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.

Lovemarks: lealtad más allá de la razón

El present treball és un estudi a nivell global i individual sobre marques, i especialment les lovemarks, i els diferents vincles emocionals que motiven i impulsen el culte de determinats béns i serveis. L’estudi està enfocat a dos nivells: el del consumidor i el dels planificadors estratègics de marca.

Más allá de los blogs personales: el periodismo participativo en la prensa electrónica

La irrupció d’Internet i les Noves Tecnologies, juntament amb una sèrie de factors socials, polítics i econòmics, han redefinit la clàssica relació unidireccional entre els mitjans i les seves audiències. En aquest context de democratització informativa, el tradicional monopoli dels mitjans ha desaparegut en pro d’un accés i una participació més gran dels lectors a la informació. Aquesta nova modalitat periodística, denominada Periodisme Participatiu o 2.0, promou tota una sèrie de canals o vies de comunicació -xats, fòrums, enquestes, entrevistes, lectors informadors etc.- que ofereixen a l’usuari la possibilitat de convertir-se en receptors i emissors de les noticies alhora. Aquesta intervenció activa de les audiències en el procés informatiu ha alterat, irremediablement, els patrons de consum informatiu i la naturalesa del periodisme tradicional

Simultaneous LC-MS/MS quantification of P-glycoprotein and cytochrome P450 probe substrates and their metabolites in DBS and plasma.

BACKGROUND: An LC-MS/MS method has been developed for the simultaneous quantification of P-glycoprotein (P-gp) and cytochrome P450 (CYP) probe substrates and their Phase I metabolites in DBS and plasma. P-gp (fexofenadine) and CYP-specific substrates (caffeine for CYP1A2, bupropion for CYP2B6, flurbiprofen for CYP2C9, omeprazole for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4) and their metabolites were extracted from DBS (10 µl) using methanol. Analytes were separated on a reversed-phase LC column followed by SRM detection within a 6 min run time. RESULTS: The method was fully validated over the expected clinical concentration range for all substances tested, in both DBS and plasma. The method has been successfully applied to a PK study where healthy male volunteers received a low dose cocktail of the here described P-gp and CYP probes. Good correlation was observed between capillary DBS and venous plasma drug concentrations. CONCLUSION: Due to its low-invasiveness, simple sample collection and minimal sample preparation, DBS represents a suitable method to simultaneously monitor in vivo activities of P-gp and CYP.

Narraciones más allá del canon. El caso de Leni Riefenstahl

L'objectiu d'aquest treball s'articula dins de l'anàlisi estètic e històric de la concepció del cos humà i del seu cànon a partir del nexe que relaciona, el Classicisme Greco–romà i l'imaginari del Nazisme. En aquest sentit, la producció de Leni Riefenstahl –la mirada del Nacionalsocialisme– es vital per entendre el desenvolupament de tal nexe; i la nostra intenció ha estat articular un discurs intercomunicatiu entre ambdós imaginaris.

A one-year monitoring of nicotine use in sport: frontier between potential performance enhancement and addiction issues.

Tobacco consumption is a global epidemic responsible for a vast burden of disease. With pharmacological properties sought-after by consumers and responsible for addiction issues, nicotine is the main reason of this phenomenon. Accordingly, smokeless tobacco products are of growing popularity in sport owing to potential performance enhancing properties and absence of adverse effects on the respiratory system. Nevertheless, nicotine does not appear on the 2011 World Anti-Doping Agency (WADA) Prohibited List or Monitoring Program by lack of a comprehensive large-scale prevalence survey. Thus, this work describes a one-year monitoring study on urine specimens from professional athletes of different disciplines covering 2010 and 2011. A method for the detection and quantification of nicotine, its major metabolites (cotinine, trans-3-hydroxycotinine, nicotine-N'-oxide and cotinine-N-oxide) and minor tobacco alkaloids (anabasine, anatabine and nornicotine) was developed, relying on ultra-high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-TQ-MS/MS). A simple and fast dilute-and-shoot sample treatment was performed, followed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) operated in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM) data acquisition. After method validation, assessing the prevalence of nicotine consumption in sport involved analysis of 2185 urine samples, accounting for 43 different sports. Concentrations distribution of major nicotine metabolites, minor nicotine metabolites and tobacco alkaloids ranged from 10 (LLOQ) to 32,223, 6670 and 538 ng/mL, respectively. Compounds of interest were detected in trace levels in 23.0% of urine specimens, with concentration levels corresponding to an exposure within the last three days for 18.3% of samples. Likewise, hypothesizing conservative concentration limits for active nicotine consumption prior and/or during sport practice (50 ng/mL for nicotine, cotinine and trans-3-hydroxycotinine and 25 ng/mL for nicotine-N'-oxide, cotinine-N-oxide, anabasine, anatabine and nornicotine) revealed a prevalence of 15.3% amongst athletes. While this number may appear lower than the worldwide smoking prevalence of around 25%, focusing the study on selected sports highlighted more alarming findings. Indeed, active nicotine consumption in ice hockey, skiing, biathlon, bobsleigh, skating, football, basketball, volleyball, rugby, American football, wrestling and gymnastics was found to range between 19.0 and 55.6%. Therefore, considering the adverse effects of smoking on the respiratory tract and numerous health threats detrimental to sport practice at top level, likelihood of smokeless tobacco consumption for performance enhancement is greatly supported.

L'evolució del règim del canvi climàtic: més enllà d'una divisió nord-sud?

Aquesta recerca se centra en les grans dinàmiques de les negociacions sobre el canvi climàtic, caracteritzades per un punt mort Nord-Sud. El working paper sosté que la primera fase de les negociacions va ser l’escenari d’una divisió Nord-Sud que s’institucionalitzà en la Convenció Marc sobre el Canvi Climàtic. Tanmateix, en rondes posteriors de negociació, els principals antagonismes passaren a tenir el seu centre entre els països desenvolupats, amb una presència de dinàmiques de cooperació Nord-Sud. Finalment, aquest article avalua el procés inacabat post-Kyoto, caracteritzat per dues tendències que ja s’han posat de manifest: d’una banda, el sorgiment d’una nova geopolítica entre els Estats Units i els principals països en vies de desenvolupament i, de l’altra, entre els països del Sud, un procés de fragmentació que el mateix Acord de Copenhaguen ha començat a institucionalitzar.

A study of the aging of fingerprints by GC/MS analysis.

Determining the time since deposition of fingermarks may prove necessary in order to assess their relevance to criminal investigations. The crucial factor is the initial composition of fingermarks because it represents the starting point of any ageing model. This study mainly aimed to characterize the initial composition of fingerprints, which show a high variability between donors (inter-variability), but also to investigate the variations among fingerprints from the same donor (intra-variability). Solutions to reduce this initial variability using squalene and cholesterol as target compounds are proposed and should be further investigated. The influence of substrates was also evaluated and the initial composition was observed to be larger on porous surface than non-porous surfaces. Preliminary aging of fingerprints over 30 days was finally studied on a porous and a non-porous substrate to evaluate the potential for dating of fingermarks. Squalene was observed to decrease in a faster rate on a non-porous substrate.

Lipid composition of fingermark residue and donor classification using GC/MS

Lipids available in fingermark residue represent important targets for enhancement and dating techniques. While it is well known that lipid composition varies among fingermarks of the same donor (intra-variability) and between fingermarks of different donors (inter-variability), the extent of this variability remains uncharacterised. Thus, this worked aimed at studying qualitatively and quantitatively the initial lipid composition of fingermark residue of 25 different donors. Among the 104 detected lipids, 43 were reported for the first time in the literature. Furthermore, palmitic acid, squalene, cholesterol, myristyl myristate and myristyl myristoleate were quantified and their correlation within fingermark residue was highlighted. Ten compounds were then selected and further studied as potential targets for dating or enhancement techniques. It was shown that their relative standard deviation was significantly lower for the intra-variability than for the inter-variability. Moreover, the use of data pretreatments could significantly reduce this variability. Based on these observations, an objective donor classification model was proposed. Hierarchical cluster analysis was conducted on the pre-treated data and the fingermarks of the 25 donors were classified into two main groups, corresponding to "poor" and "rich" lipid donors. The robustness of this classification was tested using fingermark replicates of selected donors. 86% of these replicates were correctly classified, showing the potential of such a donor classification model for research purposes in order to select representative donors based on compounds of interest.

Exploration of immune competencies of viral-specific CD8+T cells in MS patients using tetramers and functional CTL assays

Introduction: Epstein-Barr Virus(EBV) has been repeatedly associatedwith multiple sclerosis (MS). Wehave previously shown that there is ahigh peripheral as well as intrathecalactivation of EBV-, but not cytomegalovirus(CMV)-specific CD8+ Tcells, early in the course of MS,strengthening the link between EBVand MS. However, the trigger of thisincreased EBV-specific CD8+ T cellresponse remains obscure. It could resultfrom a higher EBV viral load. Alternatively,it could be due to an intrinsicallydeficient EBV-specificCTL response, cytotoxic granulesmediated.Thus, we performed anin-depth study of the phenotype of exvivo EBV- and CMV-specific CD8+T cells in MS patients and control patients,assessing their cytotoxic activity.Methods:We analyzed the profileof cytotoxic granules in EBV- andCMV-specific CD8+ T cells in a cohortof 13 early MS patients, 20 lateMS, 30 other neurological diseases(OND) patients and 7 healthy controlsubjects. Ex vivo analysis of EBV- orCMV-specific CD8+ T cells was performedusing HLA class I/tetramercomplexes coupled to CCR7 andCD57 markers in conjunction withperforin, granzymes A, BandKstaining.In a sub-cohort of MS patientsand controls, cytotoxic activity ofEBV- and CMV-specific CD8+ Tcells was investigated using a functionalCFSE CTL assay. Results: UsingHLA Class I tetramers for EBVand CMV, we found that the frequencyof EBV- or CMV-specificCD8+ T cells were similar in all studysubjects. Most of EBV- and CMVspecificCD8+Tcells were highly differentiated(CCR7-) and a variousproportion expressed the exhaustionmarker CD57. MS and OND patientshad increased perforin expression inEBV-specific CD8+ T cells. Most importantly,we found that MS patientswith longer disease duration tended tohave lower CTL cytotoxicity as comparedto earlyMSpatients or controls.Conclusions: Effector EBV-specificCD8+ T cells are increased in earlyMS, however their cytotoxic granuleprofile does not seem to be fully alteredand the cytotoxic activity ofthese cells is normal. However, thecytotoxic activity of CTL decreasedin late MS patients suggesting an exhaustionof EBV-specific CD8+ Tcells possibly due to EBV reactivation.This work was supported by theSwiss National Foundation PP00B3-124893, the Swiss Society for MS,and the Biaggi Foundation to RADP.

Assessing the value of CAN-gene mutations using MALDI-TOF MS.

PURPOSE: To identify cancer-linked genes, Sjöblom et al. and Wood et al. performed a genome-wide mutation screening in human breast and colorectal cancers. 140 CAN-genes were found in breast cancer, which in turn contained overall 334 mutations. These mutations could prove useful for diagnostic and therapeutic purposes. METHODS: We used a MALDI-TOF MS 40-plex assay for testing 40 loci within 21 high-ranking breast cancer CAN-genes. To confirm mutations, we performed single-plex assays and sequencing. RESULTS: In general, the mutation rate of the analyzed loci in our sample cohort was very low. No mutation from the 40 loci analyzed could be found in the 6 cell lines. In tissue samples, a single breast cancer tissue sample showed heterozygosity at locus c.5834G>A within the ZFYVE26 gene (Zinc finger FYVE domain-containing gene 26). CONCLUSIONS: Sjöblom et al./Wood et al. already showed that the vast majority of CAN-genes are mutated at very low frequency. Due to the fact that we only found one mutation in our cohort, we therefore assume that at the selected loci, mutations might be low-frequency events and therefore, more rarely detectable. However, further evaluation of the CAN-gene mutations in larger cohorts should be the aim of further studies.

Reacción a "Pyricularia grisea" de las variedades más importantes de arroz cultivadas en el Delta del Ebro, durante el período 2000-2008

La pyriculariosis del arroz, causada por el hongo Pyricularia grisea (Cooke) Sacc., es una enfermedad que provoca daños considerables en la zona arrocera del Delta del Ebro. El hongo puede infectar el cultivo en todos los estadios de crecimiento y también en las partes aéreas de la planta: hoja, nudo del tallo, cuello y panícula. El uso de variedades resistentes para el control de la enfermedad es un método económico y efectivo, pero esta resistencia puede verse modificada con la presencia en la zona de nuevas poblaciones de P. grisea de tipo virulento, por lo que esta herramienta se debe utilizar bajo un concepto dinámico. El presente trabajo se centra en el estudio del comportamiento frente a P. grisea de un grupo de variedades de arroz cultivadas en el Delta del Ebro durante el período 2000-2008. El perfil varietal del Delta del Ebro durante este período ha ido variando constantemente y la mayoría de variedades principales que se han cultivado o se cultivan actualmente han presentado un comportamiento de tipo moderado frente a P. grisea.

Estado actual de pacientes trasplantados en edad pediátrica con más de 20 años de seguimiento

L'objectiu d'aquest treball és analitzar els portadors d'un empelt hepàtic trasplantats en edat pediàtrica amb més de 20 anys de seguiment i per a això hem analitzat un total de 27 pacients. La principal indicació del trasplantament va ser l'atrèsia de vies biliars. S'han analitzat les complicacions quirúrgiques mèdiques i immunològiques, la immunosupressió, infecció per VHC, dades antropromètriques i adaptació social. Hem conclòs que la majoria dels pacients trasplantats en edat pediàtrica amb més de 20 anys d'evolució presenten una adaptació social excel•lent i pocs efectes adversos de la immunosupressió comparada amb la població adulta.