Role of Membrane Transporters, P-Glycoprotein and Mrp1, in The Placental Transfer of Drugs With Special Reference to Saquinavir and Quetiapine

Drug transporting membrane proteins are expressed in various human tissues and blood-tissue barriers, regulating the transfer of drugs, toxins and endogenous compounds into or out of the cells. Various in vitro and animal experiments suggest that P-glycoprotein (P-gp) forms a functional barrier between maternal and fetal blood circulation in the placenta thereby protecting the fetus from exposure to xenobiotics during pregnancy. The multidrug resistance-associated protein 1 (MRP1) is a relatively less studied transporter protein in the human placenta. The aim of this study series was to study the role of placental transporters, apical P-gp and basal MRP1, using saquinavir as a probe drug, and to study transfer of quetiapine and the role of P-gp in its transfer in the dually perfused human placenta/cotyledon. Furthermore, two ABCB1 (encoding P-gp) polymorphisms (c.3435C>T, p.Ile1145Ile and c.2677G>T/A, p.Ala893Ser/Thr) were studied to determine their impact on P-gp protein expression level and on the transfer of the study drugs. Also, the influence of the P-gp protein expression level on the transfer of the study drugs was addressed. Because P-gp and MRP1 are ATP-dependent drug-efflux pumps, it was studied whether exogenous ATP is needed for the function of ATP-dependent transporter in the present experimental model. The present results indicated that the addition of exogenous ATP was not necessary for transporter function in the perfused human placental cotyledon. Saquinavir and quetiapine were both found to cross the human placenta; transplacental transfer (TPTAUC %) for saquinavir was <0.5% and for quetiapine 3.7%. Pharmacologic blocking of P-gp led to disruption of the blood-placental barrier (BPB) and increased the placental transfer of P-gp substrate, saquinavir, into the fetal circulation by 6- to 8-fold. In reversed perfusions P-gp, MRP1 and possibly OATP2B1 had a negligible role in the fetal-to-maternal transfer of saquinavir. The TPTAUC % of saquinavir was about 100-fold greater from the fetal side to the maternal side compared with the maternal-to-fetal transfer. P-gp activity is not likely to modify the placental transfer of quetiapine. Higher P-gp protein expression levels were associated with the variant allele 3435T, but no correlation was found between the TPTAUC % of saquinavir and placental P-gp protein expression. The present results indicate that P-gp activity drastically affects the fetal exposure to saquinavir, and suggest that pharmacological blockade of the P-gp activity during pregnancy may pose an increased risk for adverse fetal outcome. The blockade of P-gp activity could be used in purpose to obtain higher drug concentration to the fetal side, for example, in prevention (to decrease virus transfer to fetal side) or in treating sick fetus.

La traduzione della letteratura per l’infanzia dal finlandese all’italiano: l’esempio degli albi illustrati di Mauri Kunnas

Despite the increasing number of research on translating for children, no study has so far taken into consideration the translations of children’s literature from Finnish into Italian. This dissertation sets out to fill this gap with a comparative study of Finnish picturebooks and their translations into Italian. Besides being the first research in the field analysing the shifts between these two systems, the study thoroughly investigates the characteristics of the translation process of picturebooks. The works chosen as case study are the Finnish picturebooks by Mauri Kunnas and their Italian translations from the period 1979-2009 because they are characterized by a high number of linguistic and cultural complexities which challenge translators’ skills and knowledge. The dissertation establishes whether and how culture-specific elements (anthroponyms, toponyms, food and allusions) and the word-image interaction have a significant impact on the quality and the nature of the target works, and also whether these aspects are still consistent after the translation and the adaptation process to the target system. Since picturebooks are multimodal texts whose message is produced by both the verbal and the visual, it has been necessary to use a multimodal comparative analysis. Such a descriptive comparative study has allowed me to describe the textual and cultural manipulations undergone by Kunnas’s picturebooks translated into Italian. Indeed, it has helped to identify what kind of shifts occur when cultural specific elements are transferred from the source system to the target one, to determine the most frequent translation strategies used to ensure a higher degree of readability, and to establish whether particular translation choices have contributed to modify the word-image interaction. The results of the multimodal comparative analysis have shown that Italian translators have been deeply influenced by the preponderance of the illustrations and for this reason they have often verbalised the visual and added information not originally contained in the source written text. Moreover, the findings of the analysis together with the interviews to the Italian translator and publishing house have also demonstrated that the latter aimed at producing works “good for the child” – and at the same time “good for the adult” – and at minimizing Finnish cultural specificity, even to the detriment of the aesthetic nature of the original picturebooks.

”Coca-Cola, sitä arkkimaagikin juo!” Suomalaisten suhtautuminen pelinsisäiseen mainontaan

Pro gradu -tutkielmani käsittelee pelinsisäistä mainontaa suomalaisten silmin. Pelinsisäisellä mainonnalla tarkoitetaan peliin sijoitettuja tuotteita ja tuotemerkkejä. Kartoitin suomalaisten mielipiteitä sekä niin sanotusta oikeasta pelinsisäisestä mainonnasta että kuvitteellisesta mainonnasta, ja tutkimusmenetelmänäni käytin sisällönanalyysia. Aineistonkeruumenetelmänä toimi syksyllä 2013 käynnissä ollut verkkokysely, ja aineistona ovat kyselyyn tulleet 221 vastausta. Tutkimuksessani selvitin, miten suomalaiset suhtauvat pelinsisäiseen mainontaan. Lisäksi käyn läpi sitä, miten erityyppiset mainokset vaikuttavat pelaajaan, ja miten pelaajien käsitykset mainonnan vaikutuksesta pelikokemukseen ja immersioon eroavat suhteessa oikeaan ja kuvitteelliseen mainontaan. Kyselytulokseni paljastivat, että vaikka kuvitteellinen mainonta oli suomalaisten pelaajien keskuudessa yleisesti hyväksytympää, suhtautuminen oikeaan mainontaan oli odotettua positiivisempaa. Esimerkiksi 28 % vastaajista näkisi peleissä mieluummin oikeita mainoksia, ja 59 % hyväksyisi mainosten määrällisen kasvun, jos pelien ostohinta saataisiin siten laskemaan. Kokosin tutkimustulosteni ja aiemman tutkimuksen perusteella onnistuneen pelinsisäisen mainonnan kulmakivet pelaajan näkökulmasta. Viisikohtaiseen malliin sisältyvät mainoksen integrointi pelimaailmaan, toisto, tilanne, jossa mainos esitetään, mainoksen ja pelin välinen yhteys sekä mainoksen tekniset ominaisuudet. Peleissä esiintyvän mainonnan muodoista tuotesijoittelu oli tutkimukseni kannalta keskeisimmässä roolissa, sillä se on monipuolinen, yleisimmin kaupallisissa peleissä esiintyvä mainostyyppi ja myös oman mielenkiintoni ensisijainen kohde. Maltillinen tuotesijoittelu osoittautui myös hyväksytyimmäksi mainostyypiksi pelaajien keskuudessa, sillä esimerkiksi ilmais- ja mobiilipeleille ominaiset mainosikkunat ja videomainokset mainittiin pelkästään negatiivisessa mielessä.