Chirality in the new generation of antidepressants: stereoselective analysis of the enantiomers of mirtazapine, N-demethylmirtazapine, and 8-hydroxymirtazapine by LC-MS.

Mirtazapine is an antidepressant that acts specifically on noradrenergic and sertonergic receptors. A LC-MS method was developed that allows the simultaneous analysis of the R-(-)- and S-(+)-enantiomers of mirtazapine (MIR), demethylmirtazapine (DMIR), and 8-hydroxymirtazapine (8-OH-MIR) in plasma of MIR-treated patients. The method involves a 3-step liquid-liquid extraction, an HPLC separation on a Chirobiotic V column, and MS detection in electrospray mode. The limit of quantification (LOQ) for all enantiomers was 0.5 ng/mL, and the intra- and interday CVs were within 3.3% to 11.7% (concentration ranges 5-50 ng/mL). A method is also presented for the quantitative analysis of glucuroconjugated MIR and 8-OH-MIR. S-(+)-8-OH-MIR is present in plasma mainly as its glucuronide. Preliminary data suggest that in all patients, except in those comedicated with CYP2D6 inhibitors such as fluoxetine and thioridazine, R-(-)-MIR concentrations were higher than those of S-(+)MIR. Moreover, fluvoxamine seems also to inhibit the metabolism of MIR. Therefore, this method seems to be suitable for the stereoselective assay of MIR and its metabolites in plasma of patients comedicated with MIR and other drugs for routine and research purposes.

Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation.

Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-kappaB activation. The current findings define a link among TCR, caspases, and the NF-kappaB pathway that occurs in a sequestered lipid raft environment in T cells.

Missed appointments in an adolescent outpatient clinic: descriptive analyses of consultations over 8 years.

Missed appointments represent an important medical and economical issue. Few studies on the subject are reported in the literature, particularly regarding adolescents. Our aim was to characterize missed and cancelled appointments in a multidisciplinary outpatient clinic for adolescents, to assess the effectiveness of a policy aimed at reducing missed appointments by introducing payment for those missed appointments not cancelled in advance, and to compare the rates between staff and resident physicians. A total of 32,816 consultations (representing 35 patients aged 12-20 years, 82.4% females) between 1999 and 200 were analysed. The missed appointment rate was 11.8% whilst another 10.9% were cancellations. Females cancelled more than males (11.3% vs. 8.4%, AOR 1.31, 99% CI 1.08-1.59), but there was no difference for missed appointments (11.6% vs. 12.3%, AOR 0.88, 99% CI 0.61-1.08). April and June to October (vacation months) were associated with more missed appointments. Globally mornings had higher rates of missed appointments than afternoons (13.6% vs. 11.2%, AOR 1.25, 99% CI 1.11-1.40). There was a slight difference in missed appointment rates between staff physicians and residents (10.4%; 11.8%, AOR 1.20, 99% CI 1.08-1.33). Missed appointment rates before and after the new policy on missed appointments were similar (1999-2003: 11.9%; 2004-2006: 11.6%, AOR 0.96, 99% CI 0.83-1.10). Conversely, cancellation rates increased from 8.4% (1999-2003) to 14.5% (2004-2006) (AOR 1.83, 99% CI 1.63-2.05). Attendance rates among adolescents show variations depending on vacation and school hours. Being attentive to these factors could help prevent missed appointments. Although having to pay for missed appointments does not increase attendance, it increases cancellations with the advantage that the appointment can be rescheduled.

Situación del recurso merluza y sus características biológicas en la primavera de 1978 crucero 7811-II TAREQ II (18 de octubre - 8 de noviembre 1978)

Evalúa el stock de la merluza y de otros recursos dermesales, determina la intensidad del desove y la distribución del stock reproductivo, así como las condiciones ambientales que están influyendo en la distribución y concentración del recurso.

El calamar gigante en el mar peruano. Crucero B/P Hakurei Maru Nº 8. Primavera 2010 y Verano 2011

El crucero se desarrolló en dos etapas, la primera en primavera 2010, de 4° a 11°25’S y la segunda en verano 2011, de 10°10’ a 17°23’S, entre 50 a 200 mn de la costa. La captura del recurso en la primera etapa fue 35.079,6 kg (25.669,1 kg de producción) y en la segunda 165.955,7 kg (123.229,5 kg de producción). La captura por unidad de esfuerzo por día de trabajo fluctuó de 2,9 a 4.292,6 kg/hora; 0,68 a 948,4 kg/línea; 0,07 a 99,8 kg/ línea*hora y 0,0017 a 2,4957 kg/pot*hora. La longitud del manto varió de 17 a 119 cm. Se registró hembras en estadio desovante III (51,5%), madurante II (21,6%); y machos en estadio evacuación III (85,1%) y virginales I (9,7%). Los grupos tróficos más importantes fueron: cefalópodos (% IRI= 66,4), crustáceos (% IRI= 23,7), peces (% IRI= 9,9). Las hembras presentaron: L∞ =111,233 cm LM, K=0,016, t0= 235 y los machos L∞ =99,718 cm LM, K=0,167 y t0=228,4; esta especie tiene una longevidad próxima o poco mayor a un año.

On the Source and Rewriting of 1 Corinthians 2.9 in Christian, Jewish and Islamic Traditions (1 Clem 34.8; GosJud 47.10-13; a ḥadīth qudsī)

The article reopens the file of sources, parallels and rewritings of 1 Cor 2.9, a saying that Paul attributes to some written source, when others sources put it into Jesus' mouth (e.g. GosThom 17). A state of research highlights that the hypothesis of an oral source is generally preferred but an accurate study of 1 Clem 34.8, a parallel too often neglected, supports the presence of a written source that existed before 1 Cor 2.9. GosJud 47.10-13 will help to understand the attribution of the saying to Jesus. The last important part of this article studies its parallel in Islamic traditions, a ḥadīth qudsī.

Suomen tiekartta Vägkarta över Finland / upprättad å lantmäteristyrelsen (8 /)

1 kartta :, vär. ;, 50 x 86 cm, kansi 26 x 12 cm, 1:1000000

8/3/20, mariage de Carpentier [avec Mlle Georgette Elsasser, mairie du 8e arrondissement, Paris] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 58384

1er mai 1920 à Paris, [grilles vandalisées à hauteur du 8 boulevard de Magenta] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 59120