bluuebunny/crossref_metadata_2025 huggingface dataset:
The Psychosocial Implications of Managing Work and Family Caregiving Roles: Gender Differences Among Information Technology Professionals
Authors: DePasquale Nicole , Polenick Courtney A. , Davis Kelly D. , Moen Phyllis , Hammer Leslie B. , Almeida David M.
Published: May 2015

An increasing number of adults, both men and women, are simultaneously managing work and family caregiving roles. Guided by the stress process model, we investigate whether 823 employees occupying diverse family caregiving roles (child caregiving only, elder caregiving only, and both child caregiving and elder caregiving, or “sandwiched” caregiving) and their noncaregiving counterparts in the information technology division of a white-collar organization differ on several indicators of psychosocial stress along with gender differences in stress exposure. Compared with noncaregivers, child caregivers reported more perceived stress and partner strain whereas elder caregivers reported greater perceived stress and psychological distress. With the exception of work-to-family conflict, sandwiched caregivers reported poorer overall psychosocial functioning. Additionally, sandwiched women reported more family-to-work conflict and less partner support than their male counterparts. Further research on the implications of combining a white-collar employment role with different family caregiving roles is warranted.
Effects of music notation reinforcement on aural memory for melodies
Authors: Buonviri Nathan
Published: May 2015

The purpose of this study was to investigate effects of music notation reinforcement on aural memory for melodies. Participants were 41 undergraduate and graduate music majors in a within-subjects design. Experimental trials tested melodic memory through a sequence of target melodies, distraction melodies, and matched and unmatched answer choices. Target melodies were presented either aurally only, or aurally with matching notation. Results of a paired samples t-test revealed no significant difference in experimental test scores based on presentation format, suggesting that music notation reinforcement of melodies does not affect aural memory for those melodies. Recommendations for further research include an aural-visual melodic memory test paired with a survey of participant learning modalities; a survey of successful melodic memory strategies employed by aural skills students; and longitudinal studies of visual imagery applied to aural skills tasks. Implications for music education at all levels center on the need to cultivate strong cognitive relationships between visual and aural aspects of music.
The Influence of Professional Identity on Teaching Practice: Experiences of Four Music Educators
Authors: Carrillo Carmen , Baguley Margaret , Vilar Mercè
Published: May 2015

This study explores the influence of professional identity on the teaching practice of four school music educators, two from Spain and two from Australia. Narrative inquiry methodology was utilized in order to investigate the full spectrum of their musical experiences, ranging from their earliest childhood memories to their current positions in the education sector. In the course of the co-construction of the narratives, two recurrent themes emerged: strategies to improve practice and teaching approaches. Despite the obvious cultural and institutional differences, there was a marked correlation of these themes in terms of their contribution to the formation of each of the participants’ professional identities. Although these findings are derived from a small number of participants they may provide insights for specialist music educators, teacher educators programs, and for those considering a career in music education.
Adult perspectives of learning musical instruments
Authors: Roulston Kathryn , Jutras Peter , Kim Seon Joo
Published: May 2015

This article reports findings from a qualitative study of adults’ perceptions and experiences of learning musical instruments. Conducted in the south-east United States, 15 adults who were learning instruments were recruited via community music groups and private instrumental teachers. Analysis of transcripts of semi-structured interviews identified adults’ prior experiences in music, their motivations to learn instruments and learning goals, learning strategies they employ, the benefits that they attribute to their engagement in musical activities, and challenges faced. Findings inform instructors of instrumental music about why adults choose to learn instruments, their perspectives of learning and teaching, as well as the strategies that they use to engage in learning. Findings demonstrate the ways in which principles from the field of adult education might inform the continuing education of adult music learners.
Video-games used in a group setting is feasible and effective to improve indicators of physical activity in individuals with chronic stroke: a randomized controlled trial
Authors: Givon Noa , Zeilig Gabi , Weingarden Harold , Rand Debbie
Published: May 2015

Objectives:

To investigate the feasibility of using video-games in a group setting and to compare the effectiveness of video-games as a group intervention to a traditional group intervention for improving physical activity in individuals with chronic stroke.

Design:

A single-blind randomized controlled trial with evaluations pre and post a 3-month intervention, and at 3-month follow-up. Compliance (session attendance), satisfaction and adverse effects were feasibility measures. Grip strength and gait speed were measures of physical activity. Hip accelerometers quantified steps/day and the Action Research Arm Test assessed the functional ability of the upper extremity.

Results:

Forty-seven community-dwelling individuals with chronic stroke (29-78 years) were randomly allocated to receive video-game ( N=24) or traditional therapy ( N=23) in a group setting. There was high treatment compliance for both interventions (video-games-78%, traditional therapy-66%), but satisfaction was rated higher for the video-game (93%) than the traditional therapy (71%) (χ2=4.98, P=0.026). Adverse effects were not reported in either group. Significant improvements were demonstrated in both groups for gait speed (F=3.9, P=0.02), grip strength of the weaker (F=6.67, P=0.002) and stronger hands (F=7.5, P=0.001). Daily steps and functional ability of the weaker hand did not increase in either group.

Conclusions:

Using video-games in a small group setting is feasible, safe and satisfying. Video-games improve indicators of physical activity of individuals with chronic stroke.
High-resolution, low-altitude aerial photography in physical geography
Authors: Barrell Jeffrey , Grant Jon
Published: May 2015

Intertidal landscapes are highly complex and dynamic habitats that exhibit variability over a range of spatial and temporal scales. The spatial arrangement of structure-forming biogenic features such as seagrasses and bivalves influences ecosystem function and the provision of important ecosystem services, though quantification and monitoring of intertidal landscape structure has been hindered by challenges collecting spatial data in the coastal zone. In this study, an intertidal landscape mosaic of eelgrass ( Zostera marina) and blue mussels ( Mytilus edulis) was observed using low-altitude aerial photography from a balloon-mounted digital camera platform. Imagery representing seagrass-bivalve landscape structure was classified and analysed using multiple metrics of landscape composition and configuration at the patch scale and the landscape scale. Patch-scale imagery was compared to a previously collected dataset in order to track temporal changes in seagrass patch metrics over a 26-month period. Seagrass and bivalve patches exhibited distinct spatial patterning at different spatial scales. At the patch scale, the change in seagrass metrics was consistent with patch border expansion at the expense of patch density and integrity. These methods demonstrate a novel approach for collecting high-resolution spatial data that could also be valuable to physical geographers dealing with similar fine-scale landscapes. The application of spatial metrics at multiple spatial scales quantified elements of the configuration and composition of a seagrass-bivalve habitat mosaic and allowed for the tracking of patch metrics through time to depict landscape change. Continued development of landscape metrics within intertidal habitats will increase understanding of the ecological function of these areas with benefits to management and monitoring of ecosystem health.
Geographical isolation and invasion ecology
Authors: Etherington Thomas R.
Published: May 2015

Isolation is a fundamental geographical characteristic that plays an important role in invasion ecology. However, risk mapping for established non-native species currently tends to ignore isolation, and instead focuses on the risk of population growth through the use of species distribution models. By focusing on how geographical isolation can be used to improve invasive species risk assessments this paper aims to: (i) provide a brief review of how methods to quantify isolation have developed, (ii) describe least-cost modelling as one approach to quantify isolation, (iii) promote catchment area mapping as a method of continuous isolation mapping that can improve invasive species risk assessments that may currently only consider risk from population growth, and (iv) discuss ways in which geographical isolation could be modified to control invasive species.
Comparison of shock wave therapy and nutraceutical composed of Echinacea angustifolia, alpha lipoic acid, conjugated linoleic acid and quercetin (perinerv) in patients with carpal tunnel syndrome
Authors: Notarnicola Angela , Maccagnano Giuseppe , Tafuri Silvio , Fiore Alessandra , Pesce Vito , Moretti Biagio
Published: May 2015

Even though the initial treatment of carpal tunnel syndrome (CTS) is conservative, knowledge of the clinical effects of supplements and of some methods of physiotherapy is still preliminary. Many biological mechanisms can support the administration of shock wave therapy (ESWT) or of alpha lipoic acid (ALA) based nutraceutical, conjugated linoleic acid (GLA), anti-oxidants and Echinacea angustifolia for CTS. The shock waves reduce the nerve compression, produce an anti-inflammatory action, and accelerate the regeneration of neuropathy. ALA and GLA induce antioxidant protective actions, reduce inflammation, promote neuroregeneration, and decrease pain. The Echinacea modulates the endogenous cannabinoid system.

The aim of study is to verify the efficiency of shock wave therapy versus nutraceutical composed of ALA, GLA, and Echinacea in CTS. Sixty patients were enrolled in this study and they were randomly assigned to one of two treatments. Both groups showed significant improvements in pain, symptoms’ severity and functional scores, and electrodiagnostic results until the sixth month. We verified a trend to a better pain regression in the nutraceutical group. The presence of the medicinal Echinacea represents an added value to the antioxidant effect in ALA and GLA, which can justify this result. ESWT or the association of ALA, GLA, and Echinacea proved to be two effective treatments for controlling symptoms and improving the evolution of CTS.
Transitions to the Top
Authors: Day Jacob C.
Published: May 2015

This study investigates the effects of job-level, task-based, segregation on racial differences in promotions to executive positions within the college football coaching profession. Using event-history methods to analyze the careers of 323 college football coaches, the results suggest that, relative to White coaches, Black coaches’ career prospects are harmed by their disproportionate placement into jobs that inhibit mobility (i.e., noncentral positions) and their differential returns from occupying jobs that induce mobility (i.e., central positions). These findings shed light on processes related to job-level racial segregation, particularism, and racialization in the coaching profession as well as more general, high-status, labor market contexts.
College Republicans and Conservative Social Identity
Authors: Kidder Jeffrey L.
Published: May 2015

Through participant-observation and interviews, I explore the conservative social identity of College Republicans at a midsize, midtier public university in the United States. Using the concepts of repertoires and frames, I analyze how individuals make claims to political social identities. Specifically, I show that symbolic appeals to the free market were an essential aspect of the conservative repertoire at my field site. Furthermore, the shifting and contradictory frames used by the College Republicans in this study demonstrate that their discursive political practices were not primarily about policy preferences; they were about affirming a conservative social identity. Understanding how stated policy preferences and identity intertwine in everyday political talk has important implications for American democracy.
Comparability of Online- and Paper-Based Tests in a Statewide Assessment Program
Authors: Seo Dong Gi , De Jong Gayle
Published: May 2015

Comparability of paper and online versions of a statewide assessment was evaluated for the purposes of test score reporting, to appropriately adjust equated score conversion tables for students testing online as warranted. In particular, comparability of online and paper tests was designed with a propensity score matching method. The propensity score was used to match the online test sample with the paper–pencil test sample. The results of this study suggest that neither a separate assessment nor a conversion table would be required in a state’s assessment. The online test appears to provide a credible and comparable option to the paper and pencil modality.
Pulmonary Hypertension in the Intensive Care Unit
Authors: Jentzer Jacob C. , Mathier Michael A.
Published: May 2015

Pulmonary hypertension occurs as the result of disease processes increasing pressure within the pulmonary circulation, eventually leading to right ventricular failure. Patients may become critically ill from complications of pulmonary hypertension and right ventricular failure or may develop pulmonary hypertension as the result of critical illness. Diagnostic testing should evaluate for common causes such as left heart failure, hypoxemic lung disease and pulmonary embolism. Relatively few patients with pulmonary hypertension encountered in clinical practice require specific pharmacologic treatment of pulmonary hypertension targeting the pulmonary vasculature. Management of right ventricular failure involves optimization of preload, maintenance of systemic blood pressure and augmentation of inotropy to restore systemic perfusion. Selected patients may require pharmacologic therapy to reduce right ventricular afterload by directly targeting the pulmonary vasculature, but only after excluding elevated left heart filling pressures and confirming increased pulmonary vascular resistance. Critically-ill patients with pulmonary hypertension remain at high risk of adverse outcomes, requiring a diligent and thoughtful approach to diagnosis and treatment.
Intimate Partner Violence Among Pregnant Young Women
Authors: Lévesque Sylvie , Chamberland Claire
Published: May 2015

This article explores intimate partner violence (IPV) as experienced by young women during the perinatal period. Using purposive sampling, data pertaining to the experiences of 10 young mothers were gathered through on-site participative observation and individual in-depth interviews. Interviews were coded in an inductive way to reflect the experiences of the participants before pregnancy and following pregnancy confirmation. Overall, the analyses of different manifestations of IPV and their contexts reveal the difficulty these young mothers experience in identifying themselves as a victim of IPV and in categorizing their partner’s acts as intimate violence. The fear of family separation and the desire to protect their child contributed to the complexity of violence experienced in a context of motherhood. This article also reflects on the limits of data collection on this subject through comparison of the results of the interviews with the results of the Revised Conflict Tactics Scale (CTS-2). Further research is needed to provide more insight into victimization among young mothers and to inform interventions with the goal of helping young women overcome the intersecting challenges of violence and motherhood.
Civil Society Participation in Advocating Interests on EU Legislation
Authors: Rūse Ilze
Published: May 2015

The article analyzes the activity of non-governmental actors in Latvia in advocating their interests on national and European Union legislative proposals. The findings draw on primary data gained from 122 responses from interest organizations in Latvia in an online survey. Despite the large number of societal actors (thirteen thousand registered organizations), the interest group population in Latvia consists of small and financially underequipped NGOs. Their lobbying activities are characterized by predominantly influencing domestic authorities, that is, national route strategies, although there is some variation across the types of interest groups.
First-Time Mothers with a History of Infertility
Authors: Ladores Sigrid , Aroian Karen
Published: May 2015

Background:

The meaning of breastfeeding and breastfeeding experiences has been studied extensively in general and specific populations. However, there is little research about the meaning of breastfeeding and breastfeeding experiences in first-time mothers who were previously infertile.

Objective:

This article aims to understand the breastfeeding experiences of new mothers with a history of infertility.

Methods:

Twelve women who were first-time mothers and conceived their infants through fertility treatments were interviewed about their early postpartum experiences as part of a larger phenomenological study. Interview transcripts were reviewed, and data about breastfeeding were extracted and analyzed using thematic analysis.

Results:

One main theme from the breastfeeding data emerged, “Internalized Pressure to Breastfeed,” with 3 subthemes: “My Only Chance to Breastfeed,” “The One Natural Thing I Should Be Able to Do,” and “Not Breastfeeding Means Failing at Motherhood.” New mothers who have undergone fertility treatment equated breastfeeding with being the perfect mother and attached special meanings to the act of breastfeeding.

Conclusion:

This study demonstrated that mothers who were previously infertile have unique breastfeeding experiences. Health care professionals need to be sensitized to these women’s internalized pressure to breastfeed. Additional research is needed to fully explore the breastfeeding experiences of this group of women.
Modelling and characterisation of roughness of moulds produced by high-speed machining with ball-nose end mill
Authors: Batista Marcelo Ferreira , Rodrigues Alessandro Roger , Coelho Reginaldo Teixeira
Published: May 2015

Cusps and scallops of hardened steel moulds produced by high-speed milling using a ball-nose end mill were mathematically modelled, characterised by microscopy and experimentally validated. The experimental results show that the part material is crushed or ploughed near the cutter centre, where the cutting speed is very low. This kinematic singularity, associated with tool feed, compresses and bends the ball-nose end mill axially. Because of this double effect, the end mill marks on the part at the end of the milling path cause surface damage and dimensional errors to the hardened mould. A mathematical model may predict the formation of the cusps and scallops and be of use in computer numerical control or computer-aided manufacturing programming to obtain the desired part topography.
Clogging behavior of an elongated bubble in uniform and diverging microchannel
Authors: Prajapati Yogesh K , Pathak Manabendra , Khan Mohd Kaleem
Published: May 2015

A numerical investigation has been performed to make a comparative study of clogging and detachment behavior of an elongated bubble during adiabatic flow through a uniform and diverging cross-sectional microchannel. The adiabatic gas–liquid two-phase flow has been numerically solved using volume of fluid approach in a finite volume code. Simulations have been made to investigate the effects of wall wettability, surface tension, and flow velocity on the bubble dynamics for both the configurations of microchannel. The net pressure drop across the bubble in the diverging channel has been calculated analytically and the results have been compared with numerical results. In both types of channels, the bubble shape goes through a transient stage followed by a steady and stable shape. The change in bubble shape during transient phase depends on the surface wettability, flow velocity, and the confinement of the channels. The bubble attains the symmetrical shape earlier in diverging channel. The formation of liquid film between the bubble and the wall plays an important role in the clogging behavior and movement of the bubble. Wall wettability has less impact on the pressure drop characteristics in the diverging channel.
Stagnation-point flow towards a stretching/shrinking sheet in a nanofluid using Buongiorno's model
Authors: Mansur Syahira , Ishak Anuar , Pop Ioan
Published: May 2015

The stagnation point flow of a nanofluid towards a permeable stretching/shrinking sheet using the Buongiorno's model is studied. Numerical results are obtained using boundary value problem solver bvp4c in MATLAB for several values of the governing parameters. The numerical results show that dual (upper and lower branch) solutions exist for the shrinking case, while for the stretching case, the solution is unique. A stability analysis is performed to determine the physical realizable in practice of the dual solutions. It is found that the skin friction decreases when the sheet is stretched, but increases when the suction effect is increased. It is also found that increasing the thermophoresis parameter reduces the heat transfer rate at the surface, while increasing the Brownian motion parameter increases the mass transfer rate at the surface.
Modulation of the Antiviral Activity of Poly (A-U) by Ethidium Bromide and Propidium Iodide
Authors: Jamison J. M. , Bonilla P. J. , Tsai C.-c.
Published: May 2015

The role of ethidium bromide (EB) and propidium iodide (PI) in modulating the antiviral and interferon-inducing activities of poly(adenylate-uridylate) (poly (A-U)) was examined using the human foreskin fibroblast-vesicular stomatitis virus (HSF-VSV) bioassay system in which the concentration of poly (A-U) was fixed at 0.05 mM or 0.2 mM while the EB or PI concentration was varied to produce variable EB (or PI)/ribonucleotide ratios ranging from 1:16 to 2:1. EB, PI and poly (A-U) tested individually were not efficacious antiviral agents. When poly (A-U) was combined with the ethidium bromide or propidium iodide the antiviral activity was potentiated 15- to 22-fold at EB (or PI)/ribonucleotide ratios in the region of 1/4. The interferon-inducing activity of the EB (or PI)/poly (A-U) combinations were equal to the sum of the interferon-inducing activity of the poly (A-U) and the EB or (PI). These results indicate that the EB and PI potentiate the antiviral activity of the poly (A-U) without superinduction of interferon. The direct viral inactivation study demonstrated that EB, PI, poly (A-U) and the EB (or PI)/poly (A-U) combinations did not inactivate the VSV at concentrations near the 50% viral inhibitory dose.
The Enzymatic Synthesis and Anti-HIV-1 Activity of 9-β-D-2′,3′-Dideoxynucleosides of N(6)-Substituted Purines
Authors: Betbeder D. , Hutchinson D. W. , Richards A. O'L. , Mahood N. , Kinchington D.
Published: May 2015

9-β-D-2′,3′-dideoxyribonucleosides of four N(6)-substituted purines and 1-deazapurine were prepared using crude nucleoside N-deoxyribosyltransferases (EC 2.4.2.6) from Lactobacillus leichmannii. The 2′,3′-dideoxynucleosides derived from N(6)-substituted purines (1–4) are inhibitors of the replication of human immunodeficiency virus type 1 (HIV-1), with EC90 values in the range 20–100 and 20–200 μm, depending on the cell line used, and have low in vitro toxicity at their effective concentrations.
Biochemical Pharmacology of 2′-Fluoro-2′,3′-Dideoxyarabinosyladenine, an Inhibitor of HIV with Improved Metabolic and Chemical Stability over 2′,3′-Dideoxyadenosine
Authors: Hitchcock M. J. M. , Woods K. , De Boeck H. , Ho H.-T.
Published: May 2015

We have investigated some properties of the acid stable, 2′-arafluoro-substituted congeners of dideoxyadenosine (ddA) and dideoxyinosine (ddl) in order to understand their potential for in vivo utility as anti-HIV agents. Activities of 2′-fluoro-2′,3′-dideoxyarabinosyl-adenine (FddA) and hypoxanthine (Fddl) against human immunodeficiency virus (HIV) in cells are similar and are about an order of magnitude lower than those of ddA and ddl. FddA is a much poorer substrate than ddA for adenosine deaminase, and is deaminated about 50-fold slower at pharmacological concentrations. The product Fddl is (in contrast to ddl) resistant to cleavage by purine nucleoside phosphorylase. As for ddl, Fddl is phosphorylated by a 5′-nucleotidase, using inosine monophosphate (IMP) as the phosphate donor. In cells, both FddA and Fddl are phosphorylated to the triphosphate of FddA (FddATP). However, the concentration of FddATP produced from FddA is about two-to five-fold higher than from Fddl. FddATP is extremely stable in cells and persists with a half-life of 20 h after removal of FddA from the medium. Using HIV reverse transcriptase, FddATP is a less efficient inhibitor than ddATP by about 20-fold. Thus the activity of these compounds against HIV in cells correlates well with the intracellular concentration and potency of their triphosphates. If the efficacy of ddl in clinical trials is the result of its activity in certain cell types, the fluoro congeners could be active in similar cells since they use the same enzymes for activation to the active triphosphorylated forms. The reduction in potency may, to some extent, be offset by the greater stability to acid and enzyme degradation. Thus further evaluation of FddA and Fddl as anti-HIV agents is warranted.
Selective Killing of HIV-Infected Cells by Liposomes Composed of dimyristoylphosphatidylcholine/phosphatidylserine/cholesterol
Authors: Kumagai K. , Nabeshima S. , Kato S. , Watanabe M. , Ikuta K.
Published: May 2015

We have previously shown that liposomes containing fragment A of diphtheria toxin, which were prepared by the detergent-dialysis method with egg phosphatidylcholine, phosphatidylserine and cholesterol, possess a selective killing activity against human immunodeficiency virus (HIV)-1-infected cells, but not against uninfected cells (Ikuta et al., 1987). Since the liposomes were found to be unstable in human plasma in vitro, we prepared improved liposomes by the extrusion method with dimyristoylphosphatidylcholine instead of egg phosphatidylcholine. These liposomes were found to be very stable in human plasma, and also possessed the selective killing activity against HIV-1-infected cells. In addition, it was found that the fragment A in the liposomes was not necessary for the selective cell killing activity. The cell killing activity and selectivity of HIV-1-infected cells of the liposomes were remarkably affected by cholesterol content and the acyl chain length of the saturated fatty acid of phosphatidylcholines. These data suggest that membranes of liposomes can interact specifically with HIV-1-infected cells, but not with uninfected cells, resulting in the inhibition of cell proliferation.
Rapid Prescreening for Antiviral Agents against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. I. The V3 Loop of gp 120 as Target
Authors: Neurath A. R. , Haberfield P. , Joshi B. , Hewlett I. K. , Strick N. , Jiang S.
Published: May 2015

The anionic triphenylmethane derivative aurintricarboxylic acid (ATA) was reported to inhibit the replication and cytopathogenicity of human immunodeficiency virus type 1 (HIV-1). This antiviral effect, ascribed to the inhibitory activity of ATA on the virus reverse transcriptase, was subsequently also explained by binding of ATA to the HIV-1 envelope glycoprotein gp120 and/or to the CD4 receptor for the virus. Results presented here show: (1) the effectiveness of ATA as a potential antiviral drug by demonstrating that HIV-1 replication in vitro can be completely aborted in the presence of ATA as measured by the polymerase chain reaction; (2) that ATA inhibited the reaction between gp120 and antibodies specific for the V3 hypervariable loop of gp120; (3) that additional compounds with anti-HIV-1 activity can be rapidly identified based on their inhibitory effects measured by radioimmunoassays and/or enzyme-linked immunoadsorbent assays; and (4) that ATA also bound to synthetic peptides representing V3 loops of several HIV-1 isolates, suggesting the possibility that selected chemicals would interfere with the biological function of V3 loops of most HIV-1 isolates and would be effective for chemotherapy, and possibly for prophylaxis, of HIV-1 infections.
Differential Activity of Polyanionic Compounds and Castanospermine against HIV Replication and HIV-Induced Syncytium Formation Depending on Virus Strain and Cell Type
Authors: Schols D. , Pauwels R. , Witvrouw M. , Desmyter J. , De Clercq E.
Published: May 2015

Polyanionic compounds [i.e. pentosan polysulphate, dextran sulphate, heparin, suramin, and aurintricarboxylic acid (ATA)] and castanospermine were examined for their inhibitory effect on human immunodeficiency virus (HIV) strains (HIV-1IIIB, HIV-1RF, HIV-2ROD and HIV-2EHO) in two different assays (HIV cytopathicity in MT-4 cells and HIV antigen expression in CEM cells). In the MT-4 assay dextran sulphate and pentosan polysulphate were more active against HIV-2ROD, suramin was more active against HIV-1RF, and ATA more active against HIV-2EHO-Heparin was less, but castanospermine was more, active against the two HIV-2 strains. In the CEM assay dextran sulphate and suramin were equally active against all HIV strains, pentosan polysulphate was more active against both HIV-2 strains, whereas heparin was less active against HIV-2ROD and ATA again was more active against HIV-2EHO. The compounds and soluble CD4 (sCD4) were also tested in the HIV-induced syncytium formation assay, where chronically infected HUT-78 cells were mixed with uninfected MOLT-4 or CEM cells. The inhibitory effect of suramin and ATA on syncytium formation was independent of the virus strain or cell type. For dextran sulphate and pentosan polysulphate, it was dependent on virus strain, and for heparin, castanospermine, and sCD4, it was dependent on both the virus strain and cell type.
The Antiviral Activity of Tetrachloro Decaoxide against Herpes Simplex Virus Type 1 and the Virucidal Effect of the Drug
Authors: Dargan D. J. , Subak-Sharpe J. H.
Published: May 2015

At the recommended clinical dose for direct application to infected wounds tetrachloro decaoxide (TCDO) (1.0 × concentration TCDO) alone or in combination with haemoglobin proved to be cytotoxic for BHK and Flow 2002 cells, but at ≤0.1 TCDO/haem concentration BHK-21 cells tolerated treatment with the drug for 24 h retaining ≥80% cell viability. The in vitro cytotoxic effect is only partially reversible; but this could not explain the strong antiviral effect of TCDO/haem against herpes simplex virus type 1 (HSV-1) growing in BHK cells. The antiviral effect produces both a reduction in the number of virus particles assembled, and a lowering of their relative infectivity (i.e. reduced virus quality). The antiviral effect was active throughout the HSV-1 replication cycle. The quality of the viral DNA that was packaged into particles was unimpaired but unpackaged DNA was less infectious than controls. The reduction in particle numbers appeared to be due to both lowered protein synthesis and reduced virus particle assembly. TCDO/haem exhibits potent virucidal activity against HSV-1; HSV-2; Semliki Forest virus; Germiston virus; Reovirus type 3; Influenza virus type A; Feline leukaemia virus; Adenovirus type 5 and Polio virus type 1. Enveloped viruses, though varying over a wide sensitivity range were more sensitive than non-enveloped viruses. The magnitude of the virucidal effect against HSV-1 in suspension could be reduced by addition of BSA. The HSV-1 virucidal effect stems mainly from an effect of the drug on virion polypeptides. We propose that the effects of TCDO/haem result from the nonspecific chemical oxidation of susceptible chemical linkages both within and between individual proteins located intracellularly (antiviral and cytotoxic effects) or on the surface of virions (virucidal effect).
Prophylactic Efficacy and Bone Toxicity Associated with Phosphonoformate Therapy against Retrovirus Infection
Authors: Swenson C. L. , Polas P. J. , Weisbrode S. E. , Nagode L. A. , Kociba G. J. , Hayes K. A. , Mathes L. E.
Published: May 2015

Phosphonoformate (PFA) is a simple pyrophosphate analogue which is a topical and parenteral treatment for human herpes virus infections and is currently undergoing evaluation for treatment of human immunodeficiency virus (HIV) and cytomegalovirus infections associated with (AIDS). In this study, antiretroviral activity of PFA was demonstrated by two separate treatment regimens. In the first, an inoculum of feline leukaemia virus (FeLV) in plasma from viraemic cats was treated with 1024 μM PFA prior to intravenous inoculation into susceptible animals. Three of four cats given the PFA treated inoculum were protected from viraemia by the PFA treatment, while 2 of 2 challenge controls receiving sham treated inoculum and 6 of 6 untreated challenge controls became viraemic. In the second regimen, a long-term continuous intravenous infusion of PFA (1000 mg kg−1 day−1) was administered to 6 young cats beginning 1–2 days prior to and extending 4 weeks following intravenous inoculation with FeLV. Five of the six PFA-treated cats also received heparin intravenously and acetyl salicylic acid (aspirin) orally to reduce risk of thrombosis. Six cats (heparin controls) received only heparin and aspirin and were inoculated with FeLV in an identical manner. Six cats served as untreated challenge controls. Four of 6 PFA-treated cats were protected from FeLV antigenaemia. In contrast, all 6 heparin-control animals and all 6 challenge-control animals became persistently viraemic as evidenced by continuous expression of FeLV p27 antigen. All challenged cats including the 4 protected by PFA treatment developed antibody to FeLV, indicating that PFA did not prevent primary virus infection. Significant toxic effects of PFA treatment were reduced weight-gain and rickets-like bone lesions in the cats receiving the 4 week treatment. Additionally, decreased serum alkaline phosphatase, phosphorus, and calcitriol concentrations, presumably related to the bone lesions, were observed. Results of this study suggest that the antiviral effect of PFA involves an immediate and direct mechanism targeted at cell-free virus and that long-term continuous intravenous infusion of PFA has significant anti-retroviral activity in vivo.
Conformational Analysis of Substituent Effects on the Sugar Puckering Mode and the anti-HIV Activity of 2′,3′-Dideoxypyrimidine Nucleosides
Authors: Everaert D. H. , Peeters O. M. , De Ranter C. J. , Blaton N. M. , van Aerschot A. , Herdewijn P.
Published: May 2015

A comparison between the conformational parameters of eleven active and inactive anti-HIV 2′,3′-dideoxypyrimidine nucleosides and a series of 73 uridine and thymidine structures, revealed that our compounds, all having N-glycosidic bond torsion angles χ in the anti range, have pseudorotation phase angles P well distributed over both N (C3′- endo) and S [C2′- endo and C3′- exo) type sugar conformations and have both + sc and ap C4′-C5′ conformations. This means that solid state conformations characterized by P, χ and γ do not provide decisive information for predicting possible anti-HIV activity. We also found that any rationalization of the activity or inactivity of nucleosides in terms of the gauche effect of electronegative substituents on the furanose ring conformation, could not be demonstrated by using the semiempirical quantum chemical AM 1 method. Calculations of C3′-X3′ bond polarities indicate that anti-HIV activity in C3′-substituted nucleoside analogues is consistent with the presence of a positive C3′-X3′ bond polarity. Exploration of the conformational space of χ vs. γ for C3′- endo, C2′- endo and C3′- exo sugar puckering modes using the same AM1 method, reveals that although the C3′- endo [ P = 10°) region is about 2 kcal mol−1 lower than the C2′- endo region ( P = 170°), the C2′ - endo sugar puckering mode is the most accessible one due to the conformational flexibility about the minima. Our results also suggest that as P increases from 10°, through 170°, to 210°, the preferred range for -y dramatically shifts from almost exclusively around 50° (+ sc) at P = 10° to almost exclusively non + sc at P = 210°.
Synergistic Anti-Human Immunodeficiency Viral (HIV-1) Effect of the Immunomodulator Ampligen (Mismatched Double-Stranded RNA) with Inhibitors of Reverse Transcriptase and HIV-1 Regulatory Proteins
Authors: Ushijima H. , Tsiapalis C. M. , Daum T. , Schröder H. C. , Matthes E. , Engels J. W. , Mag M. , Muth J. , Müller W. E. G.
Published: May 2015

The potent antiviral effect of double stranded RNA, such as the mismatched poly(l)·poly(C12U) [Ampligen], 2′,3′-dideoxy-3′-fluorothymidine (FddThd) and antisense oligodeoxynucleotides (ODN) has been established in in vitro systems using cells infected with the human immunodeficiency virus type 1 (HIV-1). We report here that the immunomodulator poly(l)·poly(C12U) interacts synergistically with (1) the reverse transcriptase inhibitor FddThd (FIC value: 0.43), (2) the modified (5′- and 3′-end capped thioates) antisense ODN-4 directed against the splice acceptor site of the HIV-1/ tat gene (FIC value: 0.66) and (3) also with pyronin Y, a compound which prevents binding of HIV-1 Rev protein to the HIV-1 RRE element. These data suggest that combinations of poly(l)·poly(C12U), a stimulator of the natural antiviral protection system of the cells, with compounds targeting HIV1-specific processes should be considered as candidate treatments of AIDS patients.
The Relationship between Conformation and Biological Activity of 8-substituted Analogues of 2′,5′-Oligoadenylates
Authors: Kanbara K. , Nagai K. , Nakashima H. , Yamamoto N. , Suhadolnik R. J. , Takaku H.
Published: May 2015

Analogues of the 2′,5′-linked adenylate trimer 5′-monophosphates, p5′A2′p5′A2′p5′A (pA3) (1a), containing 8-hydroxyadenosine and 8-mercaptoadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. The oligomer, p5′ASH2′p5′ASH2′p5′ASH (pASH3) (1c) had little capacity to bind to RNase L. On the other hand, an analogue of the p5′AOH2′p5′AOH2′p5′AOH (pAOH3) (1b) bound almost as well as the parent 2-5A [pppA(2′p5′A)2] (P3A3) (1d) to RNase L. The 8-substituted analogues of 2-5A were more resistant to degradation by (2′,5′) phosphodiesterase. Finally, the monophosphate, pASH3 (1c) which possessed higher anti-HIV activity than pAg (1a) or pAOH3 (1b).
Cross-Resistance between AZT, ddl and other Antiretroviral Drugs in Primary Isolates of HIV-1
Authors: Cox S. W. , Aperia K. , Sandström E. , Holmberg V. , Morfeldt-Månson L. , Broström C. , Wahren B. , Albert J.
Published: May 2015

Primary isolates of human immunodeficiency virus type 1 (HIV-1) were tested for sensitivity to 3′-azido-3′-deoxythymidine (AZT), 3′-fluoro-3′-deoxythymidine (FLT), 2′,3′-dideoxyinosine (ddl), 2′,3′-dideoxycytidine (ddC), and phosphonoformate (PFA) in peripheral blood mononuclear cells (PBMC). Forty-eight isolates from HIV-1-infected patients treated with AZT for various lengths of time were investigated. More than half of the patients harboured virus resistant to AZT after treatment. There was no correlation between resistance and length of therapy. A significant correlation between resistance to AZT and reduced susceptibility to ddl and ddC was apparent. These results indicate that development of resistance to AZT is common in patients treated with AZT and may be associated with reduced sensitivity to ddl and ddC.
Decomposition Pathways of the Mono- and Bis(Pivaloyloxymethyl) Esters of Azidothymidine 5′-Monophosphate in Cell Extract and in Tissue Culture Medium: An Application of the ‘on-line ISRP-Cleaning’ HPLC Technique
Authors: Pompon A. , Lefebvre I. , Imbach J.-L. , Kahn S. , Farquhar D.
Published: May 2015

Bis(pivaloyloxymethyl) azidothymidine 5′-monophosphate (piv2-AZTMP) was designed as a cell membrane-permeable precursor of AZTMP. We have reported previously that when incubated with CEM cells deficient in thymidine kinase, piv2-AZTMP gives rise to intracellular AZTMP and the corresponding diphosphate (AZTDP) and triphosphate (AZTTP). Under similar conditions, no intracellular nucleotides were formed with AZT. However, the mechanism by which piv2-AZTMP is converted to AZTMP has not been established. To address this question, we have used the recently developed ‘on-line ISRP-cleaning’ HPLC technique to investigate the stability and metabolic fate of piv2-AZTMP (1) in RPMI 1640 medium, (2) in RPMI containing 10% heat-inactivated fetal calf serum, and (3) in CEM cell extracts. Similar studies were conducted starting with mono(pivaloyloxymethyl) azidothymidine 5′-monophosphate (piv2 AZTMP).

From the kinetics of these reactions, it appears that piv2-AZTMP is slowly hydrolyzed to piv1-AZTMP in RPMI and that the metabolic sequence in cell extract and in tissue culture medium is clearly: piv2-AZTMP→ piv1AZTMP→ AZTMP→ AZT. The rate constants are quite different in these three media. Although it is evident that the first step in the metabolism of piv2-AZTMP is catalysed by carboxylate esterase, the enzyme(s) responsible for the second step, piv1-AZTMP→ AZTMP, is less apparent, as carboxylate esterases and/or phosphodiesterases can be taken in account. However, analysis of the kinetic data strongly suggests that carboxylate esterase does not play a significant role and that this second step is mediated by phosphodiesterases. Collectively, these studies demonstrate that piv2-AZTMP is an effective prodrug of AZTMP. They also establish that prv1-AZTMP is an intermediate in this process, and define the sequence of the overall metabolic reaction. With this increased understanding of the metabolism of piv2-AZTMP, it should be possible rationally to design analogues with optimal structural and pharmacological properties for use in vivo.
Orobol: An Inhibitor of Vesicular Stomatitis Virus that Blocks the Synthesis of Viral Nucleic Acids and the Glycosylation of G Protein
Authors: Almela M. J. , Irurzun A. , Carrasco L.
Published: May 2015

The naturally occurring isoflavonoid orobol exhibits antiviral effects against some animal viruses. Addition of the compound after virus entry inhibits the appearance of late viral protein synthesis in Vesicular Stomatitis Virus, influenza, or vaccinia virus-infected cells, but has no effect on poliovirus protein synthesis. Concentrations of the compound above 10–50 Mg ml−1 are sufficient to decrease the synthesis of VSV proteins when added early during infection, but have no effect on viral translation if added later, indicating that orobol does not block VSV translation directly. The synthesis of VSV nucleic acids is one of the targets of this flavonoid. The synthesis of both minus and plus-stranded viral RNA are inhibited by orobol when added during the first 2 h of infection. In addition, this compound interferes potently with the glycosylation of VSV G protein, indicating that orobol has several targets of antiviral action. The possibility that orobol interferes with the function of the cellular vesicular system is discussed.
Purification and Partial Characterization of an Antiviral Active Peptide from Melia Azedarach L.
Authors: Andrei G. , Couto A. S. , de Lederkremer R. M. , Coto C. E.
Published: May 2015

A peptide associated with antiviral activity, isolated from the high plant Melia azedarach L. was purified and partially characterized. Crude extracts of green leaf were purified by gel filtration on Sephadex G-100 followed by DEAE-Sephadex A-25. After column chromatography purification, an active compound II was revealed by elution with chloroform: methanol (95:5). Further analysis using thin-layer chromatography (TLC) revealed three components. With Rf 0.37 (component II), one of these had the highest antiviral activity as determined by inhibition of VSV replication. Compound II (meliacine) also inhibited the in vitro replication of PrV, HSV-1, HSV-2, Junin virus, Tacaribe virus, and Sindbis virus. Chemical analysis showed the antiviral compound to be a cyclic peptide with aMW 2200–2300 containing only aliphatic aminoacids. An unusual feature of the peptide was the presence of a single glucose unit that could be released by mild alkaline treatment which caused degradation of the peptide.
5-Substituted-2′-deoxyuridines as anti-HSV-1 Agents: Synthesis and Structure Activity Relationship
Authors: Herdewijn P. A. M. M.
Published: May 2015

Nucleoside and pyrophosphate analogues are currently in use to treat infection with Human herpesvirus 1 (HSV-1). Both series of compounds exert their activity by inhibition of the viral DNA polymerase either directly, or after anabolic phosphorylation. As the X-ray structure of the viral-specific DNA polymerase is not known, it is difficult to design a nucleoside or non-nucleoside antiviral agent which specifically inhibits this enzyme. Therefore, alternative strategies have relied on extensive structure activity relationship studies of anti-HSV-1 agents in an endeavour to understand the essential structural requirements for activity and hence the design of drugs with increased selectivity. A virus-specific enzyme which plays a crucial role in the selective activation of nucleoside analogues is thymidine kinase. Present knowledge regarding the specificity of herpesvirus thymidine kinase for its 5-substituted-2′-deoxyuridine substrates is reviewed herein.