Chester Medical School run research programmes jointly with the Countess of Chester Hospital NHS Foundation Trust (COCH) and other hospital trusts that are relevant at regional, national and international level.

Recent Submissions

  • Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca

    Law, Betty Yuen Kwan; Michelangeli, Francesco; Qu, Yuan Qing; orcid: 0000-0003-3733-3661; Xu, Su-Wei; Han, Yu; Mok, Simon Wing Fai; Dias, Ivo Ricardo De Seabra Rodrigues; Javed, Masood-Ul-Hassan; Chan, Wai-Kit; Xue, Wei-Wei; et al. (2019-12-27)
    Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.
  • Stent Migration Following Endovascular Sealing of Abdominal Aortic Aneurysms

    Yafawi, Asma; McWilliams, Richard G.; Fisher, Robert K.; England, Andrew; Karouki, Maria; Torella, Francesco (Elsevier, 2019-12-09)
  • Alzheimer’s Amyloidopathy: An Alternative Aspect

    Regland, Björn; McCaddon, Andrew (IOS Press, 2019-03-29)
  • Size at birth and cognitive ability in late life: A systematic review

    Krishna, Murali; orcid: 0000-0002-5354-9027; Jones, Steven; Maden, Michelle; Du, Bharath; Mc, Ramya; Kumaran, Kalyanaraman; Karat, Samuel Christraprasad; Fall, Caroline H.D. (Wiley, 2019-06-13)
  • Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells

    Austin, James A.; orcid: 0000-0002-5384-5221; Jenkins, Rosalind E.; Austin, Gemma M.; Glenn, Mark A.; Dunn, Karen; Scott, Laura; Lucas, Claire M.; Clark, Richard E. (Portland Press Ltd., 2019-08-15)
    Abstract Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5′ AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.
  • Office workers’ experiences of attempts to reduce sitting-time: An exploratory, mixed- methods uncontrolled intervention pilot study

    Dewitt, Stephen; Hall, Jennifer; Smith, Lee; Buckley, John P.; Biddle, Stuart J. H.; Mansfield, Louise; Gardner, Benjamin; University of Chester (BMC Springer Nature, 2019-06-25)
    Background: Office workers typically sit for most of the workday, which has been linked to physical and mental ill- health and premature death. This mixed-methods study sought to identify barriers and facilitators to reducing sitting and increasing standing among office workers who received an intervention prototype (the ‘ReSiT [Reducing Sitting Time] Study’). The intervention comprised a sit-stand workstation and tailored advice to enhance motivation, capability and opportunity to displace sitting with standing. Methods: Twenty-nine UK university office workers (aged ≥18y, working ≥3 days per week, most time spent at a seated desk) participated in a 13-week uncontrolled study. They were initially monitored for one-week. In a subsequent face-to-face consultation, participants received sitting time feedback from a prior one-week monitoring period, and selected from a set of tailored sitting-reduction techniques. Quantitative data comprising sitting, standing and stepping time, which were objectively monitored for 7 consecutive days across three post- intervention timepoints, were descriptively analysed. Qualitative data, from semi-structured interviews conducted at 1, 6 and 12-weeks post-intervention, were thematically analysed. Results: Compared to baseline, mean sitting time decreased at weeks 1, 6 and 12 by 49.7mins, 118.2mins, and 109.7mins respectively. Despite prior concerns about colleagues’ reactions to standing, many reported encouragement from others, and standing could be equally conducive to social interaction or creating private, personal space. Some perceived less cognitively-demanding tasks to be more conducive to standing, though some found standing offered a valued break from challenging tasks. Participants prioritised workload over sitting reduction and were more likely to stand after rather than during work task completion. Temporary context changes, such as holidays, threatened to derail newfound routines. Conclusions: Our findings emphasise the importance of understanding workers’ mental representations of their work, and the social functions of sitting and standing in the workplace. Workplace intervention developers should incorporate a pre-intervention sitting time monitoring period, encourage workers to identify personally meaningful tasks and cues for standing, and build organisational support for sitting-reduction. We will use these insights to refine our intervention for self-administered delivery. Trial registration: ISRCTN29395780 (registered 21 November 2016). Keywords: Sedentary behaviour, Workplace, Qualitative, Occupational health
  • Promoting patient utilization of outpatient cardiac rehabilitation: A joint International Council and Canadian Association of Cardiovascular Prevention and Rehabilitation position statement

    Santiago de Araújo Pio, Carolina; Varnfield, Marlien; Sarrafzadegan, Nizal; Beckie, Theresa M.; Babu, Abraham S.; Baidya, Sumana; Buckley, John P.; Chen, Ssu-Yuan; Gagliardi, Anna; Heine, Martin; et al. (Elsevier, 2019-07-04)
    Background: Cardiac Rehabilitation (CR) is a recommendation in international clinical practice guidelines given its’ benefits, however use is suboptimal. The purpose of this position statement was to translate evidence on interventions that increase CR enrolment and adherence into implementable recommendations. Methods: The writing panel was constituted by representatives of societies internationally concerned with preventive cardiology, and included disciplines that would be implementing the recommendations. Patient partners served, as well as policy-makers. The statement was developed in accordance with AGREE II, among other guideline checklists. Recommendations were based on our update of the Cochrane review on interventions to promote patient utilization of CR. These were circulated to panel members, who were asked to rate each on a 7-point Likert scale in terms of scientific acceptability, actionability, and feasibility of assessment. A web call was convened to achieve consensus and confirm strength of the recommendations (based on GRADE). The draft underwent external review and public comment. Results: The 3 drafted recommendations were that to increase enrolment, healthcare providers, particularly nurses (strong), should promote CR to patients face-to-face (strong), and that to increase adherence part of CR could be delivered remotely (weak). Ratings for the 3 recommendations were 5.95±0.69 (mean ± standard deviation), 5.33±1.12 and 5.64±1.08, respectively. Conclusions: Interventions can significantly increase utilization of CR, and hence should be widely applied. We call upon cardiac care institutions to implement these strategies to augment CR utilization, and to ensure CR programs are adequately resourced to serve enrolling patients and support them to complete programs.
  • Quantifying the impact of tissue metabolism on solute transport in feto-placental microvascular networks

    Nye, Gareth; Erlich, Alexander; Brownbill, Paul; Chernyavsky, Igor; Jenson, Oliver; University of Manchester (Royal Society, 2019-08-16)
    The primary exchange units in the human placenta are terminal villi, in which fetal capillary networks are surrounded by a thin layer of villous tissue, separating fetal from maternal blood. To understand how the complex spatial structure of villi influences their function, we use an image-based theoretical model to study the effect of tissue metabolism on the transport of solutes from maternal blood into the fetal circulation. For solute that is taken up under first-order kinetics, we show that the transition between flow-limited and diffusion-limited transport depends on two new dimensionless parameters defined in terms of key geometric quantities, with strong solute uptake promoting flow-limited transport conditions. We present a simple algebraic approximation for solute uptake rate as a function of flow conditions, metabolic rate and villous geometry. For oxygen, accounting for nonlinear kinetics using physiological parameter values, our model predicts that villous metabolism does not significantly impact oxygen transfer to fetal blood, although the partitioning of fluxes between the villous tissue and the capillary network depends strongly on the flow regime
  • Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy

    Šoltić, Darija; Shorrock, Hannah K.; Allardyce, Hazel; Wilson, Emma L.; Holt, Ian; Synowsky, Silvia A.; Shirran, Sally L.; Parson, Simon H.; Gillingwater, Thomas H.; Fuller, Heidi R. (Oxford University Press (OUP), 2019-08-09)
    Abstract Cardiac pathology is emerging as a prominent systemic feature of spinal muscular atrophy (SMA), but little is known about the underlying molecular pathways. Using quantitative proteomics analysis, we demonstrate widespread molecular defects in heart tissue from the Taiwanese mouse model of severe SMA. We identify increased levels of lamin A/C as a robust molecular phenotype in the heart of SMA mice, and show that lamin A/C dysregulation is also apparent in SMA patient fibroblast cells and other tissues from SMA mice. Lamin A/C expression was regulated in-vitro by knockdown of the E1 ubiquitination factor UBA1, a key downstream mediator of SMN-dependent disease pathways, converging on β-catenin signalling. Increased levels of lamin A are known to increase the rigidity of nuclei, inevitably disrupting contractile activity in cardiomyocytes. The increased lamin A/C levels in the hearts of SMA mice therefore provide a likely mechanism explaining morphological and functional cardiac defects, leading to blood pooling. Therapeutic strategies directed at lamin A/C may therefore offer a new approach to target cardiac pathology in SMA.
  • What is the effect of aerobic exercise intensity on cardiorespiratory fitness in those undergoing cardiac rehabilitation? A systematic review with meta-analysis

    Mitchell, Braden L.; Lock, Merilyn J.; Parfitt, Gaynor; Buckley, John P.; Davison, Kade; Eston, Roger; University of South Australia, University Centre Shrewsbury/University of Chester (BMJ, 2018-08-18)
    18 Objective: Assess the role of exercise intensity on changes in cardiorespiratory fitness (CRF) in 19 patients with cardiac conditions attending exercise-based cardiac rehabilitation. 20 Design: Systematic review with meta-analysis. 21 Data sources: MEDLINE, Embase, CINAHL, SPORTDiscus, PsycINFO and Web of Science. 22 Eligibility criteria for selection: Studies assessing change in CRF (reported as peak oxygen uptake; 23 V̇O2peak) in patients post-myocardial infarction and revascularisation, following exercise-based 24 cardiac rehabilitation. Studies establishing V̇O2peak via symptom-limited exercise test with ventilatory 25 gas analysis and reported intensity of exercise during rehabilitation were included. Studies with 26 mean ejection fraction <40% were excluded. 27 Results: 128 studies including 13,220 patients were included. Interventions were classified as 28 moderate, moderate-to-vigorous or vigorous intensity based on published recommendations. 29 Moderate and moderate-to-vigorous intensity interventions were associated with a moderate 30 increase in relative V̇O2peak (standardised mean difference ± 95% CI = 0.94 ± 0.30 and 0.93 ± 0.17, 31 respectively), and vigorous-intensity exercise with a large increase (1.10 ± 0.25). Moderate and 32 vigorous intensity interventions were associated with moderate improvements in absolute V̇O2peak 33 (0.63 ± 0.34 and 0.93 ± 0.20, respectively), whereas moderate-to-vigorous intensity interventions 34 elicited a large effect (1.27 ± 0.75). Large heterogeneity among studies was observed for all analyses. 35 Subgroup analyses yielded statistically significant, but inconsistent, improvements in CRF. 36 Conclusion: Engagement in exercise-based cardiac rehabilitation was associated with significant 37 improvements in both absolute and relative V̇O2peak. Although exercise of vigorous intensity 38 produced the greatest pooled effect for change in relative V̇O2peak, differences in pooled effects 39 between intensities could not be considered clinically meaningful.
  • Comment on "PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia".

    Perrotti, Danilo; Agarwal, Anupriya; Lucas, Claire; Narla, Goutham; Neviani, Paolo; Odero, Maria D.; Ruvolo, Peter P.; Verrills, Nicole M. (American Association for the Advancement of Science, 2019-07-17)
    LB100 does not sensitize CML stem cells to tyrosine kinase inhibitor–induced apoptosis.
  • Muscling in on mitochondrial sexual dimorphism; role of mitochondrial dimorphism in skeletal muscle health and disease

    Nye, Gareth; Lightfoot, Adam; Sakellariou, Giorgos; Degans, Hans; University of Manchester, Manchester Metropolitan University (Portland Press, 2017-07-07)
    Mitochondria are no longer solely regarded as the cellular powerhouse; instead, they are now implicated in mediating a wide-range of cellular processes, in the context of health and disease. A recent article in Clinical Science, Ventura-Clapier et al. highlights the role of sexual dimorphism in mitochondrial function in health and disease. However, we feel the authors have overlooked arguably one of the most mitochondria-rich organs in skeletal muscle. Many studies have demonstrated that mitochondria have a central role in mediating the pathogenesis of myopathologies. However, the impact of sexual dimorphism in this context is less clear, with several studies reporting conflicting observations. For instance in ageing studies, a rodent model reported female muscles have higher antioxidant capacity compared with males; in contrast, human studies demonstrate no sex difference in mitochondrial bioenergetics and oxidative damage. These divergent observations highlight the importance of considering models and methods used to examine mitochondrial function, when interpreting these data. The use of either isolated or intact mitochondrial preparations in many studies appears likely to be a source of discord, when comparing many studies. Overall, it is now clear that more research is needed to determine if sexual dimorphism is a contributing factor in the development of myopathologies.
  • Mechanisms of skeletal muscle ageing: avenues for therapeutic intervention

    Nye, Gareth; McCormick, Rachel; Lightfoot, Adam; McArdle, Anne; University of Liverpool (Elsevier, 2014-05-28)
    Age-related loss of muscle mass and function, termed sarcopenia, is a catastrophic process, which impacts severely on quality of life of older people. The mechanisms underlying sarcopenia are unclear and the development of optimal therapeutic interventions remains elusive. Impaired regenerative capacity, attenuated ability to respond to stress, elevated reactive oxygen species production and low-grade systemic inflammation are all key contributors to sarcopenia. Pharmacological intervention using compounds such as 17AAG, SS-31 and Bimagrumab or naturally occurring polyphenols to target specific pathways show potential benefit to combat sarcopenia although further research is required, particularly to identify the mechanisms by which muscle fibres are completely lost with increasing age.
  • Comparison of whole body SOD1 knockout with muscle specific SOD1 knockout mice reveals a role for nerve redox signaling in regulation of degenerative pathways in skeletal muscle.

    Nye, Gareth; Sakellariou, Giorgos; McDonagh, Brian; Porter, Helen; Giakoumaki, Ifigeneia; Earl, Kate; Vasilaki, Aphrodite; Brooks, Susan; Richardson, Arlan; Van Remmen, Holly; et al. (Mary Ann Liebert, 2017-12-12)
    Aims: Lack of Cu,Zn-superoxide dismutase (CuZnSOD) in homozygous knockout mice (Sod1−/−) leads to accelerated age-related muscle loss and weakness, but specific deletion of CuZnSOD in skeletal muscle (mSod1KO mice) or neurons (nSod1KO mice) resulted in only mild muscle functional deficits and failed to recapitulate the loss of mass and function observed in Sod1−/− mice. To dissect any underlying cross-talk between motor neurons and skeletal muscle in the degeneration in Sod1−/− mice, we characterized neuromuscular changes in the Sod1−/− model compared with mSod1KO mice and examined degenerative molecular mechanisms and pathways in peripheral nerve and skeletal muscle. Results: In contrast to mSod1KO mice, myofiber atrophy in Sod1−/− mice was associated with increased muscle oxidative damage, neuromuscular junction degeneration, denervation, nerve demyelination, and upregulation of proteins involved in maintenance of myelin sheaths. Proteomic analyses confirmed increased proteasomal activity and adaptive stress responses in muscle of Sod1−/− mice that were absent in mSod1KO mice. Peripheral nerve from neither Sod1−/− nor mSod1KO mice showed increased oxidative damage or molecular responses to increased oxidation compared with wild type mice. Differential cysteine (Cys) labeling revealed a specific redox shift in the catalytic Cys residue of peroxiredoxin 6 (Cys47) in the peripheral nerve from Sod1−/− mice. Innovation and Conclusion: These findings demonstrate that neuromuscular integrity, redox mechanisms, and pathways are differentially altered in nerve and muscle of Sod1−/− and mSod1KO mice. Results support the concept that impaired redox signaling, rather than oxidative damage, in peripheral nerve plays a key role in muscle loss in Sod1−/− mice and potentially sarcopenia during aging. Antioxid. Redox Signal. 28, 275–295. Innovation This is the first study to compare the molecular mechanisms and pathways that occur in both skeletal muscle and peripheral nerve of Sod1−/− and mSod1KO mice in an effort to examine the relative cross-talk and role of pre- and postsynaptic changes in redox homeostasis in loss of neuromuscular integrity and function that occurs with aging. This study highlights that impaired redox signaling in peripheral nerve rather than oxidative damage appears to play a key role in altering the integrity of peripheral nerves and motor neurons and potentially age-associated muscle atrophy and functional deficits. These results are potentially clinically significant and have widespread implications for the understanding of sarcopenia during aging.
  • A preliminary cohort study assessing routine blood analyte levels and neurological outcome following spinal cord injury.

    Brown, Sharon J.; Bernardo Harrington,; Hulme, Charlotte; Morris, Rachel; Bennett, Anna; Tsang, Wai-Hung; Osman, Aheed; Chowdhury, Joy; Kumar, Naveen; Wright, Karina T. (2019-07-16)
    There is increasing interest in the identification of biomarkers that could predict neurological outcome following a spinal cord injury (SCI). Although initial American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade is a good indicator of neurological outcome, for the patient and clinicians, an element of uncertainty remains. This preliminary study aimed to assess the additive potential of routine blood analytes following Principal Component Analysis (PCA) to develop prognostic models for neurological outcome following spinal cord injury. Routine blood and clinical data were collected from SCI patients (n=82) and PCA used to reduce the number of blood analytes into related factors. Outcome neurology was obtained from AIS scores at 3- and 12-months post-injury, with Motor (AIS and Total including all myotomes) and Sensory (AIS, Touch and Pain) being assessed individually. Multiple regression models were created for all outcome measures. Blood analytes relating to 'liver function' and 'acute inflammation and liver function' factors were found to significantly increase prediction of neurological outcome at both 3 months (Touch, Pain and AIS Sensory) and at 1 year (Pain, R2 increased by 0.025 and Total Motor, R2 increased by 0.016). For some models 'liver function' and 'acute inflammation and liver function' factors were both significantly predictive with the greatest combined R2 improvement of 0.043 occurring for 3m Pain prediction. These preliminary findings support ongoing research into the use of routine blood analytes in the prediction of neurological outcome in SCI patients.
  • A pilot randomised controlled trial of a programme of psychosocial interventions (Resettle) for high risk personality disordered offenders

    Nathan, Rajan; Centifanti, Luna; Baker, Vikki; Hill, Jonathan (Elsevier, 2019-07-08)
    Abstract Background Offenders with personality disorder experience significant co-morbid mental health problems and present with an increased risk of offending. The evidence for the effectiveness of interventions for personality disordered offenders in the community is limited. This study was a pilot study to determine the feasibility of a randomised controlled trial (RCT) of an intervention known as Resettle for personality disordered offenders and to explore the possible effects of this intervention. Methods Potential participants were recruited from referrals of male prisoners to Resettle. Those consenting underwent baseline assessments before being randomised to Resettle or treatment as usual. Officially recorded and self-report offending was assessed over two years following release from custody. Of the 110 eligible participants, 72 (65%) participated in the study of whom 38 were randomised to Resettle and 34 to treatment as usual. The two groups had a similar psychiatric and offending profile. Results Analysis of officially recorded offences at two years found mixed results, but whether adopting an intent-to-treat approach or including only those who received the intervention there was no clear evidence of an effect of the intervention. A comparison of self-report offending found no effect of Resettle in an intent-to-treat analysis, but there was an effect when the analysis involved only those participating in the intervention. Conclusions This study demonstrated that with some adjustments it was possible to carry out an RCT of a complex intervention for personality disordered offenders in a criminal justice setting. Some, but not conclusive, evidence was found in favour of the intervention.
  • Palliative opioid use, palliative sedation and euthanasia: reaffirming the distinction.

    Schofield, Guy; Baker, Idris; Bullock, Rachel; Clare, Hannah; Clark, Paul; Willis, Derek; Gannon, Craig; George, Rob (2019-06-20)
    We read with interest the extended essay published from Riisfeldt and are encouraged by an empirical ethics article which attempts to ground theory and its claims in the real world. However, such attempts also have real-world consequences. We are concerned to read the paper's conclusion that clinical evidence weakens the distinction between euthanasia and normal palliative care prescribing. This is important. Globally, the most significant barrier to adequate symptom control in people with life-limiting illness is poor access to opioid analgesia. Opiophobia makes clinicians reluctant to prescribe and their patients reluctant to take opioids that might provide significant improvements in quality of life. We argue that the evidence base for the safety of opioid prescribing is broader than that presented, restricting the search to palliative care literature produces significant bias as safety experience and literature for opioids and sedatives exists in many fields. This is not acknowledged in the synthesis presented. By considering additional evidence, we reject the need for agnosticism and reaffirm that palliative opioid prescribing is safe. Second, palliative sedation in a clinical context is a poorly defined concept covering multiple interventions and treatment intentions. We detail these and show that continuous deep palliative sedation (CDPS) is a specific practice that remains controversial globally and is not considered routine practice. Rejecting agnosticism towards opioids and excluding CDPS from the definition of routine care allows the rejection of Riisfeldt's headline conclusion. On these grounds, we reaffirm the important distinction between palliative care prescribing and euthanasia in practice. [Abstract copyright: © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.]
  • Ca

    Wong, Vincent K-W.; Qiu, Congling; Xu, Su-Wei; Law, Betty Yuen Kwan; Zeng, Wu; Wang, Hui; Michelangeli, Francesco; Dias, Ivo Ricardo De Seabra Rodrigues; Qu, Yuan Qing; Chan, Tsz Wai; et al. (2019-05-23)
    Celastrol exhibits anti-arthritic effect in rheumatoid arthritis (RA), but the role of celastrol-mediated Ca mobilization in treatment of RA remains unelucidated. Here, we illustrate the regulatory role of celastrol-induced Ca signalling in synovial fibroblasts of RA patients and adjuvant-induced arthritis (AIA) in rats. Molecular target of celastrol was determined by computational docking, Ca dynamic and functional assays on SERCA. Ca -mediated autophagy in RASFs/RAFLS and the underlying mechanism were verified by quantification of endogenous LC3-II puncta, immunoblotting, and flow cytometry with the Ca chelator (BAPTA/AM) or suitable inhibitors. The anti-arthritic effect of celastrol, autophagy induction and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes. The role of Ca in regulating the identified genes was investigated by knockdown of calmodulin, calpains, and calcineurin. Celastrol inhibited SERCA to induce autophagy-dependent cytotoxicity in RASFs/RAFLS via CaMKKβ-AMPK-mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory- and autoimmunity-associated genes downregulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca in celastrol-regulated gene expression. Celastrol triggered Ca signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium-dependent/-binding proteins facilitating the exploitation of anti-arthritic drugs based on manipulation of Ca signalling. [Abstract copyright: This article is protected by copyright. All rights reserved.]
  • Embedding recovery based approaches into mental health nurse training- a reflective account

    Jones, Steven; Bifarin, Oladayo O.; University of Chester (Mark Allen Healthcare, 2018-11-02)
    Background: Mental health nursing has undoubtedly progressed as a profession but is at a hiatus that is not assisted by government policy and decreased resources. Aims: This reflective account explores some of the considerable expectations placed upon qualified nurses and the real tensions that influence care delivery standards. Methods: Reflecting on experiences gained in clinical settings, underpinned by literature on recovery, some of the expectations placed on qualified nurses in contemporary mental health service delivery are examined. Conclusion: In order to adequately inform the practices and skill set of contemporary mental health nurses, recovery models and clinical staff input should play a central role in nurse education. Education and clinical practice areas should continue to move towards each other and seize every initiative to ensure both are on the same page.
  • Comparisons of attempted suicide between India and UK

    Jones, Steven; Keenan, Paul; Krishna, Murali; University of Chester (Mental Health Nursing Association, 2014)
    This paper aims to raise the issues and dilemmas within India by suicide and attempted suicide. In the UK evidence-based interventions have progressed over the past 20 years and changes are having positive benefits on standards of interventions and reducing deaths in some areas by suicide. However, when comparing one culture’s custom and practice with another, deficits of some areas of practice present and this facilitates some interesting insights for investigation. Fundamentally, the aim is not to place one above another but to aid identification for cross-cultural comparisons leading to practice advancements.

View more