• 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.
    • Neuropsychiatric symptoms following metal-on-metal implant failure with cobalt and chromium toxicity

      Green, Ben; Griffiths, Emily; Almond, Solomon; University of Chester; Public Health England (BioMed Central, 2016-01-24)
      Background: There were at least 31,171 metal-on-metal (MoM) hip implants in the UK between 2003 and 2011. Some of these were subject to failure and widescale recalls and revisions followed. Method This is a presentation of ten cases (mean age 60 years) where we evaluated neuropsychiatric morbidity following metal-on-metal hip implant failure and revision. Implants were ASR total hip replacement (acetabular implant, taper sleeve adaptor and unipolar femoral implants) performed between 2005 and 2009. This case series describes, for the first time, neuropsychiatric complications after revision where there has been cobalt and chromium toxicity. Results Pre-revision surgery, nine patients had toxic levels of chromium and cobalt (mean level chromium 338 nmol/l, mean cobalt 669.4 nmol/l). Depression assessment showed 9 of 9 respondents fulfilled the BDI criteria for depression and 3 of these were being treated. 7 of 9 patients showing short term memory deficit with mean mini mental state examination score of 24.2. The normal population mean MMSE for this group would be expected to be 28 with <25 indicating possible dementia. Conclusions We found neurocognitive and depressive deficits after cobalt and chromium metallosis following MoM implant failure. Larger studies of neurocognitive effects are indicated in this group. There may be implications for public health.
    • Nicotinamide alone accelerates the conversion of mouse embryonic stem cells into mature neuronal populations.

      Griffin, Sile M.; Pickard, Mark R.; Orme, Rowan P.; Hawkins, Clive P.; Williams, Adrian C.; Fricker, Rosemary; Keele University; University of Chester; University Hospital of North Staffordshire; University of Birmingham (Public Library of Science, 2017-08-17)
      Vitamin B3 has been shown to play an important role during embryogenesis. Specifically, there is growing evidence that nicotinamide, the biologically active form of vitamin B3, plays a critical role as a morphogen in the differentiation of stem cells to mature cell phenotypes, including those of the central nervous system (CNS). Detailed knowledge of the action of small molecules during neuronal differentiation is not only critical for uncovering mechanisms underlying lineage-specification, but also to establish more effective differentiation protocols to obtain clinically relevant cells for regenerative therapies for neurodegenerative conditions such as Huntington's disease (HD). Thus, this study aimed to investigate the potential of nicotinamide to promote the conversion of stem cells to mature CNS neurons. METHODS: Nicotinamide was applied to differentiating mouse embryonic stem cells (mESC; Sox1GFP knock-in 46C cell line) during their conversion towards a neural fate. Cells were assessed for changes in their proliferation, differentiation and maturation; using immunocytochemistry and morphometric analysis methods. RESULTS: Results presented indicate that 10 mM nicotinamide, when added at the initial stages of differentiation, promoted accelerated progression of ESCs to a neural lineage in adherent monolayer cultures. By 14 days in vitro (DIV), early exposure to nicotinamide was shown to increase the numbers of differentiated βIII-tubulin-positive neurons. Nicotinamide decreased the proportion of pluripotent stem cells, concomitantly increasing numbers of neural progenitors at 4 DIV. These progenitors then underwent rapid conversion to neurons, observed by a reduction in Sox 1 expression and decreased numbers of neural progenitors in the cultures at 14 DIV. Furthermore, GABAergic neurons generated in the presence of nicotinamide showed increased maturity and complexity of neurites at 14 DIV. Therefore, addition of nicotinamide alone caused an accelerated passage of pluripotent cells through lineage specification and further to non-dividing mature neurons. CONCLUSIONS: Our results show that, within an optimal dose range, nicotinamide is able to singly and selectively direct the conversion of embryonic stem cells to mature neurons, and therefore may be a critical factor for normal brain development, thus supporting previous evidence of the fundamental role of vitamins and their metabolites during early CNS development. In addition, nicotinamide may offer a simple effective supplement to enhance the conversion of stem cells to clinically relevant neurons.
    • Nicotinamide restricts neural precursor proliferation to enhance catecholaminergic neuronal subtype differentiation from mouse embryonic stem cells

      Borlongan, Cesar V.; Griffin, Síle M.; orcid: 0000-0002-6670-5084; email: silemgriffin@gmail.com; Pickard, Mark R.; Hawkins, Clive P.; Williams, Adrian C.; Fricker, Rosemary A.; orcid: 0000-0001-8768-510X (Public Library of Science, 2020-09-14)
      Emerging evidence indicates that a strong relationship exists between brain regenerative therapies and nutrition. Early life nutrition plays an important role during embryonic brain development, and there are clear consequences to an imbalance in nutritional factors on both the production and survival of mature neuronal populations and the infant’s risk of diseases in later life. Our research and that of others suggest that vitamins play a fundamental role in the formation of neurons and their survival. There is a growing body of evidence that nicotinamide, the water-soluble amide form of vitamin B3, is implicated in the conversion of pluripotent stem cells to clinically relevant cells for regenerative therapies. This study investigated the ability of nicotinamide to promote the development of mature catecholaminergic neuronal populations (associated with Parkinson’s disease) from mouse embryonic stem cells, as well as investigating the underlying mechanisms of nicotinamide’s action. Nicotinamide selectively enhanced the production of tyrosine hydroxylase-expressing neurons and serotonergic neurons from mouse embryonic stem cell cultures (Sox1GFP knock-in 46C cell line). A 5-Ethynyl-2´-deoxyuridine (EdU) assay ascertained that nicotinamide, when added in the initial phase, reduced cell proliferation. Nicotinamide drove tyrosine hydroxylase-expressing neuron differentiation as effectively as an established cocktail of signalling factors, reducing the proliferation of neural progenitors and accelerating neuronal maturation, neurite outgrowth and neurotransmitter expression. These novel findings show that nicotinamide enhanced and enriched catecholaminergic differentiation and inhibited cell proliferation by directing cell cycle arrest in mouse embryonic stem cell cultures, thus driving a critical neural proliferation-to-differentiation switch from neural progenitors to neurons. Further research into the role of vitamin metabolites in embryogenesis will significantly advance cell-based regenerative medicine, and help realize their role as crucial developmental signalling molecules in brain development.
    • Non-Alcoholic Fatty Liver Disease (NAFLD) and Potential Links to Depression, Anxiety, and Chronic Stress

      Shea, Sue; Lionis, Christos; Kite, Chris; Atkinson, Lou; Chaggar, Surinderjeet; Randeva, Harpal S; Kyrou, Ioannis; University of Warwick; University Hospitals Coventry and Warwickshire NHS Trust; University of Crete; University of Chester; Coventry University; Aston University; Forum Health Centre; Agricultural University of Athens (MDPI, 2021-11-16)
      Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease worldwide, and is frequently linked to the metabolic syndrome. The latter represents a clustering of related cardio-metabolic components, which are often observed in patients with NAFLD and increase the risk of cardiovascular disease. Furthermore, growing evidence suggests a positive association between metabolic syndrome and certain mental health problems (e.g., depression, anxiety, and chronic stress). Given the strong overlap between metabolic syndrome and NAFLD, and the common underlying mechanisms that link the two conditions, it is probable that potentially bidirectional associations are also present between NAFLD and mental health comorbidity. The identification of such links is worthy of further investigation, as this can inform more targeted interventions for patients with NAFLD. Therefore, the present review discusses published evidence in relation to associations of depression, anxiety, stress, and impaired health-related quality of life with NAFLD and metabolic syndrome. Attention is also drawn to the complex nature of affective disorders and potential overlapping symptoms between such conditions and NAFLD, while a focus is also placed on the postulated mechanisms mediating associations between mental health and both NAFLD and metabolic syndrome. Relevant gaps/weaknesses of the available literature are also highlighted, together with future research directions that need to be further explored.
    • A novel model of nephrotic syndrome results from a point mutation in Lama5 and is modified by genetic background

      Falcone, Sara; Nicol, Thomas; Blease, Andrew; Randles, Michael J.; Angus, Elizabeth; Page, Anton; Tam, Frederick W. K.; Pusey, Charles D.; Lennon, Rachel; Potter, Paul K.; et al. (Elsevier, 2021-11-10)
      Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminaemia, edema and hyperlipidaemia. Genetic studies of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signaling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. The laminin α5 chain is essential for embryonic development and, in association with laminin β2 and laminin γ1, is a major component of the glomerular basement membrane, a critical component of the glomerular filtration barrier. Mutations in LAMA5 were recently identified in children with nephrotic syndrome. Here, we have identified a novel missense mutation (E884G) in the uncharacterized L4a domain of LAMA5 where homozygous mice develop nephrotic syndrome with severe proteinuria with histological and ultrastructural changes in the glomerulus mimicking the progression seen in most patients. The levels of LAMA5 are reduced in vivo and the assembly of the laminin 521 heterotrimer significantly reduced in vitro. Proteomic analysis of the glomerular extracellular fraction revealed changes in the matrix composition. Importantly, the genetic background of the mice had a significant effect on aspects of disease progression from proteinuria to changes in podocyte morphology. Thus, our novel model will provide insights into pathologic mechanisms of nephrotic syndrome and pathways that influence the response to a dysfunctional glomerular basement membrane that may be important in a range of kidney diseases.
    • Nurses attitudes and beliefs to attempted suicide in Southern India

      Jones, Steven; Krishna, Murali; Rajendra, Raj G.; Keenan, Paul; University of Chester (Taylor and Francis, 2015-05-20)
      Background: There is growing global interest into the attitudes and clinical management of persons who have attempted suicide. Aims: The principal purpose was to determine senior nursing staff attitudes towards patients who had attempted suicide from a professional and cultural perspective, which might influence care following hospital admission. The focus concerned nursing staff interactions at a psychological level that compete with physical tasks on general hospital wards. Methods: A qualitative methodology was employed with audio-taped interviews utilising four level data coding. This article reports on a group of 15 nursing staff from a large general hospital in Mysore, Southern India. Results: Findings suggested that patient care and treatment is directly influenced by the nurse’s religious beliefs within a general hospital setting with physical duties prioritised over psychological support, which was underdeveloped throughout the participant group. Conclusion: The results allow a series of recommendations for educational and skills initiatives before progressing to patient assessment and treatment projects and cross-cultural comparison studies. In addition, interventions must focus on current resources and context to move the evidence-based suicide prevention forward.
    • Occurrence of chemical pollutants in major e-waste sites in West Africa and usefulness of cytotoxicity and induction of ethoxyresorufin-O-deethylase (EROD) in determining the effects of some detected brominated flame retardants and e-waste soil-derived extracts.

      Eze, Chukwuebuka ThankGod; orcid: 0000-0001-8076-2926; email: thankgod.eze@fuoye.edu.ng; Michelangeli, Francesco; Otitoloju, Adebayo Akeem; Eze, Obianuju Oluchukwu; Ibraheem, Omodele; Ogbuene, Emeka Bright; Ogunwole, Germaine Akinola (2020-10-25)
      We investigated the occurrence of chemical pollutants in major e-waste sites in West Africa and usefulness of cytotoxicity and induction of ethoxyresorufin-O-deethylase (EROD) in determining the effects of some detected brominated flame retardants (BFRs) and e-waste soil-derived extracts. Analysis of the e-waste site samples using AAS and GC-MS techniques revealed the presence of a range of toxic metals as well as persistent and toxic organic pollutants, respectively, in the vicinity of the e-waste sites. As expected, the occurrence (%) of all the detected chemical pollutants in experimental soils significantly (P < 0.05) differs from occurrence (%) in control soil. The calculated LC values on RBL-2H3 cells of the detected tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD) were 3.75 μM and 4.2 μM, respectively. Tribromophenol (TBP), dibromobiphenyl (DBB), and decabromodiphenyl ether (DBDE) were remarkably less toxic on RBL-2H3 cells compared with TBBPA and HBCD as they did not reduce RBL-2H3 cell viability below 50% in the tested concentration range (0-20 μM). The study revealed that TBBPA and HBCD could induce significant RBL-2H3 cell death through caspase-dependent apoptosis. The study further shows that the cytotoxicity of some of these BFRs could increase synergistically when in mixtures and potentially activate inflammation through the stimulation of mast cell degranulation. The e-waste soil-derived extracts induced a concentration-dependent increase in EROD activity in the exposed RTG-W1 cells. Ultimately, nonpolar extracts had higher EROD-inducing potency compared with polar extracts and hence suggesting the presence in higher amounts of AhR agonists in nonpolar e-waste soil-derived extracts than polar extracts. Overall, there is urgent need for actions in order to improve the environmental quality of the e-waste sites.
    • Oesophageal stenting: Status quo and future challenges.

      Kaltsidis, Harry; Mansoor, Wasat; Park, Jung-Hoon; Song, Ho-Young; Edwards, Derek W.; Laasch, Hans-Ulrich (2018-06-11)
      Oesophageal stents are widely used for palliating dysphagia from malignant obstruction. They are also used with increasing frequency in the treatment of oesophageal perforation, as well as benign strictures from a variety of causes. Improved oncological treatments have led to prolonged survival of patients treated with palliative intent; as a consequence, stents need to function and last longer in order to avoid repeat procedures. There is also increasing need for meticulous procedure planning, careful selection of the device most appropriate for the individual patient and planned follow-up. Furthermore, as more patients are cured, there will be more issues with resultant long-term side-effects, such as recalcitrant strictures due to radiotherapy or anastomotic scarring, which will have to be addressed. Stent design needs to keep up with the progress of cancer treatment, in order to offer patients the best possible long-term result. This review article attempts to illustrate the changing realities in oesophageal stenting, differences in current stent designs and behaviour, as well as the pressing need to refine and modify devices in order to meet the new challenges.
    • 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
    • Oxygen Costs of the Incremental Shuttle Walk Test in Cardiac Rehabilitation Participants: An Historical and Contemporary Analysis

      Buckley, John P.; Cardoso, Fernando M. F.; Birkett, Stefan T.; Sandercock, Gavin R. H.; University Centre Shrewsbury (Springer, 2016-04-07)
      Background The incremental shuttle walk test (ISWT) is a standardised assessment for cardiac rehabilitation. Three studies have reported oxygen costs (VO2)/metabolic equivalents (METs) of the ISWT. In spite of classic rep- resentations from these studies graphically showing curvilinear VO2 responses to incremented walking speeds, linear regression techniques (also used by the American College of Sports Medicine [ACSM]) have been used to estimate VO2. Purpose The two main aims of this study were to (i) re- solve currently reported discrepancies in the ISWT VO2- walking speed relationship, and (ii) derive an appropriate VO2 versus walking speed regression equation. Methods VO2 was measured continuously during an ISWT in 32 coronary heart disease [cardiac] rehabilitation (CHD-CR) participants and 30 age-matched controls. Results Both CHD-CR and control group VO2 responses were curvilinear in nature. For CHD-CR VO2 = 4.4- e0.23 9 walkingspeed (km/h). The integrated area under the curve (iAUC) VO2 across nine ISWT stages was greater in the CHD-CR group versus the control group (p \ 0.001): & John P. Buckley j.buckley@chester.ac.uk 1 (±86) ml􏰀kg-1􏰀min-1􏰀km􏰀h-1; con- trol = 316 (±52) ml􏰀kg-1􏰀min-1􏰀km􏰀h-1. Conclusions CHD-CR group vs. control VO2 was up to 30 % greater at higher ISWT stages. The curvilinear nature of VO2 responses during the ISWT concur with classic studies reported over 100 years. VO2 estimates for walking using linear regression models (including the ACSM) clearly underestimate values in healthy and CHD-CR par- ticipants, and this study provides a resolution to this when the ISWT is used for CHD-CR populations.
    • 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.]
    • Patients’ Perspectives of Oral and Injectable Type 2 Diabetes Medicines, Their Body Weight and Medicine-Taking Behavior in the UK: A Systematic Review and Meta-Ethnography

      Psarou, Aikaterini; Cooper, Helen; Wilding, John P. H. (Springer Healthcare, 2018-08-17)
      AbstractThe aim of this review is to identify peoples’ perspectives of their glucose-lowering and anti-obesity drugs in relation to diabetes and weight control and to explore how these views affect medication adherence. Theoretical perspectives associated with medicine-taking behavior are also explored. The systematic review was based on a meta-ethnography of qualitative studies identified through a search of 12 medical and social science databases and subsequent citation searches. The quality of all studies was assessed. Sixteen studies were included with data from 360 UK individuals. No relevant studies were identified which focused on anti-obesity and non-insulin injectable drugs. The review revealed that the patients’ perspectives and emotional state were influenced by starting and/or changing to a new glucose-lowering medicine. These were also influenced by prior medication experience, disease perceptions and interactions with clinicians. Despite reports of positive experiences with and positive perceptions of medicines, and of participation in strategies to regain life control, medication non-adherence was common. Accepting glucose-lowering medicines impacted on the individual’s perception of lifestyle changes, and it was notable that weight loss was not perceived as a strategy to support diabetes management. Synthesis revealed that more than one theory is required to explain medicine-taking behavior. New insights into the underlying factors of poor adherence and the specific practical issues identified in this review can help in the development of patient-centered interventions.Funding: Diabetes UK.
    • Physical health impairment, disability and suicidal intent among self-harm survivors in South India

      Jones, Steven; Somashekar, R; Bharath, D. U.; Maiji, Sumanth M; Taylor, Lou; Nagaraj, Santhosh; Krishna, Murali; Mysore Medical College and Research Institute; University of Chester; CSI Holdsworth Memorial Hospital; FRAMe; Viveka Hospital (Medip Academy, 2021-04-27)
      Background: Suicide is major public health concern in India. There are limited data examining the relationship between health impairment, disability and severity of suicidal intent. The aim of the study was to examine the associations of health impairment and disability with severity of suicidal intent among survivors following an act of self-harm. Methods: A pilot exploratory study of 453 self-harm survivors from a specialist hospital in South India. Sociodemographics, physical health impairment, disability (WHO Disability Schedule-II), suicidal intent, (Pierce suicide intent scale) and mental disorders were studied. Results: Arthritis was the most common physical impairment among self-harm survivors followed by gastrointestinal, sensory impairment and difficulty with mobilization. Nearly 10% of participants had some degree of functional impairment, with 38% experiencing severe physical pain in the week prior to self-harm. Past history of depression treatment, age, education and occupation influenced positively PSIS scores. There were significant associations between suicidal intent and disability. Conclusions: Indian self-harm survivors indicated complex relationships between physical health, disability and suicidal intent. Understanding these associations may help to develop suicide prevention strategies. Our findings suggest a need for integrating a comprehensive of physical health assessment in self harm survivors.
    • Postnatal Protein Intake as a Determinant of Skeletal Muscle Structure and Function in Mice-A Pilot Study

      Giakoumaki, Ifigeneia; Pollock, Natalie; Aljuaid, Turki; Sannicandro, Anthony J.; Alameddine, Moussira; Owen, Euan; Myrtziou, Ioanna; Ozanne, Susan E.; Kanakis, Ioannis; Goljanek-Whysall, Katarzyna; et al. (MDPI, 2022-08-08)
      Sarcopenia is characterised by an age-related decrease in the number of muscle fibres and additional weakening of the remaining fibres, resulting in a reduction in muscle mass and function. Many studies associate poor maternal nutrition during gestation and/or lactation with altered skeletal muscle homeostasis in the offspring and the development of sarcopenia. The aim of this study was to determine whether the musculoskeletal physiology in offspring born to mouse dams fed a low-protein diet during pregnancy was altered and whether any physiological changes could be modulated by the nutritional protein content in early postnatal stages. Thy1-YFP female mice were fed ad libitum on either a normal (20%) or a low-protein (5%) diet. Newborn pups were cross-fostered to different lactating dams (maintained on a 20% or 5% diet) to generate three groups analysed at weaning (21 days): Normal-to-Normal (NN), Normal-to-Low (NL) and Low-to-Normal (LN). Further offspring were maintained ad libitum on the same diet as during lactation until 12 weeks of age, creating another three groups (NNN, NLL, LNN). Mice on a low protein diet postnatally (NL, NLL) exhibited a significant reduction in body and muscle weight persisting up to 12 weeks, unlike mice on a low protein diet only prenatally (LN, LNN). Muscle fibre size was reduced in mice from the NL but not LN group, showing recovery at 12 weeks of age. Muscle force was reduced in NLL mice, concomitant with changes in the NMJ site and changes in atrophy-related and myosin genes. In addition, μCT scans of mouse tibiae at 12 weeks of age revealed changes in bone mass and morphology, resulting in a higher bone mass in the NLL group than the control NNN group. Finally, changes in the expression of miR-133 in the muscle of NLL mice suggest a regulatory role for this microRNA in muscle development in response to postnatal diet changes. Overall, this data shows that a low maternal protein diet and early postnatal life low-protein intake in mice can impact skeletal muscle physiology and function in early life while postnatal low protein diet favours bone integrity in adulthood.
    • Prescribing in mental health practice - the balancing act

      Green, Ben; University of Chester (SAGE, 2013-01-15)
      This book chapter aims to discuss the potential impact of psychiatric pharmacology on the physical health of people with mental health problems; discuss the potential impact of medical prescibing on those with mental health problems; and reflect on the role of the mental health practitioner in medication management.
    • Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

      Hyland, Mairead; Mennan, Claire; Wilson, Emma; Clayton, Aled; Kehoe, Oksana; School of Medicine, Keele University, School of Pharmacy and Bioengineering at the RJAH Orthopaedic Hospital, Chester Medical School, School of Medicine, Cardiff
      Umbilical cord mesenchymal stromal cells (UCMSCs) have shown an ability to modulate the immune system through the secretion of paracrine mediators, such as extracellular vesicles (EVs). However, the culture conditions that UCMSCs are grown in can alter their secretome and thereby affect their immunomodulatory potential. UCMSCs are commonly cultured at 21% O2 in vitro, but recent research is exploring their growth at lower oxygen conditions to emulate circulating oxygen levels in vivo. Additionally, a pro-inflammatory culture environment is known to enhance UCMSC anti-inflammatory potential. Therefore, this paper examined EVs from UCMSCs grown in normal oxygen (21% O2), low oxygen (5% O2) and pro-inflammatory conditions to see the impact of culture conditions on the EV profile. EVs were isolated from UCMSC conditioned media and characterised based on size, morphology and surface marker expression. EV protein cargo was analysed using a proximity-based extension assay. Results showed that EVs had a similar size and morphology. Differences were found in EV protein cargo, with pro-inflammatory primed EVs showing an increase in proteins associated with chemotaxis and angiogenesis. This showed that the UCMSC culture environment could alter the EV protein profile and might have downstream implications for their functions in immunomodulation.
    • 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.
    • The protein phosphatase 4 - PEA15 axis regulates the survival of breast cancer cells

      Mohammed, Hiba N.; Pickard, Mark R.; Mourtada-Maarabouni, Mirna; Keele University; University of Chester (Elsevier, 2016-06-15)
      BACKGROUND: The control of breast cell survival is of critical importance for preventing breast cancer initiation and progression. The activity of many proteins which regulate cell survival is controlled by reversible phosphorylation, so that the relevant kinases and phosphatases play crucial roles in determining cell fate. Several protein kinases act as oncoproteins in breast cancer and changes in their activities contribute to the process of transformation. Through counteracting the activity of oncogenic kinases, the protein phosphatases are also likely to be important players in breast cancer development, but this class of molecules is relatively poorly understood. Here we have investigated the role of the serine/threonine protein phosphatase 4 in the control of cell survival of breast cancer cells. METHODS: The breast cancer cell lines, MCF7 and MDA-MB-231, were transfected with expression vectors encoding the catalytic subunit of protein phosphatase 4 (PP4c) or with PP4c siRNAs. Culture viability, apoptosis, cell migration and cell cycle were assessed. The involvement of phosphoprotein enriched in astrocytes 15kDa (PEA15) in PP4c action was investigated by immunoblotting approaches and by siRNA-mediated silencing of PEA15. RESULTS: In this study we showed that PP4c over-expression inhibited cell proliferation, enhanced spontaneous apoptosis and decreased the migratory and colony forming abilities of breast cancer cells. Moreover, PP4c down-regulation produced complementary effects. PP4c is demonstrated to regulate the phosphorylation of PEA15, and PEA15 itself regulates the apoptosis of breast cancer cells. The inhibitory effects of PP4c on breast cancer cell survival and growth were lost in PEA15 knockdown cells, confirming that PP4c action is mediated, at least in part, through the de-phosphorylation of apoptosis regulator PEA15. CONCLUSION: Our work shows that PP4 regulates breast cancer cell survival and identifies a novel PP4c-PEA15 signalling axis in the control of breast cancer cell survival. The dysfunction of this axis may be important in the development and progression of breast cancer.
    • PWE-055 Stigma in inflammatory bowel disease: building resilience

      Dibley, Lesley; Norton, C.; Mason-Whitehead, Elizabeth; Kings College; University of Chester (BMJ Publishing Group, 2015-06-01)
      qualitative study aimed to: a) understand the experience of stigma in people with IBD and whether stigma derives from the bowel disorder diagnosis or from related FI; b) understand how stigma affects social, personal and emotional wellbeing, and how people with IBD manage these issues. Using purposive stratified sampling, 40 members of a UK IBD charity were recruited. Participants self-identified as having FI or not, and feeling stigmatised or not.