Rice G.I.,University of Manchester |
Forte G.M.A.,University of Manchester |
Szynkiewicz M.,University of Manchester |
Chase D.S.,University of Manchester |
And 54 more authors.
The Lancet Neurology | Year: 2013
Background: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods: In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings: 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation: AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. Funding: European Union's Seventh Framework Programme; European Research Council. © 2013 Elsevier Ltd.
Tatton-Brown K.,Institute of Cancer Research |
Tatton-Brown K.,St George's, University of London |
Hanks S.,Institute of Cancer Research |
Ruark E.,Institute of Cancer Research |
And 23 more authors.
Oncotarget | Year: 2011
The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth. © Tatton-Brown et al.
Turner C.L.S.,University of Southampton |
MacKay D.M.,University of Southampton |
Callaway J.L.A.,University of Southampton |
Docherty L.E.,University of Southampton |
And 13 more authors.
European Journal of Human Genetics | Year: 2010
This study was an investigation of 79 patients referred to the Wessex Regional Genetics Laboratory with suspected Russell-Silver Syndrome or unexplained short stature/intra uterine growth restriction, warranting genetic investigation. Methylation status was analysed at target sequences within eleven imprinted loci (PLAGL1, IGF2R, PEG10, MEST1, GRB10, KCNQ1OT1, H19, IGF2P0, DLK1, PEG3, NESPAS). Thirty seven percent (37%) (29 of 79) of samples were shown to have a methylation abnormality. The commonest finding was a loss of methylation at H19 (23 of 29), as previously reported in Russell-Silver Syndrome. In addition, four of these patients had methylation anomalies at other loci, of whom two showed hypomethylation of multiple imprinted loci, and two showed a complete gain of methylation at IGF2R. This latter finding was also present in five other patients who did not have demonstrable changes at H19. In total, 7 of 79 patients showed a gain of methylation at IGF2R and this was significantly different from a normal control population of 267 individuals (P=0.002). This study in patients with growth restriction shows the importance of widening the epigenetic investigation to include multiple imprinted loci and highlights potential involvement of the IGF2R locus. © 2010 Macmillan Publishers Limited All rights reserved.
Gibbons M.A.,Queens Medical Research Institute |
Gibbons M.A.,Royal Devon and Exeter Foundation NHS Trust |
MacKinnon A.C.,Queens Medical Research Institute |
Ramachandran P.,Queens Medical Research Institute |
And 15 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011
Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial. Objectives: To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved. Methods:We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF. Measurements and Main Results: Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogatemarkers of fibrosis Col1 (P =0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase1. The alternativemacrophagemarker CD163was expressed on lungmacrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P =0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice. Conclusions: We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis.
MacKinnon A.C.,Queens Medical Research Institute |
Gibbons M.A.,Royal Devon and Exeter Foundation NHS Trust |
Farnworth S.L.,Queens Medical Research Institute |
Leffler H.,Lund University |
And 8 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012
Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers.Galectin-3 is a β-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. Objectives: To examine the role of galectin-3 in pulmonary fibrosis. Methods: We used genetic deletion and pharmacologic inhibition in well-characterizedmurinemodels of lung fibrosis. Further mechanistic studieswere performed in vitro and on samples from patientswith IPF. Measurements and Main Results: Transforming growth factor (TGF)-β and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-β1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of β-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin-3, TD139, blocked TGF-β-induced β-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3maybe effective in treating acute fibrotic exacerbations of IPF. Conclusions: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF. Copyright © 2012 by the American Thoracic Society.
Alkhouli N.,University of Exeter |
Mansfield J.,University of Exeter |
Green E.,University of Exeter |
Bel J.,University of Exeter |
And 7 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2013
Adipose tissue (AT) expansion in obesity is characterized by cellular growth and continuous extracellular matrix (ECM) remodeling with increased fibrillar collagen deposition. It is hypothesized that the matrix can inhibit cellular expansion and lipid storage. Therefore, it is important to fully characterize the ECM's biomechanical properties and its interactions with cells. In this study, we characterize and compare the mechanical properties of human subcutaneous and omental tissues, which have different physiological functions. AT was obtained from 44 subjects undergoing surgery. Force/extension and stress/relaxation data were obtained. The effects of osmotic challenge were measured to investigate the cellular contribution to tissue mechanics. Tissue structure and its response to tensile strain were determined using nonlinear microscopy. AT showed nonlinear stress/strain characteristics of up to a 30% strain. Comparing paired subcutaneous and omental samples (n = 19), the moduli were lower in subcutaneous: initial 1.6 ± 0.8 (means ± SD) and 2.9 ± 1.5 kPa (P = 0.001), final 11.7 ± 6.4 and 32 ± 15.6 kPa (P < 0.001), respectively. The energy dissipation density was lower in subcutaneous AT (n = 13): 0.1 ± 0.1 and 0.3 ± 0.2 kPa, respectively (P = 0.006). Stress/relaxation followed a two-exponential time course. When the incubation medium was exchanged for deionized water in specimens held at 30% strain, force decreased by 31%, and the final modulus increased significantly. Nonlinear microscopy revealed collagen and elastin networks in close proximity to adipocytes and a larger-scale network of larger fiber bundles. There was considerable microscale heterogeneity in the response to strain in both cells and matrix fibers. These results suggest that subcutaneous AT has greater capacity for expansion and recovery from mechanical deformation than omental AT. © 2013 the American Physiological Society.
Gosling O.E.,Musgrove Park Hospital |
Morgan-Hughes G.,Derriford Hospital |
Bellenger N.G.,Royal Devon and Exeter Foundation NHS Trust
Clinical Medicine, Journal of the Royal College of Physicians of London | Year: 2014
Symptomatic cardiovascular disease is one of the leading causes of hospital admissions in the UK; along with emergency attendances, over 100,000 patients are investigated using treadmill testing via rapid access chest pain clinics each year. With the introduction of new technologies, clinicians have a wide choice of investigations including nuclear perfusion scanning, dobutamine stress echocardiography, cardiac computed tomography and stress cardiac magnetic resonance imaging. These imaging modalities have their strengths and weaknesses, which depend not only on the pre-test likelihood of significant coronary artery disease but also the clinical characteristics of the patient. This article will review the differing imaging modalities, the patient experience, accuracy, prognostic data and future prospects for cardiac computed tomography and magnetic resonance imaging. © Royal College of Physicians 2014. All rights reserved.
Williams P.L.,Derriford Hospital |
Coote J.M.,Royal Devon and Exeter Foundation NHS Trust |
Watkinson A.F.,Royal Devon and Exeter Foundation NHS Trust
CardioVascular and Interventional Radiology | Year: 2011
Uterine leiomyomata, or fibroids, although benign, cause debilitating symptoms in many women. Symptoms are often nonspecific and may be the presenting complaint in a number of other conditions. Furthermore, because the presence of fibroids may be coincident with other symptomatic conditions that result in similar complaints, there may be diagnostic difficulty and consequent difficulty in planning therapeutic strategy. Uterine artery embolization (UAE) is a safe and effective treatment for symptomatic fibroids and is increasingly being performed. Magnetic resonance imaging (MRI) evaluation before and after treatment is routine practice with the potential to significantly alter management in up to a fifth of patients. It is well recognized that significant incidental findings may be demonstrated during imaging investigations, and in particular that abnormalities that are not directly related to the clinical question may be overlooked. Radiologists evaluating pre-UAE MRI studies must be aware of the MRI appearances of gynecological pathologies that may cause similar symptoms or that may affect the success or complication rates of UAE, and they must also be wary of "satisfaction of search," reviewing imaging thoroughly so that relevant other pathologies are not missed. We demonstrate the appearances of coincidental pathologies found on pre-UAE MRI, with the potential to change patient management. © Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2011.
Parker M.J.,Sheffield Childrens NHS Foundation Trust |
Deshpande C.,South East Thames Regional Genetics Unit |
Rankin J.,Royal Devon and Exeter Foundation NHS Trust |
Wilson L.C.,Great Ormond Street Hospital and Institute of Child Health |
And 6 more authors.
American Journal of Medical Genetics, Part A | Year: 2011
Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. It exhibits a broad spectrum of clinical severity, ranging from multiple fractures in utero and perinatal death, to normal adult stature and low fracture incidence. Extra-skeletal features of OI include blue sclera, hearing loss, skin hyperlaxity, joint hyperextensibility, and dentinogenesis imperfecta. The proα1(I) and proα2(I) chains of collagen 1 are encoded by the COL1A1 and COL1A2 genes, respectively; quantitative or qualitative defects in type I collagen synthesis usually manifest as types of OI or some sub-types of EDS. The majority of patients (about 90%) with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2 genes, which shows an autosomal dominant pattern of inheritance. Six other genes, CRTAP, LEPRE1, FKBP10, PP1B, SP7/Osterix (OSX), and SERPINH1, are associated with autosomal recessive forms of OI. However, other, rare phenotypes have also been described. There are many differential diagnoses of the short, syndromic child, including chromosomal, single gene, and multifactorial causes. However, one condition of particular relevance in the context of this report is the Russell-Silver syndrome (RSS). As originally described, the RSS is a very specific condition. However, it has subsequently become an umbrella term for a heterogeneous group of conditions presenting with short stature and triangular shape to the face. A significant proportion of these are now believed to be due to imprinting defects at 11p15. However, the cause in many cases remains unknown. We describe two cases with a phenotypic overlap between OI and RSS who both have COL1A1 mutations. Thus, a type 1 collagenopathy should be considered in the differential diagnosis of syndromic short stature. © 2011 Wiley-Liss, Inc.
Telford R.J.,Royal Devon and Exeter Foundation NHS Trust
Anaesthesia and Intensive Care Medicine | Year: 2013
Peripheral arterial surgery is challenging; operations are frequently long and associated with insidious blood loss. Because of the high incidence of comorbidities these patients are a high-risk group with a high incidence of morbidity and mortality. They key to successful outcome is meticulous attention to detail by all those professions involved in their care. © 2013 Elsevier Ltd. All rights reserved.