bluuebunny/crossref_metadata_2025 huggingface dataset:
Diferenças entre dialogismo e polifonia
Authors: Maciel Lucas Vinício de Carvalho
Published: March 2016

Resumo: É por vezes polêmico o uso que se tem feito dos termos “dialogismo” e “polifonia” em estudos que se valem das discussões bakhtinianas. Ao lado de pesquisadores que tomam os vocábulos praticamente como sinônimos, outros estudiosos condenam veemente o emprego de uma expressão por outra. Dada essa conjuntura, pretende-se, no escopo deste artigo, indicar alguns pontos a serem considerados quando se fizer necessário distinguir dialogismo e polifonia. São esses pontos: a amplitude do diálogo; as relações entre microdiálogo, diálogo composicionalmente expresso e grande diálogo; a questão do diálogo inconcluso (BAKHTIN, 1929/1963). A partir dessa discussão, esboça-se um conciso painel dos modos pelos quais os conceitos de polifonia e dialogismo veem sendo abordados em pesquisas atuais, discutindo as possibilidades e os limites dessas diferentes assimilações. O intuito não é criticar quaisquer usos dos termos ou apropriações dos conceitos, mas reforçar que a polifonia não se diferencia dialogismo simplesmente porque, à diferença deste, conjugaria várias vozes ou vozes polemicamente orientadas.Palavras-chave: polifonia; dialogismo; relações dialógicas; Círculo de Bakhtin; romance polifônico.Abstract: There are controversies regarding the use of the terms “dialogism” and “polyphony”. Some researchers practically turn the two words into synonyms, while another part of the academy condemns vehemently the use of these terms as if they had the same meaning. Given this situation, some points that can be taken into consideration when there is a need to point out the difference between dialogism and polyphony are indicated along this article. The dialogue amplitudes, the relations between microdialogue, compositionally expressed dialogue and great dialogue, and the inconclusive dialogue (BAKHTIN, 1929 [1963]) are the points we aim to work with. From this discussion, a brief framework is outlined to present the ways through which the concepts of polyphony and dialogism have been approached in current researches, discussing the possibilities and the limits of these different assimilations. It is not our intention to criticize any of the uses or appropriations of these concepts, but to reinforce that polyphony’s characteristic of putting several voices or polemically oriented voices together is not the only thing that differentiates it from dialogism.Keywords: Polyphony; Dialogism; Dialogic Relations; Bakhtin Circle; Polyphonic Novel.
Helmer J. Helmers, The Royalist Republic: Literature, Politics and Religion in the Anglo-Dutch Public Sphere, 1639-1660
Authors: Nieuwstraten Jaap
Published: March 2016

Helmer J. Helmers, The Royalist Republic: Literature, Politics and Religion in the Anglo-Dutch Public Sphere, 1639-1660 (PhD 2011 Leiden University; Cambridge: Cambridge University Press, 2015, 325 pp., isbn 978 1 107 08761 3).
De sacra militia contra iconomachos: Civic Strategies to Counter Iconoclasm in the Low Countries (1566)
Authors: Suykerbuyk Ruben
Published: March 2016

Although the iconoclastic scare must have been enormous and the actual impact of the attacks of summer and autumn 1566 can hardly be exaggerated, the Beeldenstorm was not as comprehensive as it seemed to contemporaries and subsequent historians. Indeed, a considerable number of important cities in the Habsburg Netherlands actually managed to ward off destruction, but until now their role has hardly been studied. The aim of this article is twofold: first, it seeks to chart the cities in question. Second, it analyses the preventive measures that they took against the violence. In so doing, it nuances the idea of theBeeldenstormas an all-destructive wave, and provides insights into the dynamics of the Iconoclastic Fury. More specifically, the cliché that the passivity of magistrates was the main reason for all losses seems in need of considerable revision. This article is part of the special issue 'Beeldenstorm'. De sacra militia contra iconomachos. Stedelijke maatregelen tegen de Beeldenstorm in de Lage Landen (1566)Ondanks de reële iconoclastische dreiging en de enorme impact van de vernielingen in de zomer en herfst van 1566, was de Beeldenstorm niet zo grondig en alomvattend als ze door tijdgenoten en latere historici werd beschreven. Een aanzienlijk aantal belangrijke steden in verschillende gewesten van de Habsburgse Nederlanden wist inderdaad aan de vernielingen te ontsnappen, maar hun rol werd tot nu toe nauwelijks bestudeerd. Het doel van dit artikel is daarom tweeledig: enerzijds worden de steden in kwestie in kaart gebracht, anderzijds wordt onderzocht welke maatregelen zij namen ter preventie van het geweld. Naast het feit dat dit het idee van de Beeldenstorm als allesverwoestend sterk kan nuanceren, leidt het tot een aantal interessante inzichten in de precieze aard van de storm. Vooral het cliché van de niet-ingrijpende magistraat als belangrijkste reden voor de massale verliezen blijkt aanzienlijk herzien te moeten worden. Dit artikel maakt deel uit van het themanummer 'Beeldenstorm'.
Under Construction?: The Catholic Community in Ghent after the Beeldenstorm
Authors: Bauwens Michal
Published: March 2016

While the iconoclasm of 1566 has been a popular topic in the historiography of the Low Countries, we know little about the people who endured iconoclasm. Generally, Catholics in the Low Countries were regarded as being rather passive bystanders in the events of this period, but the case of Ghent illustrates that Catholics took various actions when faced with the threat of iconoclasm and the subsequent destruction. Even though religious militancy was lacking, certain aspects of Catholic religion were strengthened throughout the Wonder Year. Parishioners put a lot of effort in the repairs of their parish churches and the interest in traditional devotions and religious knowledge also increased. Rather than rendering them passive, the troubled period seems to have motivated Ghent Catholics to research their faith. This article is part of the special issue 'Beeldenstorm'. De Beeldenstorm van 1566 is een populair thema in de historiografie van de Lage Landen, maar desalniettemin is onze kennis over de mensen die het iconoclasme ondergingen beperkt. De Nederlandse katholieken worden vaak als passieve toeschouwers van de troebelen omschreven, maar de casus van Gent toont aan dat katholieken wel degelijk actief waren in de aanloop naar de Beeldenstorm en tijdens de maanden na de vernielingen. Een religieuze militante houding was inderdaad afwezig, maar andere aspecten van het katholieke geloof werden tijdens het Wonderjaar juist versterkt. Parochianen focusten op een snel herstel van hun parochiekerk en versterkten bepaalde devoties. Ook de aandacht voor religieuze kennis nam toe. In plaats van passief, toonden de Gentse katholieken zich door de ‘troebele tijden’ gemotiveerd om hun geloof nader te onderzoeken. Dit artikel maakt deel uit van het themanummer 'Beeldenstorm'.
The Beeldenstorm and the Spanish Habsburg Response (1566-1570)
Authors: Soen Violet
Published: March 2016

In most textbooks, the punitive and military mission of the Duke of Alba to the Netherlands in 1567 embodies the Spanish Habsburg response to the Beeldenstorm of the previous year. This representation however, obscures the measures taken in the heat of the moment by Governor General Margaret of Parma, while it also downplays the numerous policy discussions to find the ‘right remedy’ for iconoclasm. This article argues that repression formed but one part of a broader pacification strategy that also included mediation, reconciliation and reform. The tactic employed by the Spanish Habsburg authorities combined the punishment of prominent leaders with a recognition that most of the participants in the ‘troubles’ could neither be apprehended nor punished properly, so that a pardon would eventually be necessary. Just such a pardon was issued in July 1570. Even if King and governor-general regarded iconoclasm as outright sacrilege and as divine lèse-majesté committed by heretics, the central authorities framed their response primarily as a legitimate action against worldly lèse-majesté and rebellion, in the short term to silence the religious violence of the iconoclasts, and in the longer term to maintain the initiative in safeguarding order, justice and peace, including in matters religious. This article is part of the special issue 'Beeldenstorm'. De Beeldenstorm en het Spaans-Habsburgse antwoord (1566-1570)De strafmissie van de hertog van Alva in 1567 verschijnt in de meeste handboeken als het Spaans-Habsburgse antwoord op de Beeldenstorm. Deze voorstelling doet weinig recht aan de onmiddellijke maatregelen van de hertogin van Parma voor de komst van Alva, en nog minder aan de voortdurende zoektocht naar de ‘juiste remedie’ om de onrust te bedaren. De repressie onder Alva vormde slechts een deel van een bredere pacificatiestrategie, die ook verzoeningsgebaren van koningswege inhield. Zo combineerde de Spaans-Habsburgse tactiek strafmaatregelen tegen de voornaamste leiders van de Beeldenstorm met de erkenning dat niet alle aanwezigen bij de ‘troebelen’ konden worden gearresteerd. Om rechtvaardigheid te doen geschieden, werd daarom in juli 1570 een generaal pardon uitgevaardigd. Daarnaast beargumenteert deze bijdrage dat hoewel Filips II en zijn landvoogden in Brussel de Beeldenstorm als regelrechte blasfemie beschouwden, ze hun optreden hoofdzakelijk rechtvaardigden als een actie tegen rebellie en wereldlijke majesteitsschennis, om zo op de korte termijn de religieuze agenda van de opstandelingen te verzwijgen, en op de lange termijn het monopolie te behouden inzake ordehandhaving en godsdienst. Dit artikel maakt deel uit van het themanummer 'Beeldenstorm'.
The history of broomcorn millet (Panicum miliaceum L.) in the Carpathian-basin in the mirror of archaeobotanical remains II. from the Roman age until the late medieval age
Authors: Gyulai Ferenc
Published: March 2016

The domestication of broomcorn millet based on latest archaeobotanical investigations occurred in the arid areas of North China and in same time in Central Asia. The knowledge of cultivation of broomcorn millet the Carpathian Basin before the 6th thousand BC. Since this time in all archaeological ages are available but in different frequency. Broomcorn millet was a widespread and favoured cereal. Knowing the eating habits of nomadic and semi-nomadic people, this find is expected, as broomcorn millet is a favoured cereal with a short growing season and rapid development requiring relatively little tending. This is expected as broomcorn millet was a key crop for Hungarians in the Middle Ages. A significant amount was grown traditionally by Hungarians through time until the appearance of maize, the new gruel plant. In the second part will be present the history of broomcorn millet in the Carpathian Basin from the Roman Age until the Late Medieval Age.
The effect of genotype and cropyear on the yield and the phytopathological traits of sunflower (Helianthus annus L.)
Authors: Pepó Péter , Novák Adrienn
Published: March 2016

The yield and the phytopathological traits of seven sunflower hybrids were studied in two crop protection models with different input levels (extensive=without fungicide treatments, mid-tech=-two fungicide treatments) on chernozem soil in two different years (2012 and 2013). The experimental results proved that the level of infection by Diaporthe (64% in the extensive model, 38% in the mid-tech model as an average of the hybrids), Phoma (53.5% and 34.0%), Sclerotinia (8.4% and 4.6%), Alternaria (76.4% and 48.7%) in the more wet year of 2012. When the precipitation before the season (294 mm from December until March) had filled up the water stock of the chernozem soil and the vegetation period had been dry (79 mm rain during the months of June, July and August), the degree of infection was considerably lower (infection by Diaporthe: 37% in the extensive model and 25% in the mid-tech model, infection by Phoma: 28.5% and 17.4%, infection by Sclerotinia: 1.5% and 0.7%, infection by Alternaria: 35.8% and 22.2% in 2013 as an average of the hybrids). Due to the higher disease infection in 2012, the yield of the hybrids ranged between 3300 – 4200 kg ha-1 and between 3900 – 4900 kg ha-1 in the extensive (control) model and mid-tech model (two fungicide treatments), respectively. In the more favourable year of 2013 (as regards the weather and the disease infection), the yields of the hybrids varied between 4200 – 5200 kg ha-1 in the extensive and between 5000 – 6000 kg ha-1 in the mid-tech crop protection model.
Effects of different biochars, compost and lime treatments on the chemical properties of sandy soils
Authors: Holes Annamária , Szegi Tamás , Fuchs Márta , Gulyás Miklós , Aleksza László
Published: March 2016

Decrease in organic matter of the soil is one of the major threats to soils in Europe and other parts of the globe. Maintaining or increasing organic carbon is a great challenge in agricultural practices. Application of composts and other organic amendments is an important way of compensation of losses of organic carbon at the same time it is solving the placement and recycling of organic wastes and residues. The favorable effect of these amendments on physical, chemical and biological properties has been proved by different studies, however the stability and the rate of the influence is an issue that can be improved.The aim of the presented study was to investigate the effect of carbonates on the solubility of applied organic materials and selected soil parameters. Different biochars, compost and carbonate were added to light textured soil. The pH and E4/E6 rates were studied under laboratory conditions. Beside the increase of soil organic matter content, all studied parameters gave promising results. The decrease in E4/E6 rate suggests that the inorganic carbonates are stabilizing the fresh organic residues and prevent the leaching processes. Improved soil organic carbon stability is very important in light textured soils.Further investigations are undergoing to determine the optimal rate of components and extend the kinds of material available for application.
Community is more than just a physical space
Authors: Schranz Edit
Published: March 2016

What happens if among the members of a society and among the smaller and larger units and groups making up the society trust and confidence seems to be disappearing at once? What happens if confidence reposed into each other fall victim to social differences as well as to the economic / cost-of-living boxing of modern information society? How to stop the crisis symptom that seems to be developing this way and which is shown in the fragmentation of communities?1 With other words, is it possible to “stick again together” a community or even a whole society started to disintegrate? The questions, even if not so characteristically phrased, provide sociologists actually with the scope of understanding our modern, individualistic world (Habermas 1994). Gusfield (1975) depicts dichotomy of community and society in a way that we should interpret community as a pervading, significant contrast. By now literature seems as if it was only be able to picture the changes taking place in the images both of the society and community describing them by even more pronounced, contradictory processes. The changes that send messages on the disintegration of categories and frames becoming insecure instead of the security and integration quasi missed by Habermas. It also seems as if—quasi as an answer given to this process—occlusion/seclusion both on the part of community members and the various communities from the seemingly unknown and insecure changes were more intensive (Légmán 2012). We intend to construe these phenomena on the next pages, but due to extension limits without the need for completeness of social interpretations. We want to do it with the help of mainly one dimension: value preference through the example of a given society, namely the Hungarian one. Thus we get to the stability and the solidarity of the members of the smallest unit of society, one which accepts and expresses various value preferences, the family.
„…nem a kortárs családi lét múló aberrációja”
Authors: Czibere Ibolya , Molnár Éva
Published: March 2016

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Inhibition of Human Liver Cytochrome P450 by Star Fruit Juice
Authors: Zhang Jiang-Wei , Liu Yong , Cheng Jie , Li Wei , Ma Hong , Liu Hong-Tao , Sun Jie , Wang Li-Ming , He Yu-Qi , Wang Yun , Wang Zheng-Tao , Yang Ling
Published: March 2016

Purpose. To examine the inhibitory effects of star fruit (Averrhoa carambola) juice towards seven major cytochrome P450 (CYP) isoforms and NADPH-cytochrome P450 reductase (CPR). Methods. The inhibitory effects of star fruit juice (0.5 to 5%, v/v) against the activities of seven CYP isoforms including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4 and CPR were examined in human liver microsomes. To identify time-dependent inhibition, star fruit juice (2.5%, v/v) was preincubated with microsomes and a NADPH-generating system for 0-15 min, and then the extent of inhibition towards seven CYP isoforms were examined. Results. Star fruit juice (5.0%, v/v) was found to inhibit all the activities of CYP isoforms tested by more than 70%. Based on the half inhibition values (%, v/v), the inhibitory effects towards different CYP isoforms were in the following order: CYP2A6 (0.9) > CYP1A2 (1.4) > CYP2D6 (1.6) > CYP2E1 (2.0) > CYP2C8 (2.2) > CYP2C9 (3.0) > CYP3A4 (3.2). Time-dependent inhibition was not observed towards any of the tested CYP isoforms. In addition, star fruit juice was found not to inhibit the activity of CPR. Conclusions. Star fruit juice inhibited the seven CYP isoforms tested, with the strongest inhibitory effect against CYP2A6 and the least towards CYP3A4.
Resveratrol Protects Against Methotrexate-Induced Hepatic Injury in Rats
Authors: Tunalı-Akbay Tugba , Sehirli Ozer , Ercan Feriha , Sener Goksel
Published: March 2016

Purpose. The aim of this study to investigate the possible protective effect of resveratrol on some liver and serum/plasma parameters in methotrexate induced toxicity in rats. Methotrexate is used widely to treat various neoplastic diseases such as acute lymphoblastic leukemia, lymphoma, solid cancers, and autoimmune diseases. We hypothesized that resveratrol has a potential to decrease the oxidant damage in MTX-induced hepatic injury. Methods. Following a single dose of methotrexate (20 mg/kg, i.p.), either saline or resveratrol (10 mg/kg, orally) was administered for 5 days. After decapitation of the rats, trunk blood was obtained and the liver was removed to measure malondialdehyde and glutathione levels, myeloperoxidase and thromboplastic activities and collagen content. Aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase activity were measured in the serum samples, while TNF-α and total antioxidant capacity were assayed in plasma samples. Results. Our results showed that MTX administration increased the hepatic malondialdehyde levels, myeloperoxidase and thromboplastic activities and collagen contents and decreased glutathione, while these alterations were reversed in resveratrol-treated group. Elevated aspartate aminotransferase and alanine aminotransferase activities and TNF-α level observed following MTX treatment was depressed with resveratrol. Conclusions. The present study showed that resveratrol protects against methotrexate-induced hepatic injury and may be of therapeutic potential in alleviating the systemic side effects of chemotherapeutics.
Determination Of Novel Antibacterial Triazolylmethyl Oxazolidinones Concentrations In Human Plasma By APCI-LC-MS: Application To Stability Study
Authors: Phillips Oludotun A. , Abdel-Hamid Mohammed E.
Published: March 2016

Triazolylmethyl oxazolidinones are novel potent antibacterial agents recently synthesized in our laboratory. PURPOSE. Development of a rapid and specific LC-MS method for evaluating the stability of three potentially active antibacterial triazolylmethyl oxazolidinone compounds, namely PH-27, PH-38 and PH-41, in human plasma. METHODS. Ion-trap mass spectrometry using +APCI-MS at m/z 348.1 (PH-27), 389.1 (PH-38) and 451.1 (PH-41) combined with liquid chromatographic analysis using C18 reversed-phase column and a mobile phase consisting of 20 mM ammonium acetate solution and acetonitrile (50:50 v/v) was used. Plasma samples were pre-treated with acetonitrile to precipitate proteins prior to LC-MS analysis. Linezolid was used as an internal standard whose predominant ion at m/z 338.1 was monitored and used to construct the calibration curves. An accelerated stability study under controlled experimental conditions was conducted at -20 oC for a 5-weeks period. RESULTS. Calibration curves of the examined oxazolidinones in human plasma were established (r: 0.99) up to the concentration of 20.0 µg ml-1 with LLQ of 0.1 (PH-27), 0.5 (PH-38) and 1.0 µg ml-1 (PH-41). Validation data showed appropriate intra- and inter-day precision and accuracy as indicated from RSD% 1.3 - 8.6 and % DEVs -12.7 to +11.3, respectively. Stability studies gave the kinetic degradation parameters of kdeg 0.0191- 0.0857 week-1, t1/2 8.1-36.3 weeks and t90 1.2 -5.5 weeks. CONCLUSIONS. The developed +APCI-LC-MS assay is simple, fast and specific method that could be applied for the routine analysis of the selected oxazolidinones during stability and pharmacokinetic studies. The examined compound PH-27 was proved to be relatively more stable and resistant to degradation in human plasma compared to PH-38 and PH-41, as indicated from the kinetics and recovery studies at -20 oC.
Effect of Desflurane versus Sevoflurane in Pediatric Anesthesia: A Meta-Analysis
Authors: He Jiaxuan , Zhang Yong , Xue Rongliang , Lv Jianrui , Ding Xiaoying , Zhang Zhenni
Published: March 2016

Purpose: To compare the effect of desflurane versus sevoflurane in pediatric anesthesia by conducting meta-analysis. Methods: Studies were searched from PubMed, Medline, Springer, Elsevier Science Direct, Cochrane Library and Google Scholar up to July 2014. Weighted mean difference (WMD) or risk ratio (RR) and 95% confidence intervals (CIs) were considered as effect sizes. Heterogeneity across studies was assessed by Cochran Q test and I2 statistic. The random effects model was performed in the meta-analysis when heterogeneity was observed, or the fixed effect model was used. Review Manager 5.1 software was applied for the meta-analysis. Results: A total of 11 studies (13 comparisons) involving 1,273 objects were included in this meta-analysis. No heterogeneity was observed between studies for any comparison but for postoperative extubation time. The results showed significant differences between desflurane and sevoflurane groups for postoperative extubation time (WMD = -3.87, 95%CI = -6.14 to -1.60, P < 0.01), eye opening time (WMD = -1.11, 95%CI = -1.49 to -0.72, P < 0.01), awakening time (WMD = -4.27, 95%CI = -5.28 to -3.26, P < 0.01) and agitation (RR = 1.44, 95%CI = 1.05 to 1.96, P = 0.02). No significant differences (P > 0.05) were detected for discharge from the recovery room, oculocardiac reflex, nausea and vomiting and severe pain. Conclusions: Desflurane may have less adverse effects than sevoflurane when used in pediatric anesthesia with significantly shorter postoperative extubation time, eye opening time and awakening time as well as slighter agitation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
ASK1-P38 Pathway is Important for Anoikis Induced by Microtubule-Targeting Aryl Chloroethylureas
Authors: Fortin Jessica S , Patenaude Alexandre , Deschesnes Rena G , Côté Marie-France , Petitclerc Eric , C.-Gaudreault René
Published: March 2016

PURPOSE. We investigated the involvement of MAPK signaling in the cell death mechanisms of classical microtubule interfering agents (MIA) and aryl-3-(2-chloroethyl)ureas (CEU) acting as antimitotics, along with CEU that don’t affect directly microtubules (non-MIA CEU). METHODS.

To ascertain the activated signaling pathway profile of MIA and non-MIA CEU, Western blot, immunoprecipitation and transfection experiments were performed. RESULTS. Non-MIA CEU do not activate p38, as opposed to MIA, and the extent of ERK and JNK activation is lower than in response to MIA. The effect of MIA and non-MIA CEU on focal adhesion associated protein was also studied; MIA were shown to induce focal adhesion dismantlement associated with a sustained increase in paxillin phosphorylation and FAK cleavage, as opposed to non-MIA CEU. In addition, bcl-2 phosphorylation and AKT cleavage, induced by all MIA tested, was not observed in response to non-MIA CEU further emphasizing the differential cell death mechanisms induced by MIA and non-MIA CEU. Pharmacologic and genetic approaches emphasize that the ASK1-p38 pathway activation contributes to the cytotoxic mechanism of MIA, in contrast to non-MIA CEU. ASK1-p38 is important for increased paxillin phosphorylation and FAK cleavage, suggesting that ASK-1-p38 is an upstream event of FA structure dismantlement induced by MIA. Moreover, the endogen inhibitor of ASK-1, thioredoxin, is released from ASK-1 in response to MIA as opposed to non-MIA CEU. CONCLUSION. Our study supports that ASK1-p38 activation is an important signaling event, induced by MIA, which impairs focal adhesion structure and induces anchorage-dependent apoptosis or anoikis.
Evaluation of the Efficacy and Safety of Changes in Antiretroviral Regimens for HIV-infected Patients
Authors: Tanaka Hiroyuki , Wada Tatsuhiko , Takayama Yoko , Matsumoto Keisuke , Atsuda Koichiro , Satoh Mitsutoshi
Published: March 2016

Purpose. Antiretroviral therapy is now available for HIV-infected patients, and so-called highly active antiretroviral therapy (HAART) now makes it possible to strongly suppress viral proliferation and restore immunity. However, the development of new drugs and regimens for HAART is still in progress, with the aim of overcoming a number of associated problems. For this purpose, changes in the prescribed anti-HIV drugs are often made. In the present study, we attempted to clarify the actual effects of such treatment modifications in patients who had been started on HAART.  Methods.  We retrospectively investigated HIV-infected patients who had been started on HAART at Kitasato University Hospital between April 1997 and March 2013. The patients’ backgrounds, characteristics and laboratory data were established from the hospital medical records.  Results.  The total follow-up time was 447.3 person-years. The patients remained on their initial regimen for a median period of 2040 days, and 39 patients took a second regimen for a median of 2714 days. There was no treatment failure due to regimen change. The reason for the regimen change was adverse effects in 49 cases, poor adherence/virological failure in 4, immunological failure in 3, patient request in 2, and proposals made by health care workers, or for simplification, in 11. The number of patients who required regimen change due to renal dysfunction showed a gradual increase. The number of times anti-HIV drugs were taken per day was not altered when the regimen changed, being mainly once or twice a day.  Conclusion.  In the present study, there were no instances of treatment failure due to regimen change. Through appropriate regimen change, it is possible to avoid serious adverse effects, and to improve patient adherence. Further adverse effects associated with long-term antiretroviral therapy, and reduction of adherence through medication fatigue should be considered. Drug selection and regimen change should be considered in relation to long-term prognosis.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
An Overview Of Tuberculosis Chemotherapy – A Literature Review
Authors: Sarkar Susmita , Suresh Mavanur R
Published: March 2016

Tuberculosis (TB) is a major threat in global public health. The emergence of HIV and also multi drug resistant (MDR) and extremely drug resistant (XDR)-TB poses a vital challenge to the control of the disease. For the last 40 years, no new anti-TB drug has been discovered.

This literature review provides a brief discussion of existing drugs and emerging drug targets, and also of the advantages of incorporating modern drug delivery systems and immune modulators in order to improve the existing treatment regimen in terms of better efficacy, reduced drug administration frequency, shortened period of treatment and reduced drug related toxicity. The investigation for new a drug target is essential in carrying on the fight against MDR and XDR-TB. However, owing to the enormous cost and time involved in new drug development, improvement of the existing treatment regimen is seen to be a valid alternative.

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Effects of Long-Term Hepatic Ischemia-Reperfusion Injury on the Function of P-glycoprotein in vivo in Rats
Authors: Thorling Camilla A , Roberts Michael S , Liu Xin , Fletcher Linda M , Crawford Darrell , Burczynski Frank J
Published: March 2016

PURPOSE: Ischemia-reperfusion injury is a common complication in liver surgery with oxidative stress related graft failure as a potential complication. The oxidative stress could affect hepatic drug transporters such as P-glycoprotein, which is crucial in the hepatic clearance of certain immunosuppressant drugs. Thus,, it is important to study its function after ischemia-reperfusion injury in vivo. Rhodamine 123 is a fluorescent substrate of P-glycoprotein and its hepatic disposition can be visualized using multiphoton microscopy in vivo using anaesthetized animals. The aim of this study was to investigate the effect of long-term ischemia-reperfusion injury on P-glycoprotein function in hepatocytes using in vivo multiphoton microscopy. METHODS: Localized ischemia was induced for 1 hour in rats. The liver was reperfused for 4, 24, 48 hours or 1 week, where-after rhodamine 123 was injected intravenously. Multiphoton microscopy imaged the liver and bile was collected continuously up to 6 hours following drug administration. The liver was harvested for histology andprotein expression of P-glycoprotein. RESULTS: Ischemia-reperfusion injury resulted in extensive liver damage, inflammatory cell infiltration and apoptosis in the midzonal and centrilobular regions of the liver acinus. P-glycoprotein protein expression decreased. Cellular concentration of rhodamine 123 increased as visualized by multiphoton microscopy, which was confirmed with decreased excretion of rhodamine 123 in collected bile. CONCLUSIONS: This study showed reduced function of P-glycoprotein in ischemia-reperfusion injury as reflected by decreased biliary excretion of Rhodamine 123, as well as reduced protein expression of the transporter. Multiphoton microscopy could be used to visualize and quantitate the intracellular levels of rhodamine 123. These findings stipulate the importance of using multiphoton microscopy to understand transmembrane drug flux and reflect on careful drug dosing after hepatic surgery. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Efficacy and Toxicity of Factor Xa Inhibitors
Authors: Bondarenko Maryna , Curti Christophe , Montana Marc , Rathelot Pascal , Vanelle Patrice
Published: March 2016

Venous thromboembolism (VTE) is a serious disease that is often neglected, and effective and safe antithrombotic treatments are a public health priority. New antithrombotics such as rivaroxaban, apixaban, betrixaban, edoxaban, darexaban, TAK-442, LY517717, eribaxaban, otamixaban are being developed to overcome current therapeutic limitations. The new oral anticoagulants and parenteral otamixaban are under evaluation in clinical trials for VTE treatment, for VTE prevention in orthopedic surgery, for stroke prevention in patients with atrial fibrillation and for cardiovascular event prevention in patients with acute coronary syndrome. These antithrombotic agents directly and selectively inhibit factor Xa, and do not require coagulation monitoring and dose adjustment. Several of these drugs have shown promising results and have the potential to either replace or act as alternatives to traditional anticoagulants (heparins, vitamin K antagonists).

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Different Storing and Processing Conditions of Human Lymphocytes do not Alter P-Glycoprotein Rhodamine 123 Efflux.
Authors: Chiva-Blanch Gemma , Giménez-Bonafe Pepita , Llaudó Inés , Torras Joan , Cruzado Josep M , Pétriz Jordi , Castaño Esther , Franquesa Marcella , Tortosa Avelina , Herrero-Fresneda Immaculada , Rama Inés , Bestard Oriol , Grinyó Josep M , LLoberas Núria
Published: March 2016

P-glycoprotein (Pgp), a protein codified by Multi Drug Resistance (MDR1) gene, has a detoxifying function and might influence the toxicity and pharmacokinetics and pharmacodynamics of drugs. Sampling strategies to improve Pgp studies could be useful to optimize the sensitivity and the reproducibility of efflux assays. This study aimed to compare Pgp expression and efflux activity by measuring Rhodamine123 (Rh123) retention in lymphocytes stored under different conditions, in order to evaluate the potential utility of any of the storing conditions in Pgp functionality. Our results show no change in protein expression of Pgp by confocal studies and Western blotting, nor changes at the mRNA level (qRT-PCR). No differences in Rh123 efflux by Pgp activity assays were found between fresh and frozen lymphocytes after 24 hours of blood extraction, using either of the two Pgp specific inhibitors (VP and PSC833). Different working conditions in the 24 hours post blood extraction do not affect Rh123 efflux. These results allow standardization of Pgp activity measurement in different individuals with different timing of blood sampling and in different geographic areas.
3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension
Authors: Satoh Mitsutoshi , Satoh Akira
Published: March 2016

PURPOSE. We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with monocrotaline-induced pulmonary hypertension. METHODS. The rat model of pulmonary hypertension was created by administration of monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a femoral artery for measurement of mean arterial pressure, another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP), and another into a femoral vein for administration of test drugs. RESULTS. Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) and simvastatin (2 mg/kg/day, p.o. 0 - 28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 - 28 days) did not reduce the monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S)) induced by a combination of a prostacyclin analogue, beraprost (100 mg/kg/day, 0 - 28 days) and simvastatin (2 mg/kg/day, 0 - 28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 - 28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) + sildenafil (5 mg/kg/day, p.o. 0 - 28 days) significantly reduced Lung/BW. CONCLUSION. Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simbastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone.
Preclinical Pharmacokinetics of MI-219, a Novel Human Double Minute 2 (HDM2) Inhibitor and Prediction of Human Pharmacokinetics
Authors: Zou Peng , Zheng Nan , Yu Yanke , Yu Shanghai , Sun Wei , McEachem Donna , Yang Yongsheng , Yu Lawrence X , Wang Shaomeg , Sun Duxin
Published: March 2016

Purpose. The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. Methods. Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration–time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima’s method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration–time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Results. Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h-1*kg-1. Human Vdss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fuT) method was between 0.93-1.40 L*kg-1. Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima’s transformations. Conclusions. The predicted human pharmacokinetics is useful for the design of first-in-human study.

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Effects of Experimental Hyperlipidemia on the Pharmacokinetics of Tadalafil in Rats
Authors: Lee Joo Hyun , Oh Ju-Hee , Lee Young-Joo
Published: March 2016

Purpose. Hyperlipidemia is associated with an increased risk of erectile dysfunction. In this study, we investigated the effects of hyperlipidemia on the pharmacokinetics of tadalafil, a novel therapeutic agent for erectile dysfunction, in rats with experimental hyperlipidemia. Methods. Tadalafil (1 mg/kg) was administered to control rats and rats with poloxamer-407-induced hyperlipidemia (1 g/kg, i.p.). In addition, we performed in vitro studies to determine the hepatic metabolism in S9 fractions, intestinal absorption, and plasma protein binding. Results. Hyperlipidemia dramatically increased tadalafil’s the total area under the plasma concentration-time curve from time 0 to infinity after intravenous (2.09-fold) and oral (11.9-fold) administration, and decreased total body clearance (0.537-fold) and apparent volume of distribution at the steady state (0.438-fold) after intravenous administration of tadalafil. Further, we observed decreased in vitro hepatic S9 metabolism, intestinal first-pass metabolism, and unbound fraction of tadalafil. Conclusions. The alterations in the pharmacokinetics of tadalafil observed in rats with poloxamer 407-induced hyperlipidemia may be attributable to a decrease in hepatic and intestinal metabolism and unbound fraction of tadalafil in the plasma. These findings have potential therapeutic implications for predicting the pharmacokinetic responses of humans to hyperlipidemia.

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An Overview of Tissue Engineering as an Alternative for Toxicity Assessment
Authors: Garrod Mathew , Chau David Yi San
Published: March 2016

Tissue engineering is a multidisciplinary field that combines aspects of biology, material sciences, engineering and medicine - the ultimate goal being able to fabricate replacement tissues and/or organs for an ageing population. However, parallel to this milestone, is the exploitation of the biomimetic constructs as feasible alternatives to in vivo/ex vivo toxicity testing models due to their accurate representation of innate tissue and organs. Herein, we summarise a range of concepts within tissue engineering with a particular emphasis on biological material selection and implications to animal testing. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Phytochemical Comparison of the Water and Ethanol Leaf Extracts of the Cree medicinal plant, Sarracenia purpurea L. (Sarraceniaceae)
Authors: Cieniak Carolina , Walshe-Roussel Brendan , Liu Rui , Muhammad Asim , Saleem Ammar , Haddad Pierre S , Cuerrier Alain , Foster Brian C , Arnason John T
Published: March 2016

Purpose: The Cree of Eeyou Istchee in Northern Quebec identified Sarracenia purpurea L. as an important plant for the treatment of Type 2 diabetes. Traditionally the plant is used as a decoction (boiling water extract) of the leaf, however, in order to study the extract in a laboratory setting, an 80% ethanol extract was used. In this study, the phytochemistry of both extracts of the leaves was compared and quantified. Methods: Two S. purpurea leaf extracts were prepared, one a traditional hot water extract and the other an 80% ethanol extract. Using UPLC-ESI-MS, the extracts were phytochemically compared for 2 triterpenes, betulinic acid and ursolic acid, using one gradient method and for 10 additional substances, including the actives quercetin-3-O-galactoside and morroniside, using a different method. Results: The concentrations of the nine phenolic substances present, as well as an active principle, the iridoid glycoside morroniside, were very similar between the two extracts, with generally slightly higher concentrations of phenolics in the ethanol extract as expected. However, two triterpenes, betulinic acid and ursolic acid, were 107 and 93 times more concentrated, respectively, in the ethanol extract compared to the water extract. Conclusion: The main phytochemical markers and most importantly the antidiabetic active principles, quercetin-3-O-galactoside and morroniside, were present in similar amounts in the two extracts, which predicts similar bioactivity.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Nanoparticle-Mediated Interleukin-12 Cancer Gene Therapy
Authors: Dass Crispin , Hallaj-Nezhadi Somayeh , Lotfipour Farzaneh
Published: March 2016

Interleukin-12 (Il-12) is a heterodimeric cytokine which has been proved to possess antitumor effects in various animal models via stimulating the immune system. The main problem associated with Il-12 protein delivery is its instability as well as cytotoxicity subsequent to systemic administration in rodents and in human clinical trials. However, gene delivery can be used to deliver genes of interest to the tumor site. Hence, a large number of studies have been undertaken to deliver genes of interest to the tumor site through viral or non-viral vectors. Viral DNA delivery systems suffer from safety concern due to the toxicity of the viruses and strong immune response; while non-viral gene delivery systems proffer lower transfection efficiency. Nevertheless, nanometer-size complex of therapeutic DNA may demonstrate more efficient for administration of therapeutic genes to solid tumors compared to administration of naked plasmid DNA. Nanoparticle-based gene delivery systems might be more pertinent, due to the enhanced tissue penetrability, improved cellular uptake. Il-12 gene delivery has already been reported with different nanoparticles containing DNA. This article provides a review on the in vivo and in vitro studies using various nanoparticles, for delivery of the Il-12 genes to neoplastic cells. The future of these promising approaches lies in the development of better techniques for preparing il-12 gene delivery systems with complete efficiency of viral vectors in addition to the highest safety for cancer patients.
Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds
Authors: Kamal Ahmed , Azeeza Shaik , Malik M. Shaheer , Shaik Ahmad Ali , Rao Maddamsetty V.
Published: March 2016

Development of new chemotherapeutic drugs is the need of the hour to improve tuberculosis control, particularly in the developing world. In the last fourty years no new compound has been brought to the market for the treatment of tuberculosis. However, in recent years there is an enhanced activity in the research and development of new drugs for TB. Some compounds are presently in clinical development, while others are being investigated pre-clinically in an attempt to explore new molecules for the target based treatment of TB. Simultaneously some new targets are being identified and validated for their practical usefulness. Structures based on thiolactomycin could have considerable potential in the development of target based anti-TB agents. The present review provides an overview of the drugs that are being clinically used and the compounds that are in advanced stages of clinical as well as preclinical studies. We have also attempted to highlight the efforts that are being made in the development of new molecules based on thiolactomycin as lead compound, including studies from this laboratory.
Drug Disease Interactions: Role of Inflammatory Mediators in Pain and Variability in Analgesic Drug Response
Authors: Kulmatycki Kenneth M. , Jamali Fakhreddin
Published: March 2016

Pain has both physical and emotional components. Physical noxious stimuli activate peripheral sensory neurons that, in turn, relay signals to the spinal and supraspinal nuclei. Subsequently, these signals activate areas within the brain associated with pain. Despite considerable knowledge in this area, analgesics may provide pain complete relief in only one out of five patients. Failure to manage pain may be due to a lack of understanding of the neurobiological processing of pain. Factors such as anticipation, anxiety and pain history play roles in the perception of pain. Non-neuronal cells such as those of the immune system influence perception and modulation of pain by the nervous system. In post-dental surgery patients, the severity of the pain and the relief following administration of anti-inflammatory analgesics has been linked to the time course of inflammatory mediators. Similarly, the relief of post-operative pain after abdominal surgery is also associated with a reduction in expression of pro-inflammatory mediators. Administration of anti-cytokines to sciatica patients and subsequent pain relief further emphasizes the role of pro-inflammatory mediators in modulation of pain. Increased expression of inflammatory mediators may also alter response to analgesia. For example, rheumatoid patients with temporal mandibular joint disease with increased expression of interleukins prior to treatment demonstrate inadequate pain relief after administration of anti-TNF-?. In addition, pain or its trauma impairs absorption of oral analgesics causing therapeutic failure. Improved analgesic pharmacotherapy may require a better understanding of the involvement of the inflammatory pathways.