• 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.
    • 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.
    • 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.
    • 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.
    • 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.
    • 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.
    • 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.
    • 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.
    • A single dose of ChAdOx1 Chik vaccine induces neutralising antibodies against four chikungunya virus lineages in a phase 1 clinical trial

      Folegatti, Pedro M.; Harrison, Kate; Preciado-Llanes, Lorena; Ramos Lopez, Fernando; Bittaye, Mustapha; Kim, Young Chan; Flaxman, Amy; Bellamy, Duncan; Makinson, Rebecca; Sheridan, Jonathan; et al. (Nature Research, 2021-07-30)
      Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18–50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and Tcell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT50 seroconversion after a single dose.
    • 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.
    • A massively multi-scale approach to characterizing tissue architecture by synchrotron micro-CT applied to the human placenta

      Tun, W. M; Poologasundarampillai, G.; Bischof, H.; Nye, Gareth; King, O. N. F.; Basham, M.; Tokudome, Y.; Lewis, R. M.; Johnstone, E. D.; Brownbill, P; et al. (The Royal Society, 2021-06-02)
      Multi-scale structural assessment of biological soft tissue is challenging but essential to gain insight into structure–function relationships of tissue/organ. Using the human placenta as an example, this study brings together sophisticated sample preparation protocols, advanced imaging and robust, validated machine-learning segmentation techniques to provide the first massively multi-scale and multi-domain information that enables detailed morphological and functional analyses of both maternal and fetal placental domains. Finally, we quantify the scale-dependent error in morphological metrics of heterogeneous placental tissue, estimating the minimal tissue scale needed in extracting meaningful biological data. The developed protocol is beneficial for high-throughput investigation of structure–function relationships in both normal and diseased placentas, allowing us to optimize therapeutic approaches for pathological pregnancies. In addition, the methodology presented is applicable in the characterization of tissue architecture and physiological behaviours of other complex organs with similarity to the placenta, where an exchange barrier possesses circulating vascular and avascular fluid spaces.
    • 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.
    • 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.
    • The Comparative Effects of Mesenchymal Stem Cell Transplantation Therapy for Spinal Cord Injury in Humans and Animal Models: A Systematic Review and Meta-Analysis

      Johnson, Louis D. V.; email: louisdvj@gmail.com; Pickard, Mark R.; email: m.pickard@chester.ac.uk; Johnson, William E. B.; email: eustace.johnson@chester.ac.uk (MDPI, 2021-03-16)
      Animal models have been used in preclinical research to examine potential new treatments for spinal cord injury (SCI), including mesenchymal stem cell (MSC) transplantation. MSC transplants have been studied in early human trials. Whether the animal models represent the human studies is unclear. This systematic review and meta-analysis has examined the effects of MSC transplants in human and animal studies. Following searches of PubMed, Clinical Trials and the Cochrane Library, published papers were screened, and data were extracted and analysed. MSC transplantation was associated with significantly improved motor and sensory function in humans, and significantly increased locomotor function in animals. However, there are discrepancies between the studies of human participants and animal models, including timing of MSC transplant post-injury and source of MSCs. Additionally, difficulty in the comparison of functional outcome measures across species limits the predictive nature of the animal research. These findings have been summarised, and recommendations for further research are discussed to better enable the translation of animal models to MSC-based human clinical therapy.
    • Acute glycaemic management before, during and after exercise for cardiac rehabilitation participants with diabetes mellitus; a joint statement of the British and Canadian Associations of Cardiovascular Prevention and Rehabilitation, the International Council for Cardiovascular Prevention and Rehabilitation and the British Association of Sport and Exercise Sciences

      Buckley, J.P.; Riddell, Michael; Mellor, Duane; Bracken, Richard; Ross, Marie-Kristelle; LaGerche, Andre; Poirier, Paul; University of Chester; University College London; York University, Toronto; LMC Healthcare; Aston University; Swansea University College of Engineering; Laval University; Baker Heart and Diabetes Institute; St Vincent's Hospital Melbourne; Institut universitaire de cardiologie et de pneumologie de Québec (BMJ, 2020-12-23)
      Type 1 (T1) and type 2 (T2) diabetes mellitus (DM) are significant precursors and comorbidities to cardiovascular disease and prevalence of both types is still rising globally. Currently,~25% of participants (and rising) attending cardiac rehabilitation in Europe, North America and Australia have been reported to have DM (>90% have T2DM). While there is some debate over whether improving glycaemic control in those with heart disease can independently improve future cardiovascular health-related outcomes, for the individual patient whose blood glucose is well controlled, it can aid the exercise programme in being more efficacious. Good glycaemic management not only helps to mitigate the risk of acute glycaemic events during exercising, it also aids in achieving the requisite physiological and psycho-social aims of the exercise component of cardiac rehabilitation (CR). These benefits are strongly associated with effective behaviour change, including increased enjoyment, adherence and self-efficacy. It is known that CR participants with DM have lower uptake and adherence rates compared with those without DM. This expert statement provides CR practitioners with nine recommendations aimed to aid in the participant’s improved blood glucose control before, during and after exercise so as to prevent the risk of glycaemic events that could mitigate their beneficial participation.
    • 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.
    • History of traction

      Flynn, Sandra (Elsevier, 2020-10-01)
    • 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.
    • Comparing physician associates and foundation year two doctors-in-training undertaking emergency medicine consultations in England: a mixed-methods study of processes and outcomes

      Halter, Mary; orcid: 0000-0001-6636-0621; Drennan, Vari; orcid: 0000-0002-8915-5185; Wang, Chao; Wheeler, Carly; Gage, Heather; Nice, Laura; de Lusignan, Simon; orcid: 0000-0001-5613-6810; Gabe, Jonathan; Brearley, Sally; Ennis, James; et al. (BMJ Publishing Group, 2020-09-01)
      Objectives: To compare the contribution of physician associates to the processes and outcomes of emergency medicine consultations with that of foundation year two doctors-in-training. Design: Mixed-methods study: retrospective chart review using 4 months’ anonymised clinical record data of all patients seen by physician associates or foundation year two doctors-in-training in 2016; review of a subsample of 40 records for clinical adequacy; semi-structured interviews with staff and patients; observations of physician associates. Setting: Three emergency departments in England. Participants: The records of 8816 patients attended by 6 physician associates and 40 foundation year two doctors-in-training; of these n=3197 had the primary outcome recorded (n=1129 physician associates, n=2068 doctor); 14 clinicians and managers and 6 patients or relatives for interview; 5 physician associates for observation. Primary and secondary outcome measures: The primary outcome was unplanned re-attendance at the same emergency department within 7 days. Secondary outcomes: consultation processes, clinical adequacy of care, and staff and patient experience. Results: Re-attendances within 7 days (n=194 (6.1%)) showed no difference between physician associates and foundation year two doctors-in-training (OR 0.87, 95% CI 0.61 to 1.24, p=0.437). If seen by a physician associate, patients were more likely receive an X-ray investigation (OR 2.10, 95% CI 1.72 to 4.24), p<0.001), after adjustment for patient characteristics, triage severity of condition and statistically significant clinician intraclass correlation. Clinical reviewers found almost all patients’ charts clinically adequate. Physician associates were evaluated as assessing patients in a similar way to foundation year two doctors-in-training and providing continuity in the team. Patients were positive about the care they had received from a physician associate, but had poor understanding of the role. Conclusions: Physician associates in emergency departments in England treated patients with a range of conditions safely, and at a similar level to foundation year two doctors-in-training, providing clinical operational efficiencies.