Institution
Medical Research Council
Government•London, United Kingdom•
About: Medical Research Council is a government organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Malaria. The organization has 16430 authors who have published 19150 publications receiving 1475494 citations.
Topics: Population, Malaria, Poison control, Gene, Antigen
Papers published on a yearly basis
Papers
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TL;DR: Polychromatic flow cytometry is used to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases.
Abstract: Genome-wide association studies (GWAS) have identified over 300 regions associated with more than 70 common diseases. However, identifying causal genes within an associated region remains a major challenge. One approach to resolving causal genes is through the dissection of gene-phenotype correlations. Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis. We confirm our strongest gene-phenotype correlation at the RNA level by allele-specific expression (ASE). We also define key parameters for the design and implementation of post-GWAS gene-phenotype investigations and demonstrate the usefulness of a large bioresource of genotype-selectable normal donors from whom fresh, primary cells can be analyzed.
273 citations
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TL;DR: In this article, it was suggested that the critical physical features of the tracks are the stochastic clusterings of ionizations, directly in or very near to DNA, resulting in clustered initial molecular damage including various combinations of breaks, base damages, cross-links, etc. in the DNA.
Abstract: Studies of ionizing radiations of different quality are discussed with particular emphasis on damage to DNA of mammalian cells. Three related themes are followed. Firstly, inactivation and mutation experiments with ultrasoft X-rays and slow heavy ions, coupled with theoretical analyses of the structures of the radiation tracks, have emphasized the biological importance of localized track features over nanometre dimensions. This led to the suggestion that the critical physical features of the tracks are the stochastic clusterings of ionizations, directly in or very near to DNA, resulting in clustered initial molecular damage including various combinations of breaks, base damages, cross-links, etc. in the DNA. The quantitative hypotheses imply that final cellular effects from high-LET radiations are dominated by their more severe, and therefore less repairable, clustered damage, and that these are qualitatively different from the dominant low-LET damage. Second, relative effectiveness of different types of ...
273 citations
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TL;DR: The value of well-defined symptoms to diagnose childhood pulmonary tuberculosis in a tuberculosis-endemic area was determined, and clinical follow-up was a valuable diagnostic tool that further improved diagnostic accuracy, particularly in the low-risk group.
Abstract: BACKGROUND. Tuberculosis control programs place an almost exclusive emphasis on adults with sputum smear-positive tuberculosis, because they are most infectious. However, children contribute a significant proportion of the global tuberculosis caseload and experience considerable tuberculosis-related morbidity and mortality, but few children in endemic areas have access to antituberculosis treatment. The diagnostic difficulty experienced in endemic areas with limited resources has been identified as a major factor contributing to poor treatment access. In general, there is a sense of scepticism regarding the potential value of symptom-based diagnostic approaches, because current clinical diagnostic approaches are often poorly validated. The natural history of childhood tuberculosis demonstrates that symptoms may offer good diagnostic value if they are well defined and if appropriate risk stratification is applied. This study aimed to determine the value of well-defined symptoms to diagnose childhood pulmonary tuberculosis in a tuberculosis-endemic area. METHODS. A prospective, community-based study was conducted in Cape Town, South Africa. Specific well-defined symptoms were documented in all children 2 weeks9 duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as “bacteriologically confirmed tuberculosis,” “radiologically certain tuberculosis,” “probable tuberculosis,” or “not tuberculosis.” Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of ≥10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion. RESULTS. In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of >2 weeks9 duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (≥3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group ( DISCUSSION. The combined presence of 3 well-defined symptoms at presentation (persistent, nonremitting cough of >2 weeks9 duration; objective weight loss [documented failure to thrive] during the preceding 3 months; and reported fatigue) provided good diagnostic accuracy in HIV-uninfected children ≥3 years of age, with clinical follow-up providing additional value. The approach performed less well in children CONCLUSIONS. Pulmonary tuberculosis can be diagnosed with a reasonable degree of accuracy in HIV-uninfected children using a simple symptom-based approach. This offers the exciting prospect of improving treatment access for children, particularly in resource-limited settings where current access to antituberculosis treatment is poor.
272 citations
University of Bristol1, Hannover Medical School2, University of Copenhagen3, Erasmus University Rotterdam4, QIMR Berghofer Medical Research Institute5, Imperial College London6, University of Kiel7, Technische Universität München8, University of Pennsylvania9, University of Western Australia10, University of Basel11, University of Manchester12, VU University Amsterdam13, Karolinska Institutet14, University of Geneva15, Wellcome Trust Sanger Institute16, University of Oulu17, University of the East18, University of Washington19, University of Melbourne20, Ludwig Maximilian University of Munich21, University of Bonn22, Aarhus University23, Tartu University Hospital24, Statens Serum Institut25, University of Iowa26, Children's Hospital of Philadelphia27, King's College London28, Telethon Institute for Child Health Research29, Children's Medical Research Institute30, Swiss Tropical and Public Health Institute31, Norwegian Institute of Public Health32, Manchester Academic Health Science Centre33, Utrecht University34, Copenhagen University Hospital35, Karolinska University Hospital36, Sahlgrenska University Hospital37, Ontario Institute for Cancer Research38, St George's, University of London39, Medical Research Council40
TL;DR: This paper conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals from 14 studies.
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
272 citations
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TL;DR: Research questions are prioritised and actions and measures for stakeholders both locally and globally, which are required to revitalise primary health care are suggested, are suggested.
272 citations
Authors
Showing all 16441 results
Name | H-index | Papers | Citations |
---|---|---|---|
Shizuo Akira | 261 | 1308 | 320561 |
Trevor W. Robbins | 231 | 1137 | 164437 |
Richard A. Flavell | 231 | 1328 | 205119 |
George Davey Smith | 224 | 2540 | 248373 |
Nicholas J. Wareham | 212 | 1657 | 204896 |
Cyrus Cooper | 204 | 1869 | 206782 |
Martin White | 196 | 2038 | 232387 |
Frank E. Speizer | 193 | 636 | 135891 |
Michael Rutter | 188 | 676 | 151592 |
Richard Peto | 183 | 683 | 231434 |
Terrie E. Moffitt | 182 | 594 | 150609 |
Kay-Tee Khaw | 174 | 1389 | 138782 |
Chris D. Frith | 173 | 524 | 130472 |
Phillip A. Sharp | 172 | 614 | 117126 |
Avshalom Caspi | 170 | 524 | 113583 |