Publications by authors named "Tara Hurst"

18 Publications

  • Page 1 of 1

Development and Assessment of a Pooled Serum as Candidate Standard to Measure Influenza A Virus Group 1 Hemagglutinin Stalk-Reactive Antibodies.

Vaccines (Basel) 2020 Nov 9;8(4). Epub 2020 Nov 9.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA.

The stalk domain of the hemagglutinin has been identified as a target for induction of protective antibody responses due to its high degree of conservation among numerous influenza subtypes and strains. However, current assays to measure stalk-based immunity are not standardized. Hence, harmonization of assay readouts would help to compare experiments conducted in different laboratories and increase confidence in results. Here, serum samples from healthy individuals ( = 110) were screened using a chimeric cH6/1 hemagglutinin enzyme-linked immunosorbent assay (ELISA) that measures stalk-reactive antibodies. We identified samples with moderate to high IgG anti-stalk antibody levels. Likewise, screening of the samples using the mini-hemagglutinin (HA) headless construct #4900 and analysis of the correlation between the two assays confirmed the presence and specificity of anti-stalk antibodies. Additionally, samples were characterized by a cH6/1N5 virus-based neutralization assay, an antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and competition ELISAs, using the stalk-reactive monoclonal antibodies KB2 (mouse) and CR9114 (human). A "pooled serum" (PS) consisting of a mixture of selected serum samples was generated. The PS exhibited high levels of stalk-reactive antibodies, had a cH6/1N5-based neutralization titer of 320, and contained high levels of stalk-specific antibodies with ADCC activity. The PS, along with blinded samples of varying anti-stalk antibody titers, was distributed to multiple collaborators worldwide in a pilot collaborative study. The samples were subjected to different assays available in the different laboratories, to measure either binding or functional properties of the stalk-reactive antibodies contained in the serum. Results from binding and neutralization assays were analyzed to determine whether use of the PS as a standard could lead to better agreement between laboratories. The work presented here points the way towards the development of a serum standard for antibodies to the HA stalk domain of phylogenetic group 1.
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http://dx.doi.org/10.3390/vaccines8040666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712758PMC
November 2020

Assessing the Concordance of Genomic Alterations between Circulating-Free DNA and Tumour Tissue in Cancer Patients.

Cancers (Basel) 2019 Dec 4;11(12). Epub 2019 Dec 4.

Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK.

Somatic alterations to the genomes of solid tumours, which in some cases represent actionable drivers, provide diagnostic and prognostic insight into these complex diseases. Spatial and longitudinal tracking of somatic genomic alterations (SGAs) in patient tumours has emerged as a new avenue of investigation, not only as a disease monitoring strategy, but also to improve our understanding of heterogeneity and clonal evolution from diagnosis through disease progression. Furthermore, analysis of circulating-free DNA (cfDNA) in the so-called "liquid biopsy" has emerged as a non-invasive method to identify genomic information to inform targeted therapy and may also capture the heterogeneity of the primary and metastatic tumours. Considering the potential of cfDNA analysis as a translational laboratory tool in clinical practice, establishing the extent to which cfDNA represents the SGAs of tumours, particularly actionable driver alterations, becomes a matter of importance, warranting standardisation of methods and practices. Here, we assess the utilisation of cfDNA for molecular profiling of SGAs in tumour tissue across a broad range of solid tumours. Moreover, we examine the underlying factors contributing to discordance of detected SGAs between cfDNA and tumour tissue.
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http://dx.doi.org/10.3390/cancers11121938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966532PMC
December 2019

Editorial: The Past and the Future of Human Immunity Under Viral Evolutionary Pressure.

Front Immunol 2019 2;10:2340. Epub 2019 Oct 2.

Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.3389/fimmu.2019.02340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783508PMC
October 2020

Interferon-Inducible Protein 16 (IFI16) Has a Broad-Spectrum Binding Ability Against ssDNA Targets: An Evolutionary Hypothesis for Antiretroviral Checkpoint.

Front Microbiol 2019 4;10:1426. Epub 2019 Jul 4.

Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

Human endogenous retroviruses (HERVs) are under genomic and epigenetic control but can be expressed in normal tissues, producing RNA transcripts some of which are translated. While it has not been demonstrated experimentally in modern humans, cDNA copies from HERV RNA (namely HERV-K HML-2 or HK2) were produced after the human-chimp split and until at least 250,000 years ago. We were interested in determining if such cDNA could be a ligand for pattern recognition receptors (PRRs) of the innate immune response. The AIM-2-like receptors for DNA, interferon-γ-inducible protein 16 (IFI16) and Cyclic GMP-AMP synthase (cGAS) were candidate PRRs. IFI16 can detect cDNA produced during HIV-1 replication, causing increased T cell death. While HIV-1 has emerged relatively recently as a human pathogen, the cDNA functionality of IFI16 could have been selected for during the course of human evolution. Here we present a novel hypothesis that the products of reverse transcription of HK2, which has been proliferating in the genome of human ancestors for 30 million years, could interact with IFI16. In support of our hypothesis, we provide preliminary data showing that IFI16 (but not cGAS) interacts with synthetic single-stranded HK2 oligos corresponding to the first product of reverse transcription. Further, we show that ssDNA detection by IFI16 has variability with respect to sequence features but is not dependent on strong secondary structures mimicking dsDNA. Among the HK2 oligos, IFI16 interacts more intensely with those derived from LTRs, suggesting these oligos have undetermined structural features that allow IFI16 to bind with greater affinity. Further, cells with stem cell features that naturally allow HK2 expression were found to express many components of the innate immune system including cGAS but not IFI16. Based on the presented preliminary data we further postulate another hypothesis: that the IFI16 functionality in human cells has been acting as "second-line" defense to control abnormal HK2 replication in somatic tissues. The absence of this protein in stem cells and a stem cell line could permit these cells to express HERVs which contribute to stem cell identity. Finally, we also comment on potential studies that could support or refute our hypothesis.
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http://dx.doi.org/10.3389/fmicb.2019.01426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621918PMC
July 2019

Human Endogenous Retrovirus-K HML-2 integration within is associated with intravenous drug abuse and modulates transcription in a cell-line model.

Proc Natl Acad Sci U S A 2018 10 24;115(41):10434-10439. Epub 2018 Sep 24.

Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom;

HERV-K HML-2 (HK2) has been proliferating in the germ line of humans at least as recently as 250,000 years ago, with some integrations that remain polymorphic in the modern human population. One of the solitary HK2 LTR polymorphic integrations lies between exons 17 and 18 of , a gene that affects dopaminergic activity and is thus related to addiction. Here we show that this antisense HK2 integration (namely RASGRF2-int) is found more frequently in persons who inject drugs compared with the general population. In a Greek HIV-1-positive population ( = 202), we found RASGRF2-int 2.5 times (14 versus 6%) more frequently in patients infected through i.v. drug use compared with other transmission route controls ( = 0.03). Independently, in a United Kingdom-based hepatitis C virus-positive population ( = 184), we found RASGRF2-int 3.6 times (34 versus 9.5%) more frequently in patients infected during chronic drug abuse compared with controls ( < 0.001). We then tested whether RASGRF2-int could be mechanistically responsible for this association by modulating transcription of We show that the CRISPR/Cas9-mediated insertion of HK2 in HEK293 cells in the exact intronic position found in the population resulted in significant transcriptional and phenotypic changes. We also explored mechanistic features of other intronic HK2 integrations and show that HK2 LTRs can be responsible for generation of -natural antisense transcripts, which could interfere with the transcription of nearby genes. Our findings suggest that RASGRF2-int is a strong candidate for dopaminergic manipulation, and emphasize the importance of accurate mapping of neglected HERV polymorphisms in human genomic studies.
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http://dx.doi.org/10.1073/pnas.1811940115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187174PMC
October 2018

Transcriptional Modulation of Human Endogenous Retroviruses in Primary CD4+ T Cells Following Vorinostat Treatment.

Front Immunol 2018 12;9:603. Epub 2018 Apr 12.

Faculty of Medicine, University of Southampton, Southampton, Hants, United Kingdom.

The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A "shock and kill" approach has been proposed as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs) are used to "shock" the silent provirus into active replication to permit "killing" by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC) inhibitor-vorinostat. Potentially, pathological off-target effects of vorinostat may result from the activation of human endogenous retroviruses (HERVs), which share common ancestry with exogenous retroviruses including HIV. To explore the effects of HDAC inhibition on HERV transcription, an unbiased pharmacogenomics approach (total RNA-Seq) was used to evaluate HERV expression following the exposure of primary CD4 T cells to a high dose of vorinostat. Over 2,000 individual HERV elements were found to be significantly modulated by vorinostat, whereby elements belonging to the ERVL family (e.g., LTR16C and LTR33) were predominantly downregulated, in contrast to LTR12 elements of the HERV-9 family, which exhibited the greatest signal, with the upregulation of 140 distinct elements. The modulation of three different LTR12 elements by vorinostat was confirmed by droplet digital PCR along a dose-response curve. The monitoring of LTR12 expression during clinical trials with vorinostat may be indicated to assess the impact of this HERV on the human genome and host immunity.
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http://dx.doi.org/10.3389/fimmu.2018.00603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906534PMC
June 2019

Epigenetic Control of Human Endogenous Retrovirus Expression: Focus on Regulation of Long-Terminal Repeats (LTRs).

Viruses 2017 05 31;9(6). Epub 2017 May 31.

Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

Transposable elements, including endogenous retroviruses (ERVs), comprise almost 45% of the human genome. This could represent a significant pathogenic burden but it is becoming more evident that many of these elements have a positive contribution to make to normal human physiology. In particular, the contributions of human ERVs (HERVs) to gene regulation and the expression of noncoding RNAs has been revealed with the help of new and emerging genomic technologies. HERVs have the common provirus structure of coding open reading frames (ORFs) flanked by two long-terminal repeats (LTRs). However, over the course of evolution and as a consequence of host defence mechanisms, most of the sequences contain INDELs, mutations or have been reduced to single LTRs by recombination. These INDELs and mutations reduce HERV activity. However, there is a trade-off for the host cells in that HERVs can provide beneficial sources of genetic variation but with this benefit comes the risk of pathogenic activity and spread within the genome. For example, the LTRs are of critical importance as they contain promoter sequences and can regulate not only HERV expression but that of human genes. This is true even when the LTRs are located in intergenic regions or are in antisense orientation to the rest of the gene. Uncontrolled, this promoter activity could disrupt normal gene expression or transcript processing (e.g., splicing). Thus, control of HERVs and particularly their LTRs is essential for the cell to manage these elements and this control is achieved at multiple levels, including epigenetic regulations that permit HERV expression in the germline but silence it in most somatic tissues. We will discuss some of the common epigenetic mechanisms and how they affect HERV expression, providing detailed discussions of HERVs in stem cell, placenta and cancer biology.
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http://dx.doi.org/10.3390/v9060130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490807PMC
May 2017

A contaminant-free assessment of Endogenous Retroviral RNA in human plasma.

Sci Rep 2016 09 19;6:33598. Epub 2016 Sep 19.

Department of Zoology, University of Oxford, Oxford, United Kingdom.

Endogenous retroviruses (ERVs) comprise 6-8% of the human genome. HERVs are silenced in most normal tissues, up-regulated in stem cells and in placenta but also in cancer and HIV-1 infection. Crucially, there are conflicting reports on detecting HERV RNA in non-cellular clinical samples such as plasma that suggest the study of HERV RNA can be daunting. Indeed, we find that the use of real-time PCR in a quality assured clinical laboratory setting can be sensitive to low-level proviral contamination. We developed a mathematical model for low-level contamination that allowed us to design a laboratory protocol and standard operating procedures for robust measurement of HERV RNA. We focus on one family, HERV-K HML-2 (HK2) that has been most recently active even though they invaded our ancestral genomes almost 30 millions ago. We extensively validated our experimental design on a model cell culture system showing high sensitivity and specificity, totally eliminating the proviral contamination. We then tested 236 plasma samples from patients infected with HIV-1, HCV or HBV and found them to be negative. The study of HERV RNA for human translational studies should be performed with extensively validated protocols and standard operating procedures to control the widespread low-level human DNA contamination.
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http://dx.doi.org/10.1038/srep33598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027517PMC
September 2016

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency.

Retrovirology 2016 Feb 6;13:10. Epub 2016 Feb 6.

Department of Zoology, University of Oxford, South Parks Road, Oxford, UK.

Background: While antiretroviral therapies have improved life expectancy and reduced viral loads in HIV-1-positive individuals, the cessation of treatment results in a rebound of viral replication. This suggests that a reservoir of latently-infected cells remains within these patients, the identity of which is ill-defined and therefore difficult to target therapeutically. Current strategies are aimed at using drugs such as histone deacetylase (HDAC) inhibitors to induce the expression of latent HIV-1 proviruses in order to activate and ultimately eradicate this reservoir of infected cells. One concern with the use of HDAC inhibitors is that they could up-regulate human endogenous retroviruses (HERVs), as well as HIV-1, with potentially pathophysiological consequences.

Results: In this study, we analysed the transcription of HERV genes in HIV-1 latency T cell (J-LAT 8.4) and monocyte (U1) models following treatment with the HDAC inhibitors, vorinostat, panobinostat and romidepsin. We examined the expression of HERV-K (HML-2) env and pol, as well as the co-opted genes HERV-W env (syncytin-1), HERV-FRD env (syncytin-2), in these cell lines. Finally, we investigated HERV expression in primary human T cells.

Conclusions: We show that HDAC inhibitors did not substantially increase the transcription of the analysed HERV env or pol genes, suggesting that histone acetylation is not crucial for controlling HERV expression in these experimental models and in ex vivo primary human T cells. Importantly, this indicates that unwanted HERV expression does not appear to be a barrier to the use of HDAC inhibitors in HIV-1 cure strategies.
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http://dx.doi.org/10.1186/s12977-016-0242-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744380PMC
February 2016

Activation of the innate immune response by endogenous retroviruses.

J Gen Virol 2015 Jun;96(Pt 6):1207-1218

Department of Zoology, University of Oxford, Tinbergen Building, South Parks Road, Oxford OX1 3PS, UK.

The human genome comprises 8 % endogenous retroviruses (ERVs), the majority of which are defective due to deleterious mutations. Nonetheless, transcripts of ERVs are found in most tissues, and these transcripts could either be reverse transcribed to generate ssDNA or expressed to generate proteins. Thus, the expression of ERVs could produce nucleic acids or proteins with viral signatures, much like the pathogen-associated molecular patterns of exogenous viruses, which would enable them to be detected by the innate immune system. The activation of some pattern recognition receptors (PRRs) in response to ERVs has been described in mice and in the context of human autoimmune diseases. Here, we review the evidence for detection of ERVs by PRRs and the resultant activation of innate immune signalling. This is an emerging area of research within the field of innate antiviral immunity, showing how ERVs could initiate immune signalling pathways and might have implications for numerous inflammatory diseases.
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http://dx.doi.org/10.1099/jgv.0.000017DOI Listing
June 2015

The early treatment in diabetic retinopathy study chart compared with the tumbling-E and Landolt-C.

Ophthalmology 2015 May 10;122(5):1062-3.e1. Epub 2015 Jan 10.

Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1016/j.ophtha.2014.11.024DOI Listing
May 2015

Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease.

Biochim Biophys Acta 2014 Nov 2;1843(11):2563-2582. Epub 2014 Jun 2.

Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, Whitechapel, London E1 2AT, United Kingdom.

Inflammation occurs as a result of exposure of tissues and organs to harmful stimuli such as microbial pathogens, irritants, or toxic cellular components. The primary physical manifestations of inflammation are redness, swelling, heat, pain, and loss of function to the affected area. These processes involve the major cells of the immune system, including monocytes, macrophages, neutrophils, basophils, dendritic cells, mast cells, T-cells, and B-cells. However, examination of a range of inflammatory lesions demonstrates the presence of specific leukocytes in any given lesion. That is, the inflammatory process is regulated in such a way as to ensure that the appropriate leukocytes are recruited. These events are in turn controlled by a host of extracellular molecular regulators, including members of the cytokine and chemokine families that mediate both immune cell recruitment and complex intracellular signalling control mechanisms that characterise inflammation. This review will focus on the role of the main cytokines, chemokines, and their receptors in the pathophysiology of auto-inflammatory disorders, pro-inflammatory disorders, and neurological disorders involving inflammation.
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http://dx.doi.org/10.1016/j.bbamcr.2014.05.014DOI Listing
November 2014

Poxviral protein A52 stimulates p38 mitogen-activated protein kinase (MAPK) activation by causing tumor necrosis factor receptor-associated factor 6 (TRAF6) self-association leading to transforming growth factor β-activated kinase 1 (TAK1) recruitment.

J Biol Chem 2013 Nov 10;288(47):33642-53. Epub 2013 Oct 10.

From the Immunology Research Centre, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

Vaccinia virus encodes a number of proteins that inhibit and manipulate innate immune signaling pathways that also have a role in virulence. These include A52, a protein shown to inhibit IL-1- and Toll-like receptor-stimulated NFκB activation, via interaction with interleukin-1 receptor-associated kinase 2 (IRAK2). Interestingly, A52 was also found to activate p38 MAPK and thus enhance Toll-like receptor-dependent IL-10 induction, which was TRAF6-dependent, but the manner in which A52 manipulates TRAF6 to stimulate p38 activation was unclear. Here, we show that A52 has a non-canonical TRAF6-binding motif that is essential for TRAF6 binding and p38 activation but dispensable for NFκB inhibition and IRAK2 interaction. Wild-type A52, but not a mutant defective in p38 activation and TRAF6 binding (F154A), caused TRAF6 oligomerization and subsequent TRAF6-TAK1 association. The crystal structure of A52 shows that it adopts a Bcl2-like fold and exists as a dimer in solution. Residue Met-65 was identified as being located in the A52 dimer interface, and consistent with that, A52-M65E was impaired in its ability to dimerize. A52-M65E although capable of interacting with TRAF6, was unable to cause either TRAF6 self-association, induce the TRAF6-TAK1 association, or activate p38 MAPK. The results suggest that an A52 dimer causes TRAF6 self-association, leading to TAK1 recruitment and p38 activation. This reveals a molecular mechanism whereby poxviruses manipulate TRAF6 to activate MAPKs (which can be proviral) without stimulating antiviral NFκB activation.
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http://dx.doi.org/10.1074/jbc.M113.485490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837111PMC
November 2013

Thiazolidinediones in the treatment of HIV/HAART-associated lipodystrophy syndrome.

AIDS Rev 2013 Jul-Sep;15(3):171-80

School of Science and Technology, Nottingham Trent University, Nottingham, UK.

The treatment of HIV-1 infected patients with HAART has resulted in long-term suppression of viral replication and reduced progression to AIDS. However, the use of HAART has been associated with adverse effects, including metabolic dysregulation and changes in body fat deposition. This syndrome, known as HIV/HAART-associated lipodystrophy syndrome, is characterized by insulin resistance, dyslipidemia, lipodystrophy, and increased visceral adiposity, which contribute to an increased risk of cardiovascular disease amongst these patients. The thiazolidinediones are a class of agonists for the nuclear receptors, the peroxisome proliferator-activated receptor. Since peroxisome proliferator-activated receptor is critically involved in the regulation of insulin sensitivity and lipid metabolism, a number of clinical trials have analyzed whether thiazolidinediones could ameliorate the signs of HIV/HAART-associated lipodystrophy syndrome. Based on these trials, thiazolidinediones appear to up-regulate peroxisome proliferator-activated receptor-dependent genes such as adiponectin, an effect that could have important physiological benefits in the long-term for HIV/HAART-associated lipodystrophy syndrome patients. Critically, many of the studies were of short duration and thus the beneficial effects of thiazolidinediones might have been missed. In addition, the few studies on the thiazolidinedione pioglitazone showed a beneficial effect on limb fat mass that was not associated with a pro-atherogenic lipid profile. Based on these studies, a large-scale clinical trial of pioglitazone use in HIV/HAART-associated lipodystrophy syndrome patients is warranted.
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August 2014

The case for intraocular delivery of PPAR agonists in the treatment of diabetic retinopathy.

BMC Ophthalmol 2012 Sep 2;12:46. Epub 2012 Sep 2.

Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2, Dublin, Ireland.

Background: Systemic therapeutics targeting the peroxisome proliferator-activated receptors have been found to be beneficial in the treatment of diabetic retinopathy. In this paper, we provide a rationale for the use of these therapeutics as intraocular agents. In addition, we introduce the peroxisome proliferator-activated receptors and describe their functions in response to the drugs.

Discussion: Based on the evidence of large-scale clinical studies investigating the systemic administration of fenofibrate, this ligand for peroxisome proliferator-activated receptor-α is potentially a good candidate for intraocular delivery. Here, we describe the mechanisms by which it might be acting to improve diabetic retinopathy, its relative safety and we speculate on how it could be developed for intraocular delivery.

Summary: In this paper, we provide a rationale for the further investigation of peroxisome proliferator-activated receptor-α agonists as intraocular agents for the treatment of diabetic retinopathy.
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http://dx.doi.org/10.1186/1471-2415-12-46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532122PMC
September 2012

Aquareovirus effects syncytiogenesis by using a novel member of the FAST protein family translated from a noncanonical translation start site.

J Virol 2009 Jun 18;83(11):5951-5. Epub 2009 Mar 18.

Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.

As nonenveloped viruses, the aquareoviruses and orthoreoviruses are unusual in their ability to induce cell-cell fusion and syncytium formation. While an extraordinary family of fusion-associated small transmembrane (FAST) proteins is responsible for orthoreovirus syncytiogenesis, the basis for aquareovirus-induced syncytiogenesis is unknown. We now report that the S7 genome segment of an Atlantic salmon reovirus is polycistronic and uses a noncanonical CUG translation start codon to produce a 22-kDa integral membrane protein responsible for syncytiogenesis. The aquareovirus p22 protein represents a fourth distinct member of the FAST family with a unique repertoire and arrangement of structural motifs.
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http://dx.doi.org/10.1128/JVI.00171-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681948PMC
June 2009

Outcome evaluation of early discharge from hospital with asthma.

Respirology 2003 Mar;8(1):77-81

School of Women's and Children's Health, University of New South Wales, Randwick, New South Wales, Australia.

Objective: The aim of the study was to determine whether it was safe to discharge children with asthma from hospital when stable on 3-hourly rather than 4-hourly doses of salbutamol.

Methodology: A retrospective study of 419 individual admissions of 359 children with asthma was undertaken. We defined a theoretical 'time ready for discharge' (TRD) for asthmatic admissions based on: (i) at least two doses of 3-hourly salbutamol and due for the third dose, (ii) no oxygen supplementation, (iii) no intravenous fluid or therapy, and (iv) time of discharge should be either before 17:30 hours or after 07:30 hours. Each admission was analysed using appropriate parameters to assess for risks and benefits of using this theoretical TRD as a guide for discharging asthmatic children from hospital.

Results: A total of 116 (27.7%) children were discharged before our theoretical TRD, including 11 children who received salbutamol no less often than 2-hourly and 37 who had a single dose of 3-hourly salbutamol before discharge. Re-admission to hospital and representation to the Emergency Department without re-admission within 1 week of discharge were less common in the group who were discharged before they had achieved theoretical TRD than in those who were discharged at or after the theoretical TRD, although the numbers were too small to reach statistical significance. Between our theoretical TRD and actual time of discharge two children who received supplemental oxygen and more frequent salbutamol may have required re-admission.

Conclusions: From the medical viewpoint discharge when the child is stable on 3-hourly rather than 4-hourly doses appears safe. This can be expected to shorten length of stay by an average of 5.5 h (P < 0.001).
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http://dx.doi.org/10.1046/j.1440-1843.2003.00431.xDOI Listing
March 2003

Emergency surgery after unsuccessful coronary angioplasty: a review of 15 years' experience.

Ann Thorac Surg 2003 May;75(5):1400-5

Cardiothoracic Surgical Unit, Royal Prince Alfred Hospital, Sydney, Australia.

Background: Emergency coronary artery bypass grafting (CABG) is occasionally necessary for failed percutaneous transluminal coronary angioplasty (PTCA). The aim of this study was to assess the outcome of patients receiving emergency CABG after unsuccessful PTCA over a 15-year study period.

Methods: From January 1982 through December 1996, 74 patients underwent emergency CABG after unsuccessful PTCA (crash group). This group was compared with a matched group of 74 patients having primary elective CABG (control group).

Results: All 74 crash group patients were to have PTCA of one coronary system. After PTCA failure, 58 patients (78.3%) developed electrocardiographic changes of evolving acute myocardial infarction (AMI). The overall rate of AMI was 8.1% for the crash group and 2.7% for the control group. Two patients in the crash group died, with no deaths in the control group. There was no significant difference between mean in-hospital length of stay.

Conclusions: With prompt, aggressive, and complete myocardial revascularization, patients who required emergency CABG after PTCA failure had an outcome not significantly different from that of patients having elective CABG.
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http://dx.doi.org/10.1016/s0003-4975(02)05026-9DOI Listing
May 2003