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    ABSTRACT: Public awareness of the impact of air quality on health is increasing worldwide. Indoor and outdoor air pollutants impair children's growing lungs, and increase the risk of respiratory infections. In many cities, children face indoor air pollution from fuels used for cooking and heating, as well as outdoor pollution from vehicle exhausts. Research identifies at-risk groups and seeks to establish biological plausibility for the associations already observed; and looks towards identifying the harmful pollutants that are responsible for respiratory morbidity and mortality. These findings may then serve to influence public debate and future policy at national and international level to improve air quality in cities, and improve children's health.
    Paediatric Respiratory Reviews 06/2014; 15(2). DOI:10.1016/j.prrv.2014.03.001
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    ABSTRACT: We conducted direct observation of 23 caregiver-infant pairs for 130 hours and recorded wash-related behaviors to identify pathways of fecal-oral transmission of bacteria among infants. In addition to testing fingers, food, and drinking water of infants, three infants actively ingested 11.3 ± 9.2 (mean ± SD) handfuls of soil and two ingested chicken feces 2 ± 1.4 times in 6 hours. Hand washing with soap was not common and drinking water was contaminated with Escherichia coli in half (12 of 22) of the households. A one-year-old infant ingesting 1 gram of chicken feces in a day and 20 grams of soil from a laundry area of the kitchen yard would consume 4,700,000-23,000,000 and 440-4,240 E. coli, respectively, from these sources. Besides standard wash and nutrition interventions, infants in low-income communities should be protected from exploratory ingestion of chicken feces, soil, and geophagia for optimal child health and growth.
    The American journal of tropical medicine and hygiene 09/2013; 89(4). DOI:10.4269/ajtmh.12-0568
  • Archives of Disease in Childhood 02/2013; 98(4). DOI:10.1136/archdischild-2012-303215
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    ABSTRACT: The course of immune maturation has evolved to favour survival at each stage of development in early life. Fetal and neonatal immune adaptations facilitate intrauterine survival and provide early postnatal protection against extracellular pathogens, but they leave infants susceptible to intracellular pathogens such as viruses that are acquired perinatally. This Review focuses on three such pathogens--HIV, hepatitis B virus and cytomegalovirus--and relates the differential impact of these infections in infants and adults to the antiviral immunity that is generated at different ages. A better understanding of age-specific antiviral immunity may inform the development of integrated prevention, treatment and vaccine strategies to minimize the global disease burden resulting from these infections.
    Nature Reviews Immunology 08/2012; 12(9):636-48. DOI:10.1038/nri3277
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    ABSTRACT: Andrew Prendergast and colleagues consider the evidence for a change in policy for the treatment of young children infected with HIV.
    PLoS Medicine 07/2012; 9(7):e1001273. DOI:10.1371/journal.pmed.1001273
  • Nanotoxicology 04/2012; 7(5). DOI:10.3109/17435390.2012.682354
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    ABSTRACT: The primary cause of aplastic anemia remains unknown in many patients. The aim of this study was to clarify the genetic cause of familial aplastic anemia. Genomic DNA of an affected individual from a multiplex consanguineous family was hybridized to a Nimblegen exome library before being sequenced on a GAIIx genome analyzer. Once the disease causing homozygous mutation had been confirmed in the consanguineous family, this gene was then analyzed for mutation in 33 uncharacterized index cases of aplastic anemia (<13 years) using denaturing HPLC. Abnormal traces were confirmed by direct sequencing. Exome sequencing identified a novel homozygous nonsense mutation in the thrombopoietin receptor gene MPL. An additional novel homozygous MPL mutation was identified in the screen of 33 aplastic anemia patients. This study shows for the first time a link between homozygous MPL mutations and familial aplastic anemia. It also highlights the important role of MPL in trilineage hematopoiesis.
    Haematologica 12/2011; 97(4):524-8. DOI:10.3324/haematol.2011.052787
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    ABSTRACT: The bone marrow failure syndrome dyskeratosis congenita (DC) has been considered to be a disorder of telomere maintenance in which disease features arise due to accelerated shortening of telomeres. By screening core components of the telomerase and shelterin complexes in patients with DC and related bone marrow failure syndromes we have identified 24 novel mutations: 11 in the RNA component of telomerase (TERC), 8 in the reverse transcriptase component (TERT), 4 in dyskerin (DKC1) and 1 in TRF1-interacting nuclear factor 2 (TINF2). This has prompted us to review these genetic subtypes in terms of telomere length, telomerase activity and clinical presentation among 194 genetically characterised index cases recruited onto the registry in London. While those with DKC1 and TINF2 mutations present at a younger age and have more disease features than those with TERC or TERT mutations, there is no difference in telomere length between these groups. There is no difference in the age of onset and numbers of disease features seen in those with TERC and TERT mutations despite the fact that the latter show higher levels of telomerase activity in vitro. The incidence of aplastic anaemia is greater in patients with TERC or TINF2 mutations compared to patients with DKC1 mutations, and cancer incidence is highest in patients with TERC mutations. These data are the first to provide robust comparisons between different genetic subtypes of telomerase and shelterin mutations (the "telomereopathies") and clearly demonstrate that disease severity is not explained by telomere length alone.
    PLoS ONE 09/2011; 6(9):e24383. DOI:10.1371/journal.pone.0024383
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    The Journal of allergy and clinical immunology 07/2011; DOI:10.1016/j.jaci.2011.05.041
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    ABSTRACT: Dyskeratosis congenita (DC) is a heterogeneous bone marrow failure disorder with known mutations in components of telomerase and telomere shelterin. Recent work in a mouse model with a dyskerin mutation has implicated an increased DNA damage response as part of the cellular pathology, while mouse models with Terc and Tert mutations displayed a normal response. To clarify how these contradictory results might apply to DC pathology in humans, we studied the cellular phenotype in primary cells from DC patients of several genetic subtypes, focussing on T lymphocytes to remain close to the haematopoietic system. We observed novel cell cycle abnormalities in conjunction with impaired growth and an increase in apoptosis. Using flow cytometry and confocal microscopy we examined induction of the DNA damage proteins γ-H2AX and 53BP1 and the cell cycle protein TP53 (p53). We found an increase in damage foci at telomeres in lymphocytes and an increase in the basal level of DNA damage in fibroblasts, but crucially no increased response to DNA damaging agents in either cell type. As the response to induced DNA damage was normal and levels of global DNA damage were inconsistent between cell types, DNA damage may contribute differently to the pathology in different tissues.
    British Journal of Haematology 06/2011; 153(5):634-43. DOI:10.1111/j.1365-2141.2011.08679.x
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