bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitors of bovine herpes mammillitis virus infections in cultured cells and in vaginally infected guinea pigs
Authors: Smee D. F. , Leonhardt J. A. , Sugiyama S. T. , Holy A.
Published: May 2015

Bovine herpes mammillitis virus or bovine herpesvirus type 2 (BHV-2) causes ulcerative lesions on the teats and udders of infected cows. The authors investigated several nucleoside and nucleotide analogues as potential BHV-2 inhibitors. These included acyclovir, ganciclovir, 5-iodo-2′-deoxyuridine (IUdR), 1-(2-deoxy-2′-fluoro-β-D-arabinofuranosyl) derivatives of 5-iodocytosine (FIAC), 5-iodouracil (FIAU), and 5-methyluracil (FMAU), and various 3-hydroxyphospho-nylmethoxypropyl (HPMP) and 2-phosphonylme-thoxyethyl (PME) derivatives of adenine (A), guanine (G), 2,6-diaminopurine (DAP), and/or cytosine (C). Of these, FIAU and FMAU were the most potent in cell culture, inhibiting 50% of BHV-2 plaques at >0.05 μm. HPMPA and HPMPG were active at 0.3 μm; FIAC, IUdR, and HPMPC at 1.3-2.3 μm; PMEDAP and ganciclovir at 20-25 μm; acyclovir and PMEA at >100 μm. The two most potent agents, FIAU and FMAU, inhibited uninfected embryonic bovine tracheal cell growth by 50% at > 100 μm and 53 μm, respectively, resulting in selectivity indices (ratio of the 50% inhibitory concentration for cell growth to the 50% inhibitory concentration for plaque formation) of >2200 and 1100. Greater degrees of antiviral activity and selectivity were obtained in infected guinea pig embryo cells treated with FIAU, FMAU, and HPMPC. Infected cell extracts containing BHV-2-induced thymidine kinase activity phosphorylated FIAU, FMAU, and lUdR at nearly the same rate as thymidine, whereas FIAC, acyclovir, and ganciclovir were phosphorylated at ≤5% the rate of thymidine. Phosphorylation by this enzyme is required to generate the antivirally active nucleoside triphosphate in infected cells. In guinea pigs infected intravaginally with BHV-2, FMAU treatments of 1, 3.2, and 10 mg kg−1 per day for 5 days starting 1 day after virus challenge reduced vaginal lesion scores and virus titres in a dose-dependent manner. FIAU (10 μm) was as effective as 1 μm FMAU by the same regimen. A single treatment with 10 μm HPMPC was as active as daily treatments with 3.2 mg FMAU kg−1. These results indicate the potential of using antiviral agents to treat bovine herpes mammillitis virus infections in cattle, and the application of guinea pigs to study BHV-2 disease.
Inhibition of Feline Immunodeficiency Virus Production and HIV Tat Activity by Thiosemicarbazone Derivatives
Authors: Teitz Y. , Barko N. , Torten M. , Ronen D.
Published: May 2015

Two thiosemicarbazone derivatives (TSCD), N-methylisatin-β-4′:4′-diethylthiosemicarbazone (M-IBDET) and N-allylisatin-β-4′:4-diallylthiosemicarbazone (A-IBDAT), were tested for their anti-feline immunodeficiency virus (FIV) activity in FL4/FIV cells. This cell line consists of feline T-lymphocytes chronically infected with FIV. FIV production in FL4/FIV cells was inhibited by M-IBDET and A-IBDAT. Virus inhibition was proportional to drug concentrations and time of treatment. The effective antiviral drug concentrations ranged from 0.06 to 0.64 μm for M-IBDET and from 0.45 to 8.7 μm for A-IBDAT. Tests performed to determine the therapeutic index (TI) value for each drug indicated TI values of 10 and 20 for M-IBDET and A-IBDAT, respectively. Continuous treatment of the cells with low doses of the drugs, given at constant time intervals, for a whole month succeeded in suppressing the chronic infection. Experiments directed towards understanding the mode of inhibition of FIV by TSCD indicated that A-IBDAT is involved in repression of the synthesis of the p24 structural protein of FIV. Examination of the possibility that the TSCD are also involved in suppression of the activity of HIV's tat regulatory protein showed a clear dose-responsive inhibition of HIV's tat-mediated transactivation by M-IBDET and A-IBDAT.
Synthesis and Biological Evaluation of New 5,6-dichlorobenzimidazole Nucleoside Derivatives
Authors: Gosselin G. , Périgaud C. , Bergogne M.-C. , Balzarini J. , De Clercq E. , Imbach J.-L.
Published: May 2015

Novel 5,6-dichlorobenzimidazole nucleoside analogues structurally related to the well-known riboside DRB have been synthesized. The 1′,2′- trans nucleosides were prepared by condensation of peracylated sugars with 5,6-dichlorobenzimidazole, whereas the 1′,2′- cis β-D-arabinofuranosyl and β-D-lyxofuranosyl nucleosides were obtained by inversion of configuration on the sugar moiety. Chiral acyclic derivatives were stereospecifically prepared by ring-opening of furano- or pyrano-nucleosides by means of periodate oxidation, followed by borohydride reduction. The in vitro activities against a range of DNA and RNA viruses, as well as the cytotoxicities in human T-lymphocyte MT-4 cells, have been determined for these novel compounds and for DRB. No truly selective activity (i.e. clearly below the cytotoxic concentration) was observed against any of the viruses used. Some of the compounds, including DRB, were cytotoxic to MT-4 cells at CC50 values of less than 10 μg ml−1.
Tin Protoporphyrin IX Used in Control of Heme Metabolism in Humans Effectively Inhibits HIV-1 Infection
Authors: Neurath A. R. , Strick N. , Lin K. , Debnath A. K. , Jiang S.
Published: May 2015

Recent observations indicated that several porphyrins bound to the V3 loop of the envelope glycoprotein gp120 of the human immunodeficiency virus type 1 (HIV-1) and inhibited infection of cells by HIV-1. The tin derivative of protoporphyrin IX (Sn-PTP-IX) has already been used clinically in humans to suppress hyperbilirubinemia. It was therefore of interest to determine whether Sn-PTP-IX has anti-HIV-1 activity. It is demonstrated here that Sn-PTP-IX effectively inhibited infection by several HIV-1 isolates (HIB, MN, RF, SF-2 and two isolates resistant to azidothymidine). This was surprising, since earlier studies indicated that incorporation of other metals into porphyrins markedly decreased their antiviral activity. Sn-PTP-IX blocked the binding to gp120 of anti-V3-loop-specific antibodies and of monoclonal antibodies specific for the CD4 binding site on gp120. The latter effect appeared to be allosteric and was not observed with a deletion mutant of gp 120 lacking the V3 loop sequence. This suggests that Sn-PTP-IX binds to the V3 loop and distorts the native conformation of the HIV-1 envelope, thereby preventing infection. These results merit the consideration of Sn-PTP-IX as a prophylactic and chemotherapeutic agent against HIV-1.
Thienyl-Substituted Nucleosides and Their Triphosphates
Authors: Persson T. , Hörnfeldt A.-B. , Gronowitz S. , Johansson N. G.
Published: May 2015

A series of thienyl-substituted nucleosides and their triphosphates has been prepared and the compounds evaluated as antiviral agents. The compounds investigated were 1-(5′-triphosphate-β-D-arabinofuranosyl)-5-(2″-thienyl)uracil (6), 1-(5′-triphosphate-β-D-arabinofuranosyl)-5-(2″-thienyl)cytosin (13) and 1-(5′-triphosphate-2′, 3′-dideoxynbofuranosyl)-5-(2″-thienyl)uracil (19). The activities of (6), (13) and (19) was shown to be inferior to that of the previously prepared compound 5-(2″-thienyl)-β-2′-deoxyuridine triphosphate (20).
Design and Synthesis of a Quenched Fluorogenic Peptide Substrate for Human Cytomegalovirus Proteinase
Authors: Handa B.K. , Keech E. , Conway E.A. , Broadhurst A. , Ritchie A.
Published: May 2015

A fluorogenic peptide substrate for HCMV proteinase was synthesized by solid-phase peptide synthesis. The amino acid sequence of this substrate is derived from the maturation cleavage site (M site) of the natural substrate, the assembly protein precursor. The minimum sequence for efficient cleavage requires at least seven residues (P4-P3′). A systematic modification of the peptide substrate was carried out to identify positions suitable for the introduction of the fluorescent donor and the quencher acceptor groups.
Zalcitabine (ddC) Phosphorylation and Drug Interactions
Authors: Veal G.J. , Barry M.G. , Back D.J.
Published: May 2015

Zalcitabine (2′,3′-dideoxycytidine; ddC) is an inhibitor of HIV reverse transcriptase. The intracellular metabolism of ddC in peripheral blood mononuclear cells (PBMCs), U937 cells and Molt 4 cells were investigated, and phosphate metabolites were determined by on-line radiometric HPLC. Comparable levels of all three ddC phosphate metabolites were formed in PHA-stimulated PBMCs, U937 cells and Molt 4 cells.

Zidovudine (ZDV), didanosine (ddl) and stavudine (d4T) had no significant effect on ddC (0.06μM) phosphorylation in PBMCs whereas the endogenous nucleoside, cytidine decreased phosphorylation in a concentration-dependent manner ( e.g. 41 % inhibition of total phosphate formation at 6μM cytidine, 85% inhibition at 60μM).

The cytotoxic anticancer drug doxorubicin caused a decrease in ddC phosphorylation in U937/Molt 4 cells (e.g. 56% inhibition of total phosphate formation in U937 cells; 55% in Molt 4 cells at a doxorubicin concentration of 60μM), whilst the antiviral agent ribavirin exhibited no inhibitory effects.
Valaciclovir – A Review of its Potential in the Management of Genital Herpes
Authors: Crooks R. J.
Published: May 2015

The continued increase in prevalence of herpes simplex virus (HSV) infection indicates a need to develop improved chemotherapeutic strategies so as to enhance options for the management of genital herpes. The clinical and psycho-social impact of genital herpes and the need to encourage patients to participate in controlling their disease create several opportunities for improvement.

The higher bioavailability of aciclovir from valaciclovir ensures that plasma aciclovir levels exceed the in vitro IC50 for clinical HSV strains with once- or twice-daily dosing regimens. The satisfactory outcome for valaciclovir in pre-clinical mutagenicity and carcinogenicity bioassays, plus aciclovir's highly specific mode of action, form the basis for the proposal that valaciclovir can match the excellent safety profile established for aciclovir.

Controlled clinical trials of valaciclovir for the acute treatment of recurrent genital herpes have demonstrated efficacy in speeding resolution of all signs and symptoms, hastening lesion healing and terminating virus shedding. Further, these results indicate that valaciclovir provides a significant improvement in increasing the numbers of patients in whom lesion development is prevented. These benefits were achieved with twice-daily valaciclovir regimens and without compromise to safety.

Studies evaluating valaciclovir in HSV infections in the immunocompromised and for long-term suppressive therapy in otherwise healthy subjects continue. To date, the valaciclovir HSV clinical development programme indicates that efficacy can be achieved with less frequent dosing without compromising safety.
Physicochemical Properties, Bioconversion and Disposition of Lipophilic Prodrugs of 2′,3′-Dideoxycytidine
Authors: Ibrahim S.S. , Boudinot F.D. , Schinazi R.F. , Chu C.K.
Published: May 2015

Lipophilic prodrugs of 2′,3′-dideoxycytidine (ddC), 4,5′-diacetyI-ddC (DAC), 4,5′-ditrimethylacetyl-ddC (DTMAC), 4,5′-dicyclopentylpropionyl-ddC (DCYPP) and 5′-cholesteryl-ddC (CHOL), were evaluated for their utility in improving brain delivery of the parent nucleoside. The lipophilicity of the prodrugs was greater, compared to ddC., with partition coefficient values increasing from 0.03 for ddC to 0.37,28, 63 and 483 for DAC., DTMAC., DCYPP and CHOL., respectively. Aqueous solubility was decreased proportionally to the increase in lipophilicity. Bioconversion studies were performed in phosphate buffer (pH 7.4), human serum, mouse serum, and mouse brain and liver homogenates. Whereas CHOL was stable in vitro in all media, DAC., DTMAC and DCYPP exhibited stability only in buffer, indicating that the hydrolytic reaction for these compounds was, predominately, enzymatically triggered. DCYPP was rapidly hydrolysed in mouse serum and liver and brain homogenates with degradation half-life values of 0.04, 0.35 and 0.34 h respectively. DAC had a longer half-life in mouse serum than did DTMAC (0.82 h vs. 0.38 h), however, in mouse brain homogenate DTMAC (t1/2=3.9 h) was more stable than DAC (t1/2= 1.6 h). Both of these pro-drugs were rapidly metabolized in the mouse liver homogenate with half-life values of 0.36 h for DAC and 0.23 h for DTMAC. In-vivo studies performed for ddC., DAC and DTMAC in mice showed that the relative brain exposure (re) of ddC was not improved by administering the prodrugs. DTMAC yielded a re value of 0.023 which was similar to that for ddC (re = 0.028), while no ddC was detected in brain after DAC administration. Thus, although all of the prodrugs were more lipophilic than ddC., delivery of ddC to the brain was not enhanced in vivo.
Inhibition of Hepatitis B Virus Replication by Nucleoside Enantiomers of β-2′,3′-Dideoxypurine Analogues
Authors: Alaoui A.M. El , Faraj A. , Pierra C. , Boudou V. , Johnson R. , Mathé C. , Gosselin G. , Korba B.E. , Imbach J.-L. , Schinazi R.F. , Sommadossi J.-P.
Published: May 2015

Various purine β-L-2′,3′-dideoxynucleoside analogues with both sugar and base modifications including β-L-ddG, β-L-ddl, β-L-ddA, 2′-azido-β-L-araddA, 2′-amino-β-L-araddA, 2′,5′-anhydro-β-L-araddA, 2′-azido-β-L-ddA, 2′-amino-β-L-ddA, 2′-fluoro-β-L-ddA, 3′-azido-β-L-ddA, 3′-amino-β-L-ddA, 3′-fluoro-β-L-ddA, 2,6-diamino-β-L-2′,3′-dideoxyfuranosylpurine, 6-cyclopropylamino-β-L-ddA, 2′-azido-6-N-triphenylphosphine-β-L-araddA, 2-amino-6-methylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopropylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopentylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2′,3′-didehydro-β-L-ddA and 2′,3′-didehydro-6-N-triphenyl phosphine-β-L-ddA were synthesized and evaluated as potential inhibitors of hepatitis B virus (HBV) replication in HBV DNA-transfected human hepatoblastoma-derived Hep-G2 cells (2.2.15 cells). β-L-ddA, 2′-azido-β-L-ddA, 3′-azido-β-L-ddA, 2″,3′-didehydro-β-L-ddA (β-L-D4A) and a modified base of β-L-D4A, inhibited HBV replication in vitro. β-L-D4A was the more potent and selective antiHBV agent with a 50% effective concentration value of 0.1 μM and a selectivity index of 1800. On the basis of this finding, studies are in progress to synthesize new purine derivatives with the β-L unnatural configuration which hopefully will lead to identifying additional potent and highly selective anti-HBV agents.
Application of a Chain Termination Assay for Characterization of Reverse Transcriptase from AZT-Resistant HIV Isolates
Authors: Lennerstrand J. , Rytting A.-S. , Vrang L. , Gronowitz J.S. , Källander C.F.R.
Published: May 2015

An enzymatic assay based on utilization of one primer/enzyme molecule was specifically designed for evaluation of the chain termination capacity of reverse transcriptase (RT) from HIV-1 isolates. In this assay system (CT assay) there was a 3.2-fold difference between the AZT-triphosphate (AZT-TP) concentrations required to terminate 50% of the primers (TC50) for a highly resistant isolate, carrying the four common mutations at positions 67, 70, 215, and 219; and two wild type isolates. Two of three other isolates with reduced sensitivity to AZT in cell culture exhibited intermediate values in CT assay, while one behaved as the wild type isolates. There was a correlation P = 0.05 ( r = 0.86, n = 6) between the ED50 values found in cell culture and the TC50 values found in CT assay. This relationship was not found in a similar assay system which measured competition between AZT-TP and 1 μM tymidine triphosphate (TTP) at the enzymatic level. The sequence data of the current isolates gave some information concerning which mutations in the RT gene specifically affect the enzymatic properties measured in CT assay. Mutation only at amino acid 70 had no effect, but the TC50 values found increased with accumulation of the other common AZT resistance mutations.
Reverse Transcription of Human Immunodeficiency Virus Type 1 is Blocked by Retroviral Zinc Finger Inhibitors
Authors: Turpin JA , Schaeffer CA , Terpening SJ , Graham L , Bu M , Rice WG
Published: May 2015

The Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys zinc fingers of retroviral nucleocapsid (NC) proteins are prime antiviral targets due to conservation of the Cys and His chelating residues and the absolute requirement of these fingers in both early and late phases of retroviral replication. Certain 2,2′-dithiobisbenzamides (DIBAs) chemically modify the Cys residues of the fingers, thereby inhibiting in vitro replication of human immunodeficiency virus type 1 (HIV-1). We examined the consequences of DIBA interaction with cell-free virions and their subsequent ability to initiate new rounds of infection. The DIBAs entered intact virions and chemically modified the p7NC proteins, resulting in extensive disulphide cross-linkage among zinc fingers of adjacent p7NC molecules. Likewise, treatment of Pr55gag-laden pseudovirions, used as a model of virion particles, with DIBAs resulted in Pr55gag cross-linkage. In contrast, monomeric p7NC protein did not form cross-linkages after DIBA treatment, indicating that the retroviral zinc finger proteins must exist in close proximity for cross-linkage to occur. Cross-linkage of p7NC in virions correlated with loss of infectivity and decreased proviral DNA synthesis during acute infection, even though DIBAs did not inhibit virus attachment to host cells or reverse transcriptase enzymatic activity. Thus, DIBA-type molecules impair the ability of HIV-1 virions to initiate reverse transcription through their action on the retroviral zinc finger, thereby blocking further rounds of replication.
Constituents of Cuscuto Reflexa are anti-HIV Agents
Authors: Mahmood N , Piacente S , Burke A , Khan Al , Pizza C
Published: May 2015

Crude water extracts of Cuscuta reflexa exhibited anti-HIV activity. Fractionation of the crude extract led to the isolation of nine pure compounds with closely related structures, showing interesting structure activity relationships. 3,5,7,4′-Tetrahydroxyflavanone (aromadendrin) inhibited infection by binding to V3 loop of gp 120 and inhibiting its interaction with CD4, whereas 3,5,7,3′,4′-pentahydroxyflavanone (taxifolin), with an extra OH group in the 3′ position in ring B was less specific and exhibited less selectivity in cell cultures. In general, flavanones containing an extra OH group in the 3′ position (taxifolin, taxifolin-7-O-β-D-glucopyranoside and coccinoside B) were less specific and inhibited viral protease, reverse transcriptase, CD4 /gp120 interaction in vitro and bound to non specific proteins. Other compounds isolated from C reflexa were derivatives of quinic acids; 3,4-O-dicaffeoylquinic acid was more active than 3-O-caffeoyl quinic acid. The anti-HIV activity of crude extract may be the result of combinatory effects with compounds of different modes of action.
2′-Fluoro-2′,3′-Dideoxyarabinosyladenine (F-ddA): Activity against Drug-Resistant Human Immunodeficiency Virus Strains and Clades A-E
Authors: Driscoll JS , Mayers DL , Bader JP , Weislow OS , Johns DG , Buckheit RW
Published: May 2015

2′-Fluoro-2′,3′-dideoxyarabinosyladenine (F-ddA), an anti-human immunodeficiency virus (HIV) drug currently in clinical trial, was compared with zidovudine (AZT), ddl and ddC for anti-HIV activity and potency in HIV-1 strains both sensitive and resistant to zidovudine, ddl and non-nucleoside reverse transcriptase inhibitors. A variety of host cell systems [MT-2, MT-4, phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC)] was used. F-ddA was effective against each of the drug-resistant isolates, including the strain resistant to ddl, the other purine dideoxynucleoside evaluated in this study. The anti-HIV-1 activities of F-ddA and zidovudine were also determined against clades A-E in PHA-PBMCs. Although activities were similar, zidovudine was significantly more potent than F-ddA in the PHA-PBMC system.
Design, Synthesis and Antiviral Activity of New Pyridinone Derivatives
Authors: Jourdan F , Renault J , Fossey C , Bureau R , Ladurée D , Robba M , Aubertin AM , Kirn A
Published: May 2015

A molecular modelling study was carried out in order to compare the structural and electronic properties of the pyridinone L-696,229 and the HEPT derivative EBPU. This comparison led to a hybrid structure, 3-(benzyloxymethyl)-5-ethyl-6-methylpyridin-2-one [18a], which revealed a good structural correlation with the models. A series of 2-[(arylmethyl)oxymethyl]pyridin-2-ones related to [18a] was synthesized and tested for antiviral activity against human immunodeficiency virus type 1 (HIV-1). Compound [18a] and four other derivatives showed anti-HIV-1 activity.
Synergistic Inhibition of Human Immunodeficiency Virus Type 1 Replication in Vitro by Two- and Three-Drug Combinations of Delavirdine, Lamivudine and Zidovudine
Authors: Pagano PJ , Chong KT
Published: May 2015

Delavirdine (DLV), a non-nucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, was evaluated in two- and three-drug combination regimens with lamivudine (3TC) and zidovudine (ZDV). The effect of continuous drug treatment on HIV-1JR-CSF replication in human peripheral blood mononuclear cells was measured by an ELISA for p24 core antigen. Drug synergy, estimated by the combination index method and the method of Pritchard & Shipman, was observed when DLV was combined with 3TC over a range of drug concentrations (DLV at 1, 3, 10, 30 and 100 nM; 3TC at 3, 10, 30, 100 and 300 nM). Two-drug combinations of ZDV and DLV at a 1: 3 ratio or ZDV and 3TC at a 1: 10 ratio were synergistic at greater than 75% inhibition levels. Three-drug combinations of ZDV, DLV and 3TC (ZDV at 0.3, 1, 3 and 10 nM; DLV at 1, 3, 10 and 30 nM; 3TC at 3, 10, 30 and 100 nM) at the ratio of 1: 3: 10 also yielded significant synergistic effects. None of the combinations studied showed significant additive or synergistic drug toxicity. These in vitro data suggest that DLV should be evaluated in two- and three-drug combinations with 3TC and ZDV in clinical trials.
Anti-Human Immunodeficiency Virus Type 1 Activity of R-95288, a Phosphodiester Hexadeoxyribonucleotide Modified by Dibenzyloxybenzyl and Hydroxyethyl Residues at the 5′- and 3′-Ends
Authors: Agatsuma T , Furukawa H , Hotoda H , Koizumi M , Koga R , Kaneko M
Published: May 2015

The phosphodiester hexadeoxyribonucleotide R-95288 is a potent anti-human immunodeficiency virus type 1 (HIV-1) agent in vitro which consists or a TGGGAG nucleoside sequence with dibenzyloxybenzyl and hydroxyethyl substituents at the 5′- and 3′-ends, respectively. In this study, the antiviral activity of R-95288 against various strains of HIV-1 in vitro was assessed and its mechanism of action was analysed. R-95288 inhibited replication of all strains of HIV-1 used including laboratory strains with the syncytium-inducing (SI) phenotype and clinical isolates with both SI and non-SI (NSI) phenotypes. The 50% inhibitory concentrations (IC50s) were 0.62–18 μg mL−1 (0.21–6.2 μM). R-95288 inhibited the binding and fusion of HIV-1-infected T cells with CD4+ cells. In addition, R-95288 specifically blocked the binding of monoclonal antibodies, recognizing the anti-V3 loop or the CD4-binding site of the virus envelope glycoprotein gp120. Furthermore, the target site of R-95288 within the V3 loop was found in the putative heparin-binding region by binding inhibition assays using various anti-V3 loop antibodies. These results suggest that R-95288 can inhibit various strains of HIV-1, possibly by specific interaction with gp120.
Enzymatic Synthesis of 2′-O-acyl Prodrugs of 1-(β-D-arabinofuranosyl)-5(E)-(2-bromovinyl)uracil and of 2′-O-acyl-araU, -araC and -araA
Authors: Manfredini S , Baraldi PG , Bazzanini R , Bortolotti F , Vertuani S , Ashida N , Machida H
Published: May 2015

Pig liver esterase (EC 3.1.1.1) catalysed regioselective hydrolysis of 1-(2,3,5-tri-O-acyl-β-D-arabinofuranosyl)uracil, -cytosine and -adenine to give the corresponding 2′-monoesters effectively and in high yield. This methodology enabled the preparation of 1-(2-O-acyl-β-D-arabinofuranosyl)-5-[( E)-(2-bromovinyl)]uracil prodrugs which, although slightly less active than the parent 1-(β-D-arabinofuranosyl)-5(E)-(2 bromovinyl)uracil (sorivudine; BV-araU), were strongly active in vitro against varicella-zoster virus (ED50 2.4–45 ng/ml). The retarded rates of enzymatic hydrolysis of the 2′-esters imply that they might function as lipophilic prodrugs, leading to increased plasma and cellular concentrations. In view of the marked in vitro activity, they represent an interesting approach to arabinofuranosyl nucleoside prodrugs with improved pharmacokinetics and enzymatic stability.
How You Get There From Here
Authors: Zhao Mintao , Warren William H.
Published: May 2015

How do people combine their sense of direction with their use of visual landmarks during navigation? Cue-integration theory predicts that such cues will be optimally integrated to reduce variability, whereas cue-competition theory predicts that one cue will dominate the response direction. We tested these theories by measuring both accuracy and variability in a homing task while manipulating information about path integration and visual landmarks. We found that the two cues were near-optimally integrated to reduce variability, even when landmarks were shifted up to 90°. Yet the homing direction was dominated by a single cue, which switched from landmarks to path integration when landmark shifts were greater than 90°. These findings suggest that cue integration and cue competition govern different aspects of the homing response: Cues are integrated to reduce response variability but compete to determine the response direction. The results are remarkably similar to data on animal navigation, which implies that visual landmarks reset the orientation, but not the precision, of the path-integration system.
A non-parametric model to address overdispersed count response in a longitudinal data setting with missingness
Authors: Zhang Hui , He Hua , Lu Naiji , Zhu Liang , Zhang Bo , Zhang Zhiwei , Tang Li
Published: May 2015

Count responses are becoming increasingly important in biostatistical analysis because of the development of new biomedical techniques such as next-generation sequencing and digital polymerase chain reaction; a commonly met problem in modeling them with the popular Poisson model is overdispersion. Although it has been studied extensively for cross-sectional observations, addressing overdispersion for longitudinal data without parametric distributional assumptions remains challenging, especially with missing data. In this paper, we propose a method to detect overdispersion in repeated measures in a non-parametric manner by extending the Mann–Whitney–Wilcoxon rank sum test to longitudinal data. In addition, we also incorporate the inverse probability weighted method to address the data missingness. The proposed model is illustrated with both simulated and real study data.
The therapeutic use of postcards in a mental health support group
Authors: Treloar Anna
Published: May 2015

Objective:

The aim of this project was to provide some group support for mental health patients in a general practice that employed a Mental Health Nurse Incentive Program nurse. Method: Group members were involved in the development of the group and in the setting of its rules and goals. Postcards were used to invite members to each meeting.

Results:

No ill effects resulted from the use of postcards and they served as a valued way to recognize individuals within the group.

Conclusion:

This use of postcards proved therapeutic in unexpected ways and was very well accepted.
A new trivalent SnSAG surface antigen chimera for efficient detection of antibodies against Sarcocystis neurona and diagnosis of equine protozoal myeloencephalitis
Authors: Yeargan Michelle , de Assis Rocha Izabela , Morrow Jennifer , Graves Amy , Reed Stephen M. , Howe Daniel K.
Published: May 2015

Enzyme-linked immunosorbent assays (ELISAs) based on the SnSAG surface antigens of Sarcocystis neurona provide reliable detection of infection by the parasite. Moreover, accurate serodiagnosis of equine protozoal myeloencephalitis (EPM) is achieved with the SnSAG ELISAs by measuring antibodies in serum and cerebrospinal fluid (CSF) to reveal active infection in the central nervous system. Two independent ELISAs based on recombinant (r)SnSAG2 or a chimeric fusion of SnSAG3 and SnSAG4 (rSnSAG4/3) are currently used together for EPM serodiagnosis to overcome varied antibody responses in different horses. To achieve reliable antibody detection with a single ELISA instead of 2 separate ELISAs, rSnSAG2 was fused with rSnSAG4/3 into a single trivalent protein, designated rSnSAG2/4/3. Paired serum and CSF from 163 horses were tested with all 3 ELISAs. When the consensus antibody titers obtained with the rSnSAG2 and rSnSAG4/3 ELISAs were compared to the single SAG2/4/3 ELISA titers, Spearman rank correlation coefficients of ρ = 0.74 and ρ = 0.90 were obtained for serum and CSF, respectively, indicating strong agreement between the tests. When the rSnSAG2 and rSnSAG4/3 consensus serum-to-CSF titer ratio was compared to the rSnSAG2/4/3 serum-to-CSF titer ratio, the Spearman correlation coefficient was ρ = 0.87, again signifying strong agreement. Importantly, comparing the diagnostic interpretation of the serum-to-CSF titer ratios yielded a Cohen kappa value of 0.77. These findings suggest that the single ELISA based on the trivalent rSnSAG2/4/3 will provide serologic and diagnostic results that are highly comparable to the consensus of the 2 independent ELISAs based on rSnSAG2 and rSnSAG4/3.
Melatonin Attenuates Aortic Endothelial Permeability and Arteriosclerosis in Streptozotocin-Induced Diabetic Rats
Authors: Tang Song-tao , Su Huan , Zhang Qiu , Tang Hai-qin , Wang Chang-jiang , Zhou Qing , Wei Wei , Zhu Hua-qing , Wang Yuan
Published: May 2015

The development of diabetic macrovascular complications is a multifactorial process, and melatonin may possess cardiovascular protective properties. This study was designed to evaluate whether melatonin attenuates arteriosclerosis and endothelial permeability by suppressing the myosin light-chain kinase (MLCK)/myosin light-chain phosphorylation (p-MLC) system via the mitogen-activated protein kinase (MAPK) signaling pathway or by suppressing the myosin phosphatase-targeting subunit phosphorylation (p-MYPT)/p-MLC system in diabetes mellitus (DM). Rats were randomly divided into 4 groups, including control, high-fat diet, DM, and DM + melatonin groups. Melatonin was administered (10 mg/kg/d) by gavage for 12 weeks. The DM significantly increased the serum fasting blood glucose and lipid levels, as well as insulin resistance and endothelial dysfunction, which were attenuated by melatonin therapy to various extents. Importantly, the aortic endothelial permeability was significantly increased in DM rats but was dramatically reversed following treatment with melatonin. Our findings further indicated that hyperglycemia and hyperlipidemia enhanced the expressions of MLCK, p-MYPT, and p-MLC, which were partly associated with decreased membrane type 1 expression, increased extracellular signal-regulated kinase (ERK) phosphorylation, and increased p38 expression. However, these changes in protein expression were also significantly reversed by melatonin. Thus, our results are the first to demonstrate that the endothelial hyperpermeability induced by DM is associated with increased expressions of MLCK, p-MYPT, and p-MLC, which can be attenuated by melatonin at least partly through the ERK/p38 signaling pathway.
Pharmacokinetic and pharmacodynamic evaluation of high doses of buprenorphine delivered via high-concentration formulations in cats
Authors: Taylor Polly M , Luangdilok Carmela H , Sear John W
Published: May 2015

Objectives

To evaluate the potential benefits of high-dose buprenorphine formulations for analgesia in cats, serial and crossover studies were undertaken to investigate their pharmacokinetics and thermal antinociceptive effects.

Methods

Twelve healthy adult domestic shorthair cats (6.0 ± 1.1 kg body weight) were studied. Aqueous solutions of buprenorphine hydrochloride at 0, 0.02, 0.06, 0.12 and 0.24 mg/kg body weight and formulations containing 0, 0.3, 0.6 and 1.2 mg/ml with and without preservatives were given subcutaneously. Blood samples were taken and thermal threshold (TT) measured prior to and at regular time points up to 72 h after dosing. Descriptive statistics and analyses of variance were applied as appropriate.

Results

Baseline TT was 47.6 ± 4.1°C, which increased in all groups treated with all buprenorphine dosages and formulations. After doses of 0.12 mg/kg and above, TT was significantly higher than baseline at most time points from 1–30 h post-treatment. The time to maximum effect (Tmax) ranged between 0.25 and 2.00 h; and plasma concentrations associated with maximum antinociceptive effect (Cmax) were 1.01–1.72 ng/ml after the 0.02 mg/kg dose, 1.4–4.9 ng/ml after the 0.06 mg/kg dose, 4.6–51.4 ng/ml after the 0.12 mg/kg dose and 5.3–22.3 ng/ml after the 0.24 mg/kg dose. The range of estimates for the buprenorphine elimination half-life were as follows: 0.02 mg/kg = 1.35–5.33 h; 0.06 mg/kg = 16.1–31.2 h; 0.12 mg/kg = 10.1–34.0 h; and 0.24 = mg/kg 16.1–31.6 h. The mean ‘plasma concentration for the offset of analgesia’ was 2.3 ± 2.0 ng/ml. No adverse effects were seen. The addition of preservatives to a high-concentration buprenorphine formulation had no impact on antinociception nor any side effects.

Conclusions and relevance

Aqueous high-concentration buprenorphine formulations administered at 0.12 or 0.24 mg/kg have potential for clinical use in cats, providing prolonged antinociception in a single subcutaneous injection of minimal dose volume.
Effects of treatment withdrawal on brachial and central aortic pressure after direct renin inhibition or angiotensin receptor blockade
Authors: Lacy Peter S , Brunel Patrick , Bader Giovanni , Jones Alexander , Baschiera Fabio , Düsing Rainer , Williams Bryan
Published: May 2015

Introduction:

Whilst sustained lowering of brachial systolic blood pressure (Br-SBP) and central aortic systolic pressure (CASP) have been demonstrated in patients with hypertension, effects of treatment withdrawal on these parameters have not been investigated. The ASSERTIVE study previously reported more sustained control of Br-SBP with aliskiren versus telmisartan in patients with hypertension, following 7-days treatment withdrawal. In this ASSERTIVE sub-study, we hypothesised that aliskiren would similarly exert more sustained control of CASP than telmisartan during treatment withdrawal.

Methods:

We investigated the effects of treatment withdrawal on both Br-SBP and CASP following 12-weeks treatment with either aliskiren (300 mg) or telmisartan (80 mg). Br-SBP and CASP were measured at the end of treatment, and at days 2 and 7 following treatment withdrawal in 303 patients (CASP randomised set).

Results:

Of the CASP randomised set, 94 patients completed CASP measurements at all time points (CASP completer set). After 7 days of treatment withdrawal, aliskiren demonstrated lesser increases in both Br-SBP and CASP than telmisartan; Br-SBP change: −2.0±1.6 vs. +5.6±1.7 mmHg, p = 0.001; CASP change: −0.4±1.6 vs. +4.6±1.7 mmHg, p = 0.041, n = 94. Similar findings were obtained for the CASP randomised set.

Conclusions:

Following treatment withdrawal, aliskiren demonstrated more sustained control of both brachial and central SBP than telmisartan.
Government, rights and legitimacy: Foucault and liberal political normativity
Authors: Patton Paul
Published: May 2015

One way to characterise the difference between analytic and Continental political philosophy concerns the different roles played by normative and descriptive analysis in each case. This article argues that, even though Michel Foucault’s genealogy of liberal and neoliberal governmentality and John Rawls’s political liberalism involve different articulations of normative and descriptive concerns, they are complementary rather than antithetical to one another. The argument is developed in three stages: first, by suggesting that Foucault offers a way to conceive of public reason as a historical phenomenon. Second, it is suggested that both Rawls and Foucault allow us to consider rights as historical and particular rather than a-historical and universal. Third, it is argued that Foucault’s genealogy of modern liberal government illuminates some of the tensions and some of the alternatives within the liberal tradition in relation to the concept of political legitimacy.
Carotid and vertebral injury study (CAVIS) technique for characterization of blunt traumatic aneurysms with reliability assessment
Authors: Griessenauer Christoph J , Foreman Paul , Shoja Mohammadali M , Kicielinski Kimberly P , Deveikis John P , Walters Beverly C , Harrigan Mark R
Published: May 2015

Traumatic aneurysms occur in up to 20% of blunt traumatic extracranial carotid artery injuries. Currently there is no standardized method for characterization of traumatic aneurysms. For the carotid and vertebral injury study (CAVIS), a prospective study of traumatic cerebrovascular injury, we established a method for aneurysm characterization and tested its reliability. Saccular aneurysm size was defined as the greatest linear distance between the expected location of the normal artery wall and the outer edge of the aneurysm lumen (“depth”). Fusiform aneurysm size was defined as the “depth” and longitudinal distance (“length”) paralleling the normal artery. The size of the aneurysm relative to the normal artery was also assessed. Reliability measurements were made using four raters who independently reviewed 15 computed tomographic angiograms (CTAs) and 13 digital subtraction angiograms (DSAs) demonstrating a traumatic aneurysm of the internal carotid artery. Raters categorized the aneurysms as either “saccular” or “fusiform” and made measurements. Five scans of each imaging modality were repeated to evaluate intra-rater reliability. Fleiss’s free-marginal multi-rater kappa (κ), Cohen’s kappa (κ), and interclass correlation coefficient (ICC) determined inter- and intra-rater reliability. Inter-rater agreement as to the aneurysm “shape” was almost perfect for CTA (κ = 0.82) and DSA (κ = 0.897). Agreements on aneurysm “depth,” “length,” “aneurysm plus parent artery,” and “parent artery” for CTA and DSA were excellent (ICC > 0.75). Intra-rater agreement as to aneurysm “shape” was substantial to almost perfect (κ > 0.60). The CAVIS method of traumatic aneurysm characterization has remarkable inter- and intra-rater reliability and will facilitate further studies of the natural history and management of extracranial cerebrovascular traumatic aneurysms.
Emergent extracranial internal carotid artery stenting and mechanical thrombectomy in acute ischaemic stroke
Authors: Mishra Ankit , Stockley Hannah , Goddard Tony , Sonwalker Hemant , Wuppalapati Siddhartha , Patankar Tufail
Published: May 2015

Objective

Tandem occlusions involving both the extracranial internal carotid artery (ICA) and an intracranial artery typically respond poorly to intravenous (IV) tissue plasminogen activator (t-PA). We retrospectively review our experience with proximal ICA stenting and stent-assisted thrombectomy of the distal artery.

Methods

The data included patients that underwent carotid stenting and mechanical thrombectomy between 2012–2013. Radiographic, clinical, and procedural data were drawn from case notes, imaging records and discharge reports. Clinical outcomes were evaluated using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin scale (mRs).

Results

Seven patients, with a mean age of 66.4 years and a mean admission NIHSS of 18.3, underwent this procedure and were included. Each presented with an occlusion of the proximal ICA, with additional occlusions of the ICA terminus ( n = 3), middle cerebral artery ( n = 5), or anterior cerebral artery ( n = 1). Recanalisation of all identified occlusions was achieved in all patients, with a Thrombolysis in Myocardial Infarction (TIMI) score of 3 and a Thrombolysis in Cerebral Infarction (TICI) score >2b achieved in each case. Mean time from onset of stroke symptoms to recanalisation was 287 min; mean time from first angiography to recanalisation was 52 min. Intracranial haemorrhages occurred in two patients, with no increase in NIHSS. There were no mortalities. Mean NIHSS at discharge was 4.9, and mRs at 90 days was one in all patients.

Conclusions

Treatment of tandem extracranial ICA and intracranial occlusions in the setting of acute ischaemic stroke with extracranial carotid artery stenting followed by adjunctive intracranial mechanical thrombectomy is both safe and effective, but further evaluation of this treatment modality is necessary.
Sufficient collateral blood supply from accessory middle cerebral artery in a patient with acute ischemic stroke
Authors: Liu Zhen-Sheng , Zhou Long-Jiang , Sun Yong , Kuang Xiong-Wei , Wang Wei , Li Cheng
Published: May 2015

We reported a case of acute embolic occlusion of the middle cerebral artery with a patent accessory middle cerebral artery. Because of the presence of sufficient collateral blood supply from the accessory middle cerebral artery, the patient only underwent transient ischemic attack and did not need endovascular treatment. There was mild infarction in the basal ganglia and temporal lobe, NIHSS score of the patient at discharge seven days after stroke onset was 0, and modified Rankin scale score at 90 days was 0.
Regular exercise improves weight stability in patients with advanced heart failure
Authors: Boyd Andrea M.
Published: May 2015

Objectives:

The purpose of this study was to determine if a progressive, prescribed home-based aerobic exercise program would alter the natural physiological processes that maintain fluid balance stability in patients with New York Heart Association (NYHA) class III/IV heart failure after medical optimization (titration of oral medical therapy with or without the infusion of an intravenous inotrope).

Methods:

A total of 56 men and women from a large tertiary trauma I hospital were enrolled with 56 subjects contributing to baseline analysis and 42 subjects at 24 weeks. Subjects were diagnosed with heart failure via NYHA classification IV or III for at least 6 months and were hospitalized for a current acute decompensation exacerbation in which they were being medically optimized. The exercise intervention was a home-based, prescribed, progressive aerobic exercise program lasting for 24 weeks. The exercise participants had weekly phone calls to gather data and progress the exercise program and one 12-week follow up. The usual care participants received random phone calls to collect data and had one 12-week follow up visit to attain physical assessment values.

Results:

Subjects were primarily female (59%), nonwhite (54%), and NYHA class IV (52%) versus class III (48%). The mean age was 58 years (±11.8 years). The subjects had a mean ejection fraction of 17.7 % (±7%) and mean maximal oxygen consumption of 12.1 (±3.4). Using a hierarchical multiple regression model, it was demonstrated that an exercise prescription (intensity, frequency, duration) significantly predicted 24 h weight fluctuations within a NYHA class III/IV heart failure population after medical optimization ( R2 linear = 0.713, F = 3.224, p = 0.015).

Conclusion:

This study demonstrated that exercise is a successful adjunctive therapy to managing the daily weight variability or fluid status instability of patients with NYHA class III/IV heart failure that is often a debilitating aspect of the syndrome.
Reply to Gangestad’s (2016) Comment on Wood, Kressel, Joshi, and Louie (2014)
Authors: Wood Wendy
Published: May 2015

Wood, Kressel, Joshi, and Louie’s (2014) meta-analysis of menstrual cycle influences on mate preferences identified three artifacts that influenced study findings: imprecise estimates of the fertile phase, decline over time, and publication effects. These artifacts also were evident in another recent meta-analysis by Gildersleeve, Haselton, and Fales (2014a). This consistent evidence of artifacts is not challenged by Gildersleeve et al.’s (2014b) failure to find another artifact–chasing significance levels. In addition, Wood et al. correctly coded the findings of Gangestad and colleagues’ research, given the variation in their reporting formats and inclusion criteria, which in some studies included only 54% of the sample. The controversy over menstrual cycle effects could be beneficial in increasing interest in publishing null results as well as in identifying evolutionary models that build on women’s capacity to regulate reproduction according to societal roles.
Mixing Pens and the Future of Diabetes Drugs
Authors: Ginsberg Barry H.
Published: May 2015

With the availability of a smaller mixing pen, mass marketing of less stable medications is possible. Bidureon is one such medication, and the properties of its pen are discussed along with the prospects for future mixing pens.
Systematic review and meta‐analysis: Efficacy and safety of POEM for achalasia
Authors: Barbieri Lavinia A , Hassan Cesare , Rosati Riccardo , Romario Uberto Fumagalli , Correale Loredana , Repici Alessandro
Published: May 2015

Background

Peroral endoscopic esophageal myotomy (POEM) represents a less invasive alternative, as compared with conventional laparoscopic Heller myotomy for treating achalasia patients. In the last years, a number of prospective and retrospective experiences with POEM use for achalasia have been published.

Methods

Relevant publications in which patients affected by achalasia underwent POEM treatment were identified by PubMed databases for the period 2010 – 2013. From each study, we extracted the number and type of major complications (defined as those requiring any additional medical or surgical intervention). Data were pooled, using random‐effects models. Heterogeneity among studies was assessed by using Cochran's Q and the I 2 statistic.

Results

We found 16 studies that provided data on 551 patients. The median surveillance period was 6 months (range: 3–12). The median of mean POEM duration was 156 minutes (range: 42–112). Median myotomy length was 10 cm (range: 6–14). Technical and clinical success were reported in 97% (95% CI: 94–98%) and 93% (407/428; 95% CI: 90–95%). No heterogeneity (I 2  = 0%) or publication bias was present in both estimates. When limiting the analysis only to adverse events that require medical or surgical interventions, major adverse events occurred in 14% (95% CI: 11–17%); however, only one patient needed post‐POEM surgery (0.2%; 95% CI: 0–0.5%).

Conclusions

POEM appeared to be a highly feasible and effective endoscopic treatment for achalasia. Despite POEM being apparently associated with relatively high morbidity, most patients are successfully managed conservatively, so that POEM appears as a very safe procedure; however, POEM should only be performed in centers able to treat POEM complications, such as pneumothorax or pneumoperitoneum.