Publications by authors named "James P Stewart"

77 Publications

Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus.

EMBO J 2021 Feb 15:e105543. Epub 2021 Feb 15.

Norwich Medical School, University of East Anglia, Norwich, UK.

Influenza A virus (IAV) and SARS-CoV-2 (COVID-19) cause pandemic infections where cytokine storm syndrome and lung inflammation lead to high mortality. Given the high social and economic cost of respiratory viruses, there is an urgent need to understand how the airways defend against virus infection. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that ATG16L1-dependent targeting of LC3 to single-membrane, non-autophagosome compartments - referred to as non-canonical autophagy - protects mice from lethal IAV infection. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV was controlled within epithelial barriers where non-canonical autophagy reduced IAV fusion with endosomes and activation of interferon signalling. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung was independent of phagocytes and other leucocytes. This establishes non-canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces.
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http://dx.doi.org/10.15252/embj.2020105543DOI Listing
February 2021

Outbreak of Severe Vomiting in Dogs Associated with a Canine Enteric Coronavirus, United Kingdom.

Emerg Infect Dis 2021 02;27(2):517-528

The lack of population health surveillance for companion animal populations leaves them vulnerable to the effects of novel diseases without means of early detection. We present evidence on the effectiveness of a system that enabled early detection and rapid response a canine gastroenteritis outbreak in the United Kingdom. In January 2020, prolific vomiting among dogs was sporadically reported in the United Kingdom. Electronic health records from a nationwide sentinel network of veterinary practices confirmed a significant increase in dogs with signs of gastroenteric disease. Male dogs and dogs living with other vomiting dogs were more likely to be affected. Diet and vaccination status were not associated with the disease; however, a canine enteric coronavirus was significantly associated with illness. The system we describe potentially fills a gap in surveillance in neglected populations and could provide a blueprint for other countries.
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http://dx.doi.org/10.3201/eid2702.202452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853541PMC
February 2021

Structural Characterization of Non-structural Protein 9 Complexed With Specific Nanobody Pinpoints Two Important Residues Involved in Porcine Reproductive and Respiratory Syndrome Virus Replication.

Front Microbiol 2020 12;11:581856. Epub 2020 Nov 12.

Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China.

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRS virus (PRRSV), is a widespread viral disease that has led to huge economic losses for the global swine industry. Non-structural protein 9 (Nsp9) of PRRSV possesses essential RNA-dependent RNA polymerase (RdRp) activity for viral RNA replication. Our previous report showed that Nsp9-specific nanobody, Nb6, was able to inhibit PRRSV replication. In this study, recombinant Nsp9 and Nsp9-Nb6 complex were prepared then characterized using bio-layer interferometry (BLI) and dynamic light scattering (DLS) analyses that demonstrated high-affinity binding of Nb6 to Nsp9 to form a homogeneous complex. Small-angle X-ray scattering (SAXS) characterization analyses revealed that spatial interactions differed between Nsp9 and Nsp9-Nb6 complex molecular envelopes. Enzyme-linked immunosorbent assays (ELISAs) revealed key involvement of Nsp9 residues Ile588, Asp590, and Leu643 and Nb6 residues Tyr62, Trp105, and Pro107 in the Nsp9-Nb6 interaction. After reverse genetics-based techniques were employed to generate recombinant Nsp9 mutant viruses, virus replication efficiencies were assessed in MARC-145 cells. The results revealed impaired viral replication of recombinant viruses bearing I588A and L643A mutations as compared with replication of wild type virus, as evidenced by reduced negative-strand genomic RNA [(-) gRNA] synthesis and attenuated viral infection. Moreover, the isoleucine at position 588 of Nsp9 was conserved across PRRSV genotypes. In conclusion, structural analysis of the Nsp9-Nb6 complex revealed novel amino acid interactions involved in viral RNA replication that will be useful for guiding development of structure-based anti-PRRSV agents.
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http://dx.doi.org/10.3389/fmicb.2020.581856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688669PMC
November 2020

Sheep-Associated Malignant Catarrhal Fever: Role of Latent Virus and Macrophages in Vasculitis.

Vet Pathol 2020 Dec 7:300985820978310. Epub 2020 Dec 7.

27217University of Zurich, Zurich, Switzerland.

Malignant catarrhal fever (MCF) is a sporadic, generally fatal disease caused by gammaherpesviruses in susceptible dead-end hosts. A key pathological process is systemic vasculitis in which productively infected cytotoxic T cells play a major role. Nonetheless, the pathogenesis of MCF vasculitis is not yet clear. We hypothesized that it develops due to an interaction between virus-infected cells and immune cells, and we undertook a retrospective in situ study on the rete mirabile arteries of confirmed ovine gammaherpesvirus-2 (OvHV-2)-associated MCF cases in cattle, buffalo, and bison. Our results suggest that the arteritis develops from an adventitial infiltration of inflammatory cells from the vasa vasorum, and recruitment of leukocytes from the arterial lumen that leads to a superimposed infiltration of the intima and media that can result in chronic changes including neointimal proliferation. We found macrophages and T cells to be the dominant infiltrating cells, and both could proliferate locally. Using RNA in situ hybridization and immunohistology, we showed that the process is accompanied by widespread viral infection, not only in infiltrating leukocytes but also in vascular endothelial cells, medial smooth muscle cells, and adventitial fibroblasts. Our results suggest that OvHV-2-infected T cells, monocytes, and locally proliferating macrophages contribute to the vasculitis in MCF. The initial trigger or insult that leads to leukocyte recruitment and activation is not yet known, but there is evidence that latently infected, activated endothelial cells play a role in this. Activated macrophages might then release the necessary pro-inflammatory mediators and, eventually, induce the characteristic vascular changes.
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http://dx.doi.org/10.1177/0300985820978310DOI Listing
December 2020

Pellino-1 Regulates the Responses of the Airway to Viral Infection.

Front Cell Infect Microbiol 2020 31;10:456. Epub 2020 Aug 31.

Department of Infection, Immunity and Cardiovascular Disease, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, United Kingdom.

Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease. Pellino-1 expression was examined in bronchial sections from patients with GOLD stage two COPD and healthy controls. Primary bronchial epithelial cells (PBECs) in which Pellino-1 expression had been knocked down were extracellularly challenged with the TLR3 agonist poly(I:C). C57BL/6 mice and wild type littermates were subjected to intranasal infection with clinically-relevant respiratory viruses: rhinovirus (RV1B) and influenza A. We found that Pellino-1 is expressed in the airways of normal subjects and those with COPD, and that Pellino-1 regulates TLR3 signaling and responses to airways viruses. In particular we observed that knockout of Pellino-1 in the murine lung resulted in increased production of proinflammatory cytokines IL-6 and TNFα upon viral infection, accompanied by enhanced recruitment of immune cells to the airways, without any change in viral replication. Pellino-1 therefore regulates inflammatory airway responses without altering replication of respiratory viruses.
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http://dx.doi.org/10.3389/fcimb.2020.00456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488214PMC
August 2020

Outcomes Following Shock Aortic Valve Replacement: Transcatheter Versus Surgical Approaches.

Cardiovasc Revasc Med 2020 Oct 16;21(10):1313-1318. Epub 2020 Mar 16.

Division of Cardiology, Emory University School of Medicine, Atlanta, GA, United States of America.

Objectives: To compare transcatheter aortic valve replacement (TAVR) with surgical aortic valve replacement (SAVR) for patients in shock.

Background: There are minimal data on the clinical and echocardiographic outcomes for patients in shock that undergo TAVR and no data comparing these outcomes to similar patients undergoing SAVR.

Methods: This is a single center, retrospective cohort study of patients having Society of Thoracic Surgeons (STS)-defined urgent or emergent AVR for aortic stenosis with clinical signs and symptoms of shock. Inclusion criteria were based on the Society of Cardiovascular Angiography & Interventions (SCAI) shock consensus statement and included: the need for inotropic or vasopressor agents, mechanical ventilation, continuous renal replacement therapy or newly initiated hemodialysis, and/or utilization of mechanical hemodynamic support. Clinical and echocardiographic outcomes for TAVR and SAVR were compared.

Results: Thirty-seven patients met the inclusion criteria for this study (17 TAVR, 20 SAVR). TAVR patients had a higher STS Predicted Risk of Mortality (PROM) score of 22.3% compared to 11.8% for SAVR patients (p = 0.001). No significant differences were found in baseline echocardiographic results. TAVR procedures required less procedure room time (185.9 min TAVR, 348.5 min SAVR, p < 0.001) and fewer intraoperative packed red blood cell (pRBC) transfusions (0.2 units TAVR, 3.4 units SAVR, p < 0.001). TAVR patients also had lower rates of prolonged postoperative ventilation compared to SAVR patients (38.5% TAVR, 75.0% SAVR, p = 0.047). TAVR and SAVR had similar rates of mortality at discharge (2 TAVR, 1 SAVR, p = 0.584), 30-days (2 TAVR, 1 SAVR, p = 0.584), and 1-year (8 TAVR, 5 SAVR, p = 0.149).

Conclusions: Despite a higher risk TAVR group, patients in shock undergoing either TAVR or SAVR have similar 30-day mortality. At one year, SAVR patients have a numerically better, though not statistically significant, survival. These findings support the use of TAVR for patients in shock with aortic stenosis.
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http://dx.doi.org/10.1016/j.carrev.2020.03.021DOI Listing
October 2020

Development of a Risk Score to Predict New Pacemaker Implantation After Transcatheter Aortic Valve Replacement.

JACC Cardiovasc Interv 2019 11;12(21):2133-2142

Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia.

Objectives: The aim of this study was to define risk factors and develop a predictive risk score for new pacemaker implantation (PMI) after transcatheter aortic valve replacement (TAVR).

Background: TAVR has become an accepted treatment alternative for patients with severe aortic stenosis at elevated surgical risk. New PMI is a common occurrence after TAVR and is associated with poorer outcomes.

Methods: All patients without prior valve procedures undergoing elective TAVR with the Edwards SAPIEN 3 at a single institution (n = 1,266) were evaluated. Multivariate analysis was performed to evaluate for predictors of PMI in this population in a derivation cohort of patients with complete data (n = 778), and this model was used to develop the Emory risk score (ERS), which was tested in a validation cohort (n = 367).

Results: Fifty-seven patients (7.3%) in the derivation cohort required PMI. In a regression model, history of syncope (odds ratio [OR]: 2.5; p = 0.026), baseline right bundle branch block (OR: 4.3; p < 0.001), QRS duration ≥138 ms (OR: 2.5; p = 0.017), and valve oversizing >15.6% (OR: 1.9; p = 0.041) remained independent predictors of PMI and were included in the ERS. The ERS was strongly associated with PMI (per point increase OR: 2.2; p < 0.001) with an area under the receiver-operating characteristic curve of 0.778 (p < 0.001), which was similar to its performance in the derivation cohort.

Conclusions: A history of syncope, right bundle branch block, longer QRS duration, and higher degree of oversizing are predictive of the need for PMI after TAVR. Additionally, the ERS for PMI was developed and validated, representing a simple bedside tool to aid in risk stratification for patients for undergoing TAVR.
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http://dx.doi.org/10.1016/j.jcin.2019.07.015DOI Listing
November 2019

Direct Interaction Between CD163 N-Terminal Domain and MYH9 C-Terminal Domain Contributes to Porcine Reproductive and Respiratory Syndrome Virus Internalization by Permissive Cells.

Front Microbiol 2019 6;10:1815. Epub 2019 Aug 6.

Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China.

Porcine reproductive and respiratory syndrome virus (PRRSV) has a highly restricted tropism for cells of the monocyte-macrophage lineage, including porcine alveolar macrophages (PAMs). PRRSV entry into permissive cells involves several mediators in addition to two required host cell receptors, CD163 and MYH9. It is unknown whether CD163 directly interacts and/or cooperates with MYH9 to facilitate PRRSV infection. In this study, CD163 and MYH9 were co-immunoprecipitated from PAMs regardless of PRRSV infection status. Further truncation analysis indicated that the CD163 N-terminal region, containing scavenger receptor cysteine-rich domains 1 to 4 (SRCR1-4), directly interacts with the MYH9 C-terminal domain region without involvement of other adaptor proteins. Meanwhile, non-permissive HEK293T cells that stably expressed truncated swine CD163 SRCR1-4 domain did not support virus attachment. However, virus attachment to cells stably expressing SRCR5-CT domain was demonstrated to occur without appreciable virus internalization. The involvement of the SRCR1-4 domain in virus internalization was further demonstrated by the fact that incubation of recombinant SRCR1-4 protein with PAMs abolished subsequent virus internalization by permissive cells. These results demonstrated that CD163 SRCR1-4 interacts with the MYH9 C-terminal domain to facilitate PRRSV virion internalization in permissive cells, thus expanding our understanding of PRRSV cell-invasion mechanisms.
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http://dx.doi.org/10.3389/fmicb.2019.01815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691103PMC
August 2019

Bioengineering commensal bacteria-derived outer membrane vesicles for delivery of biologics to the gastrointestinal and respiratory tract.

J Extracell Vesicles 2019 24;8(1):1632100. Epub 2019 Jun 24.

Gut Microbes and Health Research Programme, Quadram Institute Bioscience, Norwich, UK.

Gram-negative bacteria naturally produce and secrete nanosized outer membrane vesicles (OMVs). In the human gastrointestinal tract, OMVs produced by commensal Gram-negative bacteria can mediate interactions amongst host cells (including between epithelial cells and immune cells) and maintain microbial homeostasis. This OMV-mediated pathway for host-microbe interactions could be exploited to deliver biologically active proteins to the body. To test this we engineered the Gram-negative bacterium (Bt), a prominent member of the intestinal microbiota of all animals, to incorporate bacteria-, virus- and human-derived proteins into its OMVs. We then used the engineered Bt OMVs to deliver these proteins to the respiratory and gastrointestinal (GI)-tract to protect against infection, tissue inflammation and injury. Our findings demonstrate the ability to express and package both ser. Typhimurium-derived vaccine antigens and influenza A virus (IAV)-derived vaccine antigens within or on the outer membrane of Bt OMVs. These antigens were in a form capable of eliciting antigen-specific immune and antibody responses in both mucosal tissues and systemically. Furthermore, immunisation with OMVs containing the core stalk region of the IAV H5 hemagglutinin from an H5N1 strain induced heterotypic protection in mice to a 10-fold lethal dose of an unrelated subtype (H1N1) of IAV. We also showed that OMVs could express the human therapeutic protein, keratinocyte growth factor-2 (KGF-2), in a stable form that, when delivered orally, reduced disease severity and promoted intestinal epithelial repair and recovery in animals administered colitis-inducing dextran sodium sulfate. Collectively, our data demonstrates the utility and effectiveness of using Bt OMVs as a mucosal biologics and drug delivery platform technology.
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http://dx.doi.org/10.1080/20013078.2019.1632100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598475PMC
June 2019

Chicken Organic Anion-Transporting Polypeptide 1A2, a Novel Avian Hepatitis E Virus (HEV) ORF2-Interacting Protein, Is Involved in Avian HEV Infection.

J Virol 2019 06 15;93(11). Epub 2019 May 15.

Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China

Avian hepatitis E virus (HEV) is the main causative agent of big liver and spleen disease in chickens. Due to the absence of a highly effective cell culture system, there are few reports about the interaction between avian HEV and host cells. In this study, organic anion-transporting polypeptide 1A2 (OATP1A2) from chicken liver cells was identified to interact with ap237, a truncated avian HEV capsid protein spanning amino acids 313 to 549, by a glutathione -transferase (GST) pulldown assay. GST pulldown and indirect enzyme-linked immunosorbent assays (ELISAs) further confirmed that the extracellular domain of OATP1A2 directly binds with ap237. The expression levels of OATP1A2 in host cells are positively correlated with the amounts of ap237 attachment and virus infection. The distribution of OATP1A2 in different tissues is consistent with avian HEV infection Finally, when the functions of OATP1A2 in cells are inhibited by its substrates or an inhibitor or blocked by ap237 or anti-OATP1A2 sera, attachment to and infection of host cells by avian HEV are significantly reduced. Collectively, these results displayed for the first time that OATP1A2 interacts with the avian HEV capsid protein and can influence viral infection in host cells. The present study provides new insight to understand the process of avian HEV infection of host cells. The process of viral infection is centered around the interaction between the virus and host cells. Due to the lack of a highly effective cell culture system , there is little understanding about the interaction between avian HEV and its host cells. In this study, a total of seven host proteins were screened in chicken liver cells by a truncated avian HEV capsid protein (ap237) in which the host protein OATP1A2 interacted with ap237. Overexpression of OATP1A2 in the cells can promote ap237 adsorption as well as avian HEV adsorption and infection of the cells. When the function of OATP1A2 in cells was inhibited by substrates or inhibitors, attachment and infection by avian HEV significantly decreased. The distribution of OATP1A2 in different chicken tissues corresponded with that in tissues during avian HEV infection. This is the first finding that OATP1A2 is involved in viral infection of host cells.
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http://dx.doi.org/10.1128/JVI.02205-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532094PMC
June 2019

Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies.

J Pathol 2018 05 25;245(1):19-28. Epub 2018 Mar 25.

Centre for Cancer Research and Cell Biology, Queens's University Belfast, Belfast, UK.

Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMSs) and colorectal cancer intrinsic subtypes (CRISs) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, particularly in pretreatment biopsies from multiple regions or at different time points, remains untested. In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets (n = 543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n = 10), (iv) multi-regional biopsies from colon tumours (n = 29 biopsies, n = 7 tumours), and (v) pretreatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n = 44). Compared to previous results obtained using CRC resection material, we demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p = 0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially- and temporally- robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS (p = 0.003 and p = 0.02, respectively). These findings have potential to inform ongoing biopsy-based patient stratification in CRC, enabling robust and stable assignment of patients into clinically-informative arms of prospective multi-arm, multi-stage clinical trials. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947827PMC
May 2018

Statistical analysis of human microarray data shows that dietary intervention with n-3 fatty acids, flavonoids and resveratrol enriches for immune response and disease pathways.

Br J Nutr 2018 02 18;119(3):239-249. Epub 2018 Jan 18.

1Department of Molecular and Clinical Pharmacology,Institute of Translational Medicine,University of Liverpool,Physiology Building,Crown Street,Liverpool L69 3BX,UK.

n-3 Fatty acids, flavonoids and resveratrol are well publicised for their beneficial effects on human health and wellbeing. Identifying common, underlying biological mechanisms targeted by these functional foods would therefore be informative for the public health sector for advising on nutritional health and disease, food and drug product development and consumer interest. The aim of this study was to explore the potential effects of gene expression changes associated with n-3 fatty acids EPA and DHA, flavonoids and resveratrol on modifying biological systems and disease pathways. To test this, publicly available human microarray data for significant gene expression changes associated with dietary intervention with EPA/DHA, flavonoids and resveratrol was subjected to pathway analysis and significance testing for overlap with signals from genome-wide association studies (GWAS) for common non-communicable diseases and biological functions. There was an enrichment of genes implicated in immune responses and disease pathways which was common to all of the treatment conditions tested. Analysis of biological functions and disease pathways indicated anti-tumorigenic properties for EPA/DHA. In line with this, significance testing of the intersection of genes associated with these functional foods and GWAS hits for common biological functions (ageing and cognition) and non-communicable diseases (breast cancer, CVD, diabesity, neurodegeneration and psychiatric disorders) identified significant overlap between the EPA/DHA and breast cancer gene sets. Dietary intervention with EPA/DHA, flavonoids and resveratrol can target important biological and disease pathways suggesting a potentially important role for these bioactive compounds in the prevention and treatment of dietary-related diseases.
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http://dx.doi.org/10.1017/S0007114517003506DOI Listing
February 2018

Identification of Equid herpesvirus 2 in tissue-engineered equine tendon.

Wellcome Open Res 2017 17;2:60. Epub 2017 Oct 17.

Institute of Ageing and Chronic Disease, University of Liverpool, William Henry Duncan Building, West Derby Street, Liverpool, UK.

Incidental findings of virus-like particles were identified following electron microscopy of tissue-engineered tendon constructs (TETC) derived from equine tenocytes. We set out to determine the nature of these particles, as there are few studies which identify virus in tendons , and their presence could have implications for tissue-engineering using allogenic grafts. Virus particles were identified in electron microscopy of TETCs. Virion morphology was used to initially hypothesise the virus identity.  Next generation sequencing was implemented to identify the virus. A pan herpesvirus PCR was used to validate the RNASeq findings using an independent platform. Histological analysis and biochemical analysis was undertaken on the TETCs. Morphological features suggested the virus to be either a retrovirus or herpesvirus. Subsequent next generation sequencing mapped reads to Equid herpesvirus 2 (EHV2). Histological examination and biochemical testing for collagen content revealed no significant differences between virally affected TETCs and non-affected TETCs. An independent set of equine superficial digital flexor tendon tissue (n=10) examined using designed primers for specific EHV2 contigs identified at sequencing were negative. These data suggest that EHV is resident in some equine tendon. EHV2 was demonstrated in equine tenocytes for the first time; likely from infection. The presence of EHV2 could have implications to both tissue-engineering and tendinopathy.
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http://dx.doi.org/10.12688/wellcomeopenres.12176.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664983PMC
October 2017

Transcatheter Aortic Valve Replacement in Patients With Aortic Stenosis and Mitral Regurgitation.

Ann Thorac Surg 2017 Dec 29;104(6):1977-1985. Epub 2017 Sep 29.

Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.

Background: Many patients undergoing transcatheter aortic valve replacement (TAVR) for aortic stenosis also have significant mitral regurgitation (MR). We sought to understand the association of concomitant MR with TAVR clinical outcomes, as well changes in MR after TAVR.

Methods: Patients who underwent TAVR in the US Transcatheter Valve Therapy Registry from January 3, 2012, to December 31, 2013, were studied, with longer-term clinical outcomes from Center for Medicare Services data.

Results: Of 11,104 patients, 3,481 (31.3%) had moderate MR, and 605 (5.5%) had severe MR. At 1 year, mortality was 21.0%, 21.5%, 26.3%, and 28.0% (p < 0.0001) and heart failure (HF) rehospitalization was 13.9%, 15.8%, 20.3%, and 23.4% (p < 0.0001) in the no, mild, moderate, and severe MR patients, respectively. After adjustment for baseline differences, significant MR was associated with increased risk of 1-year mortality or HF rehospitalization, with a HR of 1.16 (95% CI, 0.99 to 1.35) for moderate MR and 1.21 (95% CI, 0.97 to 1.50) for severe MR, compared with no MR. MR improved early after TAVR grade ≥ 1 in 79% of the severe MR patients and 66% of the moderate MR patients. Patients whose baseline moderate or severe MR improved had lower mortality (p = 0.022) and HF rehospitalization (p < 0.001) compared with patients whose MR did not improve.

Conclusions: Moderate or severe MR accompanying severe AS treated with TAVR is associated with increased mortality or HF rehospitalization. This increased risk may be attributable to the minority of patients whose MR does not improve, suggesting a potential role for surveillance and targeted intervention for those patients.
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http://dx.doi.org/10.1016/j.athoracsur.2017.05.065DOI Listing
December 2017

Assessment of Commonly Used Frailty Markers for High- and Extreme-Risk Patients Undergoing Transcatheter Aortic Valve Replacement.

Ann Thorac Surg 2017 Dec 21;104(6):1939-1946. Epub 2017 Sep 21.

Structural Heart and Valve Center, Division of Cardiothoracic Surgery, Joseph B. Whitehead Department of Surgery, Emory University School of Medicine, Atlanta, Georgia. Electronic address:

Background: The effect of frailty on outcomes after transcatheter aortic valve replacement (TAVR) remains incompletely understood. The objective of this study was to evaluate the performance of four commonly used frailty markers as predictors of early and late outcomes among patients undergoing TAVR.

Methods: A review was performed of 361 high- and extreme-risk patients undergoing TAVR from 2011 to 2015. Four frailty variables were assessed: serum albumin (g/dL), 5-m walk (seconds), grip strength (kg), and Katz index of independence in activities of daily living. Logistic regression was used to examine the association between the frailty indicators and 30-day composite of mortality, stroke, new heart block requiring permanent pacemaker, major or life-threatening bleeding, acute renal failure, major vascular complication, and 30-day readmission rate. Minimum distance to the perfect point (0, 1) was performed to delineate a cutoff point for each frailty indicator, and risk models were compared using receiver-operating characteristics curves.

Results: The composite of outcomes occurred in 28% of patients. Serum albumin, activities of daily living, and 5-m walk were independent predictors for 30-day composite outcomes, but only albumin was predictive of 30-day mortality. A new frailty model (four frailty indicators, age, and sex) to predict 30-day mortality was created and compared with The Society of Thoracic Surgeons predicted risk of mortality. Better discrimination was found with the new frailty model (area under the curve 0.74 versus 0.58). New individual frailty variable cutoff values were found to predict our composite of events.

Conclusions: Among high- and extreme-risk patients undergoing TAVR, our new frailty model was more discriminative of 30-day mortality than The Society of Thoracic Surgeons predicted risk of mortality. New cutoff values for frailty indicators were identified and will require further validation.
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http://dx.doi.org/10.1016/j.athoracsur.2017.05.067DOI Listing
December 2017

Standardising RNA profiling based biomarker application in cancer-The need for robust control of technical variables.

Biochim Biophys Acta Rev Cancer 2017 Aug 23;1868(1):258-272. Epub 2017 May 23.

Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK; Northern Ireland Molecular Pathology Laboratory, Queen's University Belfast, UK. Electronic address:

Histopathology-based staging of colorectal cancer (CRC) has utility in assessing the prognosis of patient subtypes, but as yet cannot accurately predict individual patient's treatment response. Transcriptomics approaches, using array based or next generation sequencing (NGS) platforms, of formalin fixed paraffin embedded tissue can be harnessed to develop multi-gene biomarkers for predicting both prognosis and treatment response, leading to stratification of treatment. While transcriptomics can shape future biomarker development, currently <1% of published biomarkers become clinically validated tests, often due to poor study design or lack of independent validation. In this review of a large number of CRC transcriptional studies, we identify recurrent sources of technical variability that encompass collection, preservation and storage of malignant tissue, nucleic acid extraction, methods to quantitate RNA transcripts and data analysis pipelines. We propose a series of defined steps for removal of these confounding issues, to ultimately aid in the development of more robust clinical biomarkers.
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http://dx.doi.org/10.1016/j.bbcan.2017.05.005DOI Listing
August 2017

A comparison of host gene expression signatures associated with infection in vitro by the Makona and Ecran (Mayinga) variants of Ebola virus.

Sci Rep 2017 02 27;7:43144. Epub 2017 Feb 27.

National Institute of Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, UK.

The Ebola virus (EBOV) variant Makona (which emerged in 2013) was the causative agent of the largest outbreak of Ebola Virus Disease recorded. Differences in virus-host interactions between viral variants have potential consequences for transmission, disease severity and mortality. A detailed profile of the cellular changes induced by the Makona variant compared with other Ebola virus variants was lacking. In this study, A549 cells, a human cell line with a robust innate response, were infected with the Makona variant or with the Ecran variant originating from the 1976 outbreak in Central Africa. The abundance of viral and cellular mRNA transcripts was profiled using RNASeq and differential gene expression analysis performed. Differences in effects of each virus on the expression of interferon-stimulated genes were also investigated in A549 NPro cells where the type 1 interferon response had been attenuated. Cellular transcriptomic changes were compared with those induced by human respiratory syncytial virus (HRSV), a virus with a similar genome organisation and replication strategy to EBOV. Pathway and gene ontology analysis revealed differential expression of functionally important genes; including genes involved in the inflammatory response, cell proliferation, leukocyte extravasation and cholesterol biosynthesis. Whilst there was overlap with HRSV, there was unique commonality to the EBOV variants.
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http://dx.doi.org/10.1038/srep43144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327407PMC
February 2017

An in vitro model of murine middle ear epithelium.

Dis Model Mech 2016 11 22;9(11):1405-1417. Epub 2016 Sep 22.

Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2JF, UK

Otitis media (OM), or middle ear inflammation, is the most common paediatric disease and leads to significant morbidity. Although understanding of underlying disease mechanisms is hampered by complex pathophysiology it is clear that epithelial abnormalities underpin the disease. There is currently a lack of a well-characterised in vitro model of the middle ear (ME) epithelium that replicates the complex cellular composition of the middle ear. Here, we report the development of a novel in vitro model of mouse middle ear epithelial cells (mMECs) at an air-liquid interface (ALI) that recapitulates the characteristics of the native murine ME epithelium. We demonstrate that mMECs undergo differentiation into the varied cell populations seen within the native middle ear. Proteomic analysis confirmed that the cultures secrete a multitude of innate defence proteins from their apical surface. We showed that the mMECs supported the growth of the otopathogen, nontypeable Haemophilus influenzae (NTHi), suggesting that the model can be successfully utilised to study host-pathogen interactions in the middle ear. Overall, our mMEC culture system can help to better understand the cell biology of the middle ear and improve our understanding of the pathophysiology of OM. The model also has the potential to serve as a platform for validation of treatments designed to reverse aspects of epithelial remodelling that underpin OM development.
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http://dx.doi.org/10.1242/dmm.026658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117233PMC
November 2016

Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.

PLoS One 2016 16;11(6):e0157887. Epub 2016 Jun 16.

National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.

Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157887PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911124PMC
July 2017

Alcelaphine herpesvirus 1 glycoprotein B: recombinant expression and antibody recognition.

Arch Virol 2016 Mar 9;161(3):613-9. Epub 2015 Dec 9.

Moredun Research Institute, Pentlands Science Park, Midlothian, EH26 0PZ, UK.

The gammaherpesvirus alcelaphine herpesvirus 1 (AlHV-1) causes fatal malignant catarrhal fever (MCF) in susceptible species including cattle, but infects its reservoir host, wildebeest, without causing disease. Pathology in cattle may be influenced by virus-host cell interactions mediated by the virus glycoproteins. Cloning and expression of a haemagglutinin-tagged version of the AlHV-1 glycoprotein B (gB) was used to demonstrate that the AlHV-1-specific monoclonal antibody 12B5 recognised gB and that gB was the main component of the gp115 complex of AlHV-1, a glycoprotein complex of five components identified on the surface of AlHV-1 by immunoprecipitation and radiolabelling. Analysis of AlHV-1 virus particles showed that the native form of gB was detected by mAb 12B5 as a band of about 70 kDa, whilst recombinant gB expressed by transfected HEK293T cells appeared to be subject to additional cleavage and incomplete post-translational processing. Antibody 12B5 recognised an epitope on the N-terminal furin-cleaved fragment of gB on AlHV-1 virus particles. It could be used to detect recombinant and virus-expressed gB on western blots and on the surface of infected cells by flow cytometry, whilst recombinant gB was detected on the surface of transfected cells by immunofluorescence. Recombinant gB has potential as an antigen for ELISA detection of MCF virus infection and as a candidate vaccine antigen.
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http://dx.doi.org/10.1007/s00705-015-2701-yDOI Listing
March 2016

Minimalist transcatheter aortic valve replacement: The new standard for surgeons and cardiologists using transfemoral access?

J Thorac Cardiovasc Surg 2015 Oct 30;150(4):833-9. Epub 2015 Jul 30.

Division of Cardiothoracic Surgery, Joseph B. Whitehead Department of Surgery, Emory Structural Heart and Valve Center, Emory University Hospital and Emory University Hospital Midtown, Atlanta, Ga. Electronic address:

Background: A minimalist approach for transcatheter aortic valve replacement (MA-TAVR) utilizing transfemoral access under conscious sedation and transthoracic echocardiography is increasing in popularity. This relatively novel technique may necessitate a learning period to achieve proficiency in performing a successful and safe procedure. This report evaluates our MA-TAVR cohort with specific characterization between our early, midterm, and recent experience.

Methods: We retrospectively reviewed 151 consecutive patients who underwent MA-TAVR with surgeons and interventionists equally as primary operator at Emory University between May 2012 and July 2014. Our institution had performed 300 TAVR procedures before implementation of MA-TAVR. Patient characteristics and early outcomes were compared using Valve Academic Research Consortium 2 definitions among 3 groups: group 1 included the first 50 patients, group 2 included patients 51 to 100, and group 3 included patients 101 to 151.

Results: Median age for all patients was 84 years and similar among groups. The majority of patients were men (56%) and the median ejection fraction for all patients was 55% (interquartile range, 38.0%-60.0%). The majority of patients were high-risk surgical candidates with a median Society of Thoracic Surgeons Predicted Risk of Mortality of 10.0% and similar among groups. The overall major stroke rate was 3.3%, major vascular complications occurred in 3% of patients, and greater-than-mild paravalvular leak rate was 7%. In-hospital mortality and morbidity were similar among all 3 groups.

Conclusions: In a high-volume TAVR center, transition to MA-TAVR is feasible with acceptable outcomes and a diminutive procedural learning curve. We advocate for TAVR centers to actively pursue the minimalist technique with equal representation by cardiologists and surgeons.
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http://dx.doi.org/10.1016/j.jtcvs.2015.07.078DOI Listing
October 2015

Outcomes for Transcatheter Aortic Valve Replacement in Nonagenarians.

Ann Thorac Surg 2015 Oct 16;100(4):1261-7; discussion 1267. Epub 2015 Jul 16.

Structural Heart and Valve Center, Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia.

Background: Transcatheter aortic valve replacement (TAVR) may offer extreme-aged patients a treatment alternative to surgical aortic valve replacement (SAVR). The objective of this study was to describe outcomes of TAVR in nonagenarians using transfemoral and alternative access techniques.

Methods: In a retrospective review, we found 95 nonagenarians who underwent TAVR from September 2007 through February 2014 at Emory University using a balloon expandable valve: transfemoral (n = 66), transapical (n = 14), transaortic (n = 14), and transcarotid (n = 1). Morbidity and 30-day and midterm mortality were assessed. Kaplan-Meier plots were used to determine midterm survival rates.

Results: The mean age of the patients was 91.8 ± 1.8 years, and 49 (52%) were female. Postoperative morbidity included 1 patient (1%) each with stroke, myocardial infarction, pneumonia, and renal failure. The mean postoperative length of stay was 6.8 ± 5.1 days for all patients. Overall 30-day mortality was 3.2%, much less than The Society of Thoracic Surgeons predicted risk of mortality of 14.5% ± 7.3%. There were no deaths in the transfemoral patients, but there were 2 transapical deaths (14.3%) and 1 transaortic death (7.1%). The Kaplan-Meier estimate of median survival was 2.6 years.

Conclusions: Extreme-aged nonagenarian patients may have excellent outcomes from TAVR at 30-day and midterm follow-up. Alternative access TAVR is associated with higher morbidity and mortality than transfemoral TAVR. Referral for TAVR of nonagenarians should not be precluded based on age alone.
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http://dx.doi.org/10.1016/j.athoracsur.2015.04.037DOI Listing
October 2015

Genome sequences of equid herpesviruses 2 and 5.

Genome Announc 2015 Mar 12;3(2). Epub 2015 Mar 12.

MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom

We resequenced the genome of equid herpesvirus 2 (EHV2) strain 86/67 and sequenced the genomes of EHV2 strain G9/92 and equid herpesvirus 5 (EHV5) strain 2-141/67. The most prominent genetic differences are the dissimilar locations of the interleukin-10 (IL-10)-like genes and the presence of an OX-2-like gene in EHV5 only.
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http://dx.doi.org/10.1128/genomeA.00119-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357765PMC
March 2015

High-risk patients with inoperative aortic stenosis: use of transapical, transaortic, and transcarotid techniques.

Ann Thorac Surg 2015 Mar 14;99(3):817-23; discussion 823-5. Epub 2015 Jan 14.

Structural Heart and Valve Center, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia.

Background: Patient characteristics and procedural outcomes from nontransfemoral (non-TF) transcatheter aortic valve replacement (TAVR) in high-risk or inoperable patients with aortic stenosis have been incompletely reported. The purpose of this study was to compare outcomes with non-TF TAVR access techniques including transapical (TA), transaortic (TAo), and transcarotid (TC) TAVR with a balloon-expandable valve.

Methods: A retrospective review was performed of all patients undergoing TA, TAo, and TC TAVR from 2007 to 2013 at Emory University. Preoperative risk factors and postoperative outcomes were evaluated using Valve Academic Research Consortium-2 definitions.

Results: Of 469 patients undergoing TAVR during that period at our institution, 139 underwent TA TAVR, 35 had Tao TAVR, and 11 had TC TAVR. Patients undergoing TC TAVR were younger than those undergoing TA TAVR and TAo TAVR (mean ages: TC, 68.9 ± 23.6 years; TA, 81.3 ± 7.7 years; Tao, 83.8 ± 8.3 years; p = 0.017). Most patients undergoing TAo TAVR were women (82.9%), whereas patients undergoing TA TAVR were more likely to be men (62.6%). Slightly more than half of patients undergoing TA TAVR (54.7%) and TC (54.6%) TAVR had undergone previous coronary artery bypass grafting (CABG), whereas no patients underwent TAo TAVR (0%). There was no preoperative difference in ejection fraction, New York Heart Association classification, significant chronic obstructive pulmonary disease, and The Society of Thoracic Surgeons predicted risk of mortality between TA TAVR, Tao TAVR, and TC TAVR, respectively. Average postoperative length of stay was 9 to 11 days and was similar among groups (p = 0.22). There were 13 (9.4%) TA TAVR operative deaths and 4 (11.4%) operative deaths in the TAo TAVR group. There were no deaths in the TC TAVR group.

Conclusions: In high-risk and inoperable patients who are not candidates for TF TAVR, careful selection of alternative access options can lead to excellent and comparable postoperative outcomes.
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http://dx.doi.org/10.1016/j.athoracsur.2014.10.012DOI Listing
March 2015

Gammaherpesvirus infection modulates the temporal and spatial expression of SCGB1A1 (CCSP) and BPIFA1 (SPLUNC1) in the respiratory tract.

Lab Invest 2015 Jun 22;95(6):610-24. Epub 2014 Dec 22.

Department of Infection Biology, University of Liverpool, Liverpool, UK.

Murine γ-herpesvirus 68 (MHV-68) infection of Mus musculus-derived strains of mice is an established model of γ-herpesvirus infection. We have previously developed an alternative system using a natural host, the wood mouse (Apodemus sylvaticus), and shown that the MHV-68 M3 chemokine-binding protein contributes significantly to MHV-68 pathogenesis. Here we demonstrate in A. sylvaticus using high-density micro-arrays that M3 influences the expression of genes involved in the host response including Scgb1a1 and Bpifa1 that encode potential innate defense proteins secreted into the respiratory tract. Further analysis of MHV-68-infected animals showed that the levels of both protein and RNA for SCGB1A1 and BPIFA1 were decreased at day 7 post infection (p.i.) but increased at day 14 p.i. as compared with M3-deficient and mock-infected animals. The modulation of expression was most pronounced in bronchioles but was also present in the bronchi and trachea. Double staining using RNA in situ hybridization and immunohistology demonstrated that much of the BPIFA1 expression occurs in club cells along with SCGB1A1 and that BPIFA1 is stored within granules in these cells. The increase in SCGB1A1 and BPIFA1 expression at day 14 p.i. was associated with the differentiation of club cells into mucus-secreting cells. Our data highlight the role of club cells and the potential of SCGB1A1 and BPIFA1 as innate defense mediators during respiratory virus infection.
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http://dx.doi.org/10.1038/labinvest.2014.162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450743PMC
June 2015

Epstein-Barr virus IL-10 gene expression by a recombinant murine gammaherpesvirus in vivo enhances acute pathogenicity but does not affect latency or reactivation.

Herpesviridae 2014 24;5. Epub 2014 Sep 24.

Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105, USA ; Current Address: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

Background: Many viral genes affect cytokine function within infected hosts, with interleukin 10 (IL-10) as a commonly targeted mediator. Epstein-Barr virus (EBV) encodes an IL-10 homologue (vIL-10) expressed during productive (lytic) infection and induces expression of cellular IL-10 (cIL-10) during latency. This study explored the role of vIL-10 in a murine gammaherpesvirus (MHV) model of viral infection.

Methods: The EBV vIL-10 gene was inserted into MHV-76, a strain which lacks the ability to induce cIL-10, by recombination in transfected mouse cells. Mice were infected intranasally with the recombinant, vIL-10-containing MHV-76 or control virus strains and assayed at various days post infection for lung virus titer, spleen cell number, percentage of latently infected spleen cells and ability to reactivate virus from spleen cells.

Results: Recombinant murine gammaherpesvirus expressing EBV vIL-10 rose to significantly higher titers in lungs and promoted an increase in spleen cell number in infected mice in comparison to MHV strains lacking the vIL-10 gene. However, vIL-10 expression did not alter the quantity of latent virus in the spleen or its ability to reactivate.

Conclusions: In this mouse model of gammaherpesvirus infection, EBV vIL-10 appears to influence acute-phase pathogenicity. Given that EBV and MHV wild-type strains contain other genes that induce cIL-10 expression in latency (e.g. LMP-1 and M2, respectively), vIL-10 may have evolved to serve the specific role in acute infection of enlarging the permissive host cell population, perhaps to facilitate initial survival and dissemination of viral-infected cells.
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http://dx.doi.org/10.1186/2042-4280-5-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199788PMC
October 2014

Comparison of transfemoral transcatheter aortic valve replacement performed in the catheterization laboratory (minimalist approach) versus hybrid operating room (standard approach): outcomes and cost analysis.

JACC Cardiovasc Interv 2014 Aug 30;7(8):898-904. Epub 2014 Jul 30.

Structural Heart and Valve Center, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia.

Objectives: The aim of this study was to compare transfemoral transcatheter aortic valve replacement (TF TAVR) performed in a catheterization laboratory (minimalist approach [MA]) with TF TAVR performed in a hybrid operating room (standard approach [SA]).

Background: A MA-TF TAVR can be performed without general anesthesia, transesophageal echocardiography, or a surgical hybrid room. The outcomes and cost of MA-TF TAVR compared with those of the SA have not been described.

Methods: Patients who underwent elective, percutaneous TF TAVR using the Edwards Sapien valve (Edwards Lifesciences, Irvine, California) were studied. Baseline characteristics, outcomes, and hospital costs of MA-TF TAVR and SA-TF TAVR were compared.

Results: A total of 142 patients were studied (MA-TF TAVR, n = 70 and SA-TF TAVR, n = 72). There were no differences in baseline comorbidities (Society of Thoracic Surgeons score, 10.6 ± 4.3 vs. 11.4 ± 5.8; p = 0.35). All procedures in the MA-TF TAVR group were successful; 1 patient was intubated. Three patients in the SA-TF TAVR group had procedure-related death. Procedure room time (150 ± 48 min vs. 218 ± 56 min, p < 0.001), total intensive care unit time (22 h vs. 28 h, p < 0.001), length of stay from procedure to discharge (3 days vs. 5 days, p < 0.001), and cost ($45,485 ± 14,397 vs. $55,377 ± 22,587, p < 0.001) were significantly less in the MA-TF TAVR group. Mortality at 30 days was not significantly different in the MA-TF TAVR group (0 vs. 6%, p = 0.12) and 30-day stroke/transient ischemic attack was similar (4.3% vs. 1.4%, p = 0.35). Moderate or severe paravalvular leak and device success were similar in the MA-TF TAVR and SA-TF TAVR groups (3% vs. 5.8%, p = 0.4 and 90% vs. 88%, p = 0.79, respectively) at 30 days. At a median follow-up of 435 days, there was no significant difference in survival (MA-TF TAVR, 83% vs. SA-TF TAVR, 82%; p = 0.639).

Conclusions: MA-TF TAVR can be performed with minimal morbidity and mortality and equivalent effectiveness compared with SA-TF TAVR. The shorter length of stay and lower resource use with MA-TF TAVR significantly lowers hospital costs.
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http://dx.doi.org/10.1016/j.jcin.2014.04.005DOI Listing
August 2014

CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease.

Blood 2014 Sep 24;124(13):2051-60. Epub 2014 Jul 24.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;

Secreted protein CCN1, encoded by CYR61, is involved in wound healing, angiogenesis, and osteoblast differentiation. We identified CCN1 as a microenvironmental factor produced by mesenchymal cells and overexpressed in bones of a subset of patients with monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma (AMM), and multiple myeloma (MM). Our analysis showed that overexpression of CYR61 was independently associated with superior overall survival of MM patients enrolled in our Total Therapy 3 protocol. Moreover, elevated CCN1 was associated with a longer time for MGUS/AMM to progress to overt MM. During remission from MM, high levels of CCN1 were associated with superior progression-free and overall survival and stratified patients with molecularly defined high-risk MM. Recombinant CCN1 directly inhibited in vitro growth of MM cells, and overexpression of CYR61 in MM cells reduced tumor growth and prevented bone destruction in vivo in severe combined immunodeficiency-hu mice. Signaling through αvβ3 was required for CCN1 prevention of bone disease. CYR61 expression may signify early perturbation of the microenvironment before conversion to overt MM and may be a compensatory mechanism to control MM progression. Therapeutics that upregulate CYR61 should be investigated for treating MM bone disease.
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http://dx.doi.org/10.1182/blood-2014-02-555813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186535PMC
September 2014

Analysis of the genetic diversity of ovine herpesvirus 2 in samples from livestock with malignant catarrhal fever.

Vet Microbiol 2014 Aug 28;172(1-2):63-71. Epub 2014 Apr 28.

Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool Science Park IC2, L3 5RF, UK.

In order to define better virus isolates from animals with malignant catarrhal fever (MCF), segments of three genes of ovine herpesvirus-2 were amplified from diagnostic samples representing MCF cases with a range of clinical presentations in cattle, including head and eye, alimentary and neurological. The variation within each gene segment was estimated by DNA sequencing, which confirmed that the newly-annotated Ov9.5 gene was significantly more polymorphic than either of the other loci tested (segments of ORF50 and ORF75), with alleles that differed at over 60% of nucleotide positions. Despite this, the nine Ov9.5 alleles characterised had identical predicted splicing patterns and could be translated into Ov9.5 polypeptides with at least 49% amino acid identity. This multi-locus approach has potential for use in epidemiological studies and in charactering chains of infection. However there was no association between specific variants of OvHV-2 and the clinical/pathological presentation of MCF in the cattle analysed.
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http://dx.doi.org/10.1016/j.vetmic.2014.04.011DOI Listing
August 2014

Identification of novel anelloviruses with broad diversity in UK rodents.

J Gen Virol 2014 Jul 17;95(Pt 7):1544-1553. Epub 2014 Apr 17.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK.

Anelloviruses are a family of small circular ssDNA viruses with a vast genetic diversity. Human infections with the prototype anellovirus, torque teno virus (TTV), are ubiquitous and related viruses have been described in a number of other mammalian hosts. Despite over 15 years of investigation, there is still little known about the pathogenesis and possible disease associations of anellovirus infections, arising in part due to the lack of a robust cell culture system for viral replication or tractable small-animal model. We report the identification of diverse anelloviruses in several species of wild rodents. The viruses are highly prevalent in wood mice (Apodemus sylvaticus) and field voles (Microtus agrestis), detectable at a low frequency in bank voles (Myodes glareolus), but absent from house mice (Mus musculus). The viruses identified have a genomic organization consistent with other anelloviruses, but form two clear phylogenetic groups that are as distinct from each other as from defined genera.
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http://dx.doi.org/10.1099/vir.0.065219-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059270PMC
July 2014