• 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.
    • A preliminary cohort study assessing routine blood analyte levels and neurological outcome following spinal cord injury.

      Brown, Sharon; 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.
    • Accelerated and efficient neuronal differentiation of Sox1GFP mouse embryonic stem cells in vitro using nicotinamide

      Griffin, Sile; Pickard, Mark R.; Fricker, Rosemary; Keele University, United Kingdom (NECTAR (Network of European CNS Transplantation and Restoration) 24th Annual Meeting, 27/28th November 2014, Galway, Ireland, 2014)
      A major challenge for advancement of clinical neuronal replacement therapies is the production of high yields of purified neuronal populations of appropriate phenotype with control over proliferation to prevent tumorigenesis. We previously reported that treatment of mouse embryonic stem cell (mESC;46CSox1GFP reporter cell line) monolayer cultures with the vitamin B3 metabolite nicotinamide at the early onset of development not only increased the efficiency of neuronal generation by two-fold but also enriched the ratio of purified neurons to non-neuronal cells in culture. This study aimed to investigate if nicotinamide enhances neural induction in this model and whether it also promotes the production/differentiation of specific neuronal subtypes. To address these aims, monolayer mESC cultures were treated with nicotinamide (10 mM) for different durations and immunocytochemistry/fluorescence microscopy was performed to assess the expression of stem cell, neural progenitor (NP) and neuronal subtype markers. Morphometric analyses were also performed to assess the extent of differentiation. Nicotinamide treatment significantly decreased Oct4+ pluripotent cells and concomitantly increased GFP+ cells at day 4, suggesting enhanced neural lineage commitment. By day 14, nicotinamide treatment (from day 0-7) reduced both Oct4+ and GFP expression concomitant with enhanced expression of neuron-specific β-tubulin, indicative of accelerated neuronal differentiation. Nicotinamide selectively enhanced the production of catecholaminergic, serotonergic and GABAergic neurons and, moreover, enhanced various aspects of neuronal morphology and maturation. Collectively, these data demonstrate a direct effect of nicotinamide at the initial stages of embryonic stem cell differentiation which could be critical for rapidly andefficiently promoting neural commitment to highly enriched neuronal lineages. The strong clinical potential of nicotinamide could successfully be applied to future neural cell-based therapies including Parkinson’s and Huntington’s disease, both to eradicate proliferating cells and for a more enhanced and specific differentiation
    • Alignment of multiple glial cell populations in 3D nanofiber scaffolds: toward the development of multicellular implantable scaffolds for repair of neural injury

      Weightman, Alan P.; Jenkins, Stuart I.; Pickard, Mark R.; Chari, Divya M.; Yang, Ying; Keele University, United Kingdom (Elsevier, 2014-02)
      Non-neuronal cells of the central nervous system (CNS), termed "neuroglia," play critical roles in neural regeneration; therefore, replacement of glial populations via implantable nanofabricated devices (providing a growth-permissive niche) is a promising strategy to enhance repair. Most constructs developed to date have lacked three-dimensionality, multiple glial populations and control over spatial orientations, limiting their ability to mimic in vivo neurocytoarchitecture. We describe a facile technique to incorporate multiple glial cell populations [astrocytes, oligodendrocyte precursor cells (OPCs) and oligodendrocytes] within a three-dimensional (3D) nanofabricated construct. Highly aligned nanofibers could induce elongation of astrocytes, while OPC survival, elongation and maturation required pre-aligned astrocytes. The potential to scale-up the numbers of constituent nanofiber layers is demonstrated with astrocytes. Such complex implantable constructs with multiple glial sub-populations in defined 3D orientations could represent an effective approach to reconstruct glial circuitry in neural injury sites.
    • Anti-epileptic drugs and bone loss: phenytoin reduces pro-collagen I and alters the electrophoretic mobility of osteonectin in cultured bone cells.

      Wilson, Emma L.; Garton, Mark; Fuller, Heidi R.; RJAH Orthopaedic Hospital; RJAH Orthopaedic NHS Foundation Trust; Keele University (Elsevier, 2016-05)
      Phenytoin is an antiepileptic drug used in the management of partial and tonic-clonic seizures. In previous studies we have shown that valproate, another antiepileptic drug, reduced the amount of two key bone proteins, pro-collagen I and osteonectin (SPARC, BM-40), in both skin fibroblasts and cultured osteoblast-like cells. Here we show that phenytoin also reduces pro-collagen I production in osteoblast-like cells, but does not appear to cause a decrease in osteonectin message or protein production. Instead, a 24h exposure to a clinically relevant concentration of phenytoin resulted in a dose-dependent change in electrophoretic mobility of osteonectin, which was suggestive of a change in post-translational modification status. The perturbation of these important bone proteins could be one of the mechanisms to explain the bone loss that has been reported following long-term treatment with phenytoin.
    • Attitudes of general hospital staff towards patients who self-harm in South India: A cross-sectional study

      Kumar, Narendra; Rajendra, Rajagopal; Majgi, Sumanth M.; Krishna, Murali; Keenan, Paul; Jones, Steven; University of Chester (Medknow, 30/11/2016)
      Background: There is growing global interest into the attitudes and clinical management of persons who deliberately self-harm. People who self-harm experience many problems and typically have many needs related to management of their psychological wellbeing. A positive attitude amongst general hospital staff should prevail with people who self-harm. The principal purpose was to determine student staff attitudes towards patients who self-harmed from a professional and cultural perspective, which might influence patient treatment following hospital admission. The focus concentrated upon staff knowledge, attitudes and beliefs regarding self-harm. Methods: A cross sectional survey of the hospital staff using a validated questionnaire was carried out. This paper reports on interdisciplinary staff from two large general hospitals in Mysuru, South India (n=773). Results: Findings suggest that within a general hospital setting there is wide variation in staff attitudes and knowledge levels related to self-harm. Whilst there is attitudinal evidence for staff attitudes, this study investigates interprofessional differences in an attempt to progress treatment approaches to a vulnerable societal group. Very few staff had any training in assessment of self harm survivors. Conclusion: There is an urgent need for training general hospital staff in self harm assessment and prevention in south India. The results allow a series of recommendations for educational and skills initiatives before progressing to patient assessment and treatment projects and opens potential for cross cultural comparison studies. In addition, interventions must focus on current resources and contexts to move the evidence base and approaches to patient care forward.
    • Autologous chondrocyte implantation-derived synovial fluids display distinct responder and non-responder proteomic profiles

      Hulme, Charlotte H.; Wilson, Emma L.; Peffers, Mandy J.; Roberts, Sally; Simpson, Deborah M.; Richardson, James B.; Gallacher, Pete; Wright, Karina T.; Keele University; Robert Jones and Agnes Hunt Orthopaedic Hospital; University of Chester; University of Liverpool (BioMed Central, 30/06/2017)
      Background Autologous chondrocyte implantation (ACI) can be used in the treatment of focal cartilage injuries to prevent the onset of osteoarthritis (OA). However, we are yet to understand fully why some individuals do not respond well to this intervention. Identification of a reliable and accurate biomarker panel that can predict which patients are likely to respond well to ACI is needed in order to assign the patient to the most appropriate therapy. This study aimed to compare the baseline and mid-treatment proteomic profiles of synovial fluids (SFs) obtained from responders and non-responders to ACI. Methods SFs were derived from 14 ACI responders (mean Lysholm improvement of 33 (17–54)) and 13 non-responders (mean Lysholm decrease of 14 (4–46)) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Label-free proteome profiling of dynamically compressed SFs was used to identify predictive markers of ACI success or failure and to investigate the biological pathways involved in the clinical response to ACI. Results Only 1 protein displayed a ≥2.0-fold differential abundance in the preclinical SF of ACI responders versus non-responders. However, there is a marked difference between these two groups with regard to their proteome shift in response to cartilage harvest, with 24 and 92 proteins showing ≥2.0-fold differential abundance between Stages I and II in responders and non-responders, respectively. Proteomic data has been uploaded to ProteomeXchange (identifier: PXD005220). We have validated two biologically relevant protein changes associated with this response, demonstrating that matrix metalloproteinase 1 was prominently elevated and S100 calcium binding protein A13 was reduced in response to cartilage harvest in non-responders. Conclusions The differential proteomic response to cartilage harvest noted in responders versus non-responders is completely novel. Our analyses suggest several pathways which appear to be altered in non-responders that are worthy of further investigation to elucidate the mechanisms of ACI failure. These protein changes highlight many putative biomarkers that may have potential for prediction of ACI treatment success.
    • c-Myc inhibition decreases CIP2A and reduces BCR-ABL1 tyrosine kinase activity in chronic myeloid leukemia.

      Lucas, Claire; Harris, Robert; Giannoudis, Athina; Clark, Richard; University of Liverpool, Royal Liverpool University hospital (Ferrata Storti Foundation, 01/05/2015)
    • 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. (23/05/2019)
      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.]
    • Cardiac Rehabilitation Delivery Model for Low-Resource Settings: An International Council of Cardiovascular Prevention and Rehabilitation Consensus Statement

      Grace, Sherry L.; Turk-Adawi, Karam I.; Contractor, Aashish; Atrey, Alison; Campbell, Norman R. C.; Derman, Wayne; Ghisi, Gabriela L. M.; Sarkar, Bidyut K.; Yeo, Tee J.; Lopez-Jimenenez, Francisco; et al. (Elsevier, 17/08/2016)
      Cardiovascular disease (CVD) is a global epidemic, which is largely preventable. Cardiac rehabilitation (CR) is demonstrated to be efficacious and cost-effective for secondary prevention in high-income countries. Given its affordability, CR should be more broadly implemented in middle-income countries as well. Hence, the International Council of Cardiovascular Prevention and Rehabilitation (ICCPR) convened a writing panel to recommend strategies to deliver all core CR components in low-resource settings, namely: (1) initial assessment, (2) lifestyle risk factor management (i.e., diet, tobacco, mental health), (3) medical risk factor management (lipids, blood pressure), (4) education for self-management; (5) return to work; and (6) outcome evaluation. Approaches to delivering these components in alternative, arguably lower-cost settings, such as the home, community and primary care, are provided. Recommendations on delivering each of these components where the most-responsible CR provider is a non-physician, such as an allied healthcare professional or community health care worker, are also provided.
    • CIP2A- and SETBP1-mediated PP2A inhibition reveals AKT S473 phosphorylation to be a new biomarker in AML

      Hills, Robert; Burnett, Alan; Lucas, Claire; Scott, Laura; Carmell, Natasha; Holcroft, Alison; Clark, Richard; University of Liverpool, Royal Liverpool University hospital, University of Cardiff (American Society for Hematology, 27/04/2018)
      Key Points PP2A inhibition occurs in AML by 2 different pathways: CIP2A in normal karyotype patients and SETBP1 in adverse karyotype patients. AKTS473 phosphorylation is a predictor of survival, and diagnostic levels of AKTS473 could be a novel biomarker in AML.
    • Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)

      Huang, Hongyun; Young, Wise; Chen, Lin; Feng, Shiqing; Zoubi, Ziad M. Al; Sharma, Hari Shanker; Saberi, Hooshang; Moviglia, Gustavo A.; He, Xijing; Muresanu, Dafin F.; et al. (SAGE Publications, 11/04/2018)
    • Cognitive function and disability in late Life: An ecological validation of the 10/66 battery of cognitive tests among community dwelling older adults in south India

      Krishna, Murali; Beulah, Eunice; Jones, Steven; Sundaracharj, Rajesh; Saroja, A.; Kumaran, Kalyanaraman; Karat, Samuel C.; Prince, Martin; Fall, Caroline H. D.; University of Chester (Wiley, 17/12/2015)
      Key Points • 10/66 cognitive tests are well suited for identification of older adults with cognitive and functional impairment at a population level in LMIC setting. • Lower scores on individual domains of the 10/66 battery of cognitive tests are associated with higher levels of disability and functional impairment. • It is feasible to administer 10/66 cognitive assessments in participant's own homes in India. • 10/66 cognitive tests are education and culture fair, suitable for use in population based research in India.
    • 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. (2019-07-17)
      LB100 does not sensitize CML stem cells to tyrosine kinase inhibitor-induced apoptosis. [Abstract copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.]
    • Commentary: Endovascular Sealing of Abdominal Aortic Aneurysms: Do Current Data Justify Wider Use?

      Torella, Francesco; McWilliams, Richard G.; Fisher, Robert K. (SAGE Publications, 12/04/2018)
    • 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.
    • 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.
    • Conscientious objection and physician-assisted suicide: a viable option in the UK?

      Willis, Derek; George, Rob (15/11/2018)
      Conscience objection is a proposed way of ensuring that medical practitioners who object to physician-assisted suicide may avoid having to be involved in such a procedure if this is legalised. This right on the part of healthcare professionals already exists in certain circumstances. This paper examines the ethical and legal grounds for conscientious objection for medical professionals and shows how it is heavily criticised in circumstances where it is already used. The paper comes to the conclusion that as the grounds and application of conscience objection are no longer as widely accepted, its future application in any legislation can be called into question. [Abstract copyright: © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate

      Hudson, William H.; Pickard, Mark R.; de Vera, Ian M.; Kuiper, Emily G.; Mourtada-Maarabouni, Mirna; Conn, Graeme L.; Kojetin, Douglas J.; Williams, Gwyn T.; Ortlund, Eric A.; Emory University School of Medicine; Keele University; Scripps Research Institute (Nature Publishing Group, 07/11/2014)
      The majority of the eukaryotic genome is transcribed, generating a significant number of long intergenic noncoding RNAs (lincRNAs). Although lincRNAs represent the most poorly understood product of transcription, recent work has shown lincRNAs fulfill important cellular functions. In addition to low sequence conservation, poor understanding of structural mechanisms driving lincRNA biology hinders systematic prediction of their function. Here we report the molecular requirements for the recognition of steroid receptors (SRs) by the lincRNA growth arrest-specific 5 (Gas5), which regulates steroid-mediated transcriptional regulation, growth arrest and apoptosis. We identify the functional Gas5-SR interface and generate point mutations that ablate the SR-Gas5 lincRNA interaction, altering Gas5-driven apoptosis in cancer cell lines. Further, we find that the Gas5 SR-recognition sequence is conserved among haplorhines, with its evolutionary origin as a splice acceptor site. This study demonstrates that lincRNAs can recognize protein targets in a conserved, sequence-specific manner in order to affect critical cell functions.
    • Decision making for refusals of treatment—a framework to consider

      Jones, Steven; Monteith, Paul; Williams, Barry (Journal of Paramedic Practice, 02/05/2014)
      Challenges to practice are encountered on a daily basis by paramedics that often share many common recurring themes around consent or refusal to treatment. The benefits of training and open debate acknowledge the often complex decisions relating to consent and mental capacity and reduce opportunities for future legal challenge. How the law should be integrated into everyday decision making will be examined and a framework proposed to assist practice for defendable decision making. This article was inspired following joint training undertaken with paramedics and local critical incident managers from the police, which highlighted a need for a practical decision-making framework to be available for application during incidents and for use as an analytical tool to aid post-decision reflection and learning at debrief.