UCL University College London Eprints
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Mostrando recursos 181 - 200 de 352,441
The role of angiogenic factors in predicting clinical outcome in severe bacterial infection in Malawian children. - Mankhambo, LA; Banda, DL; IPD Study Group,; Jeffers, G; White, SA; Balmer, P; Nkhoma, S; Phiri, H; Molyneux, EM; Hart, CA; Molyneux, ME; Heyderman, RS; Carrol, ED
Severe sepsis is a disease of the microcirculation, with endothelial dysfunction playing a key role in its pathogenesis and subsequent associated mortality. Angiogenesis in damaged small vessels may ameliorate this dysfunction. The aim of the study was to determine whether the angiogenic factors (vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and angiopoietin-1 (Ang-1) and -2 (Ang-2)) are mortality indicators in Malawian children with severe bacterial infection.
Potential role for mucosally active vaccines against pneumococcal pneumonia. - Jambo, KC; Sepako, E; Heyderman, RS; Gordon, SB
Pneumococcal pneumonia is a life-threatening disease with high mortality and morbidity among children under 5 years of age, the elderly and immunocompromised individuals worldwide. Protection against pneumococcal pneumonia relies on successful regulation of colonisation in the nasopharynx and a brisk alveolar macrophage-mediated immune response in the lung. Therefore, enhancing pulmonary mucosal immunity (which includes a combination of innate, humoral and cell-mediated immunity) through mucosal vaccination might be the key to prevention of pneumococcal infection. Current challenges include a lack of information in humans on mucosal immunity against pneumococci and a lack of suitable adjuvants for new vaccines. Data from mouse...
Human immunodeficiency virus (HIV) infection during pregnancy induces CD4 T-cell differentiation and modulates responses to Bacille Calmette-Guérin (BCG) vaccine in HIV-uninfected infants. - Miles, DJ; Gadama, L; Gumbi, A; Nyalo, F; Makanani, B; Heyderman, RS
Human immunodeficiency virus (HIV)-negative infants born to HIV-positive mothers frequently exhibit a range of immunological abnormalities. We tested the hypothesis that HIV during pregnancy affects the ability of CD4 T cells of HIV-negative infants to respond to vaccine challenge by recruiting HIV-negative infants born to HIV-negative and HIV-positive mothers and measuring their responses to Bacille Calmette-Guérin (BCG) vaccine given at birth. At 2 weeks, maternal HIV status did not influence CD4 T-cell counts or differentiation, but by 10 weeks CD4 counts of infants born to HIV-positive mothers fell to a level characteristic of HIV-positive infants. Among the CD4 T-cell populations,...
Epidemic multiple drug resistant Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype. - Kingsley, RA; Msefula, CL; Thomson, NR; Kariuki, S; Holt, KE; Gordon, MA; Harris, D; Clarke, L; Whitehead, S; Sangal, V; Marsh, K; Achtman, M; Molyneux, ME; Cormican, M; Parkhill, J; MacLennan, CA; Heyderman, RS; Dougan, G
Whereas most nontyphoidal Salmonella (NTS) are associated with gastroenteritis, there has been a dramatic increase in reports of NTS-associated invasive disease in sub-Saharan Africa. Salmonella enterica serovar Typhimurium isolates are responsible for a significant proportion of the reported invasive NTS in this region. Multilocus sequence analysis of invasive S. Typhimurium from Malawi and Kenya identified a dominant type, designated ST313, which currently is rarely reported outside of Africa. Whole-genome sequencing of a multiple drug resistant (MDR) ST313 NTS isolate, D23580, identified a distinct prophage repertoire and a composite genetic element encoding MDR genes located on a virulence-associated plasmid. Further, there...
T cell memory response to pneumococcal protein antigens in an area of high pneumococcal carriage and disease. - Mureithi, MW; Finn, A; Ota, MO; Zhang, Q; Davenport, V; Mitchell, TJ; Williams, NA; Adegbola, RA; Heyderman, RS
Streptococcus pneumoniae is a leading cause of vaccine-preventable disease worldwide. Pneumococcal protein antigens are currently under study as components of potential vaccines that offer protection against multiple serotypes. We have therefore characterized T cell pneumococcal immunity acquired through asymptomatic carriage.
The diagnostic and prognostic accuracy of five markers of serious bacterial infection in Malawian children with signs of severe infection. - Carrol, ED; Mankhambo, LA; Jeffers, G; Parker, D; Guiver, M; Newland, P; Banda, DL; IPD Study Group,; Molyneux, EM; Heyderman, RS; Molyneux, ME; Hart, CA
Early recognition and prompt and appropriate antibiotic treatment can significantly reduce mortality from serious bacterial infections (SBI). The aim of this study was to evaluate the utility of five markers of infection: C-reactive protein (CRP), procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), CD163 and high mobility group box-1 (HMGB1), as markers of SBI in severely ill Malawian children.
The macrophage marches on its phagosome: dynamic assays of phagosome function. - Russell, DG; Vanderven, BC; Glennie, S; Mwandumba, H; Heyderman, RS
Professional phagocytes ingest particulate material to fulfil a diverse array of functions in a multicellular organism. The ancestral function of phagosomes is digestion; however, through evolution this degradative capacity has become pivotal to the adaptive immune response by processing antigens to be presented to lymphocytes. Moreover, phagocytes have also acquired an active role in microbial killing. This Innovation article describes new assays that probe the biological activities which occur within phagosomes. These assays provide functional insights into how the phagosome fulfils its diverse roles in homeostasis and in innate and adaptive immune responses.
IgA1 antibodies specific for outer membrane protein PorA modulate the interaction between Neisseria meningitidis and the epithelium. - Horton, RE; Vidarsson, G; Virji, M; Williams, NA; Heyderman, RS
Despite high carriage rates of Neisseria meningitidis, incidence of meningococcal disease remains low, partially due to development of natural immunity. We have previously demonstrated an inverse relationship between salivary anti-meningococcal IgA and disease incidence, but little is known about the contribution of IgA to immunity at mucosal surfaces. Here we show strong immunoreactivity by human salivary IgA against the meningococcal outer membrane porin, PorA. Monomeric anti-PorA IgA1 (humanized chimeric antibodies) but not IgG increased the association of unencapsulated serogroup B N. meningitidis (H44/76) with Chang (conjunctival) but not with either Detroit (pharyngeal) cells or with A549 (alveolar) epithelial cells. Association...
Dysregulation of coagulation in cerebral malaria. - Moxon, CA; Heyderman, RS; Wassmer, SC
Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection and represents a major cause of morbidity and mortality worldwide. The nature of the pathogenetic processes leading to the cerebral complications remains poorly understood. It has recently emerged that in addition to their conventional role in the regulation of haemostasis, coagulation factors have an inflammatory role that is pivotal in the pathogenesis of a number of acute and chronic conditions, including CM. This new insight offers important therapeutic potential. This review explores the clinical, histological and molecular evidence for the dysregulation of the coagulation system in CM, looking at...
Impaired maintenance of naturally acquired T-cell memory to the meningococcus in patients with B-cell immunodeficiency. - Morales-Aza, B; Glennie, SJ; Garcez, TP; Davenport, V; Johnston, SL; Williams, NA; Heyderman, RS
The importance of T cells in the generation of antigen-specific B-cell immunity has been extensively described, but the role B cells play in shaping T-cell memory is uncertain. In healthy controls, exposure to Neisseria meningitidis in the upper respiratory tract is associated with the generation of memory T cells in the mucosal and systemic compartments. However, we demonstrate that in B cell-deficient subjects with X-linked agammaglobulinemia (XLA), naturally acquired T-cell memory responses to meningococcal antigens are reduced compared with healthy control patients. This difference is not found in T-cell memory to an obligate respiratory pathogen, influenza virus. Accordingly, we show...
IFN-gamma amplifies NFkappaB-dependent Neisseria meningitidis invasion of epithelial cells via specific upregulation of CEA-related cell adhesion molecule 1. - Griffiths, NJ; Bradley, CJ; Heyderman, RS; Virji, M
Temporal relationship between viral and bacterial infections has been observed, and may arise via the action of virus-induced inflammatory cytokines. These, by upregulating epithelial receptors targeted by bacteria, may encourage greater bacterial infiltration. In this study, human epithelial cells exposed to interferon-gamma but not tumour necrosis factor-alpha or interleukin 1-beta supported increased meningococcal adhesion and invasion. The increase was related to Opa but not Opc or pili adhesin expression. De novo synthesis of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a major Opa receptor, occurred in epithelial cells exposed to the cytokine, or when infected with Opa-expressing bacteria. Cell line-dependent...
Regulation of Th-1 T cell-dominated immunity to Neisseria meningitidis within the human mucosa. - Davenport, V; Groves, E; Hobbs, CG; Williams, NA; Heyderman, RS
Neisseria meningitidis is commonly carried asymptomatically in the upper respiratory tract and only occasionally invades the bloodstream and meninges to cause disease. Naturally acquired immunity appears protective but the nature of the cellular immune response within the mucosa is uncertain. We show that following in vitro stimulation with N. meningitidis serogroup B (MenB) antigens, approximately 66% of the dividing mucosal CD4(+)CD45RO(+) memory population express the Th1-associated IL18-R while the remainder express CRTH2, a Th2-associated marker. The pro-inflammatory bias of this anti-MenB response is not evident in blood, demonstrating compartmentalization at the induction site; and occurs in the presence or absence...
Current concepts in the treatment of bacterial meningitis beyond the neonatal period. - Clarke, ET; Heyderman, RS
The epidemiology and treatment approach to bacterial meningitis has changed dramatically since the advent of antimicrobial therapy. New vaccines against meningeal pathogens have been implemented into national immunization programs successfully around the world. Antibiotic resistance has had a considerable impact on the efficacy of several therapeutic agents. In this review, the authors will discuss the principles of antibiotic chemotherapy, focusing on new agents for the treatment of penicillin-resistant pneumococci and adjunctive treatments to reduce the inflammatory response to bacterial infection of the meninges.
Changing epidemiology of bacterial meningitis among adults in England and Wales 1991-2002. - Gjini, AB; Stuart, JM; Lawlor, DA; Cartwright, KA; Christensen, H; Ramsay, M; Heyderman, RS
We examined the epidemiology of community-acquired bacterial meningitis among adults in England and Wales between 1991 and 2002. Among 3169 cases, meningococcal infection was predominant among young adults and pneumococcal meningitis among older adults. Whilst infection due to most causes decreased, the incidence of tuberculous (TB) meningitis doubled over the 12 years. The mortality rate among meningococcal and pneumococcal infections fell from 0.45/10(5) to 0.31/10(5) (P=0.0001). This study demonstrates important changes in the epidemiology of bacterial meningitis among UK adults. Improvements in clinical management, childhood vaccination programmes and the re-emergence of tuberculosis are likely to be drivers of these changes.