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  • The Lancet 11/2013; 382(9904):1552. DOI:10.1016/S0140-6736(13)62321-1
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    ABSTRACT: To overcome the potential drawbacks of a short half-life and dose-related adverse effects of using active transforming growth factor-beta 1 for cartilage engineering, a cell-mediated latent growth factor activation strategy was developed incorporating latent transforming growth factor-β1 (LTGF) into an electrospun poly(L-lactide) scaffold. The electrospun scaffold was surface modified with NH3 plasma and biofunctionalised with LTGF to produce both random and orientated biofunctionalised electrospun scaffolds. Scaffold surface chemical analysis and growth factor bioavailability assays were performed. In vitro biocompatibility and human nasal chondrocyte gene expression with these biofunctionalised electrospun scaffold templates were assessed. In vivo chondrogenic activity and chondrocyte gene expression were evaluated in athymic rats. Chemical analysis demonstrated that LTGF anchored to the scaffolds was available for enzymatic, chemical and cell activation. The biofunctionalised scaffolds were non-toxic. Gene expression suggested chondrocyte re-differentiation after 14 days in culture. By 6 weeks, the implanted biofunctionalised scaffolds had induced highly passaged chondrocytes to re-express Col2A1 and produce type II collagen. We have demonstrated a proof of concept for cell-mediated activation of anchored growth factors using a novel biofunctionalised scaffold in cartilage engineering. This presents a platform for development of protein delivery systems and for tissue engineering.
    Archives of Plastic Surgery 11/2013; 40(6):676-686. DOI:10.5999/aps.2013.40.6.676
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    ABSTRACT: In this article, we give an overview of new technologies for the diagnosis of tuberculosis (TB) and drug resistance, consider their advantages over existing methodologies, broad issues of cost, cost-effectiveness and programmatic implementation, and their clinical as well as public health impact, focusing on the industrialized world. Molecular nucleic-acid amplification diagnostic systems have high specificity for TB diagnosis (and rifampicin resistance) but sensitivity for TB detection is more variable. Nevertheless, it is possible to diagnose TB and rifampicin resistance within a day and commercial automated systems make this possible with minimal training. Although studies are limited, these systems appear to be cost-effective. Most of these tools are of value clinically and for public health use. For example, whole genome sequencing of Mycobacterium tuberculosis offers a powerful new approach to the identification of drug resistance and to map transmission at a community and population level.
    BMC Medicine 08/2013; 11(1):190. DOI:10.1186/1741-7015-11-190
  • The Journal of trauma 08/2013; DOI:10.1097/TA.0b013e318298efb9
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    ABSTRACT: In nonhuman primates, Vγ9Vδ2(+) (Vδ2)T cells proliferate and accumulate in mucosal tissues following microbial activation. Human Vδ2T cells produce proinflammatory cytokines in response to bacterial species that colonize the gut, but the role played by Vδ2T cells in intestinal immunity is unknown. We hypothesized that circulating Vδ2T cells can populate the human intestine and contribute to mucosal inflammation. Cell suspensions prepared from peripheral blood and intestinal biopsies were stimulated with microbial phosphoantigen (1-hydroxy-2-methyl-2-buten-4-yl 4-diphosphate [HDMAPP]) and analyzed by flow cytometry to determine Vδ2T cell phenotype, cytokine production, and proliferative potential. Circulating Vδ2T cells expressed gut-homing integrin α4β7 (>70%), which was coexpressed with skin-associated cutaneous leukocyte Ag by up to 15% of the total population. However, Vδ2T cell activation with HDMAPP and exposure to retinoic acid (signaling via retinoic acid receptor α) increased α4β7 expression and enhanced binding to mucosal addressin cell adhesion molecule-1 in vitro while simultaneously suppressing cutaneous leukocyte Ag, thereby generating a committed gut-tropic phenotype. Confocal microscopy and flow cytometry identified frequent Vδ2T cells that migrated out of human intestinal biopsies and comprised both CD103(+) and CD103(-) subsets that produced TNF-α and IFN-γ upon phosphoantigen exposure, with more frequent cytokine-producing cells in the CD103(-) population. Activated intestinal Vδ2T cells expressed CD70 and HLA-DR but were unable to drive the proliferation of allogeneic naive CD4(+) T cells. Instead, phosphoantigen-activated CD103(-) Vδ2T cells increased T-bet expression and enhanced IFN-γ production by autologous colonic αβ T cells via an IFN-γ-dependent mechanism. These data demonstrate that circulating Vδ2T cells display enhanced gut-homing potential upon microbial activation and populate the human intestinal mucosa, generating functionally distinct CD103(+) and CD103(-) subsets that can promote inflammation by colonic αβ T cells.
    The Journal of Immunology 07/2013; 191(5). DOI:10.4049/jimmunol.1202959
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    ABSTRACT: Galactomannan (GM) is widely used for detection of invasive aspergillosis in high-risk haemato-oncology patients. Recent publications have reported a lack of repeatability of GM detection. The objective of this retrospective study was to assess the repeatability of GM levels during storage of clinical samples. In a GM screening strategy, positive sera were repeat tested as per manufacturer's recommendations. Short-term (ST) storage of samples was at +4 °C while long-term (LT) storage was at -80 °C. Bronchoalveolar (BAL) fluid was also repeating tested after ST storage and LT storage. Wilcoxon Signed Ranks Test was employed to assess the repeatability of GM levels. In a subset of 14 GM positive sera, repeat testing was performed on both the original serum and ethylenediaminetetraacetic acid (EDTA) pre-treated sample. There was a significant reduction in GM signals on repeat testing following ST storage (median GM index: 0.65 vs. 0.19; p < 0.001) and LT storage (median GM index: 0.56 vs. 0.10; p < 0.001) of serum samples. Of samples that were initially GM positive, an average GM index reduction of 50% was seen, with approximately two-thirds becoming GM negative on repeat testing of the same sample. In contrast, GM signal loss was not seen on repeat testing of BAL fluid following ST or LT storage. When GM positive serum samples were repeat tested using EDTA pre-treated serum from the first step of the testing protocol, all samples remained GM positive. In contrast, when the same samples were repeat tested from the original collected serum, 9 samples (64%) became GM negative. The significant reduction in GM signals during ST and LT storage of serum samples has implications for clinical management. Although the reasons for GM decline are unknown, they occur prior to the EDTA pre-treatment stage, indicating that the time from phlebotomy to testing should be minimized. BAL fluid GM index values remain stable.
    International Journal of Molecular Sciences 07/2013; 14(7):12970-12977. DOI:10.3390/ijms140712970
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    ABSTRACT: Epigenome-wide association studies (EWAS) are being extensively performed to identify epigenetic variants associated to complex diseases. However, EWAS may identify variants that are disease-induced rather than disease-causal. Recent studies have highlighted the use of Guthrie cards to profile the methylome at birth, permitting researchers to find epigenetic variants present in patients before they are diagnosed with clinical disease, with the implicit suggestion that these variants are more likely to be disease causal. The use of Guthrie cards for research purposes throws up a number of ethical issues. We review here the promises and pitfalls of Guthrie cards for disease research.
    Epigenetics: official journal of the DNA Methylation Society 06/2013; 8(8). DOI:10.4161/epi.25357
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    ABSTRACT: Inheritance of non-genetic factors permits ancestral environmental history to inform the development of subsequent generations. This form of soft inheritance has been shown in mammals, yet the molecular underpinnings of this phenomenon are poorly understood. In the present article, we focus on gametic inheritance of non-genetic factors, utilizing examples of paternal transmission to explore the core issues that need to be addressed in order to gain greater insight into the molecular mechanisms. Three essential processes are identified: (i) how the environment affects the germline to establish an altered molecular milieu, (ii) the molecular nature of the inherited mark, and (iii) how this affects genome function in the developing embryo to elicit an alternative developmental outcome.
    Biochemical Society Transactions 06/2013; 41(3):769-776. DOI:10.1042/BST20130043
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    ABSTRACT: Pancreatic secretory trypsin inhibitor is expressed in most bladder carcinomas where its pathophysiological relevance is unclear. Using recombinant normal sequence PSTI/TATI, a variant associated with familial pancreatitis (N34S), an active site inactivated variant (R18/V19) and immunoneutralization and RNA interference-mediated knockdown (KD) techniques, we investigated the actions of PSTI/TATI on cell migration (wounding monolayers), collagen invasion (gel invasion assays) and proliferation (Alamar blue) on 253J, RT4 and HT1376 human bladder carcinoma cell lines. All three forms of PSTI/TATI stimulated migration two-fold and normal sequence PSTI/TATI showed synergistic promigratory effects when added with EGF. Addition of structurally unrelated soya bean trypsin inhibitor had no pro-migratory activity. Similar results were seen using collagen invasion assays although the active site mutated variant had no pro-invasive activity, probably due to reduced Akt2 activation. PSTI/TATI did not stimulate proliferation despite acting, at least partially, through the EGF receptor as effects of PSTI/TATI were truncated by adding an EGFR blocking antibody or the tyrosine kinase inhibitor Tyrphostin. Cell lines produced endogenous PSTI/TATI and PSTI/TATI RNA interference knockdown or addition of PSTI/TATI, EGF-receptor or Tyrphostin blocking agents reduced migration and invasion below baseline. PSTI/TATI induced phosphorylation of the EGF receptor, ERK1 and 2, Akt2 and 3, JNK1, MKK3 and RSK1. This profile was more limited than that induced by EGF and did not include Akt1, probably explaining lack of pro-proliferative activity. Our findings of autocrine stimulation and synergistic responses between EGF & PSTI/TATI at concentrations found in urine and tissue suggest PSTI/TATI has pathophysiological relevance.
    AJP Renal Physiology 05/2013; 305(3). DOI:10.1152/ajprenal.00357.2012
  • Movement Disorders 04/2013; 28(4). DOI:10.1002/mds.25419
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