Claire Hogg

Guy's and St Thomas' NHS Foundation Trust

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Amelia Shoemark

University of Dundee

Jane S. Lucas

University Hospital Southampton NHS Foundation Trust

Andrew Bush

Royal Brompton Hospital

Hannah M. Mitchison

University College London

S.B. Carr

Guy's and St Thomas' NHS Foundation Trust

Kim G. Nielsen

Rigshospitalet

Thomas Burgoyne

University College London

Heymut Omran

Klinik und Poliklinik für Kinder- und Jugendmedizin

Claudia E. Kuehni

Institute of Social and Preventive Medicine

Mitali Patel

MRC Prion Unit

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University College London

221

Imperial College London

109

Royal Brompton Hospital

105

Great Ormond Street Hospital

Royal Brompton & Harefield NHS Foundation Trust

European Organization for Nuclear Research

University of Southampton

University Hospital Southampton NHS Foundation Trust

Genomics England

University of Edinburgh

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Generation of a Three-Dimensional Ultrastructural Model of Human Respiratory Cilia

American Journal of Respiratory Cell and Molecular Biology (2012)

Thomas Burgoyne Mellisa Dixon Pradeep K. Luther Claire Hogg Amelia Shoemark

The ultrastructures of cilia and flagella are highly similar and well conserved through evolution. Consequently, Chlamydomonas is commonly used as a model organism for the study of human respiratory cilia. Since detailed models of Chlamydomonas axonemes were generated using cryoelectron tomography, disparities among some of the ultrastructural features have become apparent when compared with human cilia. Extrapolating information on human disease from the Chlamydomonas model may lead to discrepancies in translational research. This study aimed to establish the first three-dimensional ultrastructural model of human cilia. Tomograms of transverse sections (n = 6) and longitudinal sections (n = 9) of human nasal respiratory cilia were generated from three healthy volunteers. Key features of the cilium were resolved using subatomic averaging, and were measured. For validation of the method, a model of the well characterized structure of Chlamydomonas reinhardtii was simultaneously generated. Data were combined to create a fully quantified three-dimensional reconstruction of human nasal respiratory cilia. We highlight key differences in the axonemal sheath, microtubular doublets, radial spokes, and dynein arms between the two structures. We show a decreased axial periodicity of the radial spokes, inner dynein arms, and central pair protrusions in the human model. We propose that this first human model will provide a basis for research into the function and structure of human respiratory cilia in health and in disease.

Motile cilium

10.1165/rcmb.2011-0440oc

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A high prevalence CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia is associated with normal diagnostic investigations

Amelia Shoemark Eduardo Moya Robert A. Hirst Mitali Patel Evelyn Robson

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous condition characterised by progressive lung disease arising from abnormal motile ciliary function. Approximately half of patients have situs inversus. The estimated prevalence of PCD in the UK South Asian population is 1:2,265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal. The aim of this study was to determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive. Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with PCD. The effect of a CCDC103 c.461A>C p.His154Pro missense variant on phenotypic variability was tested and variant pathogenicity was assessed by oligomerisation assay. Sixteen of 86(19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels (7/15 patients tested), normal ciliary beat pattern or frequency (9/16 cases) and a spectrum of partial and normal dynein arm retention (9/16 cases). Fifteen (94%) patients or their sibling (s) had situs inversus suggesting in CCDC103 p.His154Pro patients without situs inversus the diagnosis is missed. In conclusion, the CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes PCD that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive or normal diagnostic tests

Kartagener Syndrome

10.1183/1393003.congress-2017.pa1851

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Primary Ciliary Dyskinesia: First Health-related Quality of Life Measures for Pediatric Patients

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2016)

Sharon Dell Margaret W. Leigh Jane S. Lucas Thomas W. Ferkol Michael R. Knowles

10.17615/pjv3-de73

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HERA and the LHC - A workshop on the implications of HERA for LHC physics: Proceedings - Part A

arXiv (Cornell University) (2006)

S. Alekhin Guido Altarelli N. Amapane Jeppe R. Andersen V. Andreev

The HERA electron--proton collider has collected 100 pb$^{-1}$ of data since its start-up in 1992, and recently moved into a high-luminosity operation mode, with upgraded detectors, aiming to increase the total integrated luminosity per experiment to more than 500 pb$^{-1}$. HERA has been a machine of excellence for the study of QCD and the structure of the proton. The Large Hadron Collider (LHC), which will collide protons with a centre-of-mass energy of 14 TeV, will be completed at CERN in 2007. The main mission of the LHC is to discover and study the mechanisms of electroweak symmetry breaking, possibly via the discovery of the Higgs particle, and search for new physics in the TeV energy scale, such as supersymmetry or extra dimensions. Besides these goals, the LHC will also make a substantial number of precision measurements and will offer a new regime to study the strong force via perturbative QCD processes and diffraction. For the full LHC physics programme a good understanding of QCD phenomena and the structure function of the proton is essential. Therefore, in March 2004, a one-year-long workshop started to study the implications of HERA on LHC physics. This included proposing new measurements to be made at HERA, extracting the maximum information from the available data, and developing/improving the theoretical and experimental tools. This report summarizes the results achieved during this workshop.

10.48550/arxiv.hep-ph/0601012

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Clinical features and management of children with primary ciliary dyskinesia in England

Archives of Disease in Childhood (2020)

Bruna Rubbo Sunayna Best Robert A. Hirst Amelia Shoemark Patricia Goggin

Objective In England, the National Health Service commissioned a National Management Service for children with primary ciliary dyskinesia (PCD). The aims of this study were to describe the health of children seen in this Service and compare lung function to children with cystic fibrosis (CF). Design Multi-centre service evaluation of the English National Management PCD Service. Setting Four nationally commissioned PCD centres in England. Patients 333 children with PCD reviewed in the Service in 2015; lung function data were also compared with 2970 children with CF. Results Median age at diagnosis for PCD was 2.6 years, significantly lower in children with situs inversus (1.0 vs 6.0 years, p<0.001). Compared with national data from the CF Registry, mean (SD) %predicted forced expiratory volume in one second (FEV 1 ) was 76.8% in PCD (n=240) and 85.0% in CF, and FEV 1 was lower in children with PCD up to the age of 15 years. Approximately half of children had some hearing impairment, with 26% requiring hearing aids. Children with a lower body mass index (BMI) had lower FEV 1 (p<0.001). One-third of children had positive respiratory cultures at review, 54% of these grew Haemophilus influenzae . Conclusions We provide evidence that children with PCD in England have worse lung function than those with CF. Nutritional status should be considered in PCD management, as those with a lower BMI have significantly lower FEV 1 . Hearing impairment is common but seems to improve with age. Well-designed and powered randomised controlled trials on management of PCD are needed to inform best clinical practice.

10.1136/archdischild-2019-317687

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Phenotypic variability of CCDC103 mutation in British Pakistani children with Primary Ciliary Dyskinesia (PCD)

Cilia (2015)

Evie Robson Eduardo Moya Thomas Burgoyne P Chetcuti Matthew A. Dixon

ObjectivesPCD is an autosomal recessive condition that affects the structure and function of motile cilia in the respiratory tract, middle ear and reproductive organs.The estimated prevalence is 1:15,000, but as high as 1:2265 in the British Asian population.Mutations in the CCDC103 gene have recently been identified as PCD disease-causing in Pakistani individuals.It is found to be an essential gene for dynein arm assembly and ciliary motility.

Motile cilium

10.1186/2046-2530-4-s1-p61

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Susceptibility of human monoclonal antibody–producing B cell lines to infection by human immunodeficiency virus

Human Antibodies (1992)

Adrian J. Shepherd Janice E. Boyd Claire Hogg D. Aw K. James

Seven immortalized B cell clones, five of which secreted specific human monoclonal antibodies (MAbs) against hepatitis B, tetanus toxoid, and Rhesus D antigens, were evaluated for their susceptibility to infection by human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Infection was confirmed in three human MAb-producing lines by detection of infectious virus and p24 antigen in culture supernates, by immunofluorescence, and by detection of viral DNA in cells by polymerase chain reaction. The infectable lines were as susceptible to HIV-1 infection as several T cell lines and remained persistently infected for several months, but in contrast to T cell controls, viral cytopathic effects were not observed. Levels of unintegrated viral DNA in the HB1 B cell line were significantly lower than in the HUT78 T cell line. Cell lines that were susceptible to HIV expressed HLA DR, CD20, and CD21, whereas the uninfectable cell lines did not express any of the markers tested. CD4 was undetectable or present on a small percentage of cells in two of the infectable cell lines. However, infection with HIV-1 was blocked more efficiently in B cells than in T cells by soluble CD4, anti-CD4 MAb, and dextran sulphate. The effect of HIV infection on human MAb secretion was variable, being reduced on a per-cell basis in one line, increased in another, and unchanged in a third.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunofluorescence

10.3233/hab-1992-3402

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Development of pediatric cross-cultural patient-reported outcome measures: QOL-PCD

Sharon Dell Margaret W. Leigh Thomas Ferkol Michael R. Knowles Adrianne Alpern

Primary Ciliary Dyskinesia (PCD) is a rare genetic disease characterised by bronchiectasis, rhinosinusitis, and ear disease. We developed harmonized (North America, Europe) pediatric health-related quality of life questionnaires for children (6-12 years), adolescents (13-18 years), and parent respondents. Methods: FDA and EMA Guidances were followed. Focus groups and open-ended interviews were conducted to evaluate the impact: n = 12 specialists in North America, n = 40 health care providers in Europe, and 14 children with PCD, plus parents. Open-ended interviews (children with PCD and parents) included: USA/Canada n = 55; UK/Ireland n = 17. Items were also rated for relevance and importance by patients (n = 110). Transcriptions were analyzed using Atlas.ti/Nvivo to generate saturation grids. Qualitative and quantitative data were used to generate items. Cognitive testing (USA/Canada n = 25; UK n = 44) refined the clarity and comprehensiveness of these measures. Results: Cognitive testing indicated the measures were comprehensive and easy to complete. Preliminary instruments consist of: 1) Child (37 items); 2) Adolescent (43 items); and 3) Parent (41 items) versions with 8-10 scales. Conclusions: PCD-QOL have demonstrated face validity and cross-cultural equivalence. Next, psychometric testing will determine their utility as outcome measures for global, multi-center trials.

Cognitive interview

Patient-reported outcome

Cross-cultural studies

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Time required to obtain endobronchial biopsies in children during fiberoptic bronchoscopy

Pediatric Pulmonology (2008)

Nicolas Regamey Ian M. Balfour‐Lynn Mark Rosenthal Claire Hogg Andrew Bush

Endobronchial biopsies are an important tool for the study of airway remodeling in children. We aimed to evaluate the impact of performing endobronchial biopsies as a part of fiberoptic bronchoscopy on the length of the procedure.Clinically indicated fiberoptic bronchoscopy at which endobronchial biopsy was attempted as a part of a research protocol was performed in 40 children (median age 6 years, range 2 months-16 years). Time needed for airway inspection, bronchoalveolar lavage (BAL) with three aliquots of 1 ml/kg of 0.9% saline, sampling of three macroscopically adequate biopsies, teaching, and other interventions (e.g., removal of plugs) was recorded. The bronchoscopist was not aware that the procedure was being timed.Median (range) duration (min) was 2.5 (1.0-8.2) for airway inspection, 2.8 (1.7-9.4) for BAL, 5.3 (2.5-16.6) for biopsy sampling, 2.4 (1.5-6.6) for teaching and 4.1 (0.8-18.5) for other interventions. Three adequate biopsies were obtained in 33 (83%) children. Use of 2.0 mm biopsy forceps (via 4.0 and 4.9 mm bronchoscopes) rather than 1.0 mm (via 2.8 and 3.6 mm bronchoscopes) significantly reduced biopsy time (4.6 min vs. 8.4 min, P < 0.001).It takes a median of just over 5 min to obtain three endobronchial biopsies in children, which we consider an acceptable increase in the duration of fiberoptic bronchoscopy for the purpose of research.

Flexible bronchoscopy

10.1002/ppul.20949

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Citations (13)

How insignificant are genetic variants of unknown significance in Primary Ciliary Dyskinesia?

Reena Bhatt S.B. Carr Claire Hogg

Inheritance in Primary ciliary dyskinesia [PCD] is primarily autosomal recessive and is caused by mutations in at least 50 known genes. We reviewed 101 patients with genetic results known to the PCD service at Royal Brompton Hospital. Genetic results were compared to diagnostics from nasal nitric oxide [nNO] measurements and nasal biopsies using light, electron microscopy [LM and EM] and immunofluorescence [IF]. We identified 16 patients under clinical management for a suspected respiratory ciliopathy who did not have bi-allelic pathogenic variants according to current clinical diagnostic guidelines but did carry one or more variants of unknown significance [VUS] detected in either known PCD genes such as DNAH11, CCDC40 or in a candidate PCD gene. These patients had abnormalities detected on LM and EM and 6 patients had low nNO. All patients had a phenotype typical of PCD including 4 patients with situs defects. These cases demonstrate a background prevalence of VUS in known PCD genes that are often inconsistent with the structural and functional findings based on currently known diagnostic geno-pheno correlations. A possible explanation for abnormal LM, EM and IF results is whether the heterozygosity causes a reduction in one structural protein combined with decrease in another protein leading to instability of the ciliary structure. Diagnosis is multifactorial in PCD and these findings raise the need for a national database to accumulate all PCD cohort genetic data, to direct novel mutation research and to understand if such a collection of VUS are significant in the diagnosis of PCD in the presence of other convincing diagnostic criteria.

Ciliopathy

Motile cilium

Compound heterozygosity

Clinical Significance

10.1183/13993003.congress-2020.325

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Citations (1)