• Investigating the Prevalence of Anaemia in Rural Gambia, in Relation to Levels of Zinc Protoporphyrin, Haemoglobin and Haptoglobin (Phenotype and Genotype)

      Bah, Ebrima; Michelangeli, Frank (Oxford University Press (OUP), 2020-05-29)
      Abstract Objectives To find out the overlapping and correlating relationships between serum haptoglobin level, haptoglobin genotype and phenotype, blood haemoglobin level and zinc protoporphyrin (measured in washed RBCs) in association to prevalence of anaemia. It will focus on comparing all the mention components in contrast to each other. The study will also look for the frequency distribution of the major HP alleles. Methods 1278 participants were randomly selected. Blood samples collected by trained nurses. Data generation was done at the Medical research council (keneba field station) research site. Data Analysis was conducted at the university of Chester with the assistance of the computer department team. Results P = 0.000 indicating anaemia prevalence with HP 1 allele. P > 0.05 when ID, IDA and AI relates with HP genotype. Positive correlation between ZnPP and HP serum level, but negative between ZnPP and Hb. P = 0.000 between ZnPP and IDA. P = 0.024 between HP genotype and Hb level. P = 0.013 between HP genotype and HP serum. P = 0.100 between HP genotype and ZnPP. P = 0.000 between ZnPP and IDA. P = 0.024 between HP genotype and Hb. ZnPP shared a positive correlation with HP serum level, and a negative correlation with Hb level. The correlation significant = 0.01 level (2-tailed) P = 0.01. The correlation between HP genotype and HP serum level was significant with P = 0.013, but the correlation between HP genotype and ZnPP was not significant with P = 0.100. Conclusions HP genotype had association with anaemia prevalence and more occurrence was observed in carriers of the type ‘1’ allele. It had no association with ID, IDA and AI. HP genotype had association with HP serum level and Hb level but had no association with ZnPP level. ZnPP level was observed to have had association with HP serum level, Hb level and IDA; but had no association with ID and AI in the region. Funding Sources All the resources used in this study were from MRC Keneba (International Nutrition Group) which is supported by funds from the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement (Hennig et al., 2015).
    • Methadone‐Assisted Opiate Withdrawal and Subsequent Heroin Abstinence: The Importance of Psychological Preparedness

      Jones, Steven; Jack, Barbara; Kirby, Julie; Wilson, Thomas; Murphy, Philip; University of Chester
      Background and Objectives: Treatment guidelines emphasize patients’ readiness for transitioning from opiate substitution treatment (OST) to opiate withdrawal and abstinence. Psychological preparedness indicators for this transition were examined. Methods: Patients (all male) were recruited from three treatment settings: prison, an inpatient detoxification unit, and an outpatient clinic. Time 1 (T1) was admission to methadone‐assisted withdrawal in all settings. Time 2 (T2) was a 6‐month follow‐up. With n = 24 at T1 for each group (N = 72), a battery of instruments relevant to psychological preparedness was administered. Results: At T1, inpatients had higher self‐efficacy beliefs for successful treatment completion than prison patients. For patients contactable at T2, T1 self‐efficacy positively predicted T2 opiate abstinence. No other variable improved prediction. T1 SOCRATES (Stages of Change Readiness and Treatment Eagerness Scale) ambivalence scores, age, and lifetime heroin use duration predicted maintenance of contact or not with treatment services and contactability by the researcher. Measures of mood did not differ between groups at T1 or predict T2 outcomes. Discussion and Conclusions: Self‐efficacy beliefs are a potentially useful indicator of readiness for transitioning from OST to a medically assisted opiate withdrawal and subsequent abstinence. Ambivalence regarding change, age, and lifetime heroin use duration are potentially useful predictors of patients maintaining contact with services, and of being retained in research. Scientific Significance: These findings advance existing literature and knowledge by highlighting the importance of self‐efficacy in psychological preparedness for opiate abstinence, and the predictive utility to clinicians of this and other variables measurable at admission, in the clinical management of opiate users
    • Adherence to Pre-operative Exercise and the Response to Prehabilitation in Oesophageal Cancer Patients

      Halliday, Laura; Doganay, Emre; Winter-Blyth, Venetia; Osbourne, Hayley; Buckley, John P; Moorthy, Krishna; Imperial College London, University Centre Shrewsbury/Chester
      BACKGROUND: Prehabilitation is thought to reduce post-operative respiratory complications by optimising fitness before surgery. This prospective, single-centre study aimed to establish the effect of pre-operative exercise on cardiorespiratory fitness in oesophageal cancer patients and characterise the effect of adherence and weekly physical activity on response to prehabilitation. METHODS: Patients received a personalised, home-based pre-operative exercise programme and self-reported their adherence each week. Cardiorespiratory fitness (pVO2max and O2 pulse) was assessed at diagnosis, following completion of neoadjuvant chemotherapy (NAC) and immediately before surgery. Study outcomes included changes in fitness and post-operative pneumonia. RESULTS: Sixty-seven patients with oesophageal cancer underwent prehabilitation followed by surgery between January 2016 and December 2018. Fitness was preserved during NAC and then increased prior to surgery (pV02max Δ = +2.6 ml min-1, 95% CI 1.2-4.0 p = 0.001; O2 pulse Δ = +1.4 ml beat-1 95% CI 0.5-2.3 p = 0.001). Patients with higher baseline fitness completed more physical activity. Regression analyses found adherence was associated with improvement in fitness immediately before surgery (p = 0.048), and the amount of physical activity completed was associated with the risk of post-operative pneumonia (p = 0.035). CONCLUSION: Pre-operative exercise can maintain cardiorespiratory fitness during NAC and facilitate an increase in fitness before surgery. Greater exercise volumes were associated with a lower risk of post-operative pneumonia, highlighting the importance progressing exercise programmes throughout prehabilitation. Patients with high baseline fitness completed more physical activity and may require less supervision to reach their exercise goals. Further research is needed to explore stratified approaches to prehabilitation. KEYWORDS: Exercise therapy; Oesophageal cancer; Pre-operative care; Surgery
    • Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy

      Soltic, Darija; Shorrock, Hannah K; Allardyce, Hazel; Wilson, Emma L; Holt, Ian; Synowsky, Silvia A; Shirran, Sally L; Parson, Simon H; Gillingwater, Thomas H; Fuller, HR; et al.
      Cardiac pathology is emerging as a prominent systemic feature of spinal muscular atrophy (SMA), but little is known about the underlying molecular pathways. Using quantitative proteomics analysis, we demonstrate widespread molecular defects in heart tissue from the Taiwanese mouse model of severe SMA. We identify increased levels of lamin A/C as a robust molecular phenotype in the heart of SMA mice and show that lamin A/C dysregulation is also apparent in SMA patient fibroblast cells and other tissues from SMA mice. Lamin A/C expression was regulated in vitro by knockdown of the E1 ubiquitination factor ubiquitin-like modifier activating enzyme 1, a key downstream mediator of SMN-dependent disease pathways, converging on β-catenin signaling. Increased levels of lamin A are known to increase the rigidity of nuclei, inevitably disrupting contractile activity in cardiomyocytes. The increased lamin A/C levels in the hearts of SMA mice therefore provide a likely mechanism explaining morphological and functional cardiac defects, leading to blood pooling. Therapeutic strategies directed at lamin A/C may therefore offer a new approach to target cardiac pathology in SMA.
    • 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.
    • Submaximal Exercise Testing in Cardiovascular Rehabilitation Settings (BEST Study)

      Reed, Jennifer L; Cotie, LM; Cole, CA; Harris, Jennifer; Moran, B; Scott, K; Buckley, John P; Pipe, Andrew L; University of Ottawa, University Centre Shrewsbury/Chester
      Abstract BACKGROUND: This study compared changes in measured versus predicted peak aerobic power (V̇O2 peak) following cardiovascular rehabilitation (CR). Peak cardiopulmonary exercise testing (CPET) results were compared to four V̇O2 peak estimation methods: the submaximal modified Bruce treadmill, Astrand-Ryhming cycle ergometer, and Chester step tests, and the Duke Activity Status Index (DASI). METHODS: Adults with cardiovascular disease (CVD) who completed a 12-week CR program were assessed at baseline and 12 weeks follow-up. CPET, the DASI and three subsequent submaximal exercise tests were performed in a random order. RESULTS: Of the 50 adults (age: 57 ± 11 years) who participated, 46 completed the 12-week CR program and exercise tests. At baseline 69, 68, and 38% of the treadmill, step and cycle tests were successfully completed, respectively. At follow-up 67, 80, and 46% of the treadmill, step and cycle tests were successfully completed, respectively. No severe adverse events occurred. Significant improvements in V̇O2 peak were observed with CPET (3.6 ± 5.5 mL.kg-1.min-1, p < 0.001) and the DASI (2.3 ± 4.2 mL.kg-1.min-1, p < 0.001). Bland-Altman plots of the change in V̇O2 peak between CPET and the four V̇O2 peak estimation methods revealed the following: a proportional bias and heteroscedastic 95% limits of agreement (95% LoA) for the treadmill test, and for the cycle and step tests and DASI, mean bias' and 95% LoA of 1.0 mL.kg-1.min-1 (21.3, -19.3), 1.4 mL.kg-1.min-1 (15.0, -12.3) and 1.0 mL.kg-1.min-1 (13.8, -11.8), respectively. CONCLUSION: Given the greater number of successful tests, no serious adverse events and acceptable mean bias, the step test appears to be a valid and safe method for assessing group-level mean changes in V̇O2 peak among patients in CR. The DASI also appears to be a valid and practical questionnaire. Wide limits of agreement, however, limit their use to predict individual-level changes. Copyright © 2020 Reed, Cotie, Cole, Harris, Moran, Scott, Terada, Buckley and Pipe. KEYWORDS: cardiovascular diseases; exercise test; physiology; rehabilitation; submaximal
    • The importance of clinician, patient and researcher collaborations in Alport syndrome

      Rheault, Michelle N.; Savige, Judith; Randles, Michael J.; Weinstock, André; Stepney, Melissa; Turner, Neil; Parziale, Gina; Gross, Oliver; Flinter, Frances A; Miner, Jeffrey H; et al. (Springer Nature, 2019-05-01)
      Alport syndrome (AS) is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, AS is rare genetic disorder but still accounts for >1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in AS genes. The mainstay of current therapy is the use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a preconference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics, basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups.
    • Social and Clinical Correlates of Stimulant Use Disorder (Mephedrone) in a Tertiary Mental Health Setting in Mumbai: A Pilot Exploratory Study

      Rao, S. Poornima; Kale, Vinayak Pandurang; Panigrahi, Sunilkumar; Krishna, Murali; Jones, Steven; Majgi, Sumanth Mallikarjuna; Bharath, D. U.; University of Chester
      Introduction: Increasing mephedrone use is a major public health concern in India. There are limited data on sociodemographic determinants and psychiatric comorbidity associated with stimulant use disorder (mephedrone) (SUD‑M) from India. Aim: The primary objective of this study was to report the clinical and social correlates of SUD‑M among those presenting to specialist mental health services in Mumbai, India. Methods: Patients with SUD-M were recruited from a clinical setting. Standardized culturally validated assessments were carried out to obtain information about sociodemographics and mental health: comorbid psychopathology Brief Psychiatric Rating Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Minnesota Multiphasic Personality Inventory‑2 for personality traits and a clinical assessment for diagnoses of mental disorders. Results: Seventy patients (aged between 21 and 30 years, of whom 58 men) with SUD-M consented. SUD‑M was more common among young men from the low socioeconomic position. The most common reasons for choosing mephedrone over other substances were better high from the drug and peer pressure. There were no associations between sociodemographic factors with the severity of SUD-M. Around 40% of the patients with SUD-M had psychiatric comorbidity. Psychotic disorders and anxiety symptoms were most common. Family history of substance use, comorbid substance use, and comorbid psychiatric disorders were directly related to the severity of SUD-M. Conclusions: This was a cross‑sectional study with a relatively smaller sample size of self‑nominating participantslimiting the generalizability of findings to a wider population. Therapeutic implication of this finding is that prompt attention and treatment of the comorbid psychiatric disorder is essential while treating patients with SUD-M. Further population-based studies are recommended for a better understanding of the burden of SUD-M.
    • Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca

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

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

      Regland, Björn; McCaddon, Andrew (IOS Press, 2019-03-29)
    • Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells

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

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

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

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

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

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

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

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

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