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.

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  • 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.
  • Small-RNA Sequencing Reveals Altered Skeletal Muscle microRNAs and snoRNAs Signatures in Weanling Male Offspring from Mouse Dams Fed a Low Protein Diet during Lactation

    Kanakis, Ioannis; Alameddine, Moussira; Folkes, Leighton; Moxon, Simon; Myrtziou, Ioanna; Ozanne, Susan E.; Peffers, Mandy J.; Goljanek-Whysall, Katarzyna; Vasilaki, Aphrodite; University of Liverpool; University of Chester; University of East Anglia; University of Cambridge; NUI Galway (MDPI, 2021-05-11)
    Maternal diet during gestation and lactation affects the development of skeletal muscles in offspring and determines muscle health in later life. In this paper, we describe the association between maternal low protein diet-induced changes in offspring skeletal muscle and the differential expression (DE) of small non-coding RNAs (sncRNAs). We used a mouse model of maternal protein restriction, where dams were fed either a normal (N, 20%) or a low protein (L, 8%) diet during gestation and newborns were cross-fostered to N or L lactating dams, resulting in the generation of NN, NL and LN offspring groups. Total body and tibialis anterior (TA) weights were decreased in weanling NL male offspring but were not different in the LN group, as compared to NN. However, histological evaluation of TA muscle revealed reduced muscle fibre size in both groups at weaning. Small RNA-sequencing demonstrated DE of multiple miRs, snoRNAs and snRNAs. Bioinformatic analyses of miRs-15a, -34a, -122 and -199a, in combination with known myomiRs, confirmed their implication in key muscle-specific biological processes. This is the first comprehensive report for the DE of sncRNAs in nutrition-associated programming of skeletal muscle development, highlighting the need for further research to unravel the detailed molecular mechanisms.
  • MicroRNAs as central regulators of adult myogenesis and proteostasis loss in skeletal muscle ageing

    Kanakis, Ioannis; Myrtziou, Ioanna; Goljanek-Whysall, Katarzyna; Vasilaki, Aphrodite; University of Liverpool; University of Chester; NUI Galway (CRC Press, 2021-11-23)
    Sarcopenia (from the Greek words sarca (σάρκα) = flesh and penia (πενία) = deficiency) is considered as an age-associated disease, characterized by dysregulation of the balance between muscle hypertrophy, atrophy and regeneration, which leads to advanced loss of skeletal muscle mass and function associated with a high risk of falls and fractures in the elderly. Numerous studies in humans and animals have explored the pathophysiology of musculoskeletal aging but the detailed mechanisms that contribute to skeletal muscle dysfunction have not been yet fully elucidated. Recently, several studies have focused on the role of microRNAs as a dynamic and promising epigenetic mechanism which may regulate post-transcriptional gene expression that modulate skeletal muscle homeostasis. In this chapter, we describe the crucial role of microRNAs in skeletal myogenesis during adulthood and their association with the pathogenesis of sarcopenia linked to proteostasis loss.
  • Age-related changes in microRNAs expression in cruciate ligaments of wild-stock house mice

    Nye, Gareth; Kharaz, Yalda; Goljanek‐Whysall, Katarzyna; Hurst, Jane; McArdle, Anne; Comerford, Eithne; University of Chester; University of Liverpool
    Cruciate ligaments (CL) of the knee joint are injured following trauma or aging. MicroRNAs (miRs) are potential therapeutic targets in musculoskeletal disorders, but there is little known about the role of miRs and their expression ligaments during aging. This study aimed to (1) identify if mice with normal physical activity, wild-stock house mice are an appropriate model to study age-related changes in the knee joint and (2) investigate the expression of miRs in aging murine cruciate ligaments. Knee joints were collected from 6 and 24 months old C57BL/6 and wild-stock house mice (Mus musculus domesticus) for ligament and cartilage (OARSI) histological analysis. Expression of miR targets in CLs was determined in 6-, 12-, 24-, and 30-month-old wild-stock house mice, followed by the analysis of predicted mRNA target genes and Ingenuity Pathway Analysis. Higher CL and knee OARSI histological scores were found in 24-month-old wild-stock house mice compared with 6- and 24-month-old C57BL/6 and 6-month-old wild-stock house mice (p < 0.05). miR-29a and miR-34a were upregulated in 30-month-old wild-stock house mice in comparison with 6-, 12-, and 24-month-old wild-stock house mice (p < 0.05). Ingenuity Pathway Analysis on miR-29a and 34a targets was associated with inflammation through interleukins, TGFβ and Notch genes, and p53 signaling. Collagen type I alpha 1 chain (COL1A1) correlated negatively with both miR-29a (r = −0.35) and miR-34a (r = −0.33). The findings of this study support wild-stock house mice as an appropriate aging model for the murine knee joint. This study also indicated that miR-29a and miR-34a may be potential regulators of COL1A1 gene expression in murine CLs.
  • Chapter 5: Applying Proteomics to Investigate Extracellular Matrix in Health and Disease

    Randles, Michael; Lennon, Rachel; University of Manchester; Manchester Academic Health Science Centre (Academic Press, 2015-11-23)
    The molecular composition of basement membranes (BMs) has traditionally been investigated by candidate-based approaches leading to the identification of key structural components as described in previous chapters. Laminins, collagen IV, nidogens, perlecan, and type XV/XVIII collagen are integral to BMs with isoforms showing tissue specificity. More recently the application of mass spectrometry (MS)-based proteomics has led to the discovery of many more structural and regulatory components of BMs and more broadly, extracellular matrix (ECM). These investigations have revealed tissue-specific signatures of between 100 and 150 ECM components, demonstrating the complexity of the extracellular niche. In addition to providing a structural scaffold for cells, ECM is a dynamic extracellular environment capable of regulating the physical properties of tissues. Global investigations of ECM with proteomics in turn enable systems level analyses and when applied to health and disease states these investigations provide insights into pathways regulating matrix dysregulation. This chapter focuses on the methods used to extract ECM and on the analysis of its composition using MS-based proteomics, and it provides examples of how these approaches have been used to investigate health and disease states.
  • Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder

    Roberts, Neil A.; Hilton, Emma N.; Lopes, Filipa M.; Singh, Subir; Randles, Michael J.; Gardiner, Natalie J.; Chopra, Karl; Coletta, Riccardo; Bajwa, Zunera; Hall, Robert J.; et al. (Elsevier, 2019-03-08)
    Mutations in leucine-rich-repeats and immunoglobulin-like-domains 2 (LRIG2) or in heparanase 2 (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that urofacial syndrome has a neural basis, but it is unknown whether defects in urinary bladder innervation are present. We hypothesized that urofacial syndrome features a peripheral neuropathy of the bladder. Mice with homozygous targeted Lrig2 mutations had urinary defects resembling those found in urofacial syndrome. There was no anatomical blockage of the outflow tract, consistent with a functional bladder outlet obstruction. Transcriptome analysis revealed differential expression of 12 known transcripts in addition to Lrig2, including 8 with established roles in neurobiology. Mice with homozygous mutations in either Lrig2 or Hpse2 had increased nerve density within the body of the urinary bladder and decreased nerve density around the urinary outflow tract. In a sample of 155 children with chronic kidney disease and urinary symptoms, we discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome, and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract.
  • Identification of an Altered Matrix Signature in Kidney Aging and Disease

    Randles, Michael; Lausecker, Franziska; Kong, Qingyang; Suleiman, Hani; Reid, Graeme; Kolatsi-Joannou, Maria; Davenport, Bernard; Tian, Pinyuan; Falcone, Sara; Potter, Paul; et al. (American Society of Nephrology, 2021-06-30)
    Background: Accumulation of extracellular matrix in organs and tissues is a feature of both aging and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in function, which current therapies cannot address, leading to organ failure. Although histologic and ultrastructural patterns of excess matrix form the basis of human disease classifications, a comprehensive molecular resolution of abnormal matrix is lacking. Methods: Using mass spectrometry–based proteomics, we resolved matrix composition over age in mouse models of kidney disease. We compared the changes in mice with a global characterization of human kidney matrix during aging and to existing kidney disease datasets to identify common molecular features. Results: Ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during aging and kidney disease progression in mice. Within the altered matrix, basement membrane components (laminins, type IV collagen, type XVIII collagen) were reduced and interstitial matrix proteins (collagens I, III, VI, and XV; fibrinogens; and nephronectin) were increased, a pattern also seen in human kidney aging. Indeed, this signature of matrix proteins was consistently modulated across all age and disease comparisons, and the increase in interstitial matrix was also observed in human kidney disease datasets. Conclusions: This study provides deep molecular resolution of matrix accumulation in kidney aging and disease, and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.
  • Basement membrane ligands initiate distinct signalling networks to direct cell shape

    Randles, Michael; Lausecker, Franziska; Humphries, Jonathan D.; Byron, Adam; Clark, Simon J.; Miner, Jeffrey H.; Zent, Roy; Humphries, Martin J.; Lennon, Rachel; The University of Manchester; University of Edinburgh; Eberhard Karls University of Tübingen; Washington University School of Medicine; Vanderbilt University Medical Center; Royal Manchester Children's Hospital; Manchester Academic Health Science Centre; University of Chester (Elsevier, 2020-03-06)
    Cells have evolved mechanisms to sense the composition of their adhesive microenvironment. Although much is known about general mechanisms employed by adhesion receptors to relay signals between the extracellular environment and the cytoskeleton, the nuances of ligand-specific signalling remain undefined. Here, we investigated how glomerular podocytes, and four other basement membrane-associated cell types, respond morphologically to different basement membrane ligands. We defined the composition of the respective adhesion complexes using mass spectrometry-based proteomics. On type IV collagen, all epithelial cell types adopted a round morphology, with a single lamellipodium and large adhesion complexes rich in actin-binding proteins. On laminin (511 or 521), all cell types attached to a similar degree but were polygonal in shape with small adhesion complexes enriched in endocytic and microtubule-binding proteins. Consistent with their distinctive morphologies, cells on type IV collagen exhibited high Rac1 activity, while those on laminin had elevated PKCa. Perturbation of PKCa was able to interchange morphology consistent with a key role for this pathway in matrix ligand-specific signalling. Therefore, this study defines the switchable basement membrane adhesome and highlights two key signalling pathways within the systems that determine distinct cell morphologies. Proteomic data are available via ProteomeXchange with identifier PXD017913.
  • 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.
  • The kidney matrisome in health, aging and disease

    Lausecker, Franziska; Lennon, Rachel; Randles, Michael J.; The University of Manchester; University of Chester (Elsevier, 2022-07-20)
    Dysregulated extracellular matrix is the hallmark of fibrosis, and it has a profound impact on kidney function in disease. Furthermore, perturbation of matrix homeostasis is a feature of aging and is associated with declining kidney function. Understanding these dynamic processes, in the hope of developing therapies to combat matrix dysregulation, requires the integration of data acquired by both well-established and novel technologies. Owing to its complexity, the extracellular proteome, or matrisome, still holds many secrets and has great potential for the identification of clinical biomarkers and drug targets. The molecular resolution of matrix composition during aging and disease has been illuminated by cutting-edge mass spectrometry-based proteomics in recent years, but there remain key questions about the mechanisms that drive altered matrix composition. Basement membrane components are particularly important in the context of kidney function; and data from proteomic studies suggest that switches between basement membrane and interstitial matrix proteins are likely to contribute to organ dysfunction during aging and disease. Understanding the impact of such changes on physical properties of the matrix, and the subsequent cellular response to altered stiffness and viscoelasticity, is of critical importance. Likewise, the comparison of proteomic datasets from multiple organs is required to identify common matrix biomarkers and shared pathways for therapeutic intervention. Coupled with single cell transcriptomics there is the potential to identify the cellular origin of matrix changes, which could enable cell targeted therapy. This review provides a contemporary perspective of the complex kidney matrisome and draws comparison to altered matrix in heart and liver disease.
  • Intellectual disability and autism in adults influence psychological treatments for mental health conditions

    Mills, Rachel; Soper, Paul; Michelet, Felix; Stewart, Alex; Jaydeokar, Sujeet; University of Chester
    Mental health conditions are often underdiagnosed in adults with intellectual disability and do not always receive psychological interventions as recommended by the National Institute for Health and Care Excellent guidelines. To realise the national UK programme’s aim of stopping overuse of medications in people with intellectual disability, it is important that these individuals have access to appropriate non-pharmacological interventions. We examined the relationship between an individual’s level of intellectual disability and presence or absence of autism with access to relevant non-pharmacological interventions from specialist community intellectual disability services. A cross-sectional study of adults accessing four specialist intellectual disability services in North West England in 2019. There was high prevalence of mental health co-morbidity, even higher for autistic adults. However, a relatively small percentage of the study population were receiving psychological interventions. The most frequent non-pharmacological intervention was positive behaviour support plan, irrespective of comorbid mental illnesses. Not having access to psychological interventions for the treatment of mental illness could result in poor health outcomes and increasing health inequalities. The study highlights the need for developing psychological interventions particularly for those with moderate to severe intellectual disability and for those with associated autism. This large sample study examined the relationship between intellectual disability level and presence of autism with accessing psychological interventions.
  • Co-production of post-diagnostic psychosocial interventions with carers of people with intellectual disability and dementia

    Acton, Daniel; Duncan, Caroline; Jaydeokar, Sujeet; Cheshire and Wirral Partnership NHS Foundation Trust; University of Chester (Emerald, 2022-04-21)
    This paper aims to underline the importance of using a collaborative approach when designing and adapting a post diagnostic psychosocial intervention of cognitive stimulation therapy (CST) for people with intellectual disability and dementia. As part of a service improvement, a manual of CST was adapted, for delivery in clinical practice. A qualitative co-production method allowed participants with a lived experience to provide regular feedback relating to the development of the adapted CST manual and intervention programme. This feedback was used to make continual development changes to the CST manual. The study demonstrated co-production with those who provide care is valuable in adapting psychosocial therapies for people with an intellectual disability and dementia. Additional findings identified the need for carer education in ageing, dementia care, and the physical health needs for older people with intellectual disability. This is the first study that has used a co-production approach with families and carers in adapting a group therapy programme for people with an intellectual disability. This paper underlines the need for post diagnostic clinical interventions for people with dementia and those who provide care.
  • An Audit on the Adherence to Antipsychotic Prescription Policy for the Management of Delirium in the Medical Wards.

    Simiyon, Manjula; Loo, Jiann; Baker, Catherine; Lepping, Peter; Jones, Steven; Betsi Cadwaladr University Health Board; University of Chester (Cambridge University Press, 2022-06-20)
    This audit aimed to assess the adherence to the antipsychotic policy for delirium in the medical wards. It aimed to assess compliance with each of the guidelines mentioned in the health board’s policy which is based on the National Institute for Health and Cares Excellence (NICE) guidelines.
  • The shock of the new! The introduction of physical methods of treatment in psychiatry in Britain and Europe, 1922-1944

    Jones, Steven; Jones, Colin; University of Chester
    Physical treatments in the UK , convulsive therapy including ECT from 1922-1944
  • A pilot study of a single intermittent arm cycling exercise programme on people affected by Facioscapulohumeral dystrophy (FSHD)

    editor: Vousden, George; Philp, Fraser; orcid: 0000-0002-8552-7869; email: f.philp@liverpool.ac.uk; Kulshrestha, Richa; Emery, Nicholas; Arkesteijn, Marco; Pandyan, Anand; Willis, Tracey (Public Library of Science, 2022-06-24)
    For patients affected by Facioscapulohumeral dystrophy (FSHD), alternate methods for increasing physical activity engagement that may benefit shoulder function and wider health are needed. Arm cycling has been proposed as a potential method for achieving this although dosage parameters and evidence is limited. The aim of this study was to conduct a pilot study evaluating the effect of a single intermittent arm cycling exercise programme on people affected by FSHD. People with confirmed genetic diagnosis of FSHD between the ages 18–60 years were recruited to attend a single session for the exercise intervention (5 exercise efforts lasting 2 minutes each with 30 seconds of rest between each effort). Prior to exercise, measures of shoulder function (Oxford shoulder score), strength and range of movement were recorded. During the exercise participants were video recorded to quantify range of movement and extract movement profile features. Participants comments were recorded and followed up four days later to check for adverse events. Fifteen participants, (6F:9M) were recruited with median (IQR) Oxford Shoulder Scores of 25 (18 to 39). All participants successfully completed the exercise intervention with only transient symptoms consistent with exercise being reported and achieving a median (IQR) rate of perceived exertion scores of 13 (12 to 13). Movement profile data was available for 12 out of 15 participants and suggests that exercise intensity did not compromise movement. An association between strength and shoulder function (R2 = 0.5147), Rate of perceived exertion (RPE) of the final effort against shoulder function and strength (R2 = 0.2344 and 0.1743 respectively) was identified. Participant comments were positive regarding the exercise intervention. Our study demonstrates that an intermittent arm cycling programme is feasible for people affected by FSHD. Further work is needed to evaluate physiological responses to exercise across variations in programme variables and equipment set up in a larger sample of people affected by FSHD.
  • Constructing and conceptualizing suicide and self-harm

    Jones, Steven; Nathan, Taj; University of Chester
    The chapter on ‘’ Contextualising suicide and self-harm’ ’provides an overview of suicide and self-harm, with particular focus to social theory, epidemiology, societal attitudes, law and ethics, and management strategies. Suicide and self-harm rates, and are explored from a national and international perspectives. The authors examine self-harm and suicide grounded in theory and practice, taking account of both societal and individual domains. The aim is to explore the conceptualisation of suicide and self-harm and relate it to the evidence base. The chapter commences with suicide models and aims to equip the reader with a framework to explore this sensitive topic; Durkheim is used to allow readers to challenge their knowledge and attitudes. Suicide and self-harm statistics are reported before offering some context to them. Suicide is a human tragedy and no amount of theories, statistics or facts will change its far-reaching impact. We have attempted to address the consequences of self-harm and suicide on the individual and their family unit. Media portrayal, assessment, prevention strategies, legislation and knowledge and attitudes to suicide are explored.
  • An Investigation of Interactions between Heat Shock Proteins and the Immune System

    Williams, John; Michelangeli, Frank; Jones, Christopher; Seabra, Laurence; Ogbodo, Emmanuel (University of Chester, 2021-03)
    The human body initiates an inflammatory immune response following exposure to certain danger signals. The Danger Model proposes that Antigen-presenting cells (APCs) can be activated by danger or alarm signals. These danger signals come from exogenous molecules such as pathogens, toxins, or even mechanical cell damage. Damage due to cellular stress can initiate the extracellular release of endogenous molecules, such as heat shock proteins (HSPs) into the extracellular environment. HSPs can act as danger signals triggering the immune response. This immune response is based on antigen recognition by specific cell surface receptor proteins, and T-cells, which then determine the type of inflammatory (pro or anti-inflammatory) cytokines produced or expressed. This thesis investigates the effects of Hsp72 and Hsp27 in the activation of immune cells to secrete cytokines, which are upregulated during inflammatory responses. In determining the role of HSPs in affecting inflammatory immune responses, U937 cells, U937 macrophages, and peripheral blood mononuclear cells (PBMCs) were used. To determine whether the effects observed with recombinant HSPs used in these studies, were due to bacterial contamination: U937 macrophages were exposed either to denatured HSPs, polymyxin B (which can neutralise bacterial lipopolysaccharides), anti-HSPs antibodies, or receptor proteins blocking peptides, and their ability to induce cytokine (ie IL-1β, TNF-α, and IL-10) secretion were analysed using enzyme-linked immunosorbent assays (ELISA). Western blotting was used to confirm the presence of Hsp72, Hsp27, and Hsp60 in U937 cells and U937 macrophage. Flow cytometry was used to identify the expression of immune responsive receptor proteins such as CD14, CD36, CD11b, TLR2, TLR4, TLR5, and TLR7, on U937 cells and U937 macrophages. The result presented in this thesis also showed that Hsp72 and Hsp27 can stimulate immune responses independent of bacterial contamination. These HSPs are able to induce an inflammatory immune response, possibly through interactions with a number of immune responsive receptor proteins, which were identified in U937 cells and U937 macrophages. Further evidence using CD14, CD36, CD11b, TLR2, TLR4, TLR5, and TLR7 blocking peptides, also confirmed that an interaction between cytokine secretion caused by, Hsp72 and Hsp27 were likely due to their interactions with specific immune responsive receptor proteins. Interestingly, some of the receptor proteins identified are not activated by lipopolysaccharide (LPS), again highlighting the fact that the results presented in this thesis, are unlikely to be artifacts caused by bacterial contamination. Furthermore, it is clear that HSPs are interacting with numerous receptor proteins, and possibly more than even demonstrated in this thesis. This therefore highlights the promiscuous nature of HSPs interaction with different signalling pathways through the different receptor proteins. The promiscuous property of HSPs could thus be used for the treatment of diseases, since HSPs have been linked with many diseases, including cancer. Therefore, understanding the full relationship between HSPs and these signalling pathways, may prove promising in using HSPs for therapeutic purposes in future.
  • 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.
  • Treatment-Free Remission in Chronic Myeloid Leukemia: Can We Identify Prognostic Factors?

    Lucas, Claire; Saifullah, Hilbeen H.; University of Chester; University of Liverpool (MDPI, 2021-08-19)
    Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40–60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon retreatment, indicating TKI discontinuation is safe. However, there is still a gap in understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it examines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.
  • Uncertainty, Anxiety and Isolation: Experiencing the COVID-19 Pandemic and Lockdown as a Woman with Polycystic Ovary Syndrome (PCOS)

    Atkinson, Lou; Kite, Chris; McGregor, G; James, Tamsin; Clark, Cain C T; Randeva, Harpal S; Kyrou, Ioannis; Aston University; University of Chester; Coventry University; University Hospitals Coventry and Warwickshire; University of Warwick
    Background: The COVID-19 pandemic and the related lockdown measures presented a significant risk to physical and mental wellbeing in affected populations. Women with polycystic ovary syndrome (PCOS) are predisposed to several cardio-metabolic risk factors which increase the susceptibility to severe COVID-19 and also exhibit increased likelihood of impaired mental health wellbeing. Therefore, these women who usually receive care from multiple primary and specialist healthcare services may be disproportionately impacted by this pandemic and the related restrictions. This study aimed to explore the lived experience of the first UK national lockdown as a woman with PCOS. Methods: As part of a larger cross-sectional study, 12 women with PCOS living in the UK during the first national COVID-19 lockdown were recruited to a qualitative study. Telephone interviews were conducted in June/July of 2020, and data collected were subjected to thematic analysis. Results: Five themes were identified. “My PCOS Journey” describes participants’ experiences of diagnosis, treatment and ongoing management of their PCOS. “Living Through Lockdown” describes the overall experience and impact of the lockdown on all aspects of participants’ lives. “Self-care and Managing Symptoms” describe multiple challenges to living well with PCOS during the lockdown, including lack of access to supplies and services, and disruption to weight management. “Healthcare on Hold” describes the uncertainty and anxiety associated with delays in accessing specialised healthcare for a range of PCOS aspects, including fertility treatment. “Exacerbating Existing Issues” captures the worsening of pre-existing mental health issues, and an increase in health anxiety and feelings of isolation. Conclusion: For the women with PCOS in this study, the COVID-19 pandemic and the first national lockdown was mostly experienced as adding to the pre-existing challenges of living with their condition. The mental health impact experienced by the study participants was increased due to lack of access to their normal support strategies, limitations on healthcare services and uncertainty about their risk of COVID-19.

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