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Publication History View all

  • Tuberculosis 07/2014; 94(4). DOI:10.1016/j.tube.2014.04.002
  • The Journal of infection 04/2014; 68(4). DOI:10.1016/j.jinf.2014.01.009
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    ABSTRACT: Assessment of transmural scar at the site of latest mechanical activation is relevant to maximize outcomes in cardiac resynchronization therapy (CRT). Few studies have assessed the ability of speckle tracking echocardiography (STE)-derived short-axis strain to identify segmental myocardial scar, defined by contrast-enhanced cardiac magnetic resonance imaging (CMR), in patients referred for CRT. A total of 26 patients with ischemic cardiomyopathy who underwent preprocedure echocardiography and CMR were studied. Extent of transmural scar was assessed using contrast-enhanced CMR and corresponding peak segmental radial and circumferential strains were derived using two-dimensional (2D) STE. Total left ventricle (LV) scar volume was compared with parameters of global strain. CRT response was defined as >15% reduction in LV end systolic volume (LVESV) at 6 months. Speckle tracking short-axis strain analysis was technically possible in over 90% of LV segments. Applying a segmental radial strain cutoff value of 10% distinguished segments with >50% scar area with a high negative predictive value (98%). Global longitudinal strain <-5% predicted CRT response. Two-dimensional STE offers potential to characterize dysfunctional myocardium and define segmental scar offering an integrated imaging approach to guide LV lead placement for CRT.
    Echocardiography 12/2013; 31(6). DOI:10.1111/echo.12458
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    ABSTRACT: Major histocompatibility complex class II (MHCII) proteins are loaded with endosomal peptides and reside at the surface of antigen-presenting cells (APCs) for a time before being degraded. In vitro, MHCII protein levels and turnover are affected by peptide loading and by rates of ubiquitin-dependent internalization from the cell surface, which is in turn affected by APC type and activation state. Prior work suggested that fast turnover of disease-associated MHCII alleles may contribute to autoimmunity. We recently developed novel stable isotope tracer techniques to test this hypothesis in vivo. In non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D), MHCII turnover was affected by APC type, but unaffected by disease-associated structural polymorphism. Differences in MHCII turnover were observed between NOD colonies with high and low T1D incidence, but fast turnover was dispensable for autoimmunity. Moreover, NOD mice with gene knockouts of peptide loading cofactors do not develop T1D. Thus, fast turnover does not appear pathogenic, and conventional antigen presentation is critical for autoimmunity in NOD mice. However, shared environmental factors may underpin colony differences in MHCII protein turnover, immune regulation, and pathogenesis.
    Frontiers in Immunology 11/2013; 4:399. DOI:10.3389/fimmu.2013.00399
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    ABSTRACT: Primary infection with human cytomegalovirus (HCMV) results in the establishment of a lifelong infection of the host which is aided by the ability of HCMV to undergo a latent infection. One site of HCMV latency in vivo is in haematopoietic progenitor cells, resident in the bone marrow, with genome carriage and reactivation being restricted to the cells of the myeloid lineage. Until recently, HCMV latency has been considered to be relatively quiescent with the virus being maintained essentially as a "silent partner" until conditions are met that trigger reactivation. However, advances in techniques to study global changes in gene expression have begun to show that HCMV latency is a highly active process which involves expression of specific latency-associated viral gene products which orchestrate major changes in the latently infected cell. These changes are argued to help maintain latent infection and to modulate the cellular environment to the benefit of latent virus. In this review, we will discuss these new findings and how they impact not only on our understanding of the biology of HCMV latency but also how they could provide tantalising glimpses into mechanisms that could become targets for the clearance of latent HCMV.
    Viruses 11/2013; 5(11):2803-2824. DOI:10.3390/v5112803
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    ABSTRACT: Genetic mutations cause primary immunodeficiencies (PIDs), which predispose to infections. Here we describe Activated PI3K-δ Syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.
    Science 10/2013; 342(6160). DOI:10.1126/science.1243292
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    ABSTRACT: Functional mitral regurgitation (FMR) is a consequence of mitral annular enlargement, leaflet tethering and reduced co-aptation. The importance of the left atrium (LA) as a cause of mitral regurgitation (MR) is less clear. We applied a co-aptation index using three-dimensional (3D) transoesophageal echocardiography to FMR and MR secondary to LA dilatation (atrial mitral regurgitation, AMR). Seventy-two patients underwent comprehensive 3D echo studies: FMR (n = 19); AMR (n = 33); and 20 controls. We recorded: LV size and function; LA dimensions; mitral annular area (MVA); and leaflet area in early and late systole. MVA fractional change was defined: (MVA late systole - MVA early systole)/MVA late systole × 100%; the co-aptation index was defined: (leaflet area early systole - leaflet area late systole)/leaflet area early systole × 100%. Despite normal LV size and function in AMR, MVA was increased similarly to FMR (AMR 12.86 cm(2) vs. FMR 12.33 cm(2), P = ns; both P < 0.01 vs. controls 8.83 cm(2)), and MVA fractional change similarly reduced (AMR 5.1% vs. FMR 6.3%; P = ns; both P < 0.001 vs. controls 14.6%). The co-aptation index was reduced in both MR groups (FMR 6.6% vs. AMR 7.0%, P = ns; both P < 0.001 vs. controls 19.6%). After multivariate analysis, the co-aptation index (χ(2) = 41.2) and MVA fractional change (χ(2) = 22.1) remained the strongest predictors of MR (both P < 0.001 for the model). A co-aptation index of ≤13% was 96% sensitive and 90% specific for the presence of MR. LA dilatation leads to MVA enlargement, reduced leaflet co-aptation and MR even without LV dilatation. A co-aptation index describes this in vivo. This work provides insights into the mechanism of AMR.
    European Heart Journal Cardiovascular Imaging 10/2013; 15(5). DOI:10.1093/ehjci/jet191
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    ABSTRACT: Burkholderia pseudomallei infection (melioidosis) is an important cause of community-acquired Gram-negative sepsis in Northeast Thailand, where it is associated with a ∼40% mortality rate despite antimicrobial chemotherapy. We showed in a previous cohort study that patients taking glyburide ( = glibenclamide) prior to admission have lower mortality and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism underlying this observation in a murine model of melioidosis. Mice (C57BL/6) with streptozocin-induced diabetes were inoculated with ∼6×10(2) cfu B. pseudomallei intranasally, then treated with therapeutic ceftazidime (600 mg/kg intraperitoneally twice daily starting 24 h after inoculation) in order to mimic the clinical scenario. Glyburide (50 mg/kg) or vehicle was started 7 d before inoculation and continued until sacrifice. The minimum inhibitory concentration of glyburide for B. pseudomallei was determined by broth microdilution. We also examined the effect of glyburide on interleukin (IL) 1β by bone-marrow-derived macrophages (BMDM). Diabetic mice had increased susceptibility to melioidosis, with increased bacterial dissemination but no effect was seen of diabetes on inflammation compared to non-diabetic controls. Glyburide treatment did not affect glucose levels but was associated with reduced pulmonary cellular influx, reduced bacterial dissemination to both liver and spleen and reduced IL1β production when compared to untreated controls. Other cytokines were not different in glyburide-treated animals. There was no direct effect of glyburide on B. pseudomallei growth in vitro or in vivo. Glyburide directly reduced the secretion of IL1β by BMDMs in a dose-dependent fashion. Diabetes increases the susceptibility to melioidosis. We further show, for the first time in any model of sepsis, that glyburide acts as an anti-inflammatory agent by reducing IL1β secretion accompanied by diminished cellular influx and reduced bacterial dissemination to distant organs. We found no evidence for a direct effect of glyburide on the bacterium.
    PLoS Neglected Tropical Diseases 10/2013; 7(10):e2500. DOI:10.1371/journal.pntd.0002500
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    ABSTRACT: Plasma exchange is used in the treatment of diseases mediated by pathogenic circulating proteins, or for transplant desensitisation. Its non-targeted nature results in the depletion of physiologically important molecules, and it is often complicated by hypocalcaemia. To determine the effects of plasma exchange onvitamin D binding proteinand associated vitamin D metabolites. Single-centre prospective cohort study of 11 patients. METHODS:DBP and vitamin D metabolites were measured before and immediately after 5 plasma exchanges, and 7 and 28 days after discontinuation of plasma exchange. RESULTS:Plasma exchange reduced plasma vitamin D binding proteinconcentrationfrom 196.9 ± 53.2 to 98.5 ± 34 μg/mL (p = 0.0001), 1,25-dihydroxyvitamin D from 103 ± 52 pmol/l to 42 ± 4pmol/l (p = 0.003), and 25-hydroxyvitamin D from 49.7 ± 29 to 22 ± 9.4 nmol/l (p = 0.0017), through their removal in effluent. After 7 days, DBP and 1,25-dihydroxyvitamin D were not significantly different from baseline, but 25-hydroxyvitamin D remained significantly lower after 7 days(26.4 ± 9.8 nmol/l, p = 0.02) and 28 days (30.8 ± 15.5 nmol/l, p = 0.048). Corrected calcium decreased from 2.23 ± 0.11 mmol/l to 1.98 ± 0.08 mmol/l(p=0.0007) immediately after 5 treatments.Plasma calcium was significantly associated with 1,25-dihydroxyvitamin D (r(2) = 0.79, p < 0.0001). Plasma exchange inducedan acute reversible decrease in plasma 1,25-dihydroxyvitamin D, DBP, calcium, and a sustained decrease in plasma 25-hydroxyvitamin D.
    QJM: monthly journal of the Association of Physicians 10/2013; 107(2). DOI:10.1093/qjmed/hct208
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    ABSTRACT: Overexpression of Z α1-antitrypsin is known to induce polymer formation, prime the cells for ER stress and initiate NF-κB signalling. However, whether endogenous expression in primary bronchial epithelial cells has similar consequences remains unclear. Moreover, the mechanism of NF-κB activation has not yet been elucidated. Here we report excessive NF-κB signalling in resting primary bronchial epithelial cells from ZZ patients compared to wild-type (MM) controls, and this appears to be mediated by MEK, EGFR and ADAM17 activity. Moreover, we show that rather than being a response to protein polymers, NF-κB signalling in airway-derived cells represents a loss of anti-inflammatory signalling by M α1-antitrypsin. Treatment of ZZ primary bronchial epithelial cells with purified plasma M α1-antitrypsin attenuates this inflammatory response, opening up new therapeutic options to modulate airway inflammation in the lung.
    Human Molecular Genetics 10/2013; 23(4). DOI:10.1093/hmg/ddt487
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