Publications
133 results found
Shovlin CL, Angus G, Manning RA, et al., 2010, Endothelial cell processing and alternatively spliced transcripts of factor VIII: potential implications for coagulation cascades and pulmonary hypertension., PLoS One, Vol: 5
BACKGROUND: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. Extrahepatic sources of plasma FVIII are implicated, but have remained elusive. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemistry of normal human lung tissue, and confocal microscopy, flow cytometry, and ELISA quantification of conditioned media from normal primary endothelial cells were used to examine endothelial expression of FVIII and coexpression with von Willebrand Factor (vWF), which protects secreted FVIII heavy chain from rapid proteloysis. FVIII transcripts predicted from database mining were identified by RT-PCR and sequencing. FVIII mAb-reactive material was demonstrated in CD31+ endothelial cells in normal human lung tissue, and in primary pulmonary artery, pulmonary microvascular, and dermal microvascular endothelial cells. In pulmonary endothelial cells, this protein occasionally colocalized with vWF, centered on Weibel Palade bodies. Pulmonary artery and pulmonary microvascular endothelial cells secreted low levels of FVIII and vWF to conditioned media, and demonstrated cell surface expression of FVIII and vWF Ab-reacting proteins compared to an isotype control. Four endothelial splice isoforms were identified. Two utilize transcription start sites in alternate 5' exons within the int22h-1 repeat responsible for intron 22 inversions in 40% of severe haemophiliacs. A reciprocal relationship between the presence of short isoforms and full-length FVIII transcript suggested potential splice-switching mechanisms. CONCLUSIONS/SIGNIFICANCE: The pulmonary endothelium is confirmed as a site of FVIII secretion, with evidence of synthesis, cell surface expression, and coexpression with vWF. There is complex alternate transcription initiation from the FVIII gene. These findings provide a framework for future re
Shovlin CL, Jackson JE, 2010, Pulmonary arteriovenous malformations and other pulmonary vascular abnormalities., Murray and Nadel’s Textbook of Respiratory Medicine, Editors: Mason, Broaddus, Martin, King, Schraufnagel, Murray, Nadel, Publisher: Saunders Elsevier, Pages: 1261-1282
Shovlin CL, 2009, Ischaemic stroke and thrombolysis- time to consider the HHT question, eBMJ
Govani FS, Shovlin CL, 2009, Hereditary haemorrhagic telangiectasia: a clinical and scientific review, European Journal of Human Genetics, Vol: 17, Pages: 860-871, ISSN: 1476-5438
Shovlin CL, Gibbs JSR, Jackson JE, 2008, Management of pulmonary arteriovenous malformations in pulmonary hypertensive patients. A pressure to embolise?, Eur Respir Rev, Vol: 18, Pages: 4-6
Shovlin CL, Bamford KB, Wray D, 2008, Post-NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia, British Dental Journal, Vol: 205, Pages: 531-533
Recently published guidance from NICE highlights that antibiotic prophylaxis is no longer required for patients with structural heart disease at risk of infective endocarditis. The American Heart Association has published similarly less interventive guidance. Individuals with pulmonary arteriovenous malformations and hereditary haemorrhagic telangiectasia are at risk of brain abscess from dental bacteraemias. In this article we explore why these patients do not fall into the groups considered by NICE and provide recommendations to reduce their risks of dental bacteraemias, including optimising dental hygiene and use of antibiotic prophylaxis prior to dental procedures.
Shovlin CL, Tighe HC, Davies RJ, et al., 2008, Embolization of pulmonary AVMs: no consistent effect on pulmonary artery pressure, European Respiratory Journal, Vol: 32, Pages: 162-169, ISSN: 1399-3003
Shovlin CL, Sodhi V, McCarthy A, et al., 2008, Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services, Bjog-An International Journal of Obstetrics and Gynaecology, Vol: 115, Pages: 1108-1115, ISSN: 1471-0528
Shovlin CL, Jackson JE, Bamford KB, et al., 2007, Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia, Thorax, Vol: 63, Pages: 259-266, ISSN: 0040-6376
Shovlin C, Sulainam N, Govani FS, et al., 2007, Elevated Factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism, Thrombosis and Haemostasis, Vol: 98, Pages: 1031-1039, ISSN: 0340-6245
Introduction: Hereditary haemorrhagic telangiectasia (HHT) causes chronic nasal and gastrointestinal haemorrhage. Prothrombotic agents are commonly used for severe haemorrhage. Thrombotic risks have not been defined. Methods To identify prothrombotic variables in HHT patients, and assess their potential functional significance, a pilot ELISA-based study comparing plasma proteins in healthy individuals with HHT to age/sex-matched non-HHT controls was validated in a full study of 309 consecutive HHT-affected individuals. Results In the pilot study, Factor VIII (FVIII) and Von Willebrand Factor antigen concentrations were elevated in the HHT group compared to non-HHT controls (p0.0013, Mann-Whitney). Service laboratory measurements confirmed high FVIII:Ag in 125 HHT-affected individuals with no recent ill-health, intervention or venous thromboemboli. FVIII:Ag levels increased with age. Logistic regression also suggested an age-independent association with HHT-associated pulmonary arteriovenous malformations (PAVMs). No association was demonstrated between FVIII:Ag and acute phase response, disseminated intravascular coagulation, ABO group, pulmonary artery pressure, or markers of HHT haemorrhage. Elevated FVIII:Ag were associated with shortened activated partial thromboplastin times (APTTs), and VTE: VTE affected 20/309 (6.5%) HHT-affected individuals, at median age 61(36-71)yr. Four VTE occurred in Factor V Leiden heterozygotes in the months following PAVM-associated brain abscess. The strongest association with VTE was with log-transformed FVIII:Ag measured 10-132 months from VTE (odds ratio 2.41 (95% confidence intervals 1.254, 4.612, p=0.008). Age made no additional contribution to VTE risk once adjusted for FVIII:Ag. Conclusions HHT-related elevation of FVIII:Ag levels may influence thrombotic risk in HHT. Individualised risk-benefit considerations may be helpful in the management of individuals with HHT.
Shovlin CL, Simonds AK, Hughes JMB, 2007, Pulmonary disease and cor pulmonale, HEART DISEASE IN PREGNANCY, 2ND EDITION, Editors: Oakley, Warnes, Publisher: BLACKWELL SCIENCE PUBL, Pages: 151-172
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- Citations: 4
Cole SG, Begbie ME, Wallace GMF, et al., 2005, A new locus for hereditary haemorrhagic telangiectasia (<i>HHT3</i>) maps to chromosome 5, JOURNAL OF MEDICAL GENETICS, Vol: 42, Pages: 577-582, ISSN: 0022-2593
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- Citations: 212
Pilcher JM, Eckersley RJ, Lim AKP, et al., 2005, Use of a Microbubble Contrast Agent in the Evaluation of Cirrhotic Patients for Hepatopulmonary Syndrome: Preliminary Assessment of a Novel Technique, Ultrasound, Vol: 13, Pages: 100-105, ISSN: 1742-271X
Hepatopulmonary syndrome (HPS) may cause profound symptomatic hypoxia in patients with chronic liver disease and can be an indication for liver transplantation. The diagnosis relies on the demonstration of intrapulmonary vascular dilatation (IVD) using either contrast-enhanced echocardiography or macro-aggregated lung perfusion scans. We sought to evaluate whether a novel technique using the microbubble agent, Echovist® (Schering AG) with Doppler intensitometry of the carotid artery would be able to identify patients who fulfilled the criteria for HPS. Contrast studies were performed in 18 patients with cirrhosis, examined in the supine and upright positions. Following injection of Echovist, continuous scanning of the common carotid was performed using grey-scale and spectral Doppler for 60 s. Positive studies were determined by online signal analysis of the Doppler signal (crackle-count). Supine and upright pulse oximetry was recorded on all patients, and formal lung function tests where clinically indicated. Two patients met the criteria for HPS. They had positive results on supine and upright scans, with an increased crackle-count when upright. Two patients had single, weakly positive results with normal pulse oximetry. No association was seen between a positive contrast study and the severity of liver disease. Contrast-enhanced carotid Doppler intensitometry is a relatively simple, non-invasive test that may help identify patients with IVD. Comparison with an established technique will be required in future trials to determine its accuracy and assess whether the crackle-count can reliably quantify the degree of IVD. © 2005, Maney Publishing. All rights reserved.
Wheatley-Price P, Shovlin C, Chao D, 2005, Interferon for metastatic renal cell cancer causing regression of hereditary hemorrhagic telangiectasia, JOURNAL OF CLINICAL GASTROENTEROLOGY, Vol: 39, Pages: 344-345, ISSN: 0192-0790
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- Citations: 12
Shovlin CL, Jackson JE, Hughes JMB, 2005, Pulmonary arteriovenous malformations and other pulmonary vascular abnormalities, Murray and Nadel's textbook of Respiratory Medicine, Editors: Mason, Broaddus, Murray, Nadel, Pennsylvania, Publisher: Elsevier Saunders, Pages: 1480-1501, ISBN: 9780721603278
Shovlin CL, Jackson JE, 2004, Pulmonary arteriovenous malformations and aneurysms, Respiratory Medicine, Editors: Gibson, Geddes, Costabel, Sterk, Corrin, London, Publisher: Harcourt Brace, Pages: 1773-1788
Easey AJ, Wallace GMF, Hughes JMB, et al., 2003, Should asymptomatic patients with hereditary haemorrhagic telangiectasia (HHT) be screened for cerebral vascular malformations? Data from 22,061 years of HHT patient life, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 74, Pages: 743-748, ISSN: 0022-3050
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- Citations: 52
Begbie ME, Wallace GMF, Shovlin CL, 2003, Hereditary haemorrhagic telangiectasia (Osier-Weber-Rendu syndrome): a view from the 21st century, POSTGRADUATE MEDICAL JOURNAL, Vol: 79, Pages: 18-24, ISSN: 0032-5473
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- Citations: 198
Gupta P, Mordin C, Curtis J, et al., 2002, Pulmonary arteriovenous malformations: Effect of embolization on right-to-left shunt, hypoxemia, and exercise tolerance in 66 patients, AMERICAN JOURNAL OF ROENTGENOLOGY, Vol: 179, Pages: 347-355, ISSN: 0361-803X
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- Citations: 86
Coker R, Boldy DAR, Buchdahl R, et al., 2002, Managing passengers with respiratory disease planning air travel: British Thoracic Society recommendations, Thorax, Vol: 57, Pages: 289-304, ISSN: 0040-6376
Whittle AT, Davis M, Shovlin CL, et al., 2001, Alveolar macrophage activity and the pulmonary complications of haematopoietic stem cell transplantation, THORAX, Vol: 56, Pages: 941-946, ISSN: 0040-6376
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- Citations: 7
Paquet ME, Pece-Barbara N, Vera S, et al., 2001, Analysis of several endoglin mutants reveals no endogenous mature or secreted protein capable of interfering with normal endoglin function, HUMAN MOLECULAR GENETICS, Vol: 10, Pages: 1347-1357, ISSN: 0964-6906
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- Citations: 70
Wilkins MR, Gibbs JSR, Shovlin CL, 2000, A gene for primary pulmonary hypertension, LANCET, Vol: 356, Pages: 1207-1208, ISSN: 0140-6736
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- Citations: 12
Wallace GMF, Shovlin CL, 2000, A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, <i>endoglin</i> and <i>ALK-1</i>, THORAX, Vol: 55, Pages: 685-690, ISSN: 0040-6376
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- Citations: 61
Shovlin CL, 2000, Genetic aspects of cerebrovascular malformations, INTERVENTIONAL NEURORADIOLOGY, Vol: 6, Pages: 107-111, ISSN: 1591-0199
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- Citations: 1
Shovlin CL, Guttmacher AE, Buscarini E, et al., 2000, Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome), AMERICAN JOURNAL OF MEDICAL GENETICS, Vol: 91, Pages: 66-67, ISSN: 0148-7299
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- Citations: 1148
Shovlin CL, 1999, Supermodels and disease: insights from the HHT mice, JOURNAL OF CLINICAL INVESTIGATION, Vol: 104, Pages: 1335-1336, ISSN: 0021-9738
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- Citations: 10
Shovlin CL, Letarte M, 1999, Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms, THORAX, Vol: 54, Pages: 714-729, ISSN: 0040-6376
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- Citations: 292
Shovlin CL, 1998, Glaxo/MRS Young Investigator Medal. Molecular studies on adenosine deaminase deficiency and hereditary haemorrhagic telangiectasia., Clin Sci (Lond), Vol: 94, Pages: 207-218, ISSN: 0143-5221
1. This manuscript describes two different strategies to progress from the clinical assessment of patients to the identification of disease-causing mutations. In the first disease, recognition of a metabolic abnormality allowed direct molecular analysis of the causal gene. In contrast, localization of the second disease gene by linkage analysis was critical to implicate a gene with a previously unsuspected disease role. 2. Two sisters with chronic respiratory disease and recurrent infections were identified as the first cases of adult onset immunodeficiency due to adenosine deaminase deficiency. Autosomal recessive inheritance of two mutations in the adenosine deaminase gene was demonstrated. Enzyme replacement therapy improved the patients' immunological and clinical status. 3. Individuals with pulmonary arteriovenous malformations were used to identify families with hereditary haemorrhagic telangiectasia (HHT, Rendu-Osler-Weber Syndrome). Linkage studies mapped the HHT disease gene in some families to chromosome 9, and demonstrated genetic heterogeneity. The chromosome 9 disease interval was refined, and several candidate genes were assessed. Following the first description of disease-segregating mutations, a complete analysis of the endoglin gene (which encodes an endothelial cell transforming growth factor-beta receptor) identified seven novel mutations. Two mutations did not produce mutant mRNA, and disease severity was comparable between families, indicating that HHT results from stoichiometric insufficiency of endoglin. 4. Each study has implications extending beyond the relatively rare disease analysed. The adenosine-deaminase-deficient patients highlight a treatable cause of HIV-negative CD4+ lymphopenia in adults, perhaps accounting for further cases of 'non-HIV AIDS'. The HHT studies have illuminated a novel area of vascular pathophysiology, with potential relevance to further disease states.
Shovlin CL, Hughes JMB, Scott J, et al., 1997, Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 61, Pages: 68-79, ISSN: 0002-9297
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- Citations: 130
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