Cytochrome P450 1A2 activity and inducibility: impact of smoking, smoking cessation and genetic polymorphisms

Aims: Cytochrome P4501A2 (CYP1A2) is involved in the metabolism of severaldrugs (clozapine, olanzapine, theopylline, caffeine, etc) and is induced by smoking.This can result in decreased plasma levels of drugs metabolized by thisisoenzyme, causing a decrease in therapeutic response. After quitting smoking,increased plasma levels can lead to adverse effects of the concerned drugs, such asconfusion and seizures, described under clozapine treatment. The present studyaimed to examine the variation of CYP1A2 activity in a large group of smokersbefore and after smoking cessation. Moreover, we aimed to determine whethergenetic polymorphisms of CYP1A2 gene could influence the inducibility ofCYP1A2. Methods: CYP1A2 activity was determined by the paraxanthine/caffeineratio in 194 smokers and in 118 of them being abstinent during a 4-weekperiod. Participants were genotyped for CYP1A2*1F (rs762551), *1D(rs35694136) and *1C (rs2069514) polymorphisms. Results: Smokers had higherCYP1A2 activity (1.55-fold; p < 0.0001). Individual change of CYP1A2 activityafter smoking cessation ranged from 1.0-fold (no change) to 7.3-fold decreasedactivity. In five participants with low initial CYP1A2 activity, an increase wasobserved after smoking cessation. During smoking, CYP1A2*1F (p = 0.005), CYP1A2*1D (p = 0.014), the number of cigarettes/day (p = 0.012), contraceptives use(p < 0.001) and - 163A/- 2467T/- 3860G haplotype (p = 0.002) influencedCYP1A2 activity, while after quitting smoking, CYP1A2*1F (p = 0.017) and contraceptives(p = 0.05) did. No influence of CYP1A2 polymorphisms on the inducibilityof CYP1A2 was observed. Conclusion: Higher CYP1A2 activity wasmeasured in smokers, but with a large interindividual variability of its inductionby smoking. Careful clinical management with the help of therapeutic drug monitoringis therefore needed for patients receiving drugs which are metabolized byCYP1A2, who stop or start smoking. Unidentified genetic variations in theCYP1A2 gene and/or in other genes controlling CYP1A2 activity and other environmentalfactors could be responsible of the observed differences in CYP1A2enzymatic activity and inducibility.

LDLs induce fibroblast spreading independently of the LDL receptor via activation of the p38 MAPK pathway.

Because adventitial fibroblasts play an important role in the repair of blood vessels, we assessed whether elevation in LDL concentrations would affect fibroblast function and whether this depended on activation of intracellular signaling pathways. We show here that in primary human fibroblasts, LDLs induced transient activation of the p38 mitogen-activated protein kinase (MAPK) pathway, but not the c-Jun N-terminal kinase MAPK pathway. This activation did not require the recruitment of the LDL receptor (LDLR), because LDLs efficiently stimulated the p38 MAPK pathway in human and mouse fibroblasts lacking functional LDLR, and because receptor-associated protein, an LDLR family antagonist, did not block the LDL-induced p38 activation. LDL particles also induced lamellipodia formation and cell spreading. These effects were blocked by SB203580, a specific p38 inhibitor. Our data demonstrate that LDLs can regulate the shape of fibroblasts in a p38 MAPK-dependent manner, a mechanism that may participate in wound healing or vessel remodeling as in atherosclerosis.

n-3 PUFAs modulate T-cell activation via protein kinase C-alpha and -epsilon and the NF-kappaB signaling pathway.

We elucidated the mechanisms of action of two n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in Jurkat T-cells. Both DHA and EPA were principally incorporated into phospholipids in the following order: phosphatidylcholine < phosphatidylethanolamine < phosphatidylinositol/phosphatidylserine. Furthermore, two isoforms of phospholipase A(2) (i.e., calcium-dependent and calcium-independent) were implicated in the release of DHA and EPA, respectively, during activation of these cells. The two fatty acids inhibited the phorbol 12-myristate 13-acetate (PMA)-induced plasma membrane translocation of protein kinase C (PKC)-alpha and -epsilon. The two n-3 PUFAs also inhibited the nuclear translocation of nuclear factor kappaB (NF-kappaB) and the transcription of the interleukin-2 (IL-2) gene in PMA-activated Jurkat T-cells. Together, these results demonstrate that DHA and EPA, being released by two isoforms of phospholipase A(2), modulate IL-2 gene expression by exerting their action on two PKC isoforms and NF-kappaB in Jurkat T-cells.

¶ COPIE DER BRIEVEN || VAN DEN GROOTẽ TURCK ghescreuẽ aẽ mijn Heere dẽ || grootẽ meestere van Rodes omtrẽt sint Ians misse || laetst ledẽ anno. M. ccccc. xxij. En oec eẽ Epistel vã || d' stadt vã Rodes / aẽ dat heylich Catholicke geloue. || Rodes. — [A la fin] : ¶ Dese Copie es vandẽ walsche ghetranslateert in || onsen tale Eñ is eerst gecõponeert par songneur/ dict || Bethune. herault darmes. ons ghenadichs heerẽ dẽ || Keysere Chaerles. || ¶ Gheprent Tantwerpẽ by mi Adriaen van || Bergen int gulden Missael. || ¶ Cum Priuilegio. In-4 goth. de 4 f. de 33 lignes à la page pleine, impr. en grosses lettres de forme, sign. A, mar. r. jans., tr. dor. (Trautz-Bauzonnet.)

Ladam (Nicaise). Epistel van de stadt van Rodes (1522)

Marseille. Collection de copies et de documents originaux concernant l'histoire de Marseille. Collection Mortreuil sur Marseille vol. 12 : Corps religieux (Préfecture des Bouches du Rhône. Archives de l’église d’Arcoules, du monastère de Saint Sauveur et des Grands Trinitaires de Marseille. Actes antérieurs au XIV e siècle. A.M. 1855.)

Copie manuscrite de documents d’archives : F. 1-91. Archives de l’Eglise d’Arcoules de Marseille. F. 92-104. Augustins. F. 105-149. Archives des Dominicains (precheurs) de Marseille. F. 150-153. Abbaye de l’Huveaune, prémontrés. F. 154-178. Frères Mineurs. F. 179-180. La Major. F. 181 -184. St Carmat. F. 185-186. St Etienne des îles Ratoneau. F. 187-191. St Jacques de Corrégie. F. 192-193. St Laurent. F. 194-195. Prieuré de St Lazare. F. 196-199. St Martin F. 200-206. St Michel et St Etienne du Plan. F. 207 -379. Archives du monastère de Saint Sauveur de Marseille. F. 381-387. Sainte Claire. F. 388-391. N.D. de Syon. F. 392 459. Archives des Grands Trinitaires de Marseille.

Assertividade e tempo de permanência de cateteres intravenosos periféricos com inserção guiada por ultrassonografia em crianças e adolescentes

Estudo randômico e controlado que objetivou verificar se a ultrassonografia vascular (USV) aumenta a assertividade na utilização do cateter intravenoso periférico e o tempo de permanência do cateter quando comparado ao método tradicional de punção. A coleta de dados ocorreu após aprovação do mérito ético, incluindo-se no estudo crianças e adolescentes submetidos a punção intravenosa periférica guiada pela USV, constituindo o grupo USV (GUSV), ou após avaliação clínica da rede venosa, denominado grupo controle (GC). Os valores de p<0,05 foram considerados significativos. A amostra foi constituída por 382 punções, 188 (49,2%) no GUSV e 194 (50,8%) no GC, realizadas em 335 crianças. Identificou-se assertividade em 73 (71,6%) cateteres do GUSV e em 84 (71,8%) do GC (p=0,970). O tempo de permanência do cateter apresentou mediana inferior a um dia nos dois grupos (p=0,121), não havendo diferença estatisticamente significativa. Concluindo-se que a USV não influenciou os resultados das variáveis dependentes investigadas. ClinicalTrials.govNCT00930254.

Vitae sanctorum. Pars I. Saints du mois de janvier.

Agnes (184). - Ascla (205). - Babillus (206 v). - Balthildis regina (243 v). - Concordius (20). -Emerentiana (204). - Felix, 19 kl. febr. (105). - Firminus (101). - Fructuosus etc. (189). - Furseus (114). - Genovefa (21 v). - Hilarius (92). - Julianus et Bas. (67). - Leucus, Tyrsus et Galenicus (227). -Lutianus (62). - Macra (59). - Marcellus papa (107 v). - Martina (7 v). - Nicolaus (258 v). - Patroclus (190 v). - Paula (213 v). - Policarpus (209 v). - Quintinus (34 v). - Remigius (98). - Rigobertus (36 v). - Sabinianus (239 v). - Saturninus, Davitus etc. (142). - Sebastianus (154 v). - Speusipphus El. et Mel. (132 v). - Sulpitius (138 v). - Symeon (49 v). - Theogenius (32). - Timotheus (202 v). - Vincentius (194).

Helsinki 12.3.1932

Kirje

Auditory motion affects visual biological motion processing.

The processing of biological motion is a critical, everyday task performed with remarkable efficiency by human sensory systems. Interest in this ability has focused to a large extent on biological motion processing in the visual modality (see, for example, Cutting, J. E., Moore, C., & Morrison, R. (1988). Masking the motions of human gait. Perception and Psychophysics, 44(4), 339-347). In naturalistic settings, however, it is often the case that biological motion is defined by input to more than one sensory modality. For this reason, here in a series of experiments we investigate behavioural correlates of multisensory, in particular audiovisual, integration in the processing of biological motion cues. More specifically, using a new psychophysical paradigm we investigate the effect of suprathreshold auditory motion on perceptions of visually defined biological motion. Unlike data from previous studies investigating audiovisual integration in linear motion processing [Meyer, G. F. & Wuerger, S. M. (2001). Cross-modal integration of auditory and visual motion signals. Neuroreport, 12(11), 2557-2560; Wuerger, S. M., Hofbauer, M., & Meyer, G. F. (2003). The integration of auditory and motion signals at threshold. Perception and Psychophysics, 65(8), 1188-1196; Alais, D. & Burr, D. (2004). No direction-specific bimodal facilitation for audiovisual motion detection. Cognitive Brain Research, 19, 185-194], we report the existence of direction-selective effects: relative to control (stationary) auditory conditions, auditory motion in the same direction as the visually defined biological motion target increased its detectability, whereas auditory motion in the opposite direction had the inverse effect. Our data suggest these effects do not arise through general shifts in visuo-spatial attention, but instead are a consequence of motion-sensitive, direction-tuned integration mechanisms that are, if not unique to biological visual motion, at least not common to all types of visual motion. Based on these data and evidence from neurophysiological and neuroimaging studies we discuss the neural mechanisms likely to underlie this effect.

Proteção Social em Cabo Verde

Durante a última década, Cabo Verde tem tido um crescimento constante, impulsionado pelo turismo, remessas da diáspora, o investimento directo estrangeiro e ajuda ao desenvolvimento, enquanto o déficit orçamentário e da dívida pública permaneceram limitados. A maioria dos indicadores de desenvolvimento humano apontam para melhorias consideráveis e estão entre os mais altos na África subsaariana. A expectativa de vida ao nascer é de 72 anos, a taxa de mortalidade infantil caiu pela metade nos últimos 20 anos, a taxa de alfabetização é de 80% e a taxa de matrícula no ensino primário recentemente chegou a 100%. A taxa de pobreza diminuiu de 36,7% em 2001 para 26,6% em 2007. Cabo Verde é um dos poucos países na África que prevê atingir todas as metas dos Objectivos de Desenvolvimento do Milênio. Em 2008, o país ganhou status de país de rendimento intermédio.