61 results found
Kaforou M, Wright VJ, Levin M, 2014, Host RNA signatures for diagnostics: An example from paediatric tuberculosis in Africa, JOURNAL OF INFECTION, Vol: 69, Pages: S28-S31, ISSN: 0163-4453
Marino LV, Pathan N, Meyer R, et al., 2014, Glutamine depletion and heat shock protein 70 (HSP70) in children with meningococcal disease, CLINICAL NUTRITION, Vol: 33, Pages: 915-921, ISSN: 0261-5614
Anderson ST, Kaforou M, Brent AJ, et al., 2014, Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa, New England Journal of Medicine, Vol: 370, Pages: 1712-1723, ISSN: 1533-4406
Herberg JA, Kaforou M, Gormley S, et al., 2013, Transcriptomic Profiling in Childhood H1N1/09 Influenza Reveals Reduced Expression of Protein Synthesis Genes, Journal of Infectious Diseases, Vol: 208, Pages: 1664-1668, ISSN: 1537-6613
We compared the blood RNA transcriptome of children hospitalized with influenza A H1N1/09, respiratory syncytial virus (RSV) or bacterial infection, and healthy controls. Compared to controls, H1N1/09 patients showed increased expression of inflammatory pathway genes and reduced expression of adaptive immune pathway genes. This was validated on an independent cohort. The most significant function distinguishing H1N1/09 patients from controls was protein synthesis, with reduced gene expression. Reduced expression of protein synthesis genes also characterized the H1N1/09 expression profile compared to children with RSV and bacterial infection, suggesting that this is a key component of the pathophysiological response in children hospitalized with H1N1/09 infection.
Kaforou M, Wright VJ, Oni T, et al., 2013, Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study., Plos Medicine, Vol: 10
Background: A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB),particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature woulddistinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simplediagnostic test.Methods and Findings: Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB]from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differentialdiagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized intotraining (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantlydifferentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcriptsignature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, weused a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on thisscore was first evaluated in the test cohort, and then validated in an independent publically available dataset(GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87–100]; specificity 90%, 95% CI[80–97]) and TB from OD (sensitivity 93%, 95% CI [83–100]; specificity 88%, 95% CI [74–97]). In the independent validationcohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85–100]; specificity 94%, 95% CI[84–100]) and OD patients (sensitivity 100%, 95% CI [100–100]; specificity 96%, 95% CI [93–100]). Limitations of our studyin
Burns JC, Herzog L, Fabri O, et al., 2013, Seasonality of kawasaki disease: a global perspective., PLOS One, Vol: 8
Fatemifar G, Hoggart CJ, Paternoster L, et al., 2013, Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 3807-3817, ISSN: 0964-6906
Levin M, Kaforou M, Herberg J, et al., 2013, METHOD FOR CALCULATING A DISEASE RISK SCORE, PCT/GB2013/050225
The present disclosure relates to a general method for converting complex gene expression data into a simple, composite disease risk score which can be used for the development of rapid diagnostic tests suitable for clinical use for the determination of the presence of an infection or disease in a host.
Aramburo Caragol A, Wright VJ, Levin M, et al., 2013, Bases Genéticas De La Enfermedad Meningocócica, La Enfermedad Meningocócica: Pasado, Presente Y Futuro., Editors: Moraga-Llop
Couto-Alves A, Wright VJ, Perumal K, et al., 2013, A new scoring system derived from base excess and platelet count at presentation predicts mortality in paediatric meningococcal sepsis, CRITICAL CARE, Vol: 17, ISSN: 1466-609X
Froghi F, Sodergren MH, Wright VJ, et al., 2012, Single-Center Experience in Systemic Stress and Short-Term Morbidity of Single-Incision Cholecystectomy, SURGICAL INNOVATION, Vol: 19, Pages: 117-122, ISSN: 1553-3506
Breunis WB, Davila S, Shimizu C, et al., 2012, Disruption of vascular homeostasis in patients with Kawasaki disease: Involvement of vascular endothelial growth factor and angiopoietins, ARTHRITIS AND RHEUMATISM, Vol: 64, Pages: 306-315, ISSN: 0004-3591
Khor CC, Davila S, Breunis WB, et al., 2011, Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease, NATURE GENETICS, Vol: 43, Pages: 1241-1246, ISSN: 1061-4036
Khor CC, Davila S, Shimizu C, et al., 2011, Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease, JOURNAL OF MEDICAL GENETICS, Vol: 48, Pages: 467-472, ISSN: 0022-2593
Pathan N, Franklin JL, Eleftherohorinou H, et al., 2011, Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase, CRITICAL CARE MEDICINE, Vol: 39, Pages: 1692-1711, ISSN: 0090-3493
Eleftherohorinou H, Hoggart CJ, Wright VJ, et al., 2011, Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways, Human Molecular Genetics, Vol: 20, Pages: 3494-3506
McGregor CGC, Sodergren MH, Aslanyan A, et al., 2011, Evaluating Systemic Stress Response in Single Port vs. Multi-Port Laparoscopic Cholecystectomy, JOURNAL OF GASTROINTESTINAL SURGERY, Vol: 15, Pages: 614-622, ISSN: 1091-255X
Shimizu C, Jain S, Davila S, et al., 2011, Transforming Growth Factor-beta Signaling Pathway in Patients With Kawasaki Disease (vol 4, pg 16, 2011), CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 4, Pages: E9-E9, ISSN: 1942-325X
Shimizu C, Jain S, Davila S, et al., 2011, Transforming Growth Factor-beta Signaling Pathway in Patients With Kawasaki Disease, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 4, Pages: 16-U99, ISSN: 1942-325X
Davila S, Wright VJ, Khor CC, et al., 2010, Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease, NATURE GENETICS, Vol: 42, Pages: 772-U63, ISSN: 1061-4036
Kung'u JK, Goodman D, Haji HJ, et al., 2009, Early helminth infections are inversely related to anemia, malnutrition, and malaria and are not associated with inflammation in 6- to 23-month-old Zanzibari children., Am J Trop Med Hyg, Vol: 81, Pages: 1062-1070
Eleftherohorinou H, Wright V, Hoggart C, et al., 2009, Analysis of GWAS Provides New Insights into Genetic Susceptibility to 3 Inflammatory Diseases, PLoS One, Vol: 4, Pages: e8068-e8068, ISSN: 1932-6203
Although the introduction of genome-wide association studies (GWAS) have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD), rheumatoid arthritis (RA) and type 1 diabetes (T1D) with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC). The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10(-3)-10(-20)) with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes) for T1D, 350 SNPs (189 genes) for RA and 493 SNPs (277 genes) for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC) and RA (85% AUC), and weakly predictive of CD (60% AUC). The predictive ability of the T1D model (without any parameter refitting) had good predictive ability (79% AUC) in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways.
Kung'u JK, Wright VJ, Haji HJ, et al., 2009, Adjusting for the acute phase response is essential to interpret iron status indicators among young Zanzibari children prone to chronic malaria and helminth infections., Journal of Nutrition, Vol: 139, Pages: 2124-2131
Wright V, Hibberd M, Levin M, 2009, Genetic polymorphisms in host response to meningococcal infection: The role of susceptibility and severity genes, VACCINE, Vol: 27, Pages: B90-B102, ISSN: 0264-410X
Wright VJ, Ame SM, Haji HS, et al., 2009, Early exposure of infants to GI nematodes induces Th2 dominant immune responses which are unaffected by periodic anthelminthic treatment., PLoS Negl Trop Dis, Vol: 3, Pages: e433-e433, ISSN: 1935-2735
We have previously shown a reduction in anaemia and wasting malnutrition in infants <3 years old in Pemba Island, Zanzibar, following repeated anthelminthic treatment for the endemic gastrointestinal (GI) nematodes Ascaris lumbricoides, hookworm and Trichuris trichiura. In view of the low intensity of worm infections in this age group, this was unexpected, and it was proposed that immune responses to the worms rather than their direct effects may play a significant role in morbidity in infants and that anthelminthic treatment may alleviate such effects. Therefore, the primary aims of this study were to characterise the immune response to initial/early GI nematode infections in infants and the effects of anthelminthic treatment on such immune responses. The frequency and levels of Th1/Th2 cytokines (IL-5, IL-13, IFN-gamma and IL-10) induced by the worms were evaluated in 666 infants aged 6-24 months using the Whole Blood Assay. Ascaris and hookworm antigens induced predominantly Th2 cytokine responses, and levels of IL-5 and IL-13 were significantly correlated. The frequencies and levels of responses were higher for both Ascaris positive and hookworm positive infants compared with worm negative individuals, but very few infants made Trichuris-specific cytokine responses. Infants treated every 3 months with mebendazole showed a significantly lower prevalence of infection compared with placebo-treated controls at one year following baseline. At follow-up, cytokine responses to Ascaris and hookworm antigens, which remained Th2 biased, were increased compared with baseline but were not significantly affected by treatment. However, blood eosinophil levels, which were elevated in worm-infected children, were significantly lower in treated children. Thus the effect of deworming in this age group on anaemia and wasting malnutrition, which were replicated in this study, could not be explained by modification of cytokine responses but may be related to eosinophil function.
Burgner D, Davila S, Breunis WB, et al., 2009, A Genome-Wide Association Study Identifies Novel and Functionally Related Susceptibility Loci for Kawasaki Disease, PLOS GENETICS, Vol: 5, ISSN: 1553-7404
Jackson JA, Turner JD, Kamal M, et al., 2006, Gastrointestinal nematode infection is associated with variation in innate immune responsiveness, MICROBES AND INFECTION, Vol: 8, Pages: 487-492, ISSN: 1286-4579
Wright V, Bickle Q, 2005, Immune responses following experimental human hookworm infection, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 142, Pages: 398-403, ISSN: 0009-9104
Albonico M, Wright V, Ramsan M, et al., 2005, Development of the egg hatch assay for detection of anthelminthic resistance in human hookworms, INTERNATIONAL JOURNAL FOR PARASITOLOGY, Vol: 35, Pages: 803-811, ISSN: 0020-7519
Albonico M, Wright V, Bickle Q, 2004, Molecular analysis of the beta-tubulin gene of human hookworms as a basis for possible benzimidazole resistance on Pemba Island, MOLECULAR AND BIOCHEMICAL PARASITOLOGY, Vol: 134, Pages: 281-284, ISSN: 0166-6851
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