bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarkers for differentiation of causes of respiratory distress in dogs and cats: Part 1 – Cardiac diseases and pulmonary hypertension
Authors: Smith Katherine F. , Quinn Rebecca L. , Rahilly Louisa J.
Published: June 2015

Objective

To review the current veterinary and relevant human literature regarding biomarkers of cardiac disease leading to respiratory compromise.

Data Sources

Veterinary and human medical literature: original research articles, scientific reviews, consensus statements, and recent textbooks.

Human Data Synthesis

Cardiac troponins (cTn) and natriuretic peptides are routinely used in human medicine.

Veterinary Data Synthesis

Although biomarkers should not be accepted in lieu of gold standard diagnostics, they may be useful in directing care in the stabilization process. Biomarkers of congestive heart failure (CHF) include natriuretic peptides, cTn, and endothelin. cTnI is useful in differentiating causes of pericardial effusion, but is unlikely to be useful in differentiating CHF from other causes of respiratory distress. The most extensively studied and promising cardiac biomarker is amino‐terminal probrain natriuretic peptide, although a bedside test is not currently available. Other natriuretic peptides have also proven useful, but have lower availability. Endothelin is unlikely to be clinically useful. Although critically evaluated for their use in cardiac diseases, many of the biomarkers are affected by more than one type of respiratory or systemic disease. Several cardiac biomarkers are increased in cases of pulmonary hypertension (PH), but discerning CHF alone from PH or a combination of heart disease and PH is challenging when evaluating biomarkers alone.

Conclusion

At this time, there are no point‐of‐care tests for biomarkers that can reliably differentiate among causes of dyspnea of cardiac origin in dogs and cats, although there are reference laboratory tests that show promise and future development of point‐of‐care tests that may be useful in certain situations.
T‐cell subsets in autologous and allogeneic peripheral blood stem cell concentrates
Authors: Strobel J. , Moellmer I. , Zingsem J. , Hauck‐Dlimi B. , Eckstein R. , Strasser E.
Published: June 2015

Background and Objectives

Regulatory T cells (Tregs) and other T‐cell subsets are of importance in the setting of autologous and allogeneic stem cell transplantations. We conducted a study to assess the content of peripheral blood stem cell concentrates and related apheresis parameters in the autologous and allogeneic setting.

Material and Methods

We characterized 53 donors, patients and peripheral blood stem cell concentrates (PBSC) regarding the content of CD45+ cells, lymphocytes, CD3+ cells, CD3+ CD4+ T cells, CD3+ CD4+ CD25+ T cells, CD3+ CD4+ CD25+ CD127low/negative Tregs and CD34+ cells and calculated cell yields, recruitment factors and collection efficiency for all cell types. We compared allogeneic data with autologous data.

Results

Autologous PBSC show significantly lower concentrations of T‐cell subsets compared to allogeneic PBSC (17 112/μl CD4+, 14 858/μl CD4+ CD25+ and 1579/μl CD3+ CD4+ CD25+ CD127low/negative Tregs in autologous compared to 65 539/μl CD4+, 44 208+/μl CD4+ CD25+ and 5040/μl CD3+ CD4+ CD25+ CD127low/negative Tregs in allogeneic PBSC, respectively), in contrast to CD34+ concentrations (5342/μl CD34+ in autologous compared to 2367/μl CD34+ in allogeneic PBSC, respectively). Accordantly, all T‐cell yields are lower in the autologous setting compared to allogeneic PBSC. However, recruitment factor and collection efficiency of all cell types are higher in autologous compared to allogeneic PBSC, but not all parameters differ significantly when groups are compared.

Conclusion

T‐cell subsets and especially Tregs are a substantial part of PBSC transplantation, as considerable recruitment during apheresis occurs. In large volume apheresis, the collection efficiency of Treg is comparable to that of CD34+ cells, while recruitment factors are even higher.
Effect of sludge retention time on inclined plate function, treatment performance and sludge characteristics of inclined plate membrane bioreactors treating municipal wastewater
Authors: Ittisupornrat Suda , Tobino Tomohiro , Yamamoto Kazuo
Published: June 2015

Two identical bench scale inclined plate membrane bioreactors (ip‐MBRs) were operated for the treatment of real municipal wastewater for 1 year. Sludge retention time (SRT) was varied over the course of operation to investigate the effects on inclined plate function, treatment performance and sludge characteristic. Removal rates of chemical oxygen demand and ammonia over 90% and of total nitrogen (TN) more than 70% were achieved when ip‐MBRs were operated under SRTs between infinite and 40 days while short SRT (20 days) negatively affected TN removal. When the sludge concentration in anoxic tank exceeded 15 g/L, the failure of the inclined plate function was observed, resulting in no difference in sludge concentrations between aerobic and anoxic tanks. To avoid severe effects on inclined plate function and treatment performance, an SRT range of 40–80 days was recommended for ip‐MBRs. Moreover, sludge floc size under prolonged SRT became smaller than that under short SRT due to increased attrition among the sludge floc particles caused by strong aeration needed for keeping a sufficient dissolved oxygen level.
Prediction of Residual Stresses During Gas Nitriding of H13 Steels Using Phase Field Approach
Authors: Akhtar Syed Sohail , Abubakar Abba Abdulhamid , Arif Abul Fazal M.
Published: June 2015

Gas nitriding is a common surface treatment practice to improve the wear resistance of AISI H13 hot extrusion die cavities. However, due to the presence of complex and sharp features of die cavities, it has been observed that nonuniform nitride layer develops in these regions. Moreover, the formation of compound layer in the surface vicinity of nitrided surfaces leads to the development of transformation-induced stresses. The present work presents the application of the phase field method in predicting the evolution of the nitride layers and associated residual stresses during the gas nitriding of AISI H13 tool steels. Nitriding process is modeled and simulated in line with experimental setup, which uses automated two-stage controlled nitriding process. Some representative samples having commonly used geometric features are manufactured and nitrided for validation purpose. Both experimental and numerical results are found in close agreement in terms of nitrogen concentration and corresponding microhardness profiles. The results show that high stresses are induced at the surface due to formation of the nitride layers, and these stresses are found to be higher at the sharp corners. In view of the current results, some process and design strategies are suggested for improved and more effective nitriding treatment of hot extrusion dies used in the industry.
Swarm Motion as Particles of a Continuum With Communication Delays
Authors: Rastgoftar Hossein , Jayasuriya Suhada
Published: June 2015

In this paper, we give an upper bound for the communication delay in a multi-agent system (MAS) that evolves under a recently developed continuum paradigm for formation control. The MAS is treated as particles of a continuum that transforms under special homeomorphic mapping, called a homogeneous map. Evolution of an MAS in ℝn is achieved under a special communication topology proposed by Rastgoftar and Jayasuriya (2014, “Evolution of Multi Agent Systems as Continua,” ASME J. Dyn. Syst. Meas. Control, 136(4), p. 041014) and (2014, “An Alignment Strategy for Evolution of Multi Agent Systems,” ASME J. Dyn. Syst. Meas. Control, 137(2), p. 021009), employing a homogeneous map specified by the trajectories of n+1 leader agents at the vertices of a polytope in ℝn, called the leading polytope. The followers that are positioned in the convex hull of the leading polytope learn the prescribed homogeneous mapping through local communication with neighboring agents using a set of communication weights prescribed by the initial positions of the agents. However, due to inevitable time-delay in getting positions and velocities of the adjacent agents through local communication, the position of each follower may not converge to the desired state given by the homogeneous map leaving the possibility that MAS evolution may get destabilized. Therefore, ascertaining the stability under time-delay is important. Stability analysis of an MAS consisting of a large number of agents, leading to higher-order dynamics, using conventional methods such as cluster treatment of characteristic roots (CTCR) or Lyapunov–Krasovskii are difficult. Instead we estimate the maximum allowable communication delay for the followers using one of the eigenvalues of the communication matrix that places MAS evolution at the margin of instability. The proposed method is advantageous because the transcendental delay terms are directly used and the characteristic equation of MAS evolution is not approximated by a finite-order polynomial. Finally, the developed framework is used to validate the effect of time-delays in our previous work.
Modeling of Dynamic Systems Using Orthogonal Endocrine Adaptive Neuro-Fuzzy Inference Systems
Authors: Milojković Marko , Antić Dragan , Milovanović Miroslav , Nikolić Saša S. , Perić Staniša , Almawlawe Muhanad
Published: June 2015

This paper presents a new method for designing adaptive neuro-fuzzy inference systems (ANFIS). Improvements are made by introducing specially developed orthogonal functions into the very structure of ANFIS, specifically, into the layer that imitates Sugeno stile defuzzification. These functions are specially tailored for analysis and synthesis of dynamic systems and they also contain an adaptive measure of the variability of the systems operating in a real environment, which can be implemented inside the ANFIS as hormonal effect.
Experimental Investigation of Pressure Distribution in Turbulent Flow Between Parallel and Inclined Disks
Authors: Eisenberg Daniel A. , Deschamps Cesar J.
Published: June 2015

Although the flow between parallel and inclined disks is a simple representation of many complex flow situations, this class of flow poses significant problems for experimental and numerical study. This paper presents experimental results of the pressure distribution for turbulent radial flow between parallel and inclined disks, considering different ratios between the diameters of the frontal disk and feeding orifice. The experimental results bolster the lack of data for both flow situations in the turbulent regime and demonstrate differences between them. The results presented have high accuracy and known uncertainty, making them useful for comparison to analytical and numerical results.
Argon–germane in situ plasma clean for reduced temperature Ge on Si epitaxy by high density plasma chemical vapor deposition
Authors: Douglas Erica A. , Sheng Josephine J. , Verley Jason C. , Carroll Malcolm S.
Published: June 2015

Demand for integration of near infrared optoelectronic functionality with silicon complementary metal oxide semiconductor (CMOS) technology has for many years motivated the investigation of low temperature germanium on silicon deposition processes. This work describes the development of a high density plasma chemical vapor deposition process that uses a low temperature (<460 °C) in situ germane/argon plasma surface preparation step for epitaxial growth of germanium on silicon. It is shown that the germane/argon plasma treatment sufficiently removes SiOx and carbon at the surface to enable germanium epitaxy. The use of this surface preparation step demonstrates an alternative way to produce germanium epitaxy at reduced temperatures, a key enabler for increased flexibility of integration with CMOS back-end-of-line fabrication.
Psychology of Sport Concussions
Authors: Wiese-Bjornstal Diane M. , White Andrew C. , Russell Hayley C. , Smith Aynsley M.
Published: June 2015

The psychology of sport concussions consists of psychological, psychiatric, and psychosocial factors that contribute to sport concussion risks, consequences, and outcomes. The purpose of this paper is to present a sport concussion-adapted version of the integrated model of psychological response to sport injury and rehabilitation (Wiese-Bjornstal, Smith, Shaffer, & Morrey, 1998) as a framework for understanding the roles of psychological, psychiatric, and psychosocial factors in sport concussions. Elements of this model include preinjury psychological risk factors, postinjury psychological response and rehabilitation processes, and postinjury psychological care components. Mapped onto each element of this model are findings from the research literature through a narrative review process. An important caveat is that the subjective nature of concussion diagnoses presents limitations in these findings. Future research should examine psychological contributors to concussion risk, influences of physical factors on psychological symptoms and responses, and efficacy of psychological treatments utilizing theory-driven approaches.
Limited scope for latitudinal extension of reef corals
Authors: Muir Paul R. , Wallace Carden C. , Done Terence , Aguirre J. David
Published: June 2015

Not as deep

As our climate warms, many species ranges are predicted to shift toward the warmer poles. Focusing solely on temperatures, however, ignores many factors that change across latitudes, such as the intensity of solar radiation. Muir
et al.
looked at global distributions of two groups of reef-building corals (see the Perspective by Kleypas). Most reef-building corals occur deep enough to be protected from surge. However, corals require sunlight to sustain their symbiotic photosynthetic algae. Because solar radiation is more limited farther away from the equator, future populations might be limited to more turbulent shallow waters.

Science
, this issue p.
1135
; see also p.
1086
Lost and found: Earth's missing heat
Authors: Gramling Carolyn
Published: June 2015

A reanalysis of surface temperatures suggests there never was a global warming hiatus.
Polar scientists to peer beneath largest ice shelf
Authors: Hand Eric
Published: June 2015

Seafloor map would offer clues to the fate of Antarctica's Ross Ice Shelf.
How to court an isolated tribe
Authors: Pringle Heather
Published: June 2015

"Attractions fronts" lured isolated tribes into contact in the past century, often with disastrous results.
Challenges of a lowered U.S. ozone standard
Authors: Cooper Owen R. , Langford Andrew O. , Parrish David D. , Fahey David W.
Published: June 2015

Source attribution science can help areas of the U.S. west
Protecting isolated tribes
Authors: Walker Robert S. , Hill Kim R.
Published: June 2015

There are about 50 isolated indigenous societies across lowland South America, with limited to no contact with the outside world. Despite displacements, epidemics, and hostile interactions with outsiders, such tribes still manage to survive. How can we ensure the well-being of humanity's last known isolated peoples under such enormous and mounting pressure from external threats?
Evaluation of the Efficacy, Potential for Vector Transmission, and Duration of Immunity of MP-12, an Attenuated Rift Valley Fever Virus Vaccine Candidate, in Sheep
Authors: Miller Myrna M. , Bennett Kristine E. , Drolet Barbara S. , Lindsay Robbin , Mecham James O. , Reeves Will K. , Weingartl Hana M. , Wilson William C.
Published: June 2015

Rift Valley fever virus (RVFV) causes serious disease in ruminants and humans in Africa. In North America, there are susceptible ruminant hosts and competent mosquito vectors, yet there are no fully licensed animal vaccines for this arthropod-borne virus, should it be introduced. Studies in sheep and cattle have found the attenuated strain of RVFV, MP-12, to be both safe and efficacious based on early testing, and a 2-year conditional license for use in U.S. livestock has been issued. The purpose of this study was to further determine the vaccine's potential to infect mosquitoes, the duration of humoral immunity to 24 months postvaccination, and the ability to prevent disease and viremia from a virulent challenge. Vaccination experiments conducted in sheep found no evidence of a potential for vector transmission to 4 North American mosquito species. Neutralizing antibodies were elicited, with titers of >1:40 still present at 24 months postvaccination. Vaccinates were protected from clinical signs and detectable viremia after challenge with virulent virus, while control sheep had fever and high-titered viremia extending for 5 days. Antibodies to three viral proteins (nucleocapsid N, the N-terminal half of glycoprotein GN, and the nonstructural protein from the short segment NSs) were also detected to 24 months using competitive enzyme-linked immunosorbent assays. This study demonstrates that the MP-12 vaccine given as a single dose in sheep generates protective immunity to a virulent challenge with antibody duration of at least 2 years, with no evidence of a risk for vector transmission.
Does the Presence of Scrapie Affect the Ability of Current Statutory Discriminatory Tests To Detect the Presence of Bovine Spongiform Encephalopathy?
Authors: Simmons M. M. , Chaplin M. J. , Vickery C. M. , Simon S. , Davis L. , Denyer M. , Lockey R. , Stack M. J. , O'Connor M. J. , Bishop K. , Gough K. C. , Maddison B. C. , Thorne L. , Spiropoulos J.
Published: June 2015

Current European Commission (EC) surveillance regulations require discriminatory testing of all transmissible spongiform encephalopathy (TSE)-positive small ruminant (SR) samples in order to classify them as bovine spongiform encephalopathy (BSE) or non-BSE. This requires a range of tests, including characterization by bioassay in mouse models. Since 2005, naturally occurring BSE has been identified in two goats. It has also been demonstrated that more than one distinct TSE strain can coinfect a single animal in natural field situations. This study assesses the ability of the statutory methods as listed in the regulation to identify BSE in a blinded series of brain samples, in which ovine BSE and distinct isolates of scrapie are mixed at various ratios ranging from 99% to 1%. Additionally, these current statutory tests were compared with a new
in vitro
discriminatory method, which uses serial protein misfolding cyclic amplification (sPMCA). Western blotting consistently detected 50% BSE within a mixture, but at higher dilutions it had variable success. The enzyme-linked immunosorbent assay (ELISA) method consistently detected BSE only when it was present as 99% of the mixture, with variable success at higher dilutions. Bioassay and sPMCA reported BSE in all samples where it was present, down to 1%. sPMCA also consistently detected the presence of BSE in mixtures at 0.1%. While bioassay is the only validated method that allows comprehensive phenotypic characterization of an unknown TSE isolate, the sPMCA assay appears to offer a fast and cost-effective alternative for the screening of unknown isolates when the purpose of the investigation was solely to determine the presence or absence of BSE.
Potential Pathogenetic Role of Bovine Herpesvirus 4 in Two Dairy Cows with Dermatitis-Pyrexia-Hemorrhagic Syndrome
Authors: Bellino Claudio , Iussich Selina , Biasato Ilaria , Peletto Simone , Caruso Claudio , Gianella Paola , Cagnasso Aurelio , D'Angelo Antonio
Published: June 2015

Dermatitis, pyrexia, and hemorrhagic syndrome (DPHS) is a rare bovine syndrome of unclear etiology. We describe two DPHS cases, the first to occur in Italy, with clinicopathological findings suggesting a potential pathogenetic role of bovine herpesvirus-4 (BoHV-4).
β-
d
-Glucan Screening for Detection of Invasive Fungal Disease in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Koltze Antonia , Rath Peter , Schöning Stefan , Steinmann Jörg , Wichelhaus Thomas A. , Bader Peter , Bochennek Konrad , Lehrnbecher Thomas
Published: June 2015

While the assessment of β-
d
-glucan (BDG) levels in adults improves the early diagnosis of invasive fungal disease (IFD), data on BDG levels in children are limited. We therefore assessed in a prospective cohort study the value of serial BDG screening for early detection of IFD in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). IFD was defined according to the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria, with the necessary modification that BDG was not included as a microbiological criterion. For the analysis, a total of 702 serum samples were obtained in 34 pediatric HSCT recipients. Proven IFD occurred in two patients (fusariosis and
Candida
sepsis, respectively), and probable invasive aspergillosis was diagnosed in four patients. Analyses including different cutoff values for BDG levels and different definitions of the onset of IFD demonstrated that the BDG assay has a relatively high sensitivity and good negative predictive value, whereas the positive predictive value has major limitations (<30%). Receiver operating characteristic analyses suggested an optimal cutoff between 60 and 70 pg/ml for different definitions of the onset of IFD. Our data show that BDG screening in pediatric HSCT recipients has a low positive predictive value and is therefore of limited usefulness.
Intracellular Transport of Vaccinia Virus in HeLa Cells Requires WASH-VPEF/FAM21-Retromer Complexes and Recycling Molecules Rab11 and Rab22
Authors: Hsiao Jye-Chian , Chu Li-Wei , Lo Yung-Tsun , Lee Sue-Ping , Chen Tzu-Jung , Huang Cheng-Yen , Ping Yueh-Hsin , Chang Wen
Published: June 2015

Vaccinia virus, the prototype of the
Orthopoxvirus
genus in the family
Poxviridae
, infects a wide range of cell lines and animals. Vaccinia mature virus particles of the WR strain reportedly enter HeLa cells through fluid-phase endocytosis. However, the intracellular trafficking process of the vaccinia mature virus between cellular uptake and membrane fusion remains unknown. We used live imaging of single virus particles with a combination of various cellular vesicle markers, to track fluorescent vaccinia mature virus particle movement in cells. Furthermore, we performed functional interference assays to perturb distinct vesicle trafficking processes in order to delineate the specific route undertaken by vaccinia mature virus prior to membrane fusion and virus core uncoating in cells. Our results showed that vaccinia virus traffics to early endosomes, where recycling endosome markers Rab11 and Rab22 are recruited to participate in subsequent virus trafficking prior to virus core uncoating in the cytoplasm. Furthermore, we identified WASH-VPEF/FAM21-retromer complexes that mediate endosome fission and sorting of virus-containing vesicles prior to virus core uncoating in the cytoplasm.

IMPORTANCE
Vaccinia mature virions of the WR strain enter HeLa cells through fluid phase endocytosis. We previously demonstrated that virus-containing vesicles are internalized into phosphatidylinositol 3-phosphate
positive macropinosomes, which are then fused with Rab5-positive early endosomes. However, the subsequent process of sorting the virion-containing vesicles prior to membrane fusion remains unclear. We dissected the intracellular trafficking pathway of vaccinia mature virions in cells up to virus core uncoating in cytoplasm. We show that vaccinia mature virions first travel to early endosomes. Subsequent trafficking events require the important endosome-tethered protein VPEF/FAM21, which recruits WASH and retromer protein complexes to the endosome. There, the complex executes endosomal membrane fission and cargo sorting to the Rab11-positive and Rab22-positive recycling pathway, resulting in membrane fusion and virus core uncoating in the cytoplasm.
Frequency, Private Specificity, and Cross-Reactivity of Preexisting Hepatitis C Virus (HCV)-Specific CD8+T Cells in HCV-Seronegative Individuals: Implications for Vaccine Responses
Authors: Zhang Shihong , Bakshi Rakesh K. , Suneetha Pothakamuri Venkata , Fytili Paraskevi , Antunes Dinler A. , Vieira Gustavo F. , Jacobs Roland , Klade Christoph S. , Manns Michael P. , Kraft Anke R. M. , Wedemeyer Heiner , Schlaphoff Verena , Cornberg Markus
Published: June 2015

T cell responses play a critical role in controlling or clearing viruses. Therefore, strategies to prevent or treat infections include boosting T cell responses. T cells specific for various pathogens have been reported in unexposed individuals and an influence of such cells on the response toward vaccines is conceivable. However, little is known about their frequency, repertoire, and impact on vaccination. We performed a detailed characterization of CD8+T cells specific to a hepatitis C virus (HCV) epitope (NS3-1073) in 121 HCV-seronegative individuals. We show thatin vitroHCV NS3-1073-specific CD8+T cell responses were rather abundantly detectable in one-third of HCV-seronegative individuals irrespective of risk factors for HCV exposure.Ex vivo, these NS3-1073-specific CD8+T cells were found to be both naive and memory cells. Importantly, recognition of various peptides derived from unrelated viruses by NS3-1073-specific CD8+T cells showed a considerable degree of T cell cross-reactivity, suggesting that they might in part originate from previous heterologous infections. Finally, we further provide evidence that preexisting NS3-1073-specific CD8+T cells can impact the T cell response toward peptide vaccination. Healthy, vaccinated individuals who showed anin vitroresponse toward NS3-1073 already before vaccination displayed a more vigorous and earlier response toward the vaccine.

IMPORTANCEPreventive and therapeutic vaccines are being developed for many viral infections and often aim on inducing T cell responses. Despite effective antiviral drugs against HCV, there is still a need for a preventive vaccine. However, the responses to vaccines can be highly variable among different individuals. Preexisting T cells in unexposed individuals could be one reason that helps to explain the variable T cell responses to vaccines. Based on our findings, we suggest that HCV CD8+T cells are abundant in HCV-seronegative individuals but that their repertoire is highly diverse due to the involvement of both naive precursors and cross-reactive memory cells of different specificities, which can influence the response to vaccines. The data may emphasize the need to personalize immune-based therapies based on the individual's T cell repertoire that is present before the immune intervention.
H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in
Ex Vivo
Cultures of Resting CD4
+
T Cells
Authors: Tripathy Manoj K. , McManamy Mary E. M. , Burch Brandon D. , Archin Nancie M. , Margolis David M.
Published: June 2015

Histone methyltransferase inhibitors (HMTis) and histone deacetylase inhibitors (HDACis) are reported to synergistically induce the expression of latent human immunodeficiency virus type 1 (HIV-1), but studies have largely been performed with cell lines. As specific and potent HMTis directed at EZH1 (enhancer of zeste 2 Polycomb repressive complex 2 subunit 1)/EZH2 are now in human testing, we wished to rigorously test such an inhibitor in a primary resting T-cell model of HIV latency. We found that GSK343, a potent and selective EZH2/EZH1 inhibitor, reduced trimethylation of histone 3 at lysine 27 (H3K27) of the HIV provirus in resting cells. Remarkably, this epigenetic change was not associated with increased proviral expression in latently infected resting cells. However, following the reduction in H3K27 at the HIV long terminal repeat (LTR), subsequent exposure to the HDACi suberoylanilide hydroxamic acid or vorinostat (VOR) resulted in increases in HIV
gag
RNA and HIV p24 antigen production that were up to 2.5-fold greater than those induced by VOR alone. Therefore, in primary resting CD4
+
T cells, true mechanistic synergy in the reversal of HIV latency may be achieved by the combination of HMTis and HDACis. Although other cellular effects of EZH2 inhibition may contribute to the sensitization of the HIV LTR to subsequent exposure to VOR, and to increase viral antigen production, this synergistic effect is directly associated with H3K27 demethylation at nucleosome 1 (Nuc-1). Based upon our findings, the combination of HMTis and HDACis should be considered for testing in animal models or clinical trials.

IMPORTANCE
Demethylation of H3K27 mediated by the histone methyltransferase inhibitor GSK343 in primary resting T cells is slow, occurring over 96 h, but by itself does not result in a significant upregulation of cell-associated HIV RNA expression or viral antigen production. However, following H3K27 demethylation, latent viral expression within infected primary resting CD4
+
T cells is synergistically increased upon exposure to the histone deacetylase inhibitor vorinostat. Demethylation at H3K27 sensitizes the HIV promoter to the effects of an HDACi and provides a proof-of-concept for the testing of combination epigenetic approaches to disrupt latent HIV infection, a necessary step toward the eradication of HIV infection.
Inhibition of O-Linked
N
-Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus
Authors: Angelova Magdalena , Ortiz-Meoz Rodrigo F. , Walker Suzanne , Knipe David M.
Published: June 2015

O-linked
N
-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential cellular enzyme that posttranslationally modifies nuclear and cytoplasmic proteins via O-linked addition of a single
N
-acetylglucosamine (GlcNAc) moiety. Among the many targets of OGT is host cell factor 1 (HCF-1), a transcriptional regulator that is required for transactivation of the immediate-early genes of herpes simplex virus (HSV). HCF-1 is synthesized as a large precursor that is proteolytically cleaved by OGT, which may regulate its biological function. In this study, we tested whether inhibition of the enzymatic activity of OGT with a small molecule inhibitor, OSMI-1, affects initiation of HSV immediate-early gene expression and viral replication. We found that inhibiting OGT's enzymatic activity significantly decreased HSV replication. The major effect of the inhibitor occurred late in the viral replication cycle, when it reduced the levels of late proteins and inhibited capsid formation. However, depleting OGT levels with small interfering RNA (siRNA) reduced the expression of HSV immediate-early genes, in addition to reducing viral yields. In this study, we identified OGT as a novel cellular factor involved in HSV replication. Our results obtained using a small molecule inhibitor and siRNA depletion suggest that OGT's glycosylation and scaffolding functions play distinct roles in the replication cycle of HSV.

IMPORTANCE
Antiviral agents can target viral or host gene products essential for viral replication. O-GlcNAc transferase (OGT) is an important cellular enzyme that catalyzes the posttranslational addition of GlcNAc sugar residues to hundreds of nuclear and cytoplasmic proteins, and this modification regulates their activity and function. Some of the known OGT targets are cellular proteins that are critical for the expression of herpes simplex virus (HSV) genes, suggesting a role for OGT in the replication cycle of HSV. In this study, we found that OGT is required for efficient expression of viral genes and for assembly of new virions. Thus, we identify OGT as a novel host factor involved in the replication of HSV and a potential target for antiviral therapy.
Arenavirus Coinfections Are Common in Snakes with Boid Inclusion Body Disease
Authors: Hepojoki J. , Salmenperä P. , Sironen T. , Hetzel U. , Korzyukov Y. , Kipar A. , Vapalahti O.
Published: June 2015

Recently, novel arenaviruses were found in snakes with boid inclusion body disease (BIBD); these form the new genus
Reptarenavirus
within the family
Arenaviridae
. We used next-generation sequencing and
de novo
sequence assembly to investigate reptarenavirus isolates from our previous study. Four of the six isolates and all of the samples from snakes with BIBD contained at least two reptarenavirus species. The viruses sequenced comprise four novel reptarenavirus species and a representative of a new arenavirus genus.
Influenza A Virus Coinfection through Transmission Can Support High Levels of Reassortment
Authors: Tao Hui , Li Lian , White Maria C. , Steel John , Lowen Anice C.
Published: June 2015

The reassortment of gene segments between influenza viruses increases genomic diversity and plays an important role in viral evolution. We have shown previously that this process is highly efficient within a coinfected cell and, given synchronous coinfection at moderate or high doses, can give rise to ∼60 to 70% of progeny shed from an animal host. Conversely, reassortment
in vivo
can be rendered undetectable by lowering viral doses or extending the time between infections. One might also predict that seeding of transmitted viruses into different sites within the target tissue could limit subsequent reassortment. Given the potential for stochastic factors to restrict reassortment during natural infection, we sought to determine its efficiency in a host coinfected through transmission. Two scenarios were tested in a guinea pig model, using influenza A/Panama/2007/99 (H3N2) virus (wt) and a silently mutated variant (var) thereof as parental virus strains. In the first, coinfection was achieved by exposing a naive guinea pig to two cagemates, one infected with wt and the other with var virus. When such exposure led to coinfection, robust reassortment was typically seen, with 50 to 100% of isolates carrying reassortant genomes at one or more time points. In the second scenario, naive guinea pigs were exposed to a cagemate that had been coinoculated with wt and var viruses. Here, reassortment occurred in the coinoculated donor host, multiple variants were transmitted, and reassortants were prevalent in the recipient host. Together, these results demonstrate the immense potential for reassortment to generate viral diversity in nature.

IMPORTANCE
Influenza viruses evolve rapidly under selection due to the generation of viral diversity through two mechanisms. The first is the introduction of random errors into the genome by the viral polymerase, which occurs with a frequency of approximately 10
−5
errors/nucleotide replicated. The second is reassortment, or the exchange of gene segments between viruses. Reassortment is known to occur readily under well-controlled laboratory conditions, but its frequency in nature is not clear. Here, we tested the hypothesis that reassortment efficiency following coinfection through transmission would be reduced compared to that seen with coinoculation. Contrary to this hypothesis, our results indicate that coinfection achieved through transmission supports high levels of reassortment. These results suggest that reassortment is not exquisitely sensitive to stochastic effects associated with transmission and likely occurs in nature whenever a host is infected productively with more than one influenza A virus.
Quantifying uncertainty in intervention effectiveness with structured expert judgement: an application to obstetric fistula
Authors: Colson Abigail R , Adhikari Sweta , Sleemi Ambereen , Laxminarayan Ramanan
Published: June 2015

Objective

To demonstrate a new application of structured expert judgement to assess the effectiveness of surgery to correct obstetric fistula in a low-income setting. Intervention effectiveness is a major input of evidence-informed priority setting in healthcare, but information on intervention effectiveness is generally lacking. This is particularly problematic in the context of poorly resourced healthcare settings where even efficacious interventions fail to translate into improvements in health. The few intervention effectiveness studies related to obstetric fistula treatment focus on the experience of single facilities and do not consider the impact of multiple factors that may affect health outcomes.

Design

We use the classical model of structured expert judgement, a method that has been used to quantify uncertainty in the areas of engineering and environmental risk assessment when data are unavailable. Under this method, experts quantify their uncertainty about rates of long-term disability in patients with fistula following treatment in different contexts, but the information content drawn from their responses is statistically conditioned on the accuracy and informativeness of their responses to a set of calibration questions. Through this method, we develop best estimates and uncertainty bounds for the rate of disability associated with each treatment scenario and setting.

Participants

Eight experts in obstetric fistula repair in low and middle income countries.

Results

Estimates developed using performance weights were statistically superior to those involving a simple averaging of expert responses. The performance-weight decision maker's assessments are narrower for 9 of the 10 calibration questions and 21 of 23 variables of interest.

Conclusions

We find that structured expert judgement is a viable approach to investigating the effectiveness of medical interventions where randomised controlled trials are not possible. Understanding the effectiveness of surgery performed at different types of facilities can guide programme planning to increase access to fistula treatment.
Patient information leaflets to reduce antibiotic use and reconsultation rates in general practice: a systematic review
Authors: de Bont Eefje G P M , Alink Marleen , Falkenberg Famke C J , Dinant Geert-Jan , Cals Jochen W L
Published: June 2015

Objective

Patients’ knowledge and expectations may influence prescription of antibiotics. Therefore, providing evidence-based information on cause of symptoms, self-management and treatment is essential. However, providing information during consultations is challenging. Patient information leaflets could facilitate consultations by increasing patients’ knowledge, decrease unnecessary prescribing of antibiotics and decrease reconsultations for similar illnesses. Our objective was to systematically review effectiveness of information leaflets used for informing patients about common infections during consultations in general practice.

Design, setting and participants

We systematically searched PubMed/MEDLINE and EMBASE for studies evaluating information leaflets on common infections in general practice. Two reviewers extracted data and assessed article quality.

Primary and secondary outcome measures

Antibiotic use and reconsultation rates.

Results

Of 2512 unique records, eight studies were eligible (7 randomised, controlled trials, 1 non-randomised study) accounting for 3407 patients. Study quality varied from reasonable to good. Five studies investigated effects of leaflets during consultations for respiratory tract infections; one concerned conjunctivitis, one urinary tract infections and one gastroenteritis and tonsillitis. Three of four studies presented data on antibiotic use and showed significant reductions of prescriptions in leaflet groups with a relative risk (RR) varying from 0.53 (0.40 to 0.69) to 0.96 (0.83 to 1.11). Effects on reconsultation varied widely. One large study showed lower reconsultation rates (RR 0.70 (0.53 to 0.91), two studies showed no effect, and one study showed increased reconsultation rates (RR 1.53 (1.03 to 2.27)). Studies were too heterogenic to perform a meta-analysis.

Conclusions

Patient information leaflets during general practitioners consultations for common infections are promising tools to reduce antibiotic prescriptions. Results on reconsultation rates for similar symptoms vary, with a tendency toward fewer reconsultations when patients are provided with a leaflet. Use of information leaflets in cases of common infections should be encouraged. Their contributing role in multifaceted interventions targeting management of common infections in primary care needs to further exploration.
Use of flow-diverting stents as salvage treatment following failed stent-assisted embolization of intracranial aneurysms
Authors: Heiferman Daniel M , Billingsley Joshua T , Kasliwal Manish K , Johnson Andrew K , Keigher Kiffon M , Frudit Michel E , Moftakhar Roham , Lopes Demetrius K
Published: June 2015

Flow-diverting stents, including the Pipeline embolization device (PED) and Silk, have been beneficial in the treatment of aneurysms previously unable to be approached via endovascular techniques. Recurrent aneurysms for which stent-assisted embolization has failed are a therapeutic challenge, given the existing intraluminal construct with continued blood flow into the aneurysm. We report our experience using flow-diverting stents in the repair of 25 aneurysms for which stent-assisted embolization had failed. Nineteen (76%) of these aneurysms at the 12-month follow-up showed improved Raymond class occlusion, with 38% being completely occluded, and all aneurysms demonstrated decreased filling. One patient developed a moderate permanent neurologic deficit. Appropriate stent sizing, proximal and distal construct coverage, and preventing flow diverter deployment between the previously deployed stent struts are important considerations to ensure wall apposition and prevention of endoleak. Flow diverters are shown to be a reasonable option for treating previously stented recurrent cerebral aneurysms.
Solitaire stents for the treatment of complex symptomatic intracranial stenosis after antithrombotic failure: safety and efficacy evaluation
Authors: Duan Guoli , Feng Zhengzhe , Zhang Lei , Zhang Ping , Chen Lei , Hong Bo , Xu Yi , Zhao Wenyuan , Liu Jianmin , Huang Qinghai
Published: June 2015

Objectives

To evaluate the feasibility, safety, and efficacy of Solitaire stent placement after balloon angioplasty for the treatment of complex symptomatic intracranial atherosclerotic stenosis (ICAS).

Methods

We retrospectively reviewed the clinical data from 44 patients who underwent Solitaire stent placement for complex symptomatic ICAS at our department between November 2010 and March 2014, with focus on the clinical factors, lesion characteristics, treatment results, and periprocedural complications. We also summarized the early outcomes and imaging findings during the follow-up period.

Results

Overall, the technical success rate was 100% (44/44). Post-stenting residual stenosis ranged from 0% to 40% (mean 15.00±12.94%). The overall 30-day rate of procedure-related complications was 9.09% (4/44). The incidence of recurrent ischemic events related to the territory artery was 4.55% during a mean clinical follow-up period of 25.5 months. Five patients (11.36%) developed in-stent restenosis during a mean angiographic follow-up period of 9.3 months.

Conclusions

This is the first case series study of ICAS treated by Solitaire stent placement. Deployment of a Solitaire stent with balloon angioplasty in the treatment of complex severe intracranial stenosis appears safe and effective, with a high technical success rate, relatively low periprocedural complication rate, and favorable outcome during follow-up.
Dural arteriovenous fistulas at the craniocervical junction: a systematic review
Authors: Zhao Jingjing , Xu Feng , Ren Jinma , Manjila Sunil , Bambakidis Nicholas C
Published: June 2015

Background

Dural arteriovenous fistulas (DAVFs) at the craniocervical junction are uncommon but clinically important abnormalities.

Objective

To investigate the clinical characteristics of patients with DAVFs at the craniocervical junction and assess angiographic features associated with bleeding at presentation.

Methods

We systematically reviewed the literature and searched PubMed and EMBASE for all relevant English language articles published between 1980 and 2014. The clinical presentation, angiographic characteristics, and treatment were assessed. The clinical differences between a subarachnoid hemorrhage (SAH) group and a non-SAH group were statistically examined.

Results

Fifty-six patients were identified after a review of the literature (mean age 55.6 years; male to female ratio=3:1). Twenty-one patients (37.5%) presented with hemorrhage including SAH and posterior fossa hemorrhage. There was no significant difference in patient age, sex, or location of the DAVF between the SAH group and the non-SAH group. Intracranial venous drainage was significantly associated with SAH (p<0.001). The presence of a varix was significantly associated with SAH (p=0.001). Open surgery had a significantly higher efficacy of initial complete obliteration than embolization (100% vs 71.4%, p<0.01).

Conclusions

DAVFs at the craniocervical junction are rare lesions, which often present with hemorrhage. Intracranial venous drainage and a venous varix are associated with increased risk of SAH. Surgical interruption of the feeding arteries or draining veins is an effective and reliable method for treating DAVFs at the craniocervical junction. Embolization is a feasible alternative to surgery in the treatment of selective DAVFs.
RCVS governance: the case for reform
Authors: Reid Stuart , Viner Bradley
Published: June 2015

On being appointed President of the RCVS in July last year, Stuart Reid set out three main ambitions for his term of office. One was to consult on whether veterinary surgeons should be allowed to use the title ‘Doctor’, and this already been realised. The second was to strengthen the College's European and international role, and a new international strategy is being considered by the RCVS Council this month. His third ambition was to continue the College's modernisation agenda and streamline the governance of the College itself. Here, he and Bradley Viner, the incoming President, briefly set out the case for reform
Predicted versus measured thoracic gas volumes of collegiate athletes made by the BOD POD air displacement plethysmography system
Authors: Wagner Dale R.
Published: June 2015

Measured (TGVm) and predicted (TGVp) thoracic gas volumes from the BOD POD were compared in 33 lean, university athletes. On average, TGVp (3.529 L) was not significantly different (p = 0.343) from TGVm (3.628 L); however, there was a bias (r = –0.703, p < 0.001). The difference in the percentage of body fat (BF) was within ±2% BF for 76% of the sample, but athletes at the extremes of height should have TGV measured.
On certain arithmetic integer additive set-indexers of graphs
Authors: Sudev N. K. , Germina K. A.
Published: June 2015

Let ℕ0 denote the set of all non-negative integers and 𝒫(ℕ0) be its power set. An integer additive set-indexer (IASI) of a graph G is an injective function f : V(G) → 𝒫(ℕ0) such that the induced function f+ : E(G) → 𝒫(ℕ0) defined by f+ (uv) = f(u) + f(v) is also injective. A graph G which admits an IASI is called an integer additive set-indexed graph (IASI-graph). An IASI of a graph G is said to be an arithmetic IASI if the elements of the set-labels of all vertices and edges of G are in arithmetic progressions. In this paper, we discuss about two special types of arithmetic IASIs.