bluuebunny/crossref_metadata_2025 huggingface dataset:
Drifting Without an Anchor: How Pitch Accents Withstand Vowel Loss
Authors: Baltazani Mary , Kainada Evia
Published: March 2015

We offer an analysis of the influence exerted by segmental rules on the suprasegmental structure in the dialect of Ipiros Greek (IG). In particular we investigated how vowel deletion (VD) affects the phonetic realization of the L*+H pitch accent. Our data empirically establish that the H tone aligns much earlier when VD applies than when it does not. Furthermore, we show that there is a phonological contrast between the nuclear L+H* and the prenuclear L*+H which hinges on early versus late H alignment respectively. We demonstrate that the contrast between the L*+H and the L+H* pitch accents is not compromised by the earlier alignment caused by VD. In other words, intonational contrasts are not endangered by fine phonetic alignment variability within the same category.
Vocative Intonation Preferences are Sensitive to Politeness Factors
Authors: Borràs-Comes Joan , Sichel-Bazin Rafèu , Prieto Pilar
Published: March 2015

Although intonation has been traditionally associated with the expression of attitudes and intentions on the part of the speaker, little is known about whether sociopragmatic factors, such as power or social distance, or situational ones, like physical distance or insistence, can constrain the use and felicity of pitch contours. This article investigates the felicity conditions underlying the choice of three vocative pitch contours in Central Catalan by means of two experiments, namely a production experiment based on the Discourse Completion Task (320 vocative contours produced by 20 speakers), and an acceptability judgment task in which 72 listeners were asked to rate the appropriateness match between a set of vocative contours and a previous discourse context (3,456 responses). The results from the two experiments show that both situational and social politeness factors govern the choice of vocative intonation. Finally, the results are discussed in line with the traditional classification of politeness strategies defined by Brown and Levinson, in the sense that the three intonation contours can be linked to negative, positive, and bald on-record politeness strategies.
The Development of Prosodic Features and their Contribution to Rhythm Production in Simultaneous Bilinguals
Authors: Schmidt Elaine , Post Brechtje
Published: March 2015

This study aims to analyse facilitatory and inhibitory effects of bilingualism on the acquisition of prosodic features, and their contribution to speech rhythm. Here, we concentrate on phrase-final lengthening and accentuation, prosodic features suggested to give rise to different rhythmic percepts even when syllable structure is kept constant across languages. In particular, we investigate whether the development of these two features in Spanish-English simultaneous bilinguals correlates with rhythm development. Our results demonstrate that, as is the case for bilingual rhythm development overall the development of prosodic head- and edge-marking suggests that the two languages are rhythmically separable from around the age of 4, with clearly separate rhythms at the age of 6. Additionally, we can confirm that bilinguals also start out with an even-timed bias in the development of final lengthening and accentuation as reflected by fewer durational differentiations between prosodic syllable types. Furthermore, we can observe the same advantages in bilingual prosodic acquisition in the structurally more complex language that were found in rhythm development. These advantages are manifested by the earlier mastery of robust durational differentiations between syllable types to an adult-like extent. Finally, the comparison with monolingual data demonstrates that bilinguals do, in fact, have an advantage in their development in comparison with monolinguals. We hypothesise that this advantage is borne out of more advanced motor control and possibly more stable mental representations as a result of the dual language input, and dual language production experience.
The use of adaptive equipment following total knee replacement
Authors: McNaught Jamie , Paul Lorna
Published: March 2015

Introduction

This study evaluates the need for adaptive equipment following total knee replacement. There are no recent studies to guide occupational therapists in the optimum time adaptive equipment is required following total knee replacement.

Method

A non-experimental, concurrent mixed methods approach was used. The study population was patients attending for total knee replacement at a large general hospital. Outcome measures were the Oxford Knee Score, the United Kingdom Functional Independence Measure and a weekly diary.

Results

A total of 19 patients were included in the study. Following assessment, 53% ( n = 10) required adaptive equipment following total knee replacement. No significant difference was found in pre-operative pain or function scores, gender or surgical pathway when comparing those who did and did not need adaptive equipment post-operatively. Patients who required adaptive equipment post-operatively had significantly worse pain ( p = 0.030) and function ( p = 0.040) at 6 weeks post-operatively and had significantly longer inpatient stay ( p = 0.041).

Conclusion

Although there are resource implications, patients requiring adaptive equipment following total knee replacement should be assessed by occupational therapy staff 6 weeks post-operatively to ensure optimal functional outcomes following surgery.
Helping occupational performance through engagement: A service evaluation of a programme for informal carers of people with dementia
Authors: Hampson Caroline , Smith Sarah Jane
Published: March 2015

Statement of context

The Helping Occupational Performance through Engagement programme is a series of workshops which aim to equip informal caregivers with the skills and knowledge they require to engage a person with dementia in meaningful daily occupations.

Reflection on practice

Following the initial implementation of the programme, a service evaluation was carried out to establish whether these aims were being met. The evaluation took a mixed methods approach, combining questionnaire and focus group data obtained from participants of the programme.

Implications for practice

Results demonstrated that whilst in general the programme is fulfilling its aims, further evaluation is required to establish the long-term impact of the programme.
An explorative study of the relationship between functional and cognitive decline in older persons with mild cognitive impairment and Alzheimer’s disease
Authors: Vermeersch Sophie , Gorus Ellen , Cornelis Elise , De Vriendt Patricia
Published: March 2015

Introduction

This study explored the relationship between functional decline on three advanced activities of daily living and cognitive decline in elderly persons. The use of everyday technology, driving a vehicle, and performing complex economic activities are advanced activities of daily living domains presumed to be sensitive to early cognitive decline and therefore of interest for the profession of occupational therapy.

Method

We included 45 persons with mild cognitive impairment, 48 persons with Alzheimer’s disease, and 50 cognitively healthy controls. Functional impairment due to cognitive decline was evaluated by the advanced activities of daily living tool. Cognitive disability indices were computed for the investigated advanced activities of daily living domains and correlated with the Mini Mental State Examination and the Cambridge Examination for Mental Disorders of the Elderly, Cognitive Part.

Results

The cognitive disability index for performing complex economic activities and the cognitive disability index for the three advanced activities of daily living domains together differed significantly between the three groups. For the whole sample, the advanced activity of daily living cognitive disability indices correlated strongly with the cognitive measures. Within each separate group, few correlations were found.

Conclusion

This study contributes to the field of knowledge for occupational therapy by emphasizing the value of assessment of advanced activities of daily living in early cognitive decline. For the occupational therapy profession, further research is required in the interaction between functional decline and cognition in early cognitive decline.
Turning evidence into practice: Barriers to research use among occupational therapists
Authors: Samuelsson Kersti , Wressle Ewa
Published: March 2015

Introduction

Research has demonstrated that occupational therapists generally have a positive attitude regarding the use of evidence in their daily practice and decision-making. In addition, occupational therapists are expected to implement evidence-based practice, which is often understood as equivalent to research. However, evidence-based practice might be difficult to reconcile with occupational therapy from a client-centred focus. This study examines what occupational therapists perceive as barriers to research use and discusses the challenge of clinical implementation.

Method

This study uses a descriptive cross-sectional design. The Barriers to Research Utilization Scale questionnaire was mailed to 807 randomly selected Swedish occupational therapists. The response rate was 59%.

Findings

The occupational therapists identified three main barriers to the use of research: insufficient facilities (82%); lack of time to read research (77%); difficulty understanding statistical analyses (75%). Degree of education was shown to affect results; occupational therapists with higher education levels indicated a higher use of research.

Conclusion

Implementing research in clinical practice is a challenge. Occupational therapists are interested but they lack the optimal prerequisites and time.
The content validity and acceptability of the Evaluation of Daily Activity Questionnaire in musculoskeletal conditions
Authors: Hammond Alison , Prior Yeliz , Tennant Alan , Tyson Sarah , Nordenskiold Ulla
Published: March 2015

Introduction

The Evaluation of Daily Activity Questionnaire is a detailed self-report measure of activity limitations. It has two parts, 10 scales of symptom severity and 14 daily activity domains, including 138 activities. It has good psychometric properties in rheumatoid arthritis. The aim was next to establish its content validity and acceptability in seven musculoskeletal conditions: ankylosing spondylitis; osteoarthritis; systemic lupus erythematosus; systemic sclerosis; chronic pain; chronic hand/upper limb musculoskeletal disorders; and primary Sjögren's syndrome.

Method

Participants completed the Evaluation of Daily Activity Questionnaire in their own time, followed by a cognitive debriefing interview to identify their views of importance of including each item and Evaluation of Daily Activity Questionnaire acceptability.

Results

Six to 12 people with each condition were interviewed ( n = 70): 17 men and 53 women, 57.38 (SD 12.83) years of age and with 13.15 (SD 11.02) years condition duration. Overall, all 10 scales and 138 activities were considered important to include. Most found it: had clear instructions (93%); was easy to complete (87%); included about the right amount of activities (77%); and would help an occupational therapist gain insight into the effects of the person's conditions (87%).

Conclusion

The Evaluation of Daily Activity Questionnaire has good content validity and acceptability in these seven conditions.
The Glass Runway
Authors: Stokes Allyson
Published: March 2015

Fashion design is a feminized occupation, but there is a widespread perception that gay male designers are advantaged in receiving awards, publicity, and praise. This article develops the notion of a “glass runway” to explain this inequality. First, using design canons and lists of award recipients, I show that men, especially gay men, receive more consecration than women. Second, I show how men and women are consecrated differently by analyzing the content of 157 entries in Voguepedia’s design canon and 96 fashion media articles. Attributions of value and legitimacy construct a gendered image of the ideal fashion designer through discourses of art and culture that reinforce essentialist ideas about gender difference. Because cultural value is ambiguous, processes of valorization are shaped by gender essentialism, pushing male cultural producers down the glass runway and into the spotlight of fame, consecration, and legitimation. Finally, the case of fashion design offers insights into how intersecting inequalities can shape the glass runway. Gay designers experience both valorization and discrimination from intersections of gender and sexuality.
A Novel Peptide Aldehyde with Activity against Human Cytomegalovirus in Two Different in Vivo Models
Authors: Weber Olaf , Reefschläger Jürgen , Rübsamen-Waigmann Helga , Raddatz Siegfried , Hesseling Matthias , Häbich Dieter
Published: March 2015

Novel peptide aldehydes (PAs) were identified as potent inhibitors of human cytomegalovirus (HCMV) in vitro. Although these compounds were highly effective against HCMV, they did not exhibit any activity against murine cytomegalovirus (MCMV). The purpose of this study was to test the antiviral activity of PA 8 as a representative of this novel class of inhibitors against HCMV in vivo. Because of the strict species specificity of HCMV we had to use two artificial animal models. In the first model, HCMV-infected human cells were entrapped into agarose plugs and transplanted into mice. In the second model, SCID mice were transplanted with human tissues that were subsequently infected with a clinical isolate of HCMV. In these two models the antiviral activity of PA 8 was clearly demonstrated, ganciclovir only being slightly superior in its in vivo antiviral activity.
Pharmacokinetics of Bis(t-butyl-SATE)-AZTMP, a Bispivaloylthioethyl Prodrug for Intracellular Delivery of Zidovudine Monophosphate, in Mice
Authors: Tan Xiaolei , Boudinot F Douglas , Chu Chung K , Egron David , Perigaud Christian , Gosselin Gilles , Imbach Jean-Louis
Published: March 2015

The pharmacokinetics of a bispivaloylthioethyl prodrug of zidovudine monophosphate (AZTMP), bis(t-butyl-SATE)-AZTMP, and intracellular conversion of the prodrug to AZTMP were characterized following intravenous (i.v.) and oral (p.o.) administration of the prodrug to mice. Concentrations of bis(t-butyl-SATE)-AZTMP, AZTMP and zidovudine (AZT) in blood, red blood cells, plasma, brain and lymph nodes were determined by HPLC. Following i.v. administration of bis(t-butyl-SATE)-AZTMP, concentrations of the prodrug declined rapidly with low levels of the prodrug detected until 4 h. Both bis(t-butyl-SATE)-AZTMP and AZTMP were detected in brain 3 min after dosing. AZTMP was found in both plasma and peripheral red blood cells, peaking at approximately 30 min and remaining detectable until 2 h. No AZTMP was detected in lymph nodes. Compared to the pharmacokinetics of AZT following its i.v. administration, i.v. administration of bis(t-butyl-SATE)-AZTMP produced lower peak concentrations of AZT in plasma, peripheral red blood cells, brain and lymph nodes. However, terminal half-lives of AZT were significantly prolonged following administration of the prodrug. Following p.o. administration of bis(t-butyl-SATE)-AZTMP, neither the prodrug nor AZTMP were detectable in whole blood. The conversion of AZT from bis(t-butyl-SATE)-AZTMP in plasma and peripheral red blood cells following p.o administration was 12.1% of that following i.v. administration of the prodrug. Bis(t-butyl-SATE)-AZTMP demonstrated promising potential for intracellular delivery of AZTMP. The prodrug also prolonged the retention of AZT in mice, and particularly increased delivery of AZT to the lymphatic and central nervous systems.
In vitro Anti-HIV-1 Activity of sn-2-Substituted 1-O-Octadecyl-sn-Glycero-3-Phosphonoformate Analogues and Synergy with Zidovudine
Authors: Hostetler Karl Y , Hammond Jennifer L , Kini Ganesh D , Hostetler Saskia E , Beadle James R , Aldern Kathy A , Chou Ting-Chao , Richman Douglas D , Mellors John W
Published: March 2015

Monoalkyl ether lipid analogues of foscarnet (phosphonoformate, PFA) exhibit substantially greater in vitro antiviral activity than unmodified PFA against human immunodeficiency virus type 1 (HIV-1). Our previous studies indicate that the length of the alkyl chain must be 14–22 carbons for optimal antiviral activity. To further evaluate the structure-activity relationship, we prepared 1-O-octadecyl- sn-glycerol analogues of PFA with various substitutions at the sn-2 position of glycerol and determined the effect of structure on in vitro antiviral activity and selectivity against HIV-1 in MT-2 and CD4-expressing HeLa cells (HT4–6C). We also studied combinations of zidovudine with PFA, 1-O-octadecyl-2-O-methyl- sn-glycero-3-PFA, or 1-O-octadecyl- sn-glycero-3-PFA and calculated their combination index values against HIV-1 in HT4–6C cells. Alkyl substitutions of one to four carbons at the sn-2 position of glycerol showed optimal antiviral activity. Both alkyl ether lipid analogues were strongly synergistic with zidovudine over a wide range of drug ratios and concentrations. 1-O-octadecyl- sn-glycerol analogues of PFA have selective antiviral properties and warrant further evaluation as potential antiretroviral drugs.
Polyanions — A Lost Chance in the Fight against HIV and other Virus Diseases?
Authors: Lüscher-Mattii M
Published: March 2015

Polyanions are known to exhibit potent antiviral activity in vitro, and may represent future therapeutic agents. This review summarizes literature reports, pertinent to anionic polymers as antiviral agents. The in vitro antiviral effects of numerous polyanionic compounds (sulphated polysaccharides, negatively charged serum albumin and milk proteins, synthetic sulphated polymers, polymerized anionic surfactants and polyphosphates) are described. This class of antiviral agent exhibits several unique properties that are not shared by other presently known antiviral agents: (i) a remarkable broad-spectrum antiviral activity against HIV-1, HIV-2 and a series of other enveloped viruses; (ii) the ability to inhibit syncytium formation between HIV-infected and normal CD4 T lymphocytes, a mechanism that drastically enhances HIV infectivity; and (iii) a low induction of viral drug-resistance. There is increasing evidence that polyanions interfere with the fusion process, a vital step in the viral replication cycle. The inhibition of virus-cell fusion appears to be the source of the antiviral activity of polyanions. In vivo, the pharmacological properties of polyanions result in a low bioavailability of the drugs to their viral targets, and hence a poor antiviral activity in vivo. It is suggested that polyanions must be used in combination with drug delivery systems in order to become therapeutically useful antiviral agents. Some drug delivery systems are briefly discussed.
Antiviral Therapy for Enteroviruses and Rhinoviruses
Authors: Rotbart Harley A
Published: March 2015

The picornaviruses are a diverse group of viral pathogens that together comprise the most common causes of infection of humans in the developed world. Within the picornavirus family are three well-known groups of human pathogens — the rhinoviruses, the enteroviruses (including polioviruses, coxsackieviruses and echoviruses) and the hepatoviruses (including hepatitis A virus). This article will focus on the rhinoviruses and enteroviruses, agents for which substantial effort has been expended, and recent successes reported, toward the development of safe and effective antiviral therapy.
The Bystander Effect Mediated by the New Murine Gammaherpesvirus 72 — Thymidine Kinase/5′-Fluoro-2′-Deoxyuridine (MHV72-TK/5-FUdR) System in Vitro
Authors: Raslova Hana , Matis Jan , Rezuchova Ingeborg , MacAkova Katarina , Berebbi Monique , Kudelova Marcela
Published: March 2015

To investigate the potential of murine gammaherpesvirus 72 thymidine kinase (MHV-72-TK) to act as a suicide gene, we used a mammalian expression vector on rat fibroblastoid cells deficient in the cellular TK gene. Substrate specificity was assessed in vitro in cells with stable expression of MHV-72-TK. The Herpes simplex virus 1-TK (HSV-1-TK) was used as a reference suicide gene. Unlike HSV-1-TK modified cells, which were sensitive to ganciclovir (GCV) (IC50=9.7 μM), cells modified by MHV-72-TK did not show sensitivity to this drug. The use of 3′-azido-3′-deoxythymidine (AZT) and (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) did not affect the growth of cells expressing either MHV-72-TK or HSV-1-TK in the range of concentration used for AZT (0–375 μM) and for BVDU (0–50 μM). In contrast, 5′-fluoro-2′-deoxyuridine (5-FUdR) was extremely cytotoxic and effectively killed MHV-72-TK expressing cells (IC50 value 2.1 μM). This value was 16 times lower than that required to kill cells expressing HSV1-TK. To test whether the bystander effect between two heterologous cell types could be mediated by the MHV-72-TK/5-FUdR system in vitro, cells expressing MHV-72-TK were co-cultured with the tumour fibroblastoid cell line NAD for 48 hours before the drug (10.8 μM) was added. The cell mixtures contained various ratios of cells expressing MHV-72-TK (0 to 50% of total cells). Only 1% of MHV-72-TK-expressing cells were needed to enhance mouse tumour cell killing and to decrease the survival rate to 25.6%. The bystander effect was more pronounced when 10% of cells expressing MHV-72-TK were used, decreasing survival to 17.4%. In parallel, the same concentration of 5-FUdR dose only marginally inhibited tumour cell growth in the absence of exogenous TK activity (84% survival). These results demonstrate the efficiency of MHV-72-TK as a suicide gene when 5-FUdR is used as a pro-drug. When sequenced, MHV-72-TK proved to be identical to MHV-68 strain TK.
Novel Mouse Models for the Investigation of Experimental Drugs with Activity against Human Varicella-Zoster Virus
Authors: Weber Olaf
Published: March 2015

Suitable small animal models for the testing of antiviral agents with activity against human varicella-zoster virus (VZV) have so far been lacking. Mice and other animals have been found to not be susceptible to VZV infection. The model of choice for drug development has been the infection of monkeys using simian varicella virus (SVV). However, while primates offer potential as models of human varicella disease, their use is limited as experimental models in antiviral research. We have developed two simple mouse models that support replication of human VZV in vivo. In the first, SCID mice were transplanted with human umbilical cord (umbilical cord cushion model) and subsequently infected with VZV. After infection, we were able to demonstrate increasing titres of viral DNA over a 9-day period. In the second model, biocompatible hollow fibres were used for encapsulation of VZV-infected cells. The hollow fibres were then transplanted into immunodeficient and immunocompetent mice and infectious virions were re-isolated. In addition, we demonstrated that both the umbilical cord cushion and the hollow fibre models are suitable tools to test antiviral compounds. Administration of BVDU [brivudine, Helpin, (E)-5-(2-bromovinyl)-2′-deoxyuridine] significantly reduced the VZV titres in both models.
Treatment of Cowpox Virus Respiratory Infections in Mice with Ribavirin as a Single Agent or Followed Sequentially by Cidofovir
Authors: Smee Donald F , Bailey Kevin W , Sidwell Robert W
Published: March 2015

To better understand the potential of ribavirin in the treatment of orthopoxvirus infections (such as those acquired through bioterrorist activities), the efficacy of the drug was studied in a cowpox respiratory infection model in mice under varying disease severity. Mice did not survive a high intranasal cowpox virus challenge [3 × 106 plaque forming units (pfu)/animal] treated with subcutaneous ribavirin (100 mg/kg/day for 5 days), but lived 3.9 days longer than placebos. In contrast, 100% of animals receiving the same dose of drug survived a 3 × 105 pfu challenge compared with 0% survival of those that received placebo. Survival rates of 50 and 30% occurred with ribavirin doses of 50 and 25 mg/kg/day, respectively. At the 100 mg/kg/day dose, ribavirin reduced lung virus titres 40-fold on day 6 of the infection relative to titres in the placebo group. Weight loss resulting from illness and mean lung weights of mice treated with ribavirin were also significantly reduced. Mice were infected intranasally with the high 3 × 106 pfu virus challenge dose and treated with 100 mg/kg/day ribavirin for 5 days, followed by single injections of 75 mg/kg cidofovir on day 6, 7, 8 or 9. Cidofovir alone (without ribavirin) administered on day 6 had no beneficial effect on disease outcome. Ribavirin alone increased the mean time to death by 3.7 days. Ribavirin treatment for 5 days followed by cidofovir treatment on days 6 and 7 significantly increased the mean time to death beyond that achieved with ribavirin alone by 8.2 and 4.4 days, respectively, with 30 and 40% of mice surviving the infection. These results suggest that many individuals infected with an orthopoxvirus by aerosol route would benefit by a course of ribavirin therapy. Later, the fewer number of very sick individuals could be treated with intravenous cidofovir.
Anti-HIV-1 Activity of Calanolides Used in Combination with other Mechanistically Diverse Inhibitors of HIV-1 Replication
Authors: Buckheit Robert W , Russell Julie D , Xu Ze-Qi , Flavin Michael
Published: March 2015

The natural product (+)-calanolide A, a unique non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 replication, is currently being evaluated in clinical trials in the USA. (+)-Calanolide A, the congeners costatolide and dihydrocostatolide, and (+)-12-oxo(+)-calanolide A, were evaluated in combination with a variety of mechanically diverse inhibitors of HIV replication to define the efficacy and cellular toxicity of potential clinical drug combinations. These assays should be useful in prioritizing the use of different combination drug strategies in a clinical setting. The calanolides exhibited synergistic antiviral interactions with other nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Additive interactions were also observed when the calanolides were used with representative compounds from each of these classes of inhibitors. No evidence of either combination toxicity or antagonistic antiviral activity was detected with any of the tested compounds. The combination antiviral efficacy of three-drug combinations involving the calanolides, and the efficacy of two- and three-drug combinations using a (+)-calanolide A-resistant challenge virus (bearing the T139I amino acid change in the reverse transcriptase), was also evaluated in vitro. These assays suggest that the best combination of agents based on in vitro anti-HIV assay results would include the calanolides in combination with lamivudine and nelfinavir, since this was the only three-drug combination exhibiting a significant level of synergy. Combination assays with the (+)-calanolide A-resistant strain yielded identical results as seen with the wild-type virus, although the concentration of the calanolides had to be increased.
Spectrum of Virus Inhibition by Consensus Interferon YM643
Authors: Yasuda Shuhei , Huffman John H , Smee Donald F , Sidwell Robert W , Miyata Keiji
Published: March 2015

The spectrum of viruses inhibited by a genetically engineered consensus interferon (IFN) YM643 (interferon alfacon-1) was evaluated using a cytopathic effect inhibition assay or plaque inhibition assay for five DNA viruses and 12 RNA viruses. This activity was compared to that of natural IFN-α derived from Namalwa lymphoblastoid cell line [IFN-a (Namalwa)]. The viruses inhibited by both IFNs were herpesvirus types 1 and 2, human cytomegalovirus, varicella-zoster virus, vesicular stomatitis virus, yellow fever virus, bovine viral diarrhoea virus, Semliki Forest virus, western equine encephalitis virus, encephalomyocarditis virus, rhinovirus type A, respiratory syncytial virus, Newcastle disease virus and influenza virus type A (H1N1). Neither IFN inhibited coxsackie virus B1, reovirus type 3 or vaccinia virus in the experimental conditions used. The specific activity of YM643 in human cells generally ranged from 3.6¥107 to 2.1¥109 IU/mg, which was greater than that of IFN-a (Namalwa), which ranged from 3.1¥106 to 4.6¥108 IU/mg against all sensitive viruses, except human cytomegalovirus and rhinovirus type 1A, which displayed approximately equal sensitivity to both IFNs. Significantly, the potency of YM643 against bovine viral diarrhoea virus and yellow fever virus, which were selected to serve as surrogates of hepatitis C virus, equalled or exceeded that of IFN-a (Namalwa). These results suggest that the genetically engineered YM643 is more potent than natural IFN-a.
Synthesis and Anti-Rhinovirus Activity of 2-Styrylchromones
Authors: Desideri N , Conti C , Mastromarino P , Mastropaolo F
Published: March 2015

2-Styrylchromones were synthesized as vinylogues of 2-phenylchromones (flavones), a broad class of anti-rhinovirus compounds. The antiviral activity of 2-styrylchromones and 3-hydroxy-1-(2-hydroxyphenyl)-5-phenyl-2,4-pentadien-1-ones, which are intermediates in the synthesis, was evaluated against two selected serotypes of human rhinovirus, 1B and 14, by a plaque reduction assay in HeLa cell cultures. All of the compounds interfered with HRV 1B replication, with the exception of 3-hydroxy-1-(2-hydroxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadien-1-one. The majority of derivatives were also found to be effective against serotype 14, often with a higher potency.
Characterization of Inhibitory Action of Concanamycins against Herpes Simplex Virus
Authors: Hayashi Kyoko , Kawauchi Mari , Nakai Chieko , Sankawa Ushio , Seto Haruo , Hayashi Toshimitsu
Published: March 2015

Concanamycins A (Conmy A) and B (Conmy B), well-known inhibitors of the vacuolar proton-ATPase, were isolated from the culture broth of Streptomyces sp. strain FK51 as antiherpetic agents. These compounds showed potent inhibition of herpes simplex virus type 1 (HSV-1) replication in an in vitro assay system, having antiviral activities with 50% inhibitory concentrations of 0.072 and 0.51 ng/ml for Conmy A and Conmy B, respectively. While the attachment of HSV-1 to Vero cells was not inhibited, both of the compounds blocked the penetration of virus into host cells. When added to the late stages of virus replication, the concanamycins also exerted marked inhibitory effects on the production of viruses. Release of progeny viruses was found to be suppressed by the agents. SDS-PAGE analysis of isotope-labelled HSV-specific proteins revealed that the synthesis of β proteins was moderately inhibited and some of the glycoproteins were synthesized with reduced molecular weights. Western blot analysis using antibodies against two HSV-specific glycoproteins (gC and gD) showed differences in their syntheses between untreated and Conmy A-treated cells. Syncytium formation by HSV-1 strain HF was inhibited, and small plaques with rounded cells were formed in Conmy A-treated cell cultures. When wild-type HSV-1 was serially propagated under the selective pressure of Conmy A, and the resulting progeny viruses were grown in drug-free medium, their plaque morphology of syncytium and sensitivity to Conmy A were the same as those of parent virus. From these findings, antiherpetic activities of Conmy A and B might be mainly dependent on their activities as vacuolar proton-ATPase inhibitors with intracellular translocation of glycoproteins and the inhibition of the maturation of virus glycoproteins.
Enhancement of Anti-Herpetic Activity of Glycyrrhizic Acid by Physiological Proteins
Authors: Lampis G , Deidda D , Pinza M , Pompei R
Published: March 2015

Some enzymes present in biological fluids, such as lysozyme (LYS) and lactoferrin (LAC), are known to possess antibacterial and antiviral activity, against herpesviruses in particular. It will be shown in this paper that their combination with a natural triterpene, namely glycyrrhizic acid (GLA), gives significant results in enhancing the antagonistic activity on HSV1 in in vitro assays. Data elaboration was carried out by calculation of the FIC index (fractional inhibitory concentration) for each combination of the three compounds and by a three-dimensional evaluation of the inhibiting combinatory effects, which indicated the percentage of the synergistic action. A FIC index equal to or below 0.5 demonstrated a significant synergistic effect between two substances. Considering each single compound, the 50% inhibiting doses on viral replication (ID50) were 252±53 μg/ml for LAC, 497±165 μg/ml for LYS and 740±125 μg/ml for GLA. The combination of LAC and GLA showed a clear synergistic effect, with a FIC index of 0.08 and a potentiating activity which, for some doses, was up to 1.5 log10 of difference (from about 5.5×106 to 105 pfu/ml). The combinations of GLA and LYS, and LYS and LAC showed a less significant synergistic activity. These findings led to the conclusion that some physiological proteins, even at concentrations usually present in some body fluids, may enhance the anti-herpetic activity of a natural compound such as GLA.
Cytokines and HIV-1: Interactions and Clinical Implications
Authors: Kedzierska Katherine , Crowe Suzanne M
Published: March 2015

Cytokines play an important role in controlling the homoeostasis of the immune system. Infection with HIV results in dysregulation of the cytokine profile in vivo and in vitro. During the course of HIV-1 infection secretion of T-helper type 1 (Th1) cytokines, such as interleukin (IL)-2, and antiviral interferon (IFN)-γ, is generally decreased, whereas production of T helper type 2 (Th2) cytokines, IL-4, IL-10, proinflammatory cytokines (IL-1, IL-6, IL-8) and tumour necrosis factor (TNF)-α;, is increased. Such abnormal cytokine production contributes to the pathogenesis of the disease by impairing cell- mediated immunity. A number of cytokines have been shown to modulate in vitro HIV-1 infection and replication in both CD4 T lymphocytes and cells of macrophage lineage. HIV-inductive cytokines include: TNF-α, TNF-p, IL-1 and IL-6, which stimulate HIV-1 replication in T cells and monocyte-derived macrophages (MDM), IL-2, IL-7 and IL-15, which upregulate HIV-1 in T cells, and macrophage-colony stimulating factor, which stimulates HIV-1 in MDM. HIV-suppressive cytokines include: IFN-α, IFN-β and IL-16, which inhibit HIV-1 replication in T cells and MDM, and IL-10 and IL-13, which inhibit HIV-1 in MDM. Bifunctional cytokines such as IFN-γ, IL-4 and granulocyte-macrophage colony-stimulating factor have been shown to have both inhibitory and stimulatory effects on HIV-1. The β-chemokines, macrophage-inflammatory protein (MIP)-1α, MIP- 1β and RANTES are important inhibitors of macrophage-tropic strains of HIV-1, whereas the α-chemokine stromal-derived factor-1 suppresses infection of T-tropic strains of HIV-1. This review outlines the interactions between cytokines and HIV-1, and presents clinical applications of cytokine therapy combined with highly active antiretroviral therapy or vaccines.
Bicyclic Nucleoside Inhibitors of Varicella-Zoster Virus (VZV): Pd-Catalysed Synthesis of 5-aryl Derivatives and Their Biological Evaluation
Authors: Carangio A , McGuigan C , Andrei G , Snoeck R , De Clercq E , Balzarini J
Published: March 2015

We have recently reported the discovery of an entirely new category of potent antiviral agents based on novel deoxynucleoside analogues with unusual fluorescent bicyclic furano base moieties. In order to probe structure activity relationships we prepared a series of 5-aryl derivatives of the lead structures. We herein report the synthesis, characterization, and antiviral evaluation of these novel compounds. 5-Aryl derivatives of the parent nucleosides were synthesized from the corresponding alkynyl deoxyuridines using a simple, versatile and efficient one-step conversion, based on a palladium-catalysed cyclization. As previously noted for the lead compounds, a long alkyl side-chain on the base moiety is essential for antiviral activity. Even with the optimal (C8-C10) side-chain, most of the present compounds are markedly less active than their parent structures. However, some of the synthesized compounds still retained antiviral activity at non-cytotoxic concentrations, being only two- to fivefold less active than the current clinical agent acyclovir. Possible reasons for this structure activity relationship are discussed.
Treatment of Chronic Viral Hepatitis
Authors: Wright Mark , Main Janice , Thomas Howard C
Published: March 2015

Significant advances have been made in the treatment of both hepatitis B and C. Cure for the majority is becoming reality. Combination regimens are now established therapy in hepatitis C and the near future will see the adoption of a similar approach to hepatitis B. Interferon alpha therapy remains important, with the development of more efficacious pegylated forms. In this article we review current therapy and discuss future strategies of the therapy for chronic viral hepatitis.
Mechanisms of Action of Ribavirin in Antiviral Therapies
Authors: Tam Robert C , Lau Johnson YN , Hong Zhi
Published: March 2015

Although ribavirin was originally synthesized over 30 years ago and has been used to treat viral infections as monotherapy (respiratory syncytial virus and Lassa fever virus) or with interferon-α (IFN-α) as combination therapy (hepatitis C virus), the precise mechanism of its therapeutic activities remains controversial. In this review we focus on two main biological properties of ribavirin: its indirect and direct antiviral activities (with particular emphasis on its efficacy against chronic hepatitis C infection). Each property could individually or collectively account for its clinical efficacy against viral infections. First, with emphasis on the evidence for indirect activities of ribavirin, we will review the clinical observations that suggest that the immunomodulatory properties of ribavirin can in part account for its antiviral activities in vivo. We will then describe the mode of ribavirin's direct antiviral activities. These direct activities can be ascribed to several possible mechanisms, including the recently described activity as an RNA mutagen, a property that may be important in driving a rapidly mutating RNA virus over the threshold to ‘error catastrophe′.
Antipoliovirus Flavonoids from Psiadia Dentata
Authors: Robin Valérie , Irurzun Alicia , Amoros Maryvonne , Boustie Joël , Carrasco Luis
Published: March 2015

The search for antiviral agents against vesicular stomatitis virus, herpes simplex virus type 1 and poliovirus type 2 in plants extracts, led to the isolation of two antipoliovirus flavonoids from the medicinal plant Psiadia dentata (Cass.) DC, Asteraceae: 3-methylkaempferol and 3,4′-dimethylkaempferol. The antipoliovirus activity of both compounds was estimated by comparison with 3-methylquercetin, guanidine and Ro-090179. The most potent inhibitor of poliovirus replication was 3-methylkaempferol, and therefore we investigated its mechanism of action. We showed, using the inhibition of [3H]uridine incorporation in viral RNA and performing a dot-blot with one RNA probe specific for the poliovirus genomic strand RNA, that 3-methylkaempferol inhibits the genomic RNA synthesis of poliovirus.
Synthesis and Antiviral Evaluation of Phosphoramidate Derivatives of (E)-5-(2-Bromovinyl)-2′-Deoxyuridine
Authors: Harris SA , McGuigan C , Andrei G , Snoeck R , De Clercq E , Balzarini J
Published: March 2015

We report the design, synthesis and antiviral evaluation of a number of lipophilic, masked phosphoramidate derivatives of the antiherpetic agent ( E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU), designed to act as membrane soluble prodrugs of the free nucleotide. The phosphoramidate derivatives of BVDU that contain L-alanine exhibited potent anti herpes simplex virus type 1 and varicella-zoster virus activity but lost marked activity against thymidine kinase-deficient virus strains. The phosphoramidate derivative bearing the amino acid α,α-dimethylglycine showed poor activity in all cell lines tested. It appears that successful kinase bypass by phosphoramidates is highly dependent on the nucleoside analogue, amino acid and ester structure, as well as the cell line to which the drugs are exposed.
Anti-HIV-1 Activity and Structure-Activity Relationship of Cepharanoline Derivatives in Chronically Infected Cells
Authors: Baba M , Okamoto M , Kashiwaba N , Ono M
Published: March 2015

Cepharanthine (12- O-methyl cepharanoline) is a plant alkaloid and has been shown to inhibit tumour necrosis factor-α- or phorbol 12-myristate 13-acetate-induced HIV-1 replication in the chronically infected promonocytic cell line, U1. Its mechanism of action is considered to be the inhibition of nuclear factor κB, a potent inducer of HIV-1 gene expression. In this study, we have synthesized 96 derivatives of cepharanoline, including cepharanthine, and examined their inhibitory effects on HIV-1 replication in U1 cells. Among the 12- O-alkyl derivatives, cepharanthine proved to be the most active, and the activity decreased as the length of the alkyl chain increased. All of the 12- O-acyl derivatives were totally inactive, while a few 12- O-carbamoyl derivatives displayed modest activity. Since 12- O-ethyl derivatives were found to be as active as cepharanthine against HIV-1 replication, we further synthesized various 12- O-ethyl derivatives of cepharanoline. Among the derivatives, five proved to be more active inhibitors than cepharanthine, and the most active compound was 12- O-ethylpiperazinyl cepharanoline. The 50% effective concentrations of this compound and cepharanthine were 0.0041 and 0.028 μg/ml (0.0060 and 0.046 μM), respectively.
Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro
Authors: Smee Donald F , Bray Mike , Huggins John W
Published: March 2015

Two inhibitors of cellular inosine monophosphate dehydrogenase, mycophenolic acid (MPA) and ribavirin, were evaluated for inhibitory activity against orthopoxviruses. Unrelated antipoxvirus agents tested for comparison included 6-azauridine, cidofovir (HPMPC) and cyclic HPMPC. MPA inhibited camelpox, cowpox, monkeypox and vaccinia viruses by 50% in plaque reduction assays at 0.2–3 μM in African green monkey kidney (Vero 76) and mouse 3T3 cells. Ribavirin was considerably more active in 3T3 cells (50% inhibition at 2-l2 μM) than in Vero 76 cells (inhibitory at 30–250 μM) against these viruses. In cytotoxicity assays, MPA and ribavirin were more toxic to replicating cells than to stationary cell monolayers, with greater toxicity seen in 3T3 than in Vero 76 cells. The superior antiviral potency and increased toxicity of ribavirin in 3T3 cells was related to greater accumulation of mono-, di- and triphosphate forms of the drug compared with Vero 76 cells. For both MPA and ribavirin, virus inhibition was closely correlated to the extent of suppression of intracellular guanosine triphosphate (GTP) pools. Treatment with extracellular guanosine (which restored intracellular GTP levels) did not lead to complete reversal of the anticowpox virus activity of ribavirin. This suggests that other modes of virus inhibition also appear to contribute to the anti-orthopoxvirus activity of ribavirin. Biological differences in mode of action and immunosuppressive potential between ribavirin and MPA may account for why the former compound is active against orthopoxvirus infections in animals and the latter inhibitor is not.
Utilization of Alpha-1-Acid Glycoprotein Levels in the Serum as a Parameter for in Vivo Assay of Influenza Virus Inhibitors
Authors: Sidwell Robert W , Wong Min-Hui , Bailey Kevin W , Barnard Dale L , Jackson M Keven , Smee Donald F
Published: March 2015

Alpha-1-acid glycoprotein (AGP), an acute phase protein in serum assayed by single radial immunodiffusion using a commercially available kit, was found to significantly increase in mice infected with influenza A and B viruses. Experiments were run to determine the rate of increase of serum AGP and its relation to other influenza disease parameters, including lung consolidation, development of lung virus titres, decline in arterial oxygen saturation (SaO2), histopathological changes in the lung, and death of the animal. Maximal AGP levels occurred by day 3 in the animals, at about the same time lung virus titres reached their peak and inflammatory effects were evident in the lung. Serum levels of AGP were then compared with other disease parameters in the evaluation of the anti-influenza A and B virus efficacy of oseltamivir and ribavirin in mice. Treatment was by oral gavage twice daily for 5 days, beginning 4 h before virus exposure using doses of 100, 10, and 1 mg/kg per day of oseltamivir and 75 mg/kg per day of ribavirin. Against the influenza A infection, significant inhibition of death, SaO2 decline, and lung consolidation was seen at all doses of each compound; day-6 AGP levels were reduced in a dose-responsive manner. Lung virus titres were lessened at this time, but to a significant degree only at the high dose of oseltamivir and by ribavirin. The influenza B virus infection, which appeared more severe than the influenza A infection, was also significantly inhibited by both compounds, but to a lesser extent. The serum AGP levels were again lessened by therapy with both compounds. The influence of challenge dose of influenza A virus on AGP level and on the antiviral activity of 20 mg/kg per day of oseltamivir, administered by oral gavage, was determined in mice. The AGP level was in proportion to the viral challenge dose; oseltamivir significantly inhibited AGP levels and all other disease parameters regardless of size of viral inoculum. These data indicate murine AGP levels to be markedly stimulated by infection with influenza A and B viruses, and the level of the protein to be an additional measure of antiviral efficacy.
Hepatic and Intestinal Contributions to Pharmacokinetic Interaction of Indinavir with Amprenavir, Nelfinavir and Saquinavir in Rats
Authors: Gao Weihua , Kishida Tomoyuki , Kageyama Michiharu , Kimura Keisuke , Yoshikawa Yukako , Shibata Nobuhito , Takada Kanji
Published: March 2015

To elucidate the aspects of pharmacokinetic interactions among HIV protease inhibitors (PIs), we investigated the effects of indinavir (IDV) on the hepatic and intestinal first-pass metabolism of other HIV PIs, amprenavir (APV), saquinavir (SQV) and nelfinavir (NFV), in rats. After oral co-administration with IDV, the area under the concentration versus time curves (AUC) of APV, SQV and NFV increased significantly by 1.6-, 9.5- and 2.3-fold, respectively, compared with mono-administration. After intravenous administration, the AUC of APV, SQV and NFV also increased in the presence of IDV by 1.4-, 1.2- and 1.5-fold, respectively. Mean concentrations of APV, SQV and NFV in the liver extracellular fluid, measured using a liver microdialysis method, were very low compared with their Michaelis constants regardless of co-administration of IDV, suggesting that APV, SQV and NFV metabolism follows linear kinetics in the liver. This finding also indicates that metabolism of PIs depended on the metabolic clearance rate in the liver microsomes. The oral bioavailability of SQV in the presence of IDV increased markedly by 8.5-fold, and that of APV and NFV also increased by 1.2- and 1.5-fold, respectively. On the basis of the well-stirred model, the hepatic availabilities of APV, SQV and NFV in the presence of IDV increased by 1.1-, 1.4- and 1.5-fold, and the intestinal availabilities increased by 1.1-, 6.2- and 1.1-fold, respectively. These results suggest that both hepatic and intestinal metabolism were essentially involved in the interactions between IDV and other HIV PIs, and the degree of those contributions varied with each combination of HIV Pls.