared nerve injury (SNI) or sham surgery was performed on 10 day old (P10) rat pups and mechanical nociceptive reflex thresholds were analysed 3, 7, 14, 21, 28, 38 and 44 days post surgery. While mechanical thresholds on the ipsilateral side are not significantly different from controls for the first 2–3 weeks post P10 surgery, after that time period, beginning at 21 days post surgery (P31), the SNI group developed following early life nerve injury significant hypersensitivity compared to the other groups. Ipsilateral mechanical nociceptive threshold was 2-fold below that of the contralateral and sham thresholds at 21 days post surgery (SNI-ipsilateral 28 (±5) g control groups 69 (±9) g, p < 0.001, 3-way ANOVA, n = 6 per group). Importantly, no effect was observed on thermal thresholds. This hypersensivity was accompanied by macrophage, microglial and astrocyte activation in the DRG and dorsal horn, but no significant change in dorsal horn p38 or JNK expression. Preemptive minocycline (daily 40 mg/kg, s.c) did not prevent the effect. Ketamine (20 mg/kg, s.c), on the other hand, produced a dose-dependent reversal of mechanical nociceptive thresholds ipsilateral to the nerve injury such that thresholds return to control levels at the highest doses of 20 mg/Kg.We report a novel consequence of early life nerve injury whereby mechanical hypersensitivity only emerges later in life. This delayed adolescent onset in mechanical pain thresholds is accompanied by neuroimmune activation and NMDA dependent central sensitization of spinal nociceptive circuits. This delayed onset in mechanical pain sensitivity may provide clues to understand the long term effects of early injury such as late onset phantom pain and the emergence of complex adolescent chronic pain syndromes.
The contribution of spinal glial cells to chronic pain behaviour in the monosodium iodoacetate model of osteoarthritic pain
Devi Sagar, James J Burston, Gareth J Hathway, Stephen G Woodhams, Richard G Pearson, Andrew J Bennett, David A Kendall, Brigitte E Scammell, Victoria Chapman
Molecular Pain , 2011, DOI: 10.1186/1744-8069-7-88
Abstract: Seven days following intra-articular injection of MIA, microglia in the ipsilateral spinal cord were activated (p < 0.05, compared to contralateral levels and compared to saline controls). Levels of activated microglia were significantly elevated at day 14 and 21 post MIA-injection. At day 28, microglia activation was significantly correlated with distal allodynia (p < 0.05). Ipsilateral spinal GFAP immunofluorescence was significantly (p < 0.01) increased at day 28, but not at earlier timepoints, in the MIA model, compared to saline controls. Repeated oral dosing (days 14-20) with nimesulide attenuated pain behaviour and the activation of microglia in the ipsilateral spinal cord at day 21. This dosing regimen also significantly attenuated distal allodynia (p < 0.001) and numbers of activated microglia (p < 0.05) and GFAP immunofluorescence (p < 0.001) one week later in MIA-treated rats, compared to vehicle-treated rats. Repeated administration of minocycline also significantly attenuated pain behaviour and reduced the number of activated microglia and decreased GFAP immunofluorescence in ipsilateral spinal cord of MIA treated rats.Here we provide evidence for a contribution of spinal glial cells to pain behaviour, in particular distal allodynia, in this model of osteoarthritic pain. Our data suggest there is a potential role of glial cells in the central sensitization associated with OA, which may provide a novel analgesic target for the treatment of OA pain.Osteoarthritis (OA) is the most prevalent joint disease and knee OA is the major cause of lower limb disability in older people worldwide [1]. The major symptoms of OA are chronic pain and disability. Current analgesic strategies for the long term treatment of OA pain have modest effects and are often associated with severe side-effects. The improved treatment of OA pain is a major unmet clinical need, which can only be addressed by a better understanding of the mechanisms that drive this chronic pain state. Al
Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury
Andrew Moss, Rachel Ingram, Stephanie Koch, Andria Theodorou, Lucie Low, Mark Baccei, Gareth J Hathway, Michael Costigan, Stephen R Salton, Maria Fitzgerald
Molecular Pain , 2008, DOI: 10.1186/1744-8069-4-62
Abstract: Prolonged upregulation of VGF mRNA and protein was observed in injured dorsal root ganglion neurons, central terminals and their target dorsal horn neurons. Intrathecal application of TLQP-62, the C-terminal active portion of VGF (5–50 nmol) to na?ve rats caused a long-lasting mechanical and cold behavioral allodynia. Direct actions of 50 nM TLQP-62 upon dorsal horn neuron excitability was demonstrated in whole cell patch recordings in spinal cord slices and in receptive field analysis in intact, anesthetized rats where significant actions of VGF were upon spontaneous activity and cold evoked responses.VGF expression is therefore highly modulated in nociceptive pathways following peripheral nerve injury and can cause dorsal horn cell excitation and behavioral hypersensitivity in na?ve animals. Together the results point to a novel and powerful role for VGF in neuropathic pain.The spontaneous burning pain, hyperalgesia and allodynia that characterize neuropathic pain are triggered and maintained by a combination of peripheral and central processes [1,2]. Peripheral mechanisms include the onset of ectopic activity in the injured sensory neurons, cross talk between sensory and sympathetic neurons and interaction with peripheral immune cells [3], while central mechanisms include central sensitization through membrane depolarization and homo and heterosynaptic potentiation maintained by loss of inhibition and immune activation [4-6].At the heart of many of these processes lie the neurotrophins, which in addition to controlling the survival and differentiation of neurons, play a key role in maintaining and modulating the function of adult nociceptive neurons. NGF and BDNF are highly regulated in skin, peripheral and central neurons, and glia following nerve injury and tissue inflammation, and have been repeatedly implicated in the development and maintenance of chronic neuropathic pain states [7-10].Microarray analysis of dorsal root ganglia (DRG) mRNA following experimen
Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint
James J. Burston, Devi Rani Sagar, Pin Shao, Mingfeng Bai, Emma King, Louis Brailsford, Jenna M. Turner, Gareth J. Hathway, Andrew J. Bennett, David A. Walsh, David A. Kendall, Aron Lichtman, Victoria Chapman
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080440
Abstract: Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies. Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration. Systemic administration of the CB2 receptor agonist JWH133 attenuated OA-induced pain behaviour, and the changes in circulating pro- and anti-inflammatory cytokines exhibited in this model. Electrophysiological studies revealed that spinal administration of JWH133 inhibited noxious-evoked responses of spinal neurones in the model of OA pain, but not in control rats, indicating a novel spinal role of this target. We further demonstrate dynamic changes in spinal CB2 receptor mRNA and protein expression in an OA pain model. The expression of CB2 receptor protein by both neurones and microglia in the spinal cord was significantly increased in the model of OA. Hallmarks of central sensitization, significant spinal astrogliosis and increases in activity of metalloproteases MMP-2 and MMP-9 in the spinal cord were evident in the model of OA pain. Systemic administration of JWH133 attenuated these markers of central sensitization, providing a neurobiological basis for analgesic effects of the CB2 receptor in this model of OA pain. Analysis of human spinal cord revealed a negative correlation between spinal cord CB2 receptor mRNA and macroscopic knee chondropathy. These data provide new clinically relevant evidence that joint damage and spinal CB2 receptor expression are correlated combined with converging pre-clinical evidence that activation of CB2 receptors inhibits central sensitization and its contribution to the manifestation of chronic OA pain. These findings suggest that targeting CB2 receptors may have therapeutic potential for treating OA pain.
A Brief Follow-Up Report on 228 Medial Rotation Total Knee Replacements at a Mean of 8.5 Years (0 - 19)  [PDF]
Sarah McMahon, Gareth Scott
International Journal of Clinical Medicine (IJCM) , 2015, DOI: 10.4236/ijcm.2015.612121
Abstract: We present an update in our earlier report on the Medial Rotation Total Knee Arthroplasty (TKA) when a cohort of 228 TKAs in 189 patients (78 M; 111 F) with a mean age of 67.9 years (28 - 90) was reported at a mean follow-up of six years (1 - 13). At that time, the ten-year survivorship for revision for any reason was 94.5% (95% confidence interval (CI): 85.1 - 100), but only 21 knees were at risk at that tenth year. The 10th annual report of the National Joint Registry (NJR) of England, Wales and Northern Ireland reported a deterioration in survivorship of the Medial Rotation TKA beyond the seventh year of follow-up. This implant previously had enjoyed the lowest rate of revision for any reported brand of prosthesis. As a result, we undertook a comprehensive audit of our original cohort at a mean follow-up of 8.5 years (0 - 19). With revision for aseptic loosening, and revision for any reason as the endpoints, with 125 prostheses at risk at ten years, the ten-year survivorship was 96.7% (95% CI: 93.3 - 100) and 92.3% (95% CI: 87.7 - 93.7) respectively. We have confirmed a decline in survivorship at ten years compared to our initial report. We believe that our results probably provide a more accurate picture of the longevity of the implant than figures available from the NJR, as they are based on detailed contemporary enquiries into each patient’s circumstances. Only ten knees in seven patients were lost to follow-up in our review.
Recently published papers: Therapies failed, disputed, and beneficent
Gareth Williams
Critical Care , 2007, DOI: 10.1186/cc5931
Abstract: In 1976, Ashbaugh first described acute lung injury/acute respiratory distress syndrome. Our subsequent understanding of the underlying pathophysiology has grown enormously and led to the development of many novel therapies. However, the high mortality rate has changed little in 40 years. Inhaled nitric oxide (NO) was one such therapy. It seemed perfect, being a selective pulmonary vasodilator resulting in reversal of pulmonary shunt, reduction in pulmonary artery pressure and improved right ventricular function, not to mention its inhibition of platelet aggregation and neutrophil adhesion. The clever money was on NO.Sadly, all that sparkles is not gold. A multitude of studies have simply failed to demonstrate improved outcomes. Despite this, its clinical application has continued, albeit somewhat piecemeal.In April the British Medical Journal published a systematic review and meta-analysis on the effect of NO in acute lung injury [1]. Outcomes included oxygenation, pulmonary artery pressure, duration of ventilation, mortality and adverse effects. Twelve randomized controlled trials (n = 1,237) were selected. The results and conclusions do not make for happy reading. NO was found not to improve mortality, duration of ventilation, or number of ventilator-free days. It bestowed a small oxygenation benefit in the first few days of use. It did not significantly reduce mean pulmonary arterial pressure. High-dose NO (80 ppm) was associated with methaemoglobinaemia and raised blood nitrogen dioxide levels. Finally, a statistically significant risk for renal dysfunction was identified in patients receiving NO, although the authors stressed cautious interpretation of this finding.This was an assiduously conducted review and the results are in keeping with previous work [2]. It leaves one begrudgingly accepting the authors' conclusions that, 'given the best available evidence suggests no survival advantage and possible increased mortality and renal dysfunction with nitric oxi
Recently published papers: Curing, caring and follow-up
Gareth Williams
Critical Care , 2003, DOI: 10.1186/cc2381
Abstract: Following the success of the activated protein C trial in 2001 [1], interest in anticoagulant therapy for severe sepsis was heightened. A systemic imbalance between procoagulant and anticoagulant pathways exists in severe sepsis, leading to thrombus formation in the microvasculature and to subsequent end-organ injury. Endothelial injury occurring in severe sepsis is thought to be a trigger for this process, initiating the clotting cascade via the transmembrane receptor, known as tissue factor, and its interaction with factor VII. Inhibition of this interaction would block the coagulation pathway at its earliest point.With this concept in mind, July witnessed the publication of a large multicentre phase 3 randomised, double-blind, placebo-controlled, clinical trial investigating the efficacy and safety of recombinant tissue factor pathway inhibitor (TFPI) in severe sepsis [3]. Two subgroups of patients were randomised to either a 96-hour infusion of active drug or to placebo: a high International Normalised Ratio (INR) group (INR ≥ 1.2, 1754 patients), and a low INR group (INR ≤ 1.2, 201 patients). The study failed to demonstrate any survival benefit in the treatment groups, although there was a trend to improve survival in the small low INR subgroup. Furthermore, the study showed that TFPI administration was associated with an increased risk of bleeding, predominantly from gastrointestinal and respiratory tracts.One of the more striking peculiarities of this study is the reversal in fortunes of the treatment and placebo groups halfway through the enrollment period. At a planned interim analysis the mortality rates favoured the TFPI group (29.1% versus 38.9%). In the latter portion of the study, however, an increase in the TFPI group mortality and a decrease in the placebo group mortality totally reversed this effect. No satisfactory explanation for this phenomenon has been found despite exhaustive efforts. If the study had been stopped following the interim analysis
Recently published papers: A number of treatment controversies
Gareth Williams
Critical Care , 2002, DOI: 10.1186/cc1877
Abstract: In a report [1] and accompanying editorial [2], the December issue of Intensive Care Medicine casts further light on the topical issue of noninvasive positive pressure ventilation (NIPPV) in the critically ill. Dr Elliot's editorial [2] eloquently reviews the evidence for use of NIPPV in ventilatory failure resulting from acute exacerbations of chronic obstructive pulmonary disease (COPD). He highlights the substantial body of evidence demonstrating the advantages of NIPPV in this group of patients, namely a reduction in the need for endotracheal intubation and associated complications (infectious complications in particular), a reduction in both intensive care and hospital duration of stay and consequently health care costs, and even a significantly improved survival rate in one large study [3].The majority of studies thus far have targeted patients with mild to moderate acute exacerbations of COPD who do not require immediate endotracheal intubation and mechanical ventilation, which most would deem to be the gold standard for management of acute severe respiratory failure. Some have even suggested that in the more severely ill the implementation of NIPPV may deleteriously delay intubation and ventilation, leading to a poorer outcome [4]. In contrast Conti and coworkers [1] targeted a sick group of patients, as evidenced by their mean pH of 7.2 and failure of standard medical therapy following initial improvement on the emergency ward. Having met predetermined criteria for mechanical ventilation, patients were randomized to either NIPPV (n = 23) or conventional intubation and ventilation (n = 26). Strikingly patients were followed up for a total of 1 year.In contrast to previous investigators, Conti and coworkers failed to show a benefit from NIPPV in terms of duration of mechanical ventilation, duration of hospital or intensive care unit (ICU) stay, and hospital mortality. Importantly, however, no harm was demonstrated either. Over half of the NIPPV group required
Elastic network model of allosteric regulation in protein kinase PDK1
Gareth Williams
BMC Structural Biology , 2010, DOI: 10.1186/1472-6807-10-11
Abstract: It is shown here that the allosteric effects of the agonist binding to the small lobe upon the activation loop in the large lobe of PDK1 are explainable within a simple 'ball and spring' elastic network model (ENM) of protein dynamics. In particular, the model shows that the bound phospho peptide mimetic fluctuations have a high degree of correlation with the activation loop of PDK1.The ENM approach to small molecule activation of proteins may offer a first pass predictive methodology where affinity is encoded in residues remote from the active site, and aid in the design of specific protein agonists that enhance the allosteric coupling and antagonist that repress it.Phosphorylation dependent protein interactions are a common feature of biological processes [1]. A relevant kinase attaches a phosphate group to a specific tyrosine, threonine or serine residue on the protein surface resulting in a considerable increase in the binding affinity for a target protein. The binding event triggers a conformational change whereby the target protein switches from inactive to active state or vice versa [2]. It is not possible to generalise the nature of the conformational change and it is only with crystallisation that light has been thrown on the mechanism. PDK1 in common with other AGC kinases have a catalytic domain consisting of an N-terminal small lobe harbouring a PDK1-interacting fragment (PIF) binding pocket, a large C-terminal lobe with an activation loop and an ATP binding site in the cleft between the two lobes [3]. The PDK1 kinase is activated by a phosphorylated peptide binding to the PIF pocket [4]. This binding triggers not only local conformational changes in the pocket and the ATP binding site, but also in the remote activation loop. Structural insight into the mechanism of activation of PDK1 has been gained by the crystallisation in the first instance of the inactive version of the protein [5] where the activation loop appears unstructured. And the recent devel
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