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  • ItemOpen AccessAccepted version Peer-reviewed
    Avoiding iatrogenic injury during portal placement in hip arthroscopy.
    (Royal Society of Medicine, 2016-11-08) Sunil Kumar, KH; Lisenda, L; Khanduja, V; Sunil Kumar, Karadi Hari [0000-0002-9461-7946]; Khanduja, Vikas [0000-0001-9454-3978]
    Hip arthroscopy has gained immense popularity in the treatment of many intra and extra-articular pathologies in and around the hip joint. The anterolateral portal is the most common portal used to establish access at arthroscopy and being the first, it has to be placed blindly under image intensifier guidance. The subsequent portals are placed under direct arthroscopic visualisation. Iatrogenic acetabular labral injury (IALI) has been reported to occur during the first portal placement and its incidence varies from 0.67% to 20%.1–3 We present an easy technique to prevens IALI.
  • ItemOpen AccessAccepted version Peer-reviewed
    Approaches and advances in the genetic causes of autoimmune disease and their implications
    (Springer Nature, 2018-06-20) Inshaw, JRJ; Cutler, AJ; Burren, OS; Stefana, MI; Todd, JA; Burren, Oliver [0000-0002-3388-5760]
    Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Although the field is just over 10 years old, advances in understanding the underlying mechanistic pathways of these conditions, which result from a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights into therapeutic possibilities. Nevertheless, the challenge of identifying the actual causal genes and pathways and their biological effects on altering disease risk remains for many identified susceptibility regions. It is this fundamental knowledge that will underpin the revolution in patient stratification, the discovery of therapeutic targets and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardized gene-expression data and other phenotypic data that are fueling a bounty of discovery and improved understanding of human physiology.
  • ItemOpen AccessAccepted version Peer-reviewed
    What Is the Risk Posed to the Lateral Femoral Cutaneous Nerve During the Use of the Anterior Portal of Supine Hip Arthroscopy and the Minimally Invasive Anterior Approach for Total Hip Arthroplasty?
    (Elsevier, 2018-06) Bartlett, Jonathan D; Lawrence, John E; Khanduja, Vikas; Khanduja, Vikas [0000-0001-9454-3978]
    PURPOSE: To determine: (1) What is the proximity of the lateral femoral cutaneous nerve (LFCN) to the anterior portal (AP) used in supine hip arthroscopy? (2) What is the proximity of the LCFN to the incision in the minimally invasive anterior approach (MIAA) for total hip arthroplasty? (3) What effect does lateralizing the AP have on the likelihood of nerve injury? (4) What branching patterns are observable in the LFCN? METHODS: Forty-five hemipelves were dissected. The LFCN was identified and its path dissected. The positions of the nerve in relation to the AP and the MIAA incision were measured. RESULTS: The AP intersected with 38% of nerves. In the remainder, the LFCN was located 5.7 ± 4.5 mm from the portal's edge. In addition, 44% of nerves crossed the incision of the MIAA. Of those that did not, the average minimum distance from the incision was 14.4 ± 7.0 mm. We found a significant reduction in risk if the AP is moved medially by 5 mm or laterally by 15 mm (P = .0054 and P = .0002). The LFCN showed considerable variation with 4 branching variants. CONCLUSIONS: These results show that the LFCN is at high risk during supine hip arthroscopy and the MIAA, emphasizing the need for meticulous dissection. We suggest that relocation of the AP 5 mm medially or 15 mm laterally will reduce the risk to the LFCN. CLINICAL RELEVANCE: These findings should aid surgeons in minimizing the risk to the LCFN during hip arthroscopy and the minimally invasive anterior approach to the hip.
  • ItemOpen AccessPublished version Peer-reviewed
    The African Genome Variation Project shapes medical genetics in Africa.
    (Springer Science and Business Media LLC, 2015-01-15) Gurdasani, Deepti; Carstensen, Tommy; Tekola-Ayele, Fasil; Pagani, Luca; Tachmazidou, Ioanna; Hatzikotoulas, Konstantinos; Karthikeyan, Savita; Iles, Louise; Pollard, Martin O; Choudhury, Ananyo; Ritchie, Graham RS; Xue, Yali; Asimit, Jennifer; Nsubuga, Rebecca N; Young, Elizabeth H; Pomilla, Cristina; Kivinen, Katja; Rockett, Kirk; Kamali, Anatoli; Doumatey, Ayo P; Asiki, Gershim; Seeley, Janet; Sisay-Joof, Fatoumatta; Jallow, Muminatou; Tollman, Stephen; Mekonnen, Ephrem; Ekong, Rosemary; Oljira, Tamiru; Bradman, Neil; Bojang, Kalifa; Ramsay, Michele; Adeyemo, Adebowale; Bekele, Endashaw; Motala, Ayesha; Norris, Shane A; Pirie, Fraser; Kaleebu, Pontiano; Kwiatkowski, Dominic; Tyler-Smith, Chris; Rotimi, Charles; Zeggini, Eleftheria; Sandhu, Manjinder S; Asimit, Jennifer [0000-0002-4857-2249]; Kivinen, Katja [0000-0002-1135-7625]; Sandhu, Manjinder [0000-0002-2725-142X]
    Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.
  • ItemOpen AccessAccepted version Peer-reviewed
    A Potential Role for Exosomal Translationally Controlled Tumor Protein Export in Vascular Remodeling in Pulmonary Arterial Hypertension.
    (American Thoracic Society, 2018-10) Ferrer, Elisabet; Dunmore, Benjamin J; Hassan, Dhiya; Ormiston, Mark L; Moore, Stephen; Deighton, John; Long, Lu; Yang, Xu Dong; Stewart, Duncan J; Morrell, Nicholas W; Morrell, Nicholas W [0000-0001-5700-9792]
    Pulmonary arterial hypertension (PAH) is characterized by increased proliferation and resistance to apoptosis of pulmonary vascular cells. Increased expression of translationally controlled tumor protein (TCTP), a prosurvival and antiapoptotic mediator, has recently been demonstrated in patients with heritable PAH; however, its role in the pathobiology of PAH remains unclear. Silencing of TCTP in blood outgrowth endothelial cells (BOECs) isolated from control subjects led to significant changes in morphology, cytoskeletal organization, increased apoptosis, and decreased directionality during migration. Because TCTP is also localized in extracellular vesicles, we isolated BOEC-derived extracellular vesicles (exosomes and microparticles) by sequential ultracentrifugation. BOECs isolated from patients harboring BMPR2 mutations released more exosomes than those derived from control subjects in proapoptotic conditions. Furthermore, TCTP expression was significantly higher in exosomes than in microparticles, indicating that TCTP is mainly exported via exosomes. Coculture assays demonstrated that exosomes transferred TCTP from ECs to pulmonary artery smooth muscle cells, suggesting a role for endothelial-derived TCTP in conferring proliferation and apoptotic resistance. In an experimental model of PAH, rats treated with monocrotaline demonstrated increased concentrations of TCTP in the lung and plasma. Consistent with this finding, we observed increased circulating TCTP levels in patients with idiopathic PAH compared with control subjects. Therefore, our data suggest an important role for TCTP in regulating the critical vascular cell phenotypes that have been implicated in the pathobiology of PAH. In addition, this research implicates TCTP as a potential biomarker for the onset and development of PAH.
  • ItemOpen AccessPublished version Peer-reviewed
    Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naïve B cells, and facilitates recruitment of transcription factors to the viral genome.
    (Public Library of Science (PLoS), 2018-02) Szymula, Agnieszka; Palermo, Richard D; Bayoumy, Amr; Groves, Ian J; Ba Abdullah, Mohammed; Holder, Beth; White, Robert E; Ba Abdullah, Mohammed [0000-0002-5696-4269]; Holder, Beth [0000-0003-2157-9819]; White, Robert E [0000-0002-5115-2173]
    The Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is the first viral latency-associated protein produced after EBV infection of resting B cells. Its role in B cell transformation is poorly defined, but it has been reported to enhance gene activation by the EBV protein EBNA2 in vitro. We generated EBNA-LP knockout (LPKO) EBVs containing a STOP codon within each repeat unit of internal repeat 1 (IR1). EBNA-LP-mutant EBVs established lymphoblastoid cell lines (LCLs) from adult B cells at reduced efficiency, but not from umbilical cord B cells, which died approximately two weeks after infection. Adult B cells only established EBNA-LP-null LCLs with a memory (CD27+) phenotype. Quantitative PCR analysis of virus gene expression after infection identified both an altered ratio of the EBNA genes, and a dramatic reduction in transcript levels of both EBNA2-regulated virus genes (LMP1 and LMP2) and the EBNA2-independent EBER genes in the first 2 weeks. By 30 days post infection, LPKO transcription was the same as wild-type EBV. In contrast, EBNA2-regulated cellular genes were induced efficiently by LPKO viruses. Chromatin immunoprecipitation revealed that EBNA2 and the host transcription factors EBF1 and RBPJ were delayed in their recruitment to all viral latency promoters tested, whereas these same factors were recruited efficiently to several host genes, which exhibited increased EBNA2 recruitment. We conclude that EBNA-LP does not simply co-operate with EBNA2 in activating gene transcription, but rather facilitates the recruitment of several transcription factors to the viral genome, to enable transcription of virus latency genes. Additionally, our findings suggest that EBNA-LP is essential for the survival of EBV-infected naïve B cells.
  • ItemOpen AccessPublished version Peer-reviewed
    Critical thresholds for intracranial pressure vary over time in non-craniectomised traumatic brain injury patients.
    (Springer Science and Business Media LLC, 2018-07) Nourallah, Basil; Zeiler, Frederick A; Calviello, Leanne; Smielewski, Peter; Czosnyka, Marek; Menon, David K; Zeiler, Frederick [0000-0003-1737-0510]; Calviello, Leanne [0000-0001-5012-2725]; Smielewski, Peter [0000-0001-5096-3938]; Czosnyka, Marek [0000-0003-2446-8006]; Menon, David [0000-0002-3228-9692]
    BACKGROUND: Intracranial pressure (ICP)- and cerebral perfusion pressure (CPP)-guided therapy is central to neurocritical care for traumatic brain injury (TBI) patients. We sought to identify time-dependent critical thresholds for mortality and unfavourable outcome for ICP and CPP in non-craniectomised TBI patients. METHODS: This is a retrospective cohort study of 355 patients with moderate-to-severe TBI who received ICP monitoring and were managed without decompressive craniectomy in a tertiary hospital neurocritical care unit. Patients were grouped in 2 × 2 tables according to survival/death or favourable/unfavourable outcomes at 6 months and serial thresholds of mean ICP and CPP, using increments of 0.1 and 0.5 mmHg respectively. Sequential chi-square analysis was performed, and the thresholds yielding the highest chi-square test statistic were taken as having the best discriminative value for outcome. This process was repeated over monitoring periods of 1, 3, 5 and 7 days and for each day of recording to establish time-dependent thresholds. The same analysis was performed for age and sex subgroups. RESULTS: Global ICP thresholds were 21.3 and 20.5 mmHg for mortality and unfavourable outcome respectively (p < 0.001). After the first day of ICP monitoring, ICP thresholds fell to between 15 and 20 mmHg and remained significant (p < 0.05). Significant time-dependent CPP thresholds for mortality or unfavourable outcome were often not identified, and no identifiable trends were produced. CONCLUSION: Critical ICP thresholds in non-craniectomised TBI patients vary with time and fall below established ICP targets after the first day of monitoring.
  • ItemOpen AccessPublished version Peer-reviewed
    The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness.
    (Springer Science and Business Media LLC, 2018-06-04) Yasmin; Maskari, Raya Al; McEniery, Carmel M; Cleary, Sarah E; Li, Ye; Siew, Keith; Figg, Nichola L; Khir, Ashraf W; Cockcroft, John R; Wilkinson, Ian B; O'Shaughnessy, Kevin M; Yasmin [0000-0002-5478-7123]; Maskari, Raya Al [0000-0002-1259-0197]; Siew, Keith [0000-0002-6502-5095]; O'Shaughnessy, Kevin M [0000-0002-1476-7566]
    Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.
  • ItemOpen AccessAccepted version Peer-reviewed
    Immune Activation in Sepsis.
    (Elsevier BV, 2018-01) Conway-Morris, Andrew; Wilson, Julie; Shankar-Hari, Manu; Conway-Morris, Andrew [0000-0002-3211-3216]; Shankar-Hari, Manu [0000-0002-5338-2538]
    Sepsis is caused by a dysregulated host response to infection. Immune responses determine the characteristics of sepsis. The body's protection against infection involves danger signal surveillance and recognition from nonself, effector functions in response to sensing danger signals, homeostatic regulation, and generation of immunologic memory. During sepsis, the immune system is activated by pathogen-associated and host-derived molecular patterns. Detecting these molecular patterns generates multisystem responses. Impaired organ function remote to the site of infection is the unifying feature. The processes by which an appropriate response to a microbial invader change from adaptive to maladaptive and dysregulated remain unclear.
  • ItemOpen AccessPublished version Peer-reviewed
    Effectiveness of biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use (VAPrapid-2): study protocol for a randomised controlled trial.
    (Springer Science and Business Media LLC, 2016-07-16) Hellyer, Thomas P; Anderson, Niall H; Parker, Jennie; Dark, Paul; Van Den Broeck, Tina; Singh, Suveer; McMullan, Ronan; Agus, Ashley M; Emerson, Lydia M; Blackwood, Bronagh; Gossain, Savita; Walsh, Tim S; Perkins, Gavin D; Conway Morris, Andrew; McAuley, Daniel F; Simpson, A John; Conway Morris, Andrew [0000-0002-3211-3216]
    BACKGROUND: Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence. METHODS/DESIGN: This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at [≥] 10(4) colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a 'biomarker-guided recommendation on antibiotics' in which BAL fluid is tested for IL-1β and IL-8 in addition to routine microbiology testing, or to 'routine use of antibiotics' in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD. DISCUSSION: This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP. TRIAL REGISTRATION: ISRCTN65937227 . Registered on 22 August 2013., NCT01972425 . Registered on 24 October 2013.
  • ItemOpen AccessPublished version Peer-reviewed
    Early PREdiction of Severe Sepsis (ExPRES-Sepsis) study: protocol for an observational derivation study to discover potential leucocyte cell surface biomarkers.
    (BMJ, 2016-08-01) Datta, Deepankar; Conway Morris, Andrew; Antonelli, Jean; Warner, Noel; Brown, Kenneth Alun; Wright, John; Simpson, A John; Rennie, Jillian; Hulme, Gillian; Lewis, Sion Marc; Mare, Tracey Anne; Cookson, Sharon; Weir, Christopher John; Dimmick, Ian; Keenan, Jim; Rossi, Adriano Giorgio; Shankar-Hari, Manu; Walsh, Timothy S; ExPRES Sepsis Investigators; Datta, Deepankar [0000-0001-9971-9434]; Conway Morris, Andrew [0000-0002-3211-3216]
    INTRODUCTION: Sepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing life-threatening severe sepsis could enable early triage and treatment, and improve outcomes. Currently available biomarkers have poor predictive value for predicting subsequent clinical course in patients with suspected infection. Circulating leucocytes provide readily accessible tissues that reflect many aspects of the complex immune responses described in sepsis. We hypothesise that measuring cellular markers of immune responses by flow cytometry will enable early identification of infected patients at risk of adverse outcomes. We aim to characterise leucocyte surface markers (biomarkers) and their abnormalities in a population of patients presenting to the hospital emergency department with suspected sepsis, and explore their ability to predict subsequent clinical course. METHODS AND ANALYSIS: We will conduct a prospective, multicentre, clinical, exploratory, cohort observational study. To answer our study question, 3 patient populations will be studied. First, patients with suspected sepsis from the emergency department (n=300). To assess performance characteristics of potential tests, critically ill patients with established sepsis, and age and gender matched patients without suspicion of infection requiring hospital admission (both n=100) will be recruited as comparator populations. In all 3 groups, we plan to assess circulating biomarker profiles using flow cytometry. We will select candidate biomarkers by cross-cohort comparison, and then explore their predictive value for clinical outcomes within the cohort with suspected sepsis. ETHICS AND DISSEMINATION: The study will be carried out based on the principles in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. Ethics approval has been granted from the Scotland A Research Ethics Committee (REC) and Oxford C REC. On conclusion of this study, the results will be disseminated via peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02188992; Pre-results.
  • ItemOpen AccessPublished version Peer-reviewed
    Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study.
    (Springer Science and Business Media LLC, 2018-05) Conway Morris, Andrew; Datta, Deepankar; Shankar-Hari, Manu; Stephen, Jacqueline; Weir, Christopher J; Rennie, Jillian; Antonelli, Jean; Bateman, Anthony; Warner, Noel; Judge, Kevin; Keenan, Jim; Wang, Alice; Burpee, Tony; Brown, K Alun; Lewis, Sion M; Mare, Tracey; Roy, Alistair I; Hulme, Gillian; Dimmick, Ian; Rossi, Adriano G; Simpson, A John; Walsh, Timothy S; Conway Morris, Andrew [0000-0002-3211-3216]
    PURPOSE: Cellular immune dysfunctions, which are common in intensive care patients, predict a number of significant complications. In order to effectively target treatments, clinically applicable measures need to be developed to detect dysfunction. The objective was to confirm the ability of cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients. METHODS: Multi-centre, prospective observational cohort study of critically ill patients in four UK intensive care units. Serial blood samples were taken, and three cell surface markers associated with immune cell dysfunction [neutrophil CD88, monocyte human leucocyte antigen-DR (HLA-DR) and percentage of regulatory T cells (Tregs)] were assayed on-site using standardized flow cytometric measures. Patients were followed up for the development of secondary infections. RESULTS: A total of 148 patients were recruited, with data available from 138. Reduced neutrophil CD88, reduced monocyte HLA-DR and elevated proportions of Tregs were all associated with subsequent development of infection with odds ratios (95% CI) of 2.18 (1.00-4.74), 3.44 (1.58-7.47) and 2.41 (1.14-5.11), respectively. Burden of immune dysfunction predicted a progressive increase in risk of infection, from 14% for patients with no dysfunction to 59% for patients with dysfunction of all three markers. The tests failed to risk stratify patients shortly after ICU admission but were effective between days 3 and 9. CONCLUSIONS: This study confirms our previous findings that three cell surface markers can predict risk of subsequent secondary infection, demonstrates the feasibility of standardized multisite flow cytometry and presents a tool which can be used to target future immunomodulatory therapies. TRIAL REGISTRATION: The study was registered with (NCT02186522).
  • ItemOpen AccessAccepted version Peer-reviewed
    Response to "Re. Abdominal Aortic Aneurysm Calcification: Are Biochemical Markers a Missing Piece of the Puzzle?".
    (Elsevier BV, 2018-06) Chowdhury, Mohammed M; Rudd, James HF; Coughlin, Patrick A; Rudd, James [0000-0003-2243-3117]
  • ItemOpen AccessPublished version Peer-reviewed
    Telomerase mediates lymphocyte proliferation but not the atherosclerosis-suppressive potential of regulatory T-cells
    (Wolters Kluwer Health, 2018-06) Richardson, Gavin; Sage, AP; Bennaceur, K; Al Zhrany, N; Coelho-Lima, J; Dookun, E; Draganova, L; Saretzki, G; Breault, D; Mallat, ziad; Spyridopoulos, Ioakim; Sage, Andrew [0000-0001-7255-3497]; Mallat, Ziad [0000-0003-0443-7878]
    Objective: Atherosclerosis is an age-related disease characterised by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence a potential causative role of telomerase in atherogenesis is critically debated. Approach and Results: In this study we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4+ cells and significantly reduced CD4+ T-cell proliferation. The latter was telomerase dependent, as oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase-knock-out mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase (TERT) deficiency had no effect on Treg numbers in vivo or suppressive function ex vivo. Adoptive transfer of TERT-/- Tregs into Rag2-/- ApoE-/- double knock out mice demonstrated that telomerase function was not required for the ability of Tregs to protect against atherosclerosis. However, telomere length was critical for Treg function. Conclusions: Telomerase contributes to lymphocyte proliferation but plays no major role in Treg function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in Tregs.
  • ItemOpen Access
    A zebrafish model for ocular tuberculosis.
    (Public Library of Science (PLoS), 2018) Takaki, Kevin; Ramakrishnan, Lalita; Basu, Soumyava; Basu, Soumyava [0000-0002-6513-8786]
    Ocular tuberculosis (TB) commonly causes severe inflammation and vision loss in TB-endemic countries. The mechanism by which tuberculous infection becomes established in the eye is poorly understood. We have developed the zebrafish larva infected with Mycobacterium marinum as a model to study the early pathogenesis of ocular TB. We find that hematogenous bacterial seeding of the eye occurs despite a functional blood retinal barrier. Prototypical early granulomas form in response to bacteria in the eye. These granulomas involve the retinal vasculature and retinal pigment epithelium-choroid complex which are characteristic locations for human ocular TB. We find that peripheral blood monocytes are recruited to the nascent ocular granuloma further suggesting that the immune privileged nature of the eye is breached by this inflammatory focus.
  • ItemOpen AccessPublished version Peer-reviewed
    18F-FDG Uptake on PET/CT in Symptomatic versus Asymptomatic Carotid Disease: a Meta-Analysis.
    (Elsevier BV, 2018-08) Chowdhury, Mohammed M; Tarkin, Jason M; Evans, Nicholas R; Le, Elizabeth; Warburton, Elizabeth A; Hayes, Paul D; Rudd, James HF; Coughlin, Patrick A; Tarkin, Jason [0000-0002-9132-120X]; Evans, Nicholas [0000-0002-7640-4701]; Le, Elizabeth [0000-0002-3065-1627]; Hayes, Paul [0000-0002-1968-5930]; Rudd, James [0000-0003-2243-3117]
    INTRODUCTION: The role of positron emission tomography (PET)/computed tomography (CT) in the determination of inflammation in arterial disease is not well defined. This can provide information about arterial wall inflammation in atherosclerotic disease, and may give insight into plaque stability. The aim of this review was to perform a meta-analysis of PET/CT with 18F-FDG (fluorodeoxyglucose) uptake in symptomatic and asymptomatic carotid artery disease. METHODS: This was a systematic review, following PRISMA guidelines, which interrogated the MEDLINE database from January 2001 to May 2017. The search combined the terms, "inflammation", "FDG", and "stroke". The search criteria included all types of studies, with a primary outcome of the degree of arterial vascular inflammation determined by 18F-FDG uptake. Analysis involved an inverse weighted variance estimate of pooled data, using a random effects model. RESULTS: A total of 14 articles (539 patients) were included in the meta-analysis. Comparing carotid artery 18F-FDG uptake in symptomatic versus asymptomatic disease yielded a standard mean difference of 0.94 (95% CI 0.58-1.130; p < .0001; I2 = 65%). CONCLUSIONS: PET/CT using 18F-FDG can demonstrate carotid plaque inflammation, and is a marker of symptomatic disease. Further studies are required to understand the clinical implication of PET/CT as a risk prediction tool.
  • ItemOpen AccessPublished version Peer-reviewed
    Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice.
    (Wiley, 2018-08) Foote, Kirsty; Reinhold, Johannes; Yu, Emma PK; Figg, Nichola L; Finigan, Alison; Murphy, Michael P; Bennett, Martin R; Murphy, Mike [0000-0003-1115-9618]; Bennett, Martin [0000-0002-2565-1825]
    Aging is the largest risk factor for cardiovascular disease, yet the molecular mechanisms underlying vascular aging remain unclear. Mitochondrial DNA (mtDNA) damage is linked to aging, but whether mtDNA damage or mitochondrial dysfunction is present and directly promotes vascular aging is unknown. Furthermore, mechanistic studies in mice are severely hampered by long study times and lack of sensitive, repeatable and reproducible parameters of arterial aging at standardized early time points. We examined the time course of multiple invasive and noninvasive arterial physiological parameters and structural changes of arterial aging in mice, how aging affects vessel mitochondrial function, and the effects of gain or loss of mitochondrial function on vascular aging. Vascular aging was first detected by 44 weeks (wk) of age, with reduced carotid compliance and distensibility, increased β-stiffness index and increased aortic pulse wave velocity (PWV). Aortic collagen content and elastin breaks also increased at 44 wk. Arterial mtDNA copy number (mtCN) and the mtCN-regulatory proteins TFAM, PGC1α and Twinkle were reduced by 44 wk, associated with reduced mitochondrial respiration. Overexpression of the mitochondrial helicase Twinkle (Tw+ ) increased mtCN and improved mitochondrial respiration in arteries, and delayed physiological and structural aging in all parameters studied. Conversely, mice with defective mitochondrial polymerase-gamma (PolG) and reduced mtDNA integrity demonstrated accelerated vascular aging. Our study identifies multiple early and reproducible parameters for assessing vascular aging in mice. Arterial mitochondrial respiration reduces markedly with age, and reduced mtDNA integrity and mitochondrial function directly promote vascular aging.
  • ItemOpen AccessPublished version Peer-reviewed
    Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement
    (Springer Science and Business Media LLC, 2017-10-01) Casanueva, FF; Barkan, AL; Buchfelder, M; Klibanski, A; Laws, ER; Loeffler, JS; Melmed, S; Mortini, P; Wass, J; Giustina, A; Lomba, AA; Abucham, J; Alvarez-Escola, C; Barkan, AL; Beckers, A; Ben-Shlomo, A; Bernabeu, I; Bidlingmaier, M; Biermasz, N; Biller, B; Boguszewski, CL; Bolanowski, M; Bollerslev, J; Bonert, V; Bronstein, M; Bruno, OD; Buchfelder, M; Carmichael, JD; Caron, P; Chanson, P; Casanueva, FF; Clayton, RN; Colao, A; Cordido, F; De Marinis, L; Fahlbusch, R; Fleseriu, M; Formenti, AM; Freda, PU; Fukuoka, H; Ghigo, E; Giustina, A; Greenman, Y; Grineva, E; Grossman, A; Gurnell, M; Heaney, A; Hoffman, AR; Ilovayskaya, I; Johannsson, G; Kadioglu, P; Karavitaki, N; Katznelson, L; Kelestimur, F; Kelly, DF; Klibanski, A; Ho, K; Krsek, M; Lacroix, A; Laws, ER; StevenLoeffler, J; Losa, M; Jørgensen, JO; Luger, A; Mallea-Gil, S; Mamelak, A; Mazziotti, G; McCormack, A; Melmed, S; Mercado, M; Mortini, P; Neggers, S; Ning, G; Oyesiku, NM; Popovic, V; Petakov, M; Petersenn, S; Pfeifer, M; Pico, A; Domingo, MP; Raverot, G; Reincke, M; Gadelha, MR; Salvatori, R; Samson, SL; Shimatsu, A; Shimon, I; Stewart, P; Strasburger, C; Swearingen, B; Trainer, P; Tritos, NA; Tsagarakis, S; van der Lely, AJ; Vilar, L; Villar-Taibo, R; Wass, J; Zatelli, MC; Gurnell, Mark [0000-0001-5745-6832]
    Introduction With the goal of generate uniform criteria among centers dealing with pituitary tumors and to enhance patient care, the Pituitary Society decided to generate criteria for developing Pituitary Tumors Centers of Excellence (PTCOE). Methods To develop that task, a group of ten experts served as a Task Force and through two years of iterative work an initial draft was elaborated. This draft was discussed, modified and finally approved by the Board of Directors of the Pituitary Society. Such document was presented and debated at a specific session of the Congress of the Pituitary Society, Orlando 2017, and suggestions were incorporated. Finally the document was distributed to a large group of global experts that introduced further modifications with final endorsement. Results After five years of iterative work a document with the ideal criteria for a PTCOE is presented. Conclusions Acknowledging that very few centers in the world, if any, likely fulfill the requirements here presented, the document may be a tool to guide improvements of care delivery to patients with pituitary disorders. All these criteria must be accommodated to the regulations and organization of Health of a given country.
  • ItemOpen AccessAccepted version Peer-reviewed
    11C-metomidate PET-CT scanning can identify aldosterone-producing adenomas after unsuccessful lateralisation with CT/MRI and adrenal venous sampling.
    (Springer Science and Business Media LLC, 2017-07) Ouyang, J; Hardy, R; Brown, M; Helliwell, T; Gurnell, M; Cuthbertson, DJ; Gurnell, Mark [0000-0001-5745-6832]
    Primary hyperaldosteronism, characterised by hypertension and hypokalaemia, is a syndrome caused by aldosterone excess most commonly from either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Subtype classification can be challenging with cross-sectional imaging and even with interventional radiological techniques such as adrenal venous sampling. Imaging with 11C-metomidate positron emission tomography-computed tomography (PET-CT) is an emerging tool that facilitates functional characterisation and potentially successful surgical intervention of aldosterone-producing adenomas. This technique has highlighted that, although unilateral adenomas and bilateral hyperplasia represent opposite ends of the disease spectrum, a relatively common intermediate phenotype exists of unilateral/bilateral multinodular disease.
  • ItemOpen AccessAccepted version Peer-reviewed
    Variation in passing standards for graduation-level knowledge items at UK medical schools.
    (Wiley, 2017-06) Taylor, Celia A; Gurnell, Mark; Melville, Colin R; Kluth, David C; Johnson, Neil; Wass, Val; Gurnell, Mark [0000-0001-5745-6832]
    OBJECTIVES: Given the absence of a common passing standard for students at UK medical schools, this paper compares independently set standards for common 'one from five' single-best-answer (multiple-choice) items used in graduation-level applied knowledge examinations and explores potential reasons for any differences. METHODS: A repeated cross-sectional study was conducted. Participating schools were sent a common set of graduation-level items (55 in 2013-2014; 60 in 2014-2015). Items were selected against a blueprint and subjected to a quality review process. Each school employed its own standard-setting process for the common items. The primary outcome was the passing standard for the common items by each medical school set using the Angoff or Ebel methods. RESULTS: Of 31 invited medical schools, 22 participated in 2013-2014 (71%) and 30 (97%) in 2014-2015. Schools used a mean of 49 and 53 common items in 2013-2014 and 2014-2015, respectively, representing around one-third of the items in the examinations in which they were embedded. Data from 19 (61%) and 26 (84%) schools, respectively, met the inclusion criteria for comparison of standards. There were statistically significant differences in the passing standards set by schools in both years (effect sizes (f2 ): 0.041 in 2013-2014 and 0.218 in 2014-2015; both p < 0.001). The interquartile range of standards was 5.7 percentage points in 2013-2014 and 6.5 percentage points in 2014-2015. There was a positive correlation between the relative standards set by schools in the 2 years (Pearson's r = 0.57, n = 18, p = 0.014). Time allowed per item, method of standard setting and timing of examination in the curriculum did not have a statistically significant impact on standards. CONCLUSIONS: Independently set standards for common single-best-answer items used in graduation-level examinations vary across UK medical schools. Further work to examine standard-setting processes in more detail is needed to help explain this variability and develop methods to reduce it.