bluuebunny/crossref_metadata_2025 huggingface dataset:
A Practical Design Exercise for First-Year Students
Authors: Hill M. , Bryant I. P.
Published: May 2015

This paper presents a rationale for a way of introducing first-year mechanical engineering students to engineering design. Emphasis is placed on practical design considerations and small group discussion during laboratory exercises, providing an experience of the process of making engineering judgements. Knowledge of component terminology and operating principles is tested. The exercise supports the findings of educational researchers on the effectiveness of small group learning in relation to practical and diagnostic tasks.
Heat Transfer from Immersed Slender Bodies
Authors: Erens P. J. , Dreyer A. A.
Published: May 2015

This article describes a simple, low-cost experiment which could be used as a good educational example for students, combining the effects of radiation, natural convection, forced convection and condensation into one experiment. Many correlations are available for the calculation of the heat transfer from single, slender bodies (or tubes) immersed in a moving fluid. Even for a simple cylindrical tube the predicted heat transfer coefficients differ significantly from correlation to correlation. For more complex tube geometries fewer correlations could be found in the literature. The correlation by Gnielinski [1] appeared the most favourable since this single correlation is valid for many tube geometries (not just for cylindrical tubes). A simple experimental technique is described to measure the heat transfer coefficient on the outside of various tubular profiles in a fluid stream. This technique was then used to evaluate heat transfer coefficients on six different tubes, ranging from a circular cylinder to a complex T-shaped tube. The experimental data for all six tubes showed very good agreement with the correlation of Gnielinski.
Do We Need Mohr's Circle?
Authors: Milner P. R.
Published: May 2015

Mohr's circle has traditionally played an important part in the presentation of stress and strain at a point to undergraduates and in analysing the output of strain-gauge rosettes. In the former role it seems to create widespread confusion among students with regard to assigning principal stresses to their associated directions. A more straightforward and fail-safe method of performing this task is described using linear transformations and eigenvalue analysis, a method which can be extended into analysis of three-dimensional stress states without introducing any new concepts. The application to examining stresses on oblique planes, in particular the octahedral stresses and the principal shear stresses, is outlined, and the response of students and colleagues to the method is reported.
How Well Prepared are Students for Undergraduate Engineering Mathematics?
Authors: Lawson Duncan A.
Published: May 2015

Many universities admit students to degree courses in mechanical engineering from a wide variety of backgrounds. The majority enter with a study of A level mathematics. An increasing proportion enter having previously studied for BTEC qualifications. The conventional rule of thumb which is used is that BTEC level 3 is equivalent to A level. In this paper this rule of thumb is examined by comparing the performance of A level and BTEC students in a diagnostic test, taken at the start of their course, and the results of the end-of-year examination. The results of students entering the mechanical engineering stream of degree courses at Coventry University in 1991 and 1992 are used to provide the data for this study. The diagnostic test results also show the key areas of weakness in the level of mathematical competence of many students on entry to universities.
Piezomechanics as a Component of Mechatronics
Authors: Bansevicius R. , Dalay B. S. , Knight J. A. G.
Published: May 2015

The introduction of smart materials based on piezo ceramics has presented a challenge for current future generations of engineering technologists. Opportunities for new ingenious products and processes through the application of a mechatronic design philosophy has led to an increased performance expectation. The task of educating engineers is recognized as being crucial to satisfying this requirement. A project-based case study is presented as a means of developing the necessary multidisciplinary skills.
The Kern of an Ellipse
Authors: Sassani F.
Published: May 2015

If the point of application of an axial force on a column falls inside a certain area within the cross-section, only stresses of one sign arise on the cross-section. This area is called the kern of the cross-section. For regular cross-sectional shapes, the dimensions of the kern can be determined analytically. In the case of irregular shapes graphical or computer techniques can be used. In this article the kern of an ellipse is analytically determined.
Solving Laminar Boundary Layers as a Sequence of Falkner—Skan Flows
Authors: von Backström Theodor W. , Furstenberg Ludwig
Published: May 2015

A method for predicting the momentum thickness and skin friction coefficient of laminar boundary layers for arbitrary free–stream velocity distributions has been formulated. The method combines the Thwaites–Walz and Falkner–Skan methods with a numerical technique. The method is simple enough for undergraduate use. It is shown to be accurate when using only a few intermediate points up to the point of separation, making the method suitable for hand-calculation. The method also allows the integration of the Falkner–Skan equation at any particular station to obtain the velocity profile through the boundary layer.
A Six-Legged Walking Robot as a Senior Design Project
Authors: Gürocak H. B. , Ancona J. M.
Published: May 2015

In this article the design of a six-legged walking robot as a mechanical engineering senior design project is presented. The design criterion was to use a minimum number of motors for leg motion while the robot would have the ability to turn when it ran into an object. The project proved to be a good example for the application of fundamental mechanical engineering concepts such as kinematics, statics and machine design. This project was funded by the Faculty Research Committee of the University of the Pacific.
Similarity Solutions: A Group-Theoretic Approach for Students
Authors: Tuttle E. R. , Welch S. W. J.
Published: May 2015

One of the most powerful methods for generating similarity solutions to problems in fluid mechanics and heat transfer is the group-theory method; it is also one of the easiest to apply. However, because of the apparent difficulty and obscurity of the underlying mathematics it is rarely mentioned in anything but advanced graduate seminars in these areas. This is unfortunate, as it is actually one of the most physically based and computationally simple of the methods available for obtaining such solutions. In this paper we give a presentation of this method which will make these group-theoretic techniques accessible and useful to advanced undergraduates and beginning graduate students. Several examples, both standard and unusual, are also given.
Photosoft_H: A Comprehensive photoelasticity simulation module for Teaching the Technique of Photoelasticity
Authors: Ramesh K.
Published: May 2015

The twin developments of (1) the application of digital image processing (DIP) techniques for automation and (2) rapid prototyping for ease of model-making have rejuvenated the role of photoelasticity in the design process. In this paper the details of a PC-based, menu-driven software namely PHOTOSOFT_H to teach the principles of photoelasticity is discussed. Capabilities of the package are illustrated with the aid of typical case studies. Information regarding how to integrate the package with a course on Experimental Stress Analysis and the student response is also given.
A Note on the Axioms of Statics
Authors: Djukic Djordje S. , Jones S. E.
Published: May 2015

This paper suggests a reformulation of the axioms of statics. The axioms treat forces and couples as two independent measures of mechanical action. Three consequences of these axioms are properties of force vector F, couple vector m, and moment of the force F about some point B.
The Pneumatics Module as Part of an in-House Practical Training Programme
Authors: Chua Patrick S. K.
Published: May 2015

This paper presents details of the pneumatics module which is one of several modules of the in-house practical training programme (IHPT) of the School of Mechanical and Production Engineering, Nanyang Technological University, Singapore. The IHPT, which is a unique and compulsory eight-week practical training programme, is an integral part of the secondyear curriculum. The programme was implemented in the early 1980s and, having undergone various improvements over the years, has now evolved into its present form. The paper discusses the merits of having the pneumatics module, the assessment criteria, how students are grouped, student feedback, the roles played by the supervisors, laboratory technicians assisting the supervisors, and the students. It also presents some typical exercises which students are required to complete in the module.
The Use of a Hypermedia System to Develop Confidence in Engineering Design
Authors: Bailey J. D. , Hill M.
Published: May 2015

A novel, open-ended hypermedia exercise has been used successfully in the mechanical engineering design course at Southampton University. The exercise is implemented using the Microcosm hypermedia system and student evaluation has shown that students' confidence in their design skills increases through their use of the package.
Teaching Flow and Thermal Characteristics of Laminar Forced Convection in Tubes with Variable Internal Straight Fins
Authors: Campo Antonio , Chang Jane
Published: May 2015

The primary goal of this educational paper is to construct, for the first time, compact and reliable correlation equations for the asymptotic friction factor and the asymptotic Nusselt numbers for internal, longitudinal finned tubes as a function of the number of fins, the relative fin height and the laminar Reynolds number. Neither textbooks nor the thermofluid dynamics literature provides this information which is extremely useful to instructors of courses on heat transfer to elucidate passive augmentation techniques using fins. The resulting correlation equations for f and NuD have been tested in classroom environments with a great amount of success.
CFM Self-Teaching in the Fluids Laboratory: Newtonian and Non-Newtonian Flow in Circular Pipes
Authors: Bullough W. A. , Cardew G. E. , Kinsella J. , Boysan F. E.
Published: May 2015

Experiences of a computer fluid mechanics based self-teaching exercise on the flow of Newtonian and non-Newtonian fluids are reported. This was restricted to the steady flow of fluids in circular pipes. The work involved keyboard-literate students in the first year of a mechanical engineering degree course finding the pipe design laws, in terms of the effects of diameter and pressure gradient increase on flow rate. Also, velocity profile plus development length effects, not easily taught via analytical or laboratory classes, were illustrated.
An Engineering Vibrations Course with Projects
Authors: Gürocak Hakan B.
Published: May 2015

An overview of the organization of a junior level engineering vibrations course is presented. To improve the students' learning experience the course was re-structured to include inclass problem-solving sessions and projects. Student teams work on the projects which involve modelling, response simulation, construction, testing and demonstration. Some of the projects require not only construction of mechanical devices, but also the use of sensors, drive electronics and computer interfacing. Four sample projects are explained in detail.
Product Investigation for First-Year Mechanical Engineering Students
Authors: Fawcett J. N. , Chan J. F. L.
Published: May 2015

A structured approach to providing real engineering interest for first-year students of Mechanical Engineering is described. This approach, which has been used successfully for a number of years, introduces students to the design and manufacturing processes through investigation of a locally manufactured product. It includes analysis of possible manufacturing methods and a visit to the plant to observe and discuss the manufacturing methods used. Interpersonal skills are developed through working in small teams and making oral and written presentations.
Position of Shelf Supports
Authors: Ward J. P.
Published: May 2015

Using the Euler–Bernoulli beam-bending differential equation we analyse the solution for a shelf deformed under gravity in two situations: (a) simple supports positioned at x = β and x = L – β and (b) Cantilever at one end with a simple support at x = β. We ask where the best position for the supports should be. A number of alternative positions are suggested though the eventual choice of support position is chosen to be that which minimizes the shelf's strain energy.
Platelet-Rich Plasma Intra-articular Knee Injections Show No Superiority Versus Viscosupplementation
Authors: Filardo Giuseppe , Di Matteo Berardo , Di Martino Alessandro , Merli Maria Letizia , Cenacchi Annarita , Fornasari PierMaria , Marcacci Maurilio , Kon Elizaveta
Published: May 2015

Background:

Osteoarthritis (OA) is a common disease that will affect almost half the population at some point in their lives through pain and decreased functional capacity. New nonoperative options are being proposed to treat earlier stages of joint degeneration to provide symptomatic relief and delay surgical intervention.

Purpose:

To evaluate the benefit provided by platelet-rich plasma (PRP) injections to treat knee joint degeneration in comparison with hyaluronic acid (HA), the most common injective treatment currently adopted for this condition.

Study Design:

Randomized controlled trial; Level of evidence, 1.

Methods:

A total of 443 patients were screened, and 192 of them were enrolled in the study according to the following inclusion criteria: (1) unilateral symptomatic knee with history of chronic pain (at least 4 months) or swelling and (2) imaging findings of degenerative changes (Kellgren-Lawrence score of 0-3 at radiographs or MRI evidence of degenerative chondropathy). Patients underwent 3 weekly intra-articular injections of either PRP or HA. Patients were prospectively evaluated at baseline and then at 2, 6, and 12 months of follow-up using the International Knee Documentation Committee (IKDC) subjective score (main outcome), Knee injury and Osteoarthritis Outcome Score, EuroQol visual analog scale, and Tegner score. Range of motion, transpatellar circumference, patient satisfaction, and adverse events were also recorded.

Results:

Two patients reported severe pain and swelling after HA injections, while no major adverse events were noted in the PRP group. However, PRP presented overall significantly more postinjection swelling and pain. Both treatments proved to be effective in improving knee functional status and reducing symptoms: the IKDC score in the PRP group rose from 52.4 ± 14.1 to 66.2 ± 16.7 at 12 months ( P < .0005), and in the HA group it rose from 49.6 ± 13.0 to 64.2 ± 18.0 at 12 months ( P < .0005). A similar trend was observed for all the clinical scores used. The comparative analysis of the 2 treatments showed no significant intergroup difference at any follow-up evaluation in any of the clinical scores adopted.

Conclusion:

PRP does not provide a superior clinical improvement with respect to HA, and therefore it should not be preferred to viscosupplementation as injective treatment of patients affected by knee cartilage degeneration and OA.
Intimate Partner Violence Victims Seeking a Temporary Restraining Order
Authors: Jose Rupa , Novaco Raymond W.
Published: May 2015

Social support has been found in many studies to be a protective factor for those exposed to intimate partner violence (IPV), but personal resilience has received far less attention. The present study concerns 136 female IPV victims seeking a temporary restraining order (TRO) from a Family Justice Center (FJC). The relationships between IPV victimization, social support, resilience, and psychological distress were examined. Hierarchical regressions found that both perceived social support and self-reported resilience were inversely associated with distress symptoms. Higher social support was associated with lower trauma symptoms, controlling for abuse history, demographics, and resilience. Higher resilience was associated with lower mood symptoms and lower perceived stress, controlling for abuse history, demographics, and social support. No significant associations were recorded for anger symptoms. These findings suggest that fostering resilience can have important health benefits for IPV victims, above and beyond the well-known benefits of social support. Ways that resilience might be cultivated in this population and other implications for practice are discussed.
Risk Factors for Social Isolation in Older Korean Americans
Authors: Jang Yuri , Park Nan Sook , Chiriboga David A. , Yoon Hyunwoo , Ko Jisook , Lee Juyoung , Kim Miyong T.
Published: May 2015

Objective: Given the importance of social ties and connectedness in the lives of older ethnic immigrants, the present study examined the prevalence of social isolation and its risk factors in older Korean Americans. Method: Using survey data from 1,301 participants ( Mage = 70.5, SD = 7.24), risk groups for marginal social ties with family and friends were identified and predictors of each type of social isolation explored. Results: Male gender and poorer rating of health were identified as common risk factors for marginal ties to both family and friends. Findings also present specific risk factors for each type of social isolation. For example, an increased risk of having marginal ties with friends was observed among individuals with perceived financial strain, greater functional impairment, and a shorter stay in the United States. Discussion: The common and specific risk factors should be incorporated in programs to reduce social isolation in older immigrant populations.
HIV-1 Aspartic Proteinase: High-Level Production and Automated Fluorometric Screening Assay of Inhibitors
Authors: Hirel Ph.-H. , Parker F. , Boiziau J. , Jung G. , Outerovitch D. , Dugué A. , Peltiers C. , Giuliacci C. , Boulay R. , Lelièvre Y. , Cambou B. , Mayaux J.-F. , Cartwright T.
Published: May 2015

The 99-amino-acid HIV-1 aspartic proteinase was expressed to high levels in Escherichia coli using a T7 expression system. About 50% of the insoluble material after sonication of the bacteria was composed of aggregated proteinase. Subsequent renaturation and purification yielded large quantities of a homogeneous enzyme able to cleave various heptapeptidic substrates in vitro with a Km around 2.5 mM. A fluorometric assay has been devised to allow automated screening of HIV proteinase inhibitors based on an analogous renin assay. We used the synthetic intramolecularly quenched fluorogenic substrate Suc-TLNFPIS-4MCA based on the heptapeptide TLNFPIS, which encompasses the proteinase/reverse transcriptase junction, coupled to the fluorophore 7-amino-4-methylcoumarin and blocked at the amino-terminus by a succinyl group. The enzyme cleaves the substrate between phenylalanine and proline, and conditions were optimized for liberation of 7AMC from the generated PIS-4MCA with aminopeptidase M as secondary enzyme. 7AMC was monitored with a microplate fluorescence scanner. The known aspartic proteinase inhibitor pepstatin A consistently gave Ki = 2 × 10−6M. Other synthetic and natural compounds are currently being tested.
Intranasal Treatment of Picornavirus and Coronavirus Respiratory Infections in Rodents Using 7-Thia-8-Oxoguanosine
Authors: Smee D. F. , Alaghamandan H. A. , Bartlett M. L. , Robins R. K.
Published: May 2015

Since common cold viruses are responsive to interferon, we developed two animal models to test the efficacy of the interferon inducer 7-thia-8-oxoguanosine: (i) an intranasal coronavirus infection in suckling rats; and (ii) an intranasal encephalomyocarditis (EMC) virus infection in adult mice. Concentrations of 0.3 and 1% 7-thia-8-oxoguanosine delivered intranasally to rats 24 and 18 hours before virus inoculation were highly protective against the otherwise lethal coronavirus infection. A 1% concentration of drug administered 4 and 8 hours after virus challenge increased mean survival times of rats but did not increase numbers of survivors. Intranasal treatment of an EMC infection produced moderate improvements in mean survival times and survival. Titrations of EMC virus indicated >300-fold reductions in nasal titres in drug-treated relative to placebo control animals on days 2–4 following virus challenge. The distribution of [14C]-7-thia-8-oxoguanosine was determined shortly after intranasal delivery to mice and rats. Approximately 50% of total doses were deposited in the inner noses and mouths of both species. Most of the rest was found on/in the outer noses, stomachs, tracheas, oesophagi, and lungs. By analogy, the infecting viruses were deposited on/in the same organs and tissues of each species. The results suggest that containment of the viruses primarily occurred in the nasopharyngeal area prior to their spread to the lungs (rat coronavirus) or the brain (EMC), where fatal pathologies were manifest. Intranasal application of an interferon-inducing nucleoside analogue represents a new approach for the study of treatment of the common cold.
The Crystal and Molecular Structure of 3′-Fluoro-3′-Deoxythymidine, a Potent Anti-HIV-1 Nucleoside
Authors: Van Roey P. , Schinazi R. F.
Published: May 2015

The crystal structure of 3′-fluoro-3′-deoxythymidine (FDT), a nucleoside analogue with high potency against human immunodeficiency virus type 1 (HIV-1) in cell culture, has been determined as part of studies aimed at determining correlations between the molecular conformations of anti-HIV nucleosides and their potency. FDT crystallizes with four molecules in the asymmetric unit. The largest differences between the four molecules are in the conformations about the glycosidic bond, but they are otherwise surprisingly similar in conformation. All four molecules have C3′- exo/C2′- endo dideoxyribose ring conformations, very similar to that of one of the two molecules of 3′-azido-3′-deoxythymidine (AZT) in its crystal structure. Revised
Comparison of the Intracellular Metabolism of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Lymphocytes in the Presence of 5-Fluoro-2′-Deoxyuridine
Authors: Cox S. , Harmenberg J.
Published: May 2015

The mechanism of action of 2′, 3′-dideoxythymidine analogues such as azidothymidine (AZT) and fluorothymidine (FLT) is thought to be chain termination and inhibition of reverse transcriptase by the triphosphate. However, little triphosphate is formed intracellularly relative to monophosphate and diphosphate. Azidothymidine and fluorothymidine are phosphorylated intracellularly by the thymidine salvage pathway and therefore must compete with thymine nucleotides for phosphorylation, which may limit the rate of phosphorylation. We have investigated the degree to which competition with thymidine limits the phosphorylation of azidothymidine and fluorothymidine. In this paper we show that inhibition of thymidylate synthase by 5-fluoro-2′-deoxyuridine monophosphate increases the phosphorylation of azidothymidine and fluorothymidine by reducing the pools of thymine nucleotides and therefore removing the competition. 5-fluoro-2′-deoxyuridine abolished the pools of TTP and dGTP and caused the appearance of dUTP in treated lymphocytes. Three times more triphosphate was formed in cells treated with 5-fluoro-2′-deoxyuridine. Ten times more fluorothymidine triphosphate than azidothymidine triphosphate was formed. The results suggest that while competition with intracellular thymine nucleotides does hinder the phosphorylation of AZT and FLT, the major limiting factor is their ability to act as substrates for the phosphorylating enzymes.
Anti-Herpes Virus Activity of 5-Methoxymethyl-2′-Deoxycytidine in Combination with Deaminase Inhibitors
Authors: Aduma P. J. , Gupta S. V. , Stuart A. L. , Tourigny G.
Published: May 2015

5-Methoxymethyl-2′-deoxycytidine (MMdCyd) is an anti-metabolite with selective anti-herpes activity and low cytotoxicity. MMdCyd is dependent upon initial activation by the viral-induced deoxythymidine-deoxycytidine (dThd/dCyd) kinase for its activity against herpes simplex virus (HSV). Antiviral activity of MMdCyd is cell-dependent and is influenced by the deaminase content of the cell line used for assays. The antiviral potency against HSV-1 in this study was higher in RK-13 cells (ED50 3–5 μm) than in Vero and HEP-2 cells (ED50 14–26 μm). The potency of MMdCyd increased approximately 20-fold against HSV-1 and twofold against HSV-2 in the presence of tetrahydrodeoxyuridine (H4dUrd; which inhibits both dCyd deaminase and dCMP deaminase) in Vero cells. MdCyd in combination with H4dUrd was effective in preventing the cytopathogenic effect of HSV-1 and decreasing the production of infectious virus particles. The IC99 (concentration required to reduce the yield of infectious virus obtained 72 h after infection by 99% relative to control cultures) was 1.6 μm. In combination with tetrahydrouridine (H4Urd; an inhibitor of Cyd/dCyd deaminase) the potency of MMdCyd was only slightly enhanced (ED50 7–8 μm). Dihydrodeoxyuridine and deoxyuridine reversed the antiviral activity of MMdCyd. The minimum cytotoxic concentration for rapidly dividing cells (RK-13, HEP-2 and Vero) for MMdCyd was greater than 3 mm. H4Urd and H4dUrd were devoid of cytotoxicity and antiviral activity up to 2.12 mm (the highest concentration tested). Diacetyl-MMdCyd (pro-drug form) was approximatewly 20 times less potent than MMdCyd.
Comparison of the Mechanism of Toxicity of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Human Lymphocytes
Authors: Cox S. , Harmenberg J.
Published: May 2015

The thymidine analogue 3′-azido-3′-deoxythymidine (AZT), whilst a useful drug for the treatment of acquired immunodeficiency syndrome, produces toxic side-effects which can be severe and can interfere with therapy. The toxic mechanism of AZT is unknown. We have investigated the relationship between the phosphorylation and effect on natural dNTP pools of 3′-azido-3′-deoxythymidine and the closely related 3′-fluoro-3′-deoxythymidine and their toxicity in human lymphocytes. We attempted to reduce the toxicity by co-administration of natural nucleosides.

The toxicity of 3′-fluoro-3′-deoxythymidine could be reduced with thymidine or deoxyuridine five- and 10-fold, respectively. The toxicity of 3′-azido-3′-deoxythymidine could be reduced twofold with cytidine or uridine but was increased by all other nucleosides, including thymidine. Neither analogue caused significant changes in the dNTP pools at cytotoxic concentrations; the effect of the nucleosides in reducing toxicity was not owing to replacement of a depleted dNTP. Thymidine reduced the phosphorylation of 3′-azido-3′-deoxythymidine and 3′-fluoro-3′-deoxythymidine 6 and 17 times, respectively.

3′-azido-3′-deoxythymidine and 3′-fluoro-3′-deoxythymidine appear to have different mechanisms of toxicity. The toxic mechanism of 3′-fluoro-3′-deoxythymidine is probably inhibition of cellular DNA synthesis by the triphosphate. The toxicity of 3′-azido-3′-deoxythymidine in lymphocytes does not appear to be directly related to the amounts of the phosphorylated forms. The mechanism may be interference with RNA metabolism or precursors, perhaps by the nucleoside.
An Appraisal of the Efficacy of the Antiviral R 61837 in Rhinovirus Infections in Human Volunteers
Authors: Barrow G. I. , Higgins P. G. , Tyrrell D. A. J. , Andries K.
Published: May 2015

The efficacy of the antiviral R 61837 in experimental colds in three previously reported volunteer trials and one new trial is reviewed here. It was dissolved in a new vehicle, hydroxy-β-cyclodextrin, and used as a nasal spray. A substantial reduction in illness occurred when given prophylactically and during the incubation period but not when used therapeutically.
Enhancement of the Antiviral Activity of Poly (A-U) by Adriamycin and Daunomycin
Authors: Jamison J. M. , Bonilla P. J. , Tsai Chun-che
Published: May 2015

The role of adriamycin (ADR) and daunomycin (DMN) in modulating the antiviral activity of poly (adeylate-uridylate) (poly (A-U)) was examined using a human foreskin fibroblast – vesicular stomatitis virus (HSF-VSV) bioassay in which the concentration of poly (A-U) was fixed at 0.05 mm or 0.2 mm while the ADR or DMN concentration was varied to produce ADR (or DMN)/ribonucleotide ratios ranging from 1:16 to 2:1. Poly (A-U), ADR and DMN were not efficacious antiviral agents when tested individually at the concentrations employed in the ADR (or DMN)/poly (A-U) combinations. When the ADR or DMN was combined with the poly (A-U) to produce ADR (or DMN)/poly (A-U) ratios of 1/6, the 50% effective doses (ED50) of the poly (A-U), ADR and DMN decreased 18, 104, and 185-fold, respectively. However, when ADR or DMN was combined with polyriboinosinic-polyribocytidylic acid [poly (I) · poly (C)], the ED50 of the ADR, DMN and the poly (I) · poly (C) were not affected. Interferon neutralization studies indicated that ADR, DMN, poly (A-U) and the ADR (or DMN)/poly (A-U) combination induced the production of interferon-beta (IFN-β). The amount of IFN produced by the ADR (or DMN)/poly (A-U) combinations was equal to the sum of the IFN prduced by their constituents. These results indicate that the ADR and DMN potentiate the antiviral activity of the poly (A-U) without affecting the amount of IFN induced. The direct viral inactivation study demonstrated that ADR, DMN, poly (A-U) and the ADR (or DMN)/poly (A-U) combinations do not inactivate the VSV at concentrations near the ED50.
Acute Infection of Cynomolgus Monkeys with Simian Immunodeficiency Virus (SIVSM) as a Model to Evaluate Antiviral Compounds. Effects of 3′-Azido, 3′-Deoxythymidine, Foscarnet and 2′,3′-Dideoxycytidine
Authors: Lundgren B. , Ståhle E. Ljungdahl , Böttiger D. , Benthin R. , Hedström K.-G. , Norrby E. , Putkonen P. , Wahren B. , Öberg B.
Published: May 2015

Screening of compounds with potential use in the treatment of human immunodeficiency virus (HIV) infections and acquired immunodeficiency syndrome (AIDS) can currently be made in cell culture systems, but there is a need for relevant animal models. We have infected cynomolgus monkeys with simian immunodeficiency virus of sooty mangabey origin (SIVSM) and investigated the influence of multiplicity of infection (MOI) and the effects of three different anti-HIV compounds, 3′-azido-3′-deoxythymidine (AZT), foscarnet (PFA) and 2′,3′-dideoxycytidine (ddC) on the acute infection. To secure a maximal effect of treatment this was started 8h before challenge with SIVSM and the drugs were given subsequently every 8h for 7–9 days. The appearance of viral antigen and antibodies in serum was determined. In control animals the mean day for SIV antigen appearance was Day 5.9 post-infection, whereas in animals treated with 3 × 25 mg kg−1 day−1 of AZT and 3 × 65 mg kg−1 day−1 of PFA there were significant delays in SIV antigen appearance of 1.0 and 3.6 days, respectively. Some delay in antigen appearance was indicated in animals treated with 3 × 0.2 mg kg−1 day−1 of ddC. A delayed antibody response was only seen in animals treated with PFA. Viral infection was not prevented at the multiplicity used with any of the drugs, despite treatment prior to virus inoculation. The animal model described offers attractive features for in vivo evaluation of potential anti-HIV compounds.
Synthesis and Anti-Rhinovirus 1B Activity of Oxazolinylflavans
Authors: Desideri N. , Sestili I. , Stein M. L. , Conti C. , Tomao P. , Orsi N.
Published: May 2015

Two series of flavans were synthesized, the first substittued at 4′ and/or 6 position with chlorine and cyano groups, and the second one with chlorine and/or oxazoline rings. The new compounds were tested in vitro against human rhinovirus 1B (HRV 1B) infection of HeLa cells by measuring the effect on the development of viral cytopathic effect and plaque formation. The compounds including both chlorine and cyano groups were the most active; 4′-(4,5-dihydro-2-oxazolyl)-6-chloroflavan was the most potent inhibitor among the oxazoline derivatives.
The Use of Antisera to the Human Herpesvirus 6 Major Capsid Protein to Determine the Effect of Antiviral Inhibitors on Virus Gene Expression
Authors: Liu M.-Y. , Arrand J. R. , Littler E.
Published: May 2015

We have recently described the production of antisera which react with the human herpesvirus 6 (HHV-6) major capsid protein (MCP). We describe here the use of these specific antisera to characterize the kinetics of expression of the HHV-6 MCP and demonstrate that it is a late virus protein, expressed after DNA replication. We have used the expression of this protein as a measure of the efficacy of the antiviral nucleoside analogues 9-(2-hydroxyethoxymethyl)guanine (ACV) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) upon HHV-6 replication and have determined 50% inhibitory concentrations to be 150 μm and 2 μm, respectively.
Treatment of HIV-1 Infected Patients with Peptide T
Authors: Julander I. , Alexius B. , Britton S. , Ehrnst A. , Jorup-Rönström C. , Kjellman B. , Strannegård Ö. , Sääf J. , Sönnerborg A. , Wahlund L.-O. , Wetterberg L.
Published: May 2015

In a pilot study 10 human immunodeficiency virus type 1 (HlV-1)-infected patients were studied. Three CDC group IVa and four CDC group IVc patients were treated with the octapeptide T (D-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2) by intravenous infusion for 4 weeks. Three CDC group IVa patients served as controls and received placebo. HIV was isolated from the blood of all patients before as well as after treatment. In two of five peptide T-treated patients with demonstrable HIV p24 antigen in serum there was a significant decline of antigen levels followed by a rise after discontinuation of treatment. There was a transient rise in the CD4+ cell count in three of the treated patients and a continuous significant decline in one of the control patients. Of the six peptide T-treated patients, evaluated by MRI, four had reduced the area of altered brain white matter. Also, there was a tendency towards improvement of neuropsychiatric symptoms in the treated group of patients. One patient showed improvement of psoriatic lesions during peptide T treatment. Taken together, the data indicated improvement in four of seven treated patients but in none of the controls. These results do not constitute firm evidence that peptide T has clinical or antiviral effect in HIV-1 infecton. However, in view of its apparent non-toxicity and in particular its possible effect on CNS function, expanded clinical trials with peptide T seem justified.
Studies on the Reversal of Azidothymidine Toxicity in Human Lymphocytes by Cytidine and Uridine
Authors: Cox S.
Published: May 2015

The toxicity of 3′-azidothymidine (AZT) in human lymphocytes has been shown previously to be reversed by co-incubation with the ribonucleosides cytidine or uridine. In the present paper, the effects of 3′-azidothymidine and cytidine/uridine, both alone and in combination, were studied upon key processes in lymphocytes in order to discover more about the mechanism of toxicity reversal.

In these experiments 3′-azidothymidine had only minor effects on the ribonucleoside triphosphate pools. Cytidine increased the CTP pool, and uridine the UTP pool. Co-incubation with AZT caused similar changes to incubation with cytidine or uridine alone. Toxicity reversal was not linked to replacement of deficient ribonucleoside triphosphate pools.

3′-Azidothymidine caused the excretion of thymidine from lymphocytes. Incubation with cytidine and uridine increased the intracellular cytidine and uridine pools, respectively. Co-incubation with 3′-azidothymidine increased still further the intracellular cytidine and uridine pools. Cytidine and uridine did not affect the intracellular 3′-azidothymidine pool.

The toxicity of 3′-azidothymidine was increased by co-incubation with the bases adenine, guanine, hypoxanthine, and uracil, but not by dihydrouracil, thymine, or xanthine.
Inhibition of Human Immunodeficiency Virus Type 1 Replication by Guanosine Analogues and Lack of Synergistic Antiviral Effect of Acyclovir with 3′-azido-3′-deoxythymidine
Authors: Smith M. S. , Pagano J. S.
Published: May 2015

Due to the reported synergy between acyclovir [9-(2-hydroxyethoxymethyl)guanine] and 3′-azido-3′-deoxythymidine (AZT) against the replication of human immunodeficiency virus (HIV) in vitro, we have examined several guanosine and other nucleoside analogues for anti-HIV activity. Four of these (2′,3′-dideoxycytidine, Carbovir, 3′-azido,-2′,3′-dideoxyguanosine, and 2′,3′-dideoxyguanosine) had EC90s of 1–4 μm in the C3 T-cell line, and three (2′,3′-dideoxyinosine, 2′,3′-dideoxyadenosine, and 2′,3′-dideoxyriboside of 2,6-diaminopurine) had EC90s of about 30 μm, in contrast to acyclovir with an EC50 of >90 μm. Acyclovir and AZT showed only additive to antagonistic effects in this cell line, with the majority of the combination indices greater than 1.0 by both reverse transcriptase activity and p24 antigen data. Additive to antagonistic effects were also produced by this combination in the Jurkat and CEM T-cell lines. Neither 3′-azido-2′,3′-dideoxyguanosine nor 2′,3′-dideoxyguanosine showed synergism with AZT in Jurkat, CEM or C3 cells.
Potent and Selective Activity of Dextrin Sulphate against Human Immunodeficiency Virus Type 1 in vitro
Authors: Ito M. , Baba M. , Shigeta S. , Wada S. , Takagi M. , Kimura T. , Okuyama T.
Published: May 2015

Several dextrin sulphate derivatives were prepared and investigated for their activity against human immunodeficiency virus type 1 (HIV-1) in vitro. These compounds have proved to be potent and selective inhibitors of HIV-1. One of the compounds, termed FG-752 [molecular weight (MW) 3000], was the most active, and its 50% antiviral effective concentration was 2.1 μg ml−1 (0.7 μm) in MT-4 cells. No toxicity for the cells was observed at a concentration of 500 μg ml−1. The compounds were also inhibitory to HIV-1-induced giant cell (syncytium) formation. These results suggest that dextrin sulphate may be useful for the chemotherapy of HIV-1 infections.
Sulphated Cyclodextrins are Potent anti-HIV Agents Acting Synergistically with 2′,3′-dideoxynucleoside Analogues
Authors: Schols D. , De Clercq E. , Witvrouw M. , Nakashima H. , Snoeck R. , Pauwels R. , Van Schepdael A. , Claes P.
Published: May 2015

Sulphated cyclodextrins proved to be potent inhibitors of human immunodeficiency virus (HIV), cytomegalovirus (CMV) and herpes simplex virus (HSV) but not other enveloped viruses (i.e. Sindbis virus, respiratory syncytial virus, Tacaribe virus, vesicular stomatitis virus or vaccinia virus). Their mechanism of action against HIV can be attributed to an inhibition of the binding of HIV-1 virions to the cells, as demonstrated by flow cytometric analysis. The sulphated cyclodextrins enhanced the anti-HIV-1 activity of pyrimidine 2′,3′-dideoxyribosides (i.e. azidothymidine, dideoxycytidine, didehydro-dideoxythymidine, fluorodide-oxychlorouridine), in a subsynergistic manner, and the anti-HIV-1 activity of purine 2′,3′-dideoxyribosides (dideoxyadenosine, dideoxyinosine, 2,6-diaminopurine dideoxyriboside) and 9-(2-phosphonylmethoxyethyl)adenine in a synergistic manner. Following intravenous administration of the sulphated cyclodextrins to rabbits, drug serum concentrations were obtained that were 100- to 1000-fold above the minimum inhibitory concentration for HIV or CMV.
Effect of IL-1, IL-6, GM-CSF and Erythropoietin on the in vitro Toxicity Associated with AZT on Human Bone Marrow Haematopoietic Progenitor Stem Cells: CFU-GM and BFU-E
Authors: Gallicchio V. S. , Hughes N. K. , Hulette B. C. , Noblitt L.
Published: May 2015

The drug azidothymidine (AZT), a synthetic thymidine analogue, has been used in the treatment of acquired immunodeficiency syndrome (AIDS). Clinical use of AZT has induced haematopoietic toxicity manifested by anaemia, neutropenia, and overall bone marrow suppression. Cytokines/growth factors, such as erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-6 (IL-6), are agents responsible for the growth and regulation of normal haematopoiesis by influencing various classes of haematopoietic progenitors. We report the results of studies designed to investigate the capacity of these factors to influence the toxicity of AZT. Low density, ≤ 1.077 g/cm3, adherent and/or T-cell depleted normal human marrow cells were co-cultured in the presence or absence of AZT and the appropriate growth factor, i.e. EPO for the early erythroid haematopoietic colony-forming progenitor stem cell (BFU-E) and GM-CSF for the granulocyte–macrophage haematopoietic colony-forming progenitor stem cell (CFU-GM), in dose escalation studies. Additional experiments measured the effect of increasing doses of the cytokines IL-1 and IL-6, alone or in combination in the presence of increasing doses of either EPO or GM-CSF. When comparing the rate of AZT-induced inhibition of BFU-E in vitro, EPO alone (from 2 to 10 U/ml) did not reduce the magnitude of AZT toxicity on BFU-E. GM-CSF alone (up to 1000 U/ml) was ineffective in reversing AZT toxicity on CFU-GM; however, in the presence of either IL-1 and IL-6, AZT toxicity was decreased. These results indicate that certain cytokines/growth factors such as IL-1 or IL-6 in combination with EPO or GM-CSF, but not EPO or GM-CSF alone, may be effective in ameliorating AZT bone marrow toxicity; therefore the use of specific cytokines may be warranted as adjuvant therapy in AIDS.
Inhibition of Duck Hepatitis B Virus Replication in vivo by the Nucleoside Analogue Ganciclovir (9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] Guanine)
Authors: Wang Y. , Bowden S. , Shaw T. , Civitico G. , Chan Y. , Qiao M. , Locarnini S.
Published: May 2015

Treatment of ducks congenitally infected with the duck hepatitis B virus (DHBV) using the guanosine analogue ganciclovir resulted in prompt and profound inhibition of viral DNA replication in serum and liver. By the end of the treatment period all the replicative intermediates, except the supercoiled DNA form, could not be detected. Within 2 weeks of cessation of treatment viral replication returned and, in some cases, rebound occurred. Sequential treatment with prednisolone followed by ganciclovir also resulted in inhibition of viral replication and, even though relapse was observed after therapy was discontinued, the rebound phenomenon was reduced. Ganciclovir significantly and selectively inhibited DHBV DNA replication but may be more efficacious if used in combination with compounds targeted to the viral supercoiled DNA form.
Reference Viruses for Use in Amantadine Sensitivity Testing of Human Influenza A Viruses
Authors: Kendal A. P.
Published: May 2015

A new reference strain of influenza A virus sensitive to amantadine was selected, and a resistant mutant derived from it; these viruses are believed to be safer for use as internal controls in diagnostic and research laboratories than previously used reference strains which are potential human pathogens.
Dextrin Sulphate and Fucoidan are Potent Inhibitors of HIV Infection in vitro
Authors: McClure M. O. , Whitby D. , Patience C. , Gooderham N. J. , Bradshaw A. , Cheingsong-Popov R. , Weber J. N. , Davies D. S. , Cook G. M. W. , Keynes R. J. , Weiss R. A.
Published: May 2015

Two sulphated polysaccharides, fucoidan (a derivative of seaweed) and the newly synthesised dextrin sulphate, were tested for their ability to inhibit human immunodeficiency virus (HIV) infection in vitro in comparison to dextran sulphate and azidothymidine. They were found to be potent inhibitors of diverse strains of HIV-1 in a variety of human cell lines and in peripheral blood lymphocytes (PBL) using a range of assays, including cell-free and cell-to-cell spread of infection. The drugs did not adversely affect cell proliferation or protein metabolism of PBL. As dextrin sulphate is less potent than dextran sulphate in prolonging thrombin-induced fibrin clotting time, it merits further development as an antiviral agent.
Towards Gene-Inhibition Therapy: A Review of Progress and Prospects in the Field of Antiviral Antisense Nucleic Acids and Ribozymes
Authors: James W.
Published: May 2015

Antisense RNA and its derivatives may provide the basis for highly selective gene inhibition therapies of virus infections. In this review, I concentrate on advances made in the study of antisense RNA and ribozymes during the last five years and their implications for the development of such therapies. It appears that antisense RNAs synthesized at realistic levels within the cell can be much more effective inhibitors than originally supposed. Looking at those experiments that enable comparisons to be made, it seems that inhibitory antisense RNAs are not those that are complementary to particular sites within mRNAs but those that are able to make stable duplexes with their targets, perhaps by virtue of their secondary structure and length. The inclusion of ribozyme sequences within antisense RNAs confers RNA-cleaving activity upon them in vitro and possibly in cells, thereby offering the possibility of markedly increasing their therapeutic potential. The varieties of natural ribozyme and their adaptation as artificial catalysts are reviewed. The implications of these developments for antiviral therapy are discussed.
Synthesis and Evaluation of Cytostatic and Antiviral Activities of 3′ and 4′-Avarone Derivatives
Authors: De Giulio A. , De Rosa S. , Strazzullo G. , Diliberto L. , Obino P. , Marongiu M. E. , Pani A , La Colla P.
Published: May 2015

A series of 3′ and 4′-substituted avarone derivatives were synthesized and tested in culture systems as antitumour and antiviral agents in comparison to avarol and avarone. 3′-alkylamino derivatives showed potent cytostatic activities against murine L1210 and human B (Raji) and T (C8166, H9) lymphoblast cells (ID50 range 1.7–3.7 μm). Avarol and avarone were six times less active. While none of the derivatives showed anti-human immunodeficiency virus (HIV) activity superior to that of the parent compounds, most of them, avarol and avarone included, were potent and selective inhibitors of poliovirus multiplication.
Antiviral 9-[2-(phosphonomethoxy)alkoxy]purines
Authors: Duckworth D. M. , Harnden M. R. , Perkins R. M. , Planterose D. N.
Published: May 2015

9-[2-(Phosphonomethoxy)alkoxy]purines have been prepared and evaluated as antiviral agents. These compounds are the first reported acyclonucleotides in which an acyclic phosphonic acid-bearing substituent is attached to N-9 of a purine via a nitrogen-oxygen bond. Some 2-(phosphonomethoxy)ethoxy derivatives, e.g. (24), (25) and (27), have potent activity against herpesviruses. Some 3-hydroxy-2-(phosphonomethoxy)propoxy derivatives, e.g. (23) and (34), and a cyclic phosphonate (35), are potent and selective inhibitors of the replication of visna virus, a retrovirus.