Paediatrics (RCH) - Research Publications

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    What the paediatrician needs to know when pandemic influenza arrives in clinical practice
    Ritz, N ; Curtis, N ; Finn, A ; Pollard, AJ (SPRINGER-VERLAG BERLIN, 2008-01-01)
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    A Genome-Wide Association Study Identifies Novel and Functionally Related Susceptibility Loci for Kawasaki Disease
    Burgner, D ; Davila, S ; Breunis, WB ; Ng, SB ; Li, Y ; Bonnard, C ; Ling, L ; Wright, VJ ; Thalamuthu, A ; Odam, M ; Shimizu, C ; Burns, JC ; Levin, M ; Kuijpers, TW ; Hibberd, ML ; Gibson, G (PUBLIC LIBRARY SCIENCE, 2009-01-01)
    Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, p(combined) = 1.13 x 10(-6)) and ZFHX3 (rs7199343, p(combined) = 2.37 x 10(-6)) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p = 10(-13)) containing five fine-mapped genes-LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1-with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases.
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    A Three-Way Comparison of Tuberculin Skin Testing, QuantiFERON-TB Gold and T-SPOT. TB in Children
    Connell, TG ; Ritz, N ; Paxton, GA ; Buttery, JP ; Curtis, N ; Ranganathan, SC ; Dheda, K (PUBLIC LIBRARY SCIENCE, 2008-07-09)
    BACKGROUND: There are limited data comparing the performance of the two commercially available interferon gamma (IFN-gamma) release assays (IGRAs) for the diagnosis of tuberculosis (TB) in children. We compared QuantiFERON-TB gold In Tube (QFT-IT), T-SPOT.TB and the tuberculin skin test (TST) in children at risk for latent TB infection or TB disease. METHODS AND FINDINGS: The results of both IGRAs were compared with diagnosis assigned by TST-based criteria and assessed in relation to TB contact history. Results from the TST and at least one assay were available for 96 of 100 children. Agreement between QFT-IT and T-SPOT.TB was high (93% agreement, kappa = 0.83). QFT-IT and T-SPOT.TB tests were positive in 8 (89%) and 9 (100%) children with suspected active TB disease. There was moderate agreement between TST and either QFT-IT (75%, kappa = 0.50) or T-SPOT.TB (75%, kappa = 0.51). Among 38 children with TST-defined latent TB infection, QFT-IT gold and T-SPOT.TB assays were positive in 47% and 39% respectively. Three TST-negative children were positive by at least one IGRA. Children with a TB contact were more likely than children without a TB contact to have a positive IGRA (QFT-IT LR 3.9; T-SPOT.TB LR 3.9) and a positive TST (LR 1.4). Multivariate linear regression analysis showed that the magnitude of both TST induration and IGRA IFN-gamma responses was significantly influenced by TB contact history, but only the TST was influenced by age. CONCLUSIONS: Although a high level of agreement between the IGRAs was observed, they are commonly discordant with the TST. The correct interpretation of a negative assay in a child with a positive skin test in clinical practice remains challenging and highlights the need for longitudinal studies to determine the negative predictive value of IGRAs.
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    Liposomal amphotericin B trial marred by conclusions
    Wolf, J ; Buttery, J ; Daley, AJ ; Hanieh, S ; Shann, F ; Starr, M ; Curtis, N (OXFORD UNIV PRESS INC, 2007-09-01)
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    Detection of Gene Expression in an Individual Cell Type within a Cell Mixture Using Microarray Analysis
    Bryant, PA ; Smyth, GK ; Robins-Browne, R ; Curtis, N ; Huang, S (PUBLIC LIBRARY SCIENCE, 2009-02-12)
    BACKGROUND: A central issue in the design of microarray-based analysis of global gene expression is the choice between using cells of single type and a mixture of cells. This study quantified the proportion of lipopolysaccharide (LPS) induced differentially expressed monocyte genes that could be measured in peripheral blood mononuclear cells (PBMC), and determined the extent to which gene expression in the non-monocyte cell fraction diluted or obscured fold changes that could be detected in the cell mixture. METHODOLOGY/PRINCIPAL FINDINGS: Human PBMC were stimulated with LPS, and monocytes were then isolated by positive (Mono+) or negative (Mono-) selection. The non-monocyte cell fraction (MonoD) remaining after positive selection of monocytes was used to determine the effect of non-monocyte cells on overall expression. RNA from LPS-stimulated PBMC, Mono+, Mono- and MonoD samples was co-hybridised with unstimulated RNA for each cell type on oligonucleotide microarrays. There was a positive correlation in gene expression between PBMC and both Mono+ (0.77) and Mono- (0.61-0.67) samples. Analysis of individual genes that were differentially expressed in Mono+ and Mono- samples showed that the ability to detect expression of some genes was similar when analysing PBMC, but for others, differential expression was either not detected or changed in the opposite direction. As a result of the dilutional or obscuring effect of gene expression in non-monocyte cells, overall about half of the statistically significant LPS-induced changes in gene expression in monocytes were not detected in PBMC. However, 97% of genes with a four fold or greater change in expression in monocytes after LPS stimulation, and almost all (96-100%) of the top 100 most differentially expressed monocyte genes were detected in PBMC. CONCLUSIONS/SIGNIFICANCE: The effect of non-responding cells in a mixture dilutes or obscures the detection of subtle changes in gene expression in an individual cell type. However, for studies in which only the most highly differentially expressed genes are of interest, separating and analysing individual cell types may be unnecessary.
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    Skin ulcers in a returned traveller
    Connell, TG ; Rele, M ; Daley, AJ ; Curtis, N (ELSEVIER SCIENCE INC, 2005-02-19)
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    Severe Bordetella holmesii infection in a previously healthy adolescent confirmed by gene sequence analysis
    Russell, FM ; Davis, JM ; Whipp, MJ ; Janssen, PH ; Ward, PB ; Vyas, JR ; Starr, M ; Sawyer, SM ; Curtis, N (UNIV CHICAGO PRESS, 2001-07-01)
    We describe an immunocompetent adolescent who presented with exceptionally severe Bordetella holmesii infection, including previously undescribed manifestations. Sequelae included a severe restrictive lung defect due to pulmonary fibrosis.
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    Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children
    Connell, TG ; Curtis, N ; Ranganathan, SC ; Buttery, JP (BMJ PUBLISHING GROUP, 2006-07-01)
    BACKGROUND: The diagnosis of latent Mycobacterium tuberculosis (MTB) infection with a tuberculin skin test (TST) in children is complicated by the potential influence of prior exposure to Bacille Calmette Geurin (BCG) vaccination or environmental mycobacteria. A whole blood assay has recently been developed to quantitatively measure interferon gamma (IFN-gamma) production by lymphocytes specific to the MTB antigens ESAT-6 and CFP-10, but its use and assessment in children has been limited. A study was undertaken to compare the performance of the whole blood IFN-gamma assay with the TST in diagnosing latent tuberculosis (TB) infection or TB disease in children in routine clinical practice. METHODS: One hundred and six children with a high risk of latent TB infection or TB disease were enrolled in the study. High risk was defined as contact with TB disease, clinical suspicion of TB disease, or recent arrival from an area of high TB prevalence. The whole blood IFN-gamma assay was undertaken in 101 children. RESULTS: Seventeen (17%) of the 101 assays yielded inconclusive results due to failure of positive or negative control assays. There was poor correlation between the whole blood IFN-gamma assay and the TST (kappa statistic 0.3) with 26 (70%) of the 37 children defined as latent TB infection by TST having a negative whole blood IFN-gamma assay. There were no instances of a positive whole blood IFN-gamma assay with a negative TST. Mitogen (positive) control IFN-gamma responses were significantly correlated with age (Spearman's coefficient = 0.53, p<0.001) and, in children with latent TB infection identified by TST, those with a positive IFN-gamma assay were older (median 12.9 v 6.92 years, respectively, p = 0.007). The whole blood IFN-gamma assay was positive in all nine children with TB disease. CONCLUSION: There was poor agreement between the whole blood IFN-gamma assay and TST for the diagnosis of latent TB. The whole blood IFN-gamma assay may have lower sensitivity than the TST in diagnosing TB infection in children. A significant proportion of whole blood IFN-gamma assays fail when used as a screening assay in routine practice.
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    Early detection of perinatal tuberculosis using a whole blood interferon-gamma release assay
    Connell, T ; Bar-Zeev, N ; Curtis, N (OXFORD UNIV PRESS INC, 2006-06-01)
    BACKGROUND: The diagnosis of perinatal tuberculosis (TB) is problematic because of its nonspecific presentation, the difficulty of obtaining microbiological confirmation, and the unreliability of the tuberculin skin test. Immunodiagnosis of TB has received new attention with the discovery of Mycobacterium tuberculosis-specific immunodominant antigens (early secreted antigenic target 6 [ESAT-6] and culture filtrate protein 10 [CFP-10]) that are encoded by the RD1 region of the pathogen. A whole blood assay has recently been developed to quantitatively measure interferon- gamma production by lymphocytes specific to these antigens, but its evaluation in the diagnosis of TB in infants and children has been limited to date. METHODS: In addition to routine diagnostic evaluation (tuberculin skin tests, culture of early-morning gastric aspirate samples, and chest radiographs), 2 infants with suspected perinatal TB were investigated with a whole blood interferon-gamma release assay. RESULTS: The results of the tuberculin skin tests were negative for both patients. The findings of the chest radiographs were abnormal with features suggestive of miliary TB. A whole blood interferon- gamma release assay was performed and yielded positive results within 48 h after admission to the hospital for both patients, prompting early antituberculous treatment. M. tuberculosis was cultured after 6 weeks from gastric aspirate samples collected on admission to the hospital from both infants. At 6 months of age, both infants were thriving and had acheived normal developmental milestones. CONCLUSIONS: The advent of interferon- gamma release assays may prove to be useful in the evaluation of infants with suspected perinatal TB.