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Article ; Online: Late Diagnosis of Infants with PCD and Neonatal Respiratory Distress

Myrofora Goutaki / Florian S. Halbeisen / Angelo Barbato / Suzanne Crowley / Amanda Harris / Robert A. Hirst / Bülent Karadag / Vendula Martinu / Lucy Morgan / Christopher O’Callaghan / Ugur Ozçelik / Sergio Scigliano / Santiago Ucros / Panayiotis Yiallouros / Sven M. Schulzke / Claudia E. Kuehni

Journal of Clinical Medicine, Vol 9, Iss 2871, p

2020 Volume 2871

Abstract: Neonatal respiratory distress (NRD) is common among infants with primary ciliary dyskinesia (PCD), but we do not know whether affected neonates receive a timely diagnosis. We used data from the international PCD cohort and assessed the proportion of ... ...

Abstract	Neonatal respiratory distress (NRD) is common among infants with primary ciliary dyskinesia (PCD), but we do not know whether affected neonates receive a timely diagnosis. We used data from the international PCD cohort and assessed the proportion of patients with PCD who had a history of NRD and their age at diagnosis, stratifying by presence of laterality defects. First we analyzed data from all participants diagnosed after 2000, followed by individuals from a subgroup diagnosed using stricter criteria. Among the 1375 patients in the study, 45% had a history of NRD and 42% had laterality defects. Out of the 476 children with definite PCD diagnosis, 55% had a history of NRD and 50% had laterality defects. Overall, 30% of children with PCD were diagnosed during the first 12 months of life. This varied from 13% in those with situs solitus and no NRD, to 21% in those with situs solitus and NRD, 33% in those with situs anomalies but no NRD, and 52% in those with both situs anomalies and NRD. Our results suggest that we need to improve our knowledge of the neonatal presentation of infants with PCD and apply it so that these patients will receive appropriate care sooner.
Keywords	primary ciliary dyskinesia ; neonatal respiratory distress ; laterality defect ; orphan diseases ; Medicine ; R
Subject code	610
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Revised Protocol for Culture of Airway Epithelial Cells as a Diagnostic Tool for Primary Ciliary Dyskinesia

Janice L. Coles / James Thompson / Katie L. Horton / Robert A. Hirst / Paul Griffin / Gwyneth M. Williams / Patricia Goggin / Regan Doherty / Peter M. Lackie / Amanda Harris / Woolf T. Walker / Christopher O’Callaghan / Claire Hogg / Jane S. Lucas / Cornelia Blume / Claire L. Jackson

Journal of Clinical Medicine, Vol 9, Iss 3753, p

2020 Volume 3753

Abstract: Air–liquid interface (ALI) culture of nasal epithelial cells is a valuable tool in the diagnosis and research of primary ciliary dyskinesia (PCD). Ex vivo samples often display secondary dyskinesia from cell damage during sampling, infection or ... ...

Abstract	Air–liquid interface (ALI) culture of nasal epithelial cells is a valuable tool in the diagnosis and research of primary ciliary dyskinesia (PCD). Ex vivo samples often display secondary dyskinesia from cell damage during sampling, infection or inflammation confounding PCD diagnostic results. ALI culture enables regeneration of healthy cilia facilitating differentiation of primary from secondary ciliary dyskinesia. We describe a revised ALI culture method adopted from April 2018 across three collaborating PCD diagnostic sites, including current University Hospital Southampton COVID-19 risk mitigation measures, and present results. Two hundred and forty nasal epithelial cell samples were seeded for ALI culture and 199 (82.9%) were ciliated. Fifty-four of 83 (63.9%) ex vivo samples which were originally equivocal or insufficient provided diagnostic information following in vitro culture. Surplus basal epithelial cells from 181 nasal brushing samples were frozen in liquid nitrogen; 39 samples were ALI-cultured after cryostorage and all ciliated. The ciliary beat patterns of ex vivo samples (by high-speed video microscopy) were recapitulated, scanning electron microscopy demonstrated excellent ciliation, and cilia could be immuno-fluorescently labelled (anti-alpha-tubulin and anti-RSPH4a) in representative cases that were ALI-cultured after cryostorage. In summary, our ALI culture protocol provides high ciliation rates across three centres, minimising patient recall for repeat brushing biopsies and improving diagnostic certainty. Cryostorage of surplus diagnostic samples was successful, facilitating PCD research.
Keywords	PCD ; ALI culture ; bio-resource ; primary nasal epithelium ; diagnostics ; Medicine ; R
Subject code	610
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders

Charlie Rowlands / Huw B. Thomas / Jenny Lord / Htoo A. Wai / Gavin Arno / Glenda Beaman / Panagiotis Sergouniotis / Beatriz Gomes-Silva / Christopher Campbell / Nicole Gossan / Claire Hardcastle / Kevin Webb / Christopher O’Callaghan / Robert A. Hirst / Simon Ramsden / Elizabeth Jones / Jill Clayton-Smith / Andrew R. Webster / Genomics England Research Consortium /

Andrew G. L. Douglas / Raymond T. O’Keefe / William G. Newman / Diana Baralle / Graeme C. M. Black / Jamie M. Ellingford

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 11

Abstract: Abstract The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 ... ...

Abstract	Abstract The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being ‘pathogenic’ or ‘benign’ is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as ‘pathogenic’ or ‘likely pathogenic’; one in five of these cases could lead to new or refined diagnoses.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Role of Toll-like receptors 2 and 4 in pulmonary inflammation and injury induced by pneumolysin in mice.

Mark C Dessing / Robert A Hirst / Alex F de Vos / Tom van der Poll

PLoS ONE, Vol 4, Iss 11, p e

2009 Volume 7993

Abstract: BACKGROUND:Pneumolysin (PLN) is an intracellular toxin of Streptococcus pneumoniae that has been implicated as a major virulence factor in infections caused by this pathogen. Conserved bacterial motifs are recognized by the immune system by pattern ... ...

Abstract	BACKGROUND:Pneumolysin (PLN) is an intracellular toxin of Streptococcus pneumoniae that has been implicated as a major virulence factor in infections caused by this pathogen. Conserved bacterial motifs are recognized by the immune system by pattern recognition receptors among which the family of Toll-like receptors (TLRs) prominently features. The primary objective of the present study was to determine the role of TLR2 and TLR4 in lung inflammation induced by intrapulmonary delivery of PLN. METHODOLOGY/RESULTS:First, we confirmed that purified PLN activates cells via TLR4 (not via TLR2) in vitro, using human embryonic kidney cells transfected with either TLR2 or TLR4. Intranasal administration of PLN induced an inflammatory response in the pulmonary compartment of mice in vivo, as reflected by influx of neutrophils, release of proinflammatory cytokines and chemokines, and a rise in total protein concentrations in bronchoalveolar lavage fluid. These PLN-induced responses were dependent in part, not only on TLR4, but also on TLR2, as indicated by studies using TLR deficient mice. CONCLUSION:These data suggest that although purified PLN is recognized by TLR4 in vitro, PLN elicits lung inflammation in vivo by mechanisms that may involve multiple TLRs.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2009-11-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Proceedings of the 4th BEAT-PCD Conference and 5th PCD Training School

Laura E. Gardner / Katie L. Horton / Amelia Shoemark / Jane S. Lucas / Kim G. Nielsen / Helene Kobbernagel / Bruna Rubbo / Robert A. Hirst / Panayiotis Kouis / Nicola Ullmann / Ana Reula / Nisreen Rumman / Hannah M. Mitchison / Andreia Pinto / Charlotte Richardson / Anne Schmidt / James Thompson / René Gaupmann / Maciej Dabrowski /

Pleasantine Mill / Siobhan B. Carr / Dominic P. Norris / Claudia E. Kuehni / Myrofora Goutaki / Claire Hogg

BMC Proceedings, Vol 14, Iss S8, Pp 1-

2020 Volume 17

Abstract: Abstract Primary ciliary dyskinesia (PCD) is an inherited ciliopathy leading to chronic suppurative lung disease, chronic rhinosinusitis, middle ear disease, sub-fertility and situs abnormalities. As PCD is rare, it is important that scientists and ... ...

Abstract	Abstract Primary ciliary dyskinesia (PCD) is an inherited ciliopathy leading to chronic suppurative lung disease, chronic rhinosinusitis, middle ear disease, sub-fertility and situs abnormalities. As PCD is rare, it is important that scientists and clinicians foster international collaborations to share expertise in order to provide the best possible diagnostic and management strategies. ‘Better Experimental Approaches to Treat Primary Ciliary Dyskinesia’ (BEAT-PCD) is a multidisciplinary network funded by EU COST Action (BM1407) to coordinate innovative basic science and clinical research from across the world to drive advances in the field. The fourth and final BEAT-PCD Conference and fifth PCD Training School were held jointly in March 2019 in Poznan, Poland. The varied program of plenaries, workshops, break-out sessions, oral and poster presentations were aimed to enhance the knowledge and skills of delegates, whilst also providing a collaborative platform to exchange ideas. In this final BEAT-PCD conference we were able to build upon programmes developed throughout the lifetime of the COST Action. These proceedings report on the conference, highlighting some of the successes of the BEAT-PCD programme.
Keywords	Primary ciliary dyskinesia ; Chronic respiratory disease ; Multidisciplinary ; Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Proceedings of the 2nd BEAT-PCD conference and 3rd PCD training school

BMC Proceedings, Vol 12, Iss S2, Pp 1-

part 1

2018 Volume 17

Abstract: Abstract Primary ciliary dyskinesia (PCD) is a rare heterogenous condition that causes progressive suppurative lung disease, chronic rhinosinusitis, chronic otitis media, infertility and abnormal situs. ‘Better Experimental Approaches to Treat Primary ... ...

Abstract	Abstract Primary ciliary dyskinesia (PCD) is a rare heterogenous condition that causes progressive suppurative lung disease, chronic rhinosinusitis, chronic otitis media, infertility and abnormal situs. ‘Better Experimental Approaches to Treat Primary Ciliary Dyskinesia’ (BEAT-PCD) is a network of scientists and clinicians coordinating research from basic science through to clinical care with the intention of developing treatments and diagnostics that lead to improved long-term outcomes for patients. BEAT-PCD activities are supported by EU funded COST Action (BM1407). The second BEAT-PCD conference, and third PCD training school were held jointly in April 2017 in Valencia, Spain. Presentations and workshops focussed on advancing the knowledge and skills relating to PCD in: basic science, epidemiology, diagnostic testing, clinical management and clinical trials. The multidisciplinary conference provided an interactive platform for exchanging ideas through a program of lectures, poster presentations, breakout sessions and workshops. Three working groups met to plan consensus statements. Progress with BEAT-PCD projects was shared and new collaborations were fostered. In this report, we summarize the meeting, highlighting developments made during the meeting.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells.

Sunil Lagah / I-Li Tan / Priya Radhakrishnan / Robert A Hirst / Jennifer H Ward / Chris O'Callaghan / Stuart J Smith / Malcolm F G Stevens / Richard G Grundy / Ruman Rahman

PLoS ONE, Vol 9, Iss 1, p e

2014 Volume 86187

Abstract: BACKGROUND: Telomeric 3' overhangs can fold into a four-stranded DNA structure termed G-quadruplex (G4), a formation which inhibits telomerase. As telomerase activation is crucial for telomere maintenance in most cancer cells, several classes of G4 ... ...

Abstract	BACKGROUND: Telomeric 3' overhangs can fold into a four-stranded DNA structure termed G-quadruplex (G4), a formation which inhibits telomerase. As telomerase activation is crucial for telomere maintenance in most cancer cells, several classes of G4 ligands have been designed to directly disrupt telomeric structure. METHODS: We exposed brain tumor cells to the G4 ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) and investigated proliferation, cell cycle dynamics, telomere length, telomerase activity and activated c-Myc levels. RESULTS: Although all cell lines tested were sensitive to RHPS4, PFSK-1 central nervous system primitive neuroectodermal cells, DAOY medulloblastoma cells and U87 glioblastoma cells exhibited up to 30-fold increased sensitivity compared to KNS42 glioblastoma, C6 glioma and Res196 ependymoma cells. An increased proportion of S-phase cells were observed in medulloblastoma and high grade glioma cells whilst CNS PNET cells showed an increased proportion of G1-phase cells. RHPS4-induced phenotypes were concomitant with telomerase inhibition, manifested in a telomere length-independent manner and not associated with activated c-Myc levels. However, anti-proliferative effects were also observed in normal neural/endothelial cells in vitro and ex vivo. CONCLUSION: This study warrants in vivo validation of RHPS4 and alternative G4 ligands as potential anti-cancer agents for brain tumors but highlights the consideration of dose-limiting tissue toxicities.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The behaviour of both Listeria monocytogenes and rat ciliated ependymal cells is altered during their co-culture.

Mina J Fadaee-Shohada / Robert A Hirst / Andrew Rutman / Ian S Roberts / Chris O'Callaghan / Peter W Andrew

PLoS ONE, Vol 5, Iss 5, p e

2010 Volume 10450

Abstract: Ciliated ependymal cells line the cerebral ventricles and aqueducts separating the infected CSF from the brain parenchyma in meningitis.Investigation of the interaction of Listeria monocytogenes with cultured rat brain ependymal cells showed that certain ...

Abstract	Ciliated ependymal cells line the cerebral ventricles and aqueducts separating the infected CSF from the brain parenchyma in meningitis.Investigation of the interaction of Listeria monocytogenes with cultured rat brain ependymal cells showed that certain strains reduced the beat frequency of the cilia but all the strains studied significantly reduced the ciliary beat amplitude (the linear distance travelled by the tip of each cilium per beat cycle).The presence of the ependyma caused aggregation of some listeria strains and in some cases extracellular material also was seen in association with bacterial aggregates. These observations were dependent on the expression of genes required for invasion, intracellular survival and listerial cell to cell spread that are regulated by the transcriptional activator, positive regulatory factor A (PrfA).
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2010-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Culture of primary ciliary dyskinesia epithelial cells at air-liquid interface can alter ciliary phenotype but remains a robust and informative diagnostic aid.

Robert A Hirst / Claire L Jackson / Janice L Coles / Gwyneth Williams / Andrew Rutman / Patricia M Goggin / Elizabeth C Adam / Anthony Page / Hazel J Evans / Peter M Lackie / Christopher O'Callaghan / Jane S Lucas

PLoS ONE, Vol 9, Iss 2, p e

2014 Volume 89675

Abstract: The diagnosis of primary ciliary dyskinesia (PCD) requires the analysis of ciliary function and ultrastructure. Diagnosis can be complicated by secondary effects on cilia such as damage during sampling, local inflammation or recent infection. To ... ...

Abstract	The diagnosis of primary ciliary dyskinesia (PCD) requires the analysis of ciliary function and ultrastructure. Diagnosis can be complicated by secondary effects on cilia such as damage during sampling, local inflammation or recent infection. To differentiate primary from secondary abnormalities, re-analysis of cilia following culture and re-differentiation of epithelial cells at an air-liquid interface (ALI) aids the diagnosis of PCD. However changes in ciliary beat pattern of cilia following epithelial cell culture has previously been described, which has brought the robustness of this method into question. This is the first systematic study to evaluate ALI culture as an aid to diagnosis of PCD in the light of these concerns.We retrospectively studied changes associated with ALI-culture in 158 subjects referred for diagnostic testing at two PCD centres. Ciliated nasal epithelium (PCD n = 54; non-PCD n 111) was analysed by high-speed digital video microscopy and transmission electron microscopy before and after culture.Ciliary function was abnormal before and after culture in all subjects with PCD; 21 PCD subjects had a combination of static and uncoordinated twitching cilia, which became completely static following culture, a further 9 demonstrated a decreased ciliary beat frequency after culture. In subjects without PCD, secondary ciliary dyskinesia was reduced.The change to ciliary phenotype in PCD samples following cell culture does not affect the diagnosis, and in certain cases can assist the ability to identify PCD cilia.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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