In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid.

Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxy-efavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxy-efavirenz (7OH-EFV). So far, most metabolite profile analyses have been restricted to 8OH-EFV, 7OH-EFV, and EFV-N-glucuronide, even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolite profile analysis by tandem mass spectrometry of plasma, cerebrospinal fluid (CSF), and urine samples in 71 human immunodeficiency virus patients taking efavirenz, prior to and after enzymatic (glucuronidase and sulfatase) hydrolysis. We have shown that phase II metabolites constitute the major part of the known circulating efavirenz species in humans. The 8OH-EFV-glucuronide (gln) and 8OH-EFV-sulfate (identified for the first time) in humans were found to be 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6, and CYP3A metabolic pathways, 8OH-EFV/EFV ratios in plasma were an index of CYP2B6 phenotypic activity (P < 0.0001), which was also reflected by phase II metabolites 8OH-EFV-glucuronide/EFV and 8OH-EFV-sulfate/EFV ratios. Neither EFV nor 8OH-EFV, nor any other considered metabolites in plasma were associated with an increased risk of central nervous system (CNS) toxicity. In CSF, 8OH-EFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV-gln, 8OH-EFV-sulfate, and 7OH-EFV-gln were present in CSF at 2- to 9-fold higher concentrations than 8OH-EFV. The potential contribution of known and previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz needs to be further examined in larger cohort studies.

Poorly differentiated clusters (PDC) in colorectal cancer: what is and ought to be known.

BACKGROUND: The counting of poorly differentiated clusters of 5 or more cancer cells lacking a gland-like structure in a tumor mass has recently been identified among the histological features predictive of poor prognosis in colorectal cancer. MAIN BODY: Poorly differentiated clusters can easily be recognized in the histological sections of colorectal cancer routinely stained with haematoxylin and eosin. Despite some limitations related to specimen fragmentation, counting can also be assessed in endoscopic biopsies. Based on the number of poorly differentiated clusters that appear under a microscopic field of a ×20 objective lens (i.e., a microscopic field with a major axis of 1 mm), colorectal cancer can be graded into malignancies as follows: tumors with <5 clusters as grade 1, tumors with 5 to 9 clusters as grade 2, and tumors with ≥10 clusters as grade 3. High poorly differentiated cluster counts are significantly associated with peri-neural and lympho-vascular invasion, the presence of nodal metastases or micrometastases, as well as shorter overall and progression free survival to colorectal cancer. CONCLUSION: The morphological aspects and clinical relevance of poorly differentiated clusters counting in colorectal cancer are discussed in this review.

Seguidilles, fandangos i boleros a les sonates ibèriques per tecla dels compositors Domenico Scarlatti, José de Nebra i Antoni Soler

Aquest projecte neix amb la finalitat d’oferir una perspectiva sobre les sonates ibèriques de les dècades centrals del segle XVIII, i en concret dels cèlebres compositors Domenico Scarlatti, José de Nebra i Antoni Soler, centrada en alguns dels balls de major popularitat a l’època com són les seguidilles, els fandangos i els boleros. Algunes de les sonates ibèriques d’aquests compositors es corresponen amb molts dels paràmetres que condicionen aquests balls i com a conseqüència són sonates que poden ser ballades, tot i que desconeixem si a l’època s’interpretaven amb ballarins. Al voltant d’aquest tema se’ns formulen algunes preguntes referents al gènere i l’estil de les sonates o a la relació dels seus compositors amb els moviments culturals de la ciutat de Madrid que podien haver propiciat aquesta connexió.

O químico e naturalista luso-brasileiro Alexandre Antonio Vandelli

Alexandre Vandelli was the heir of two illustrious scientific traditions in the Luso-Brazilian world of the late eighteenth and early nineteenth centuries, that of his father, the celebrated Italian-Portuguese naturalist and chemist Domingos (Domenico) Vandelli, and that of his father-in-law, that protean figure in several scientific specialties as well as in politics, José Bonifácio de Andrada e Silva, who in later life was of paramount importance in the process of Brazilian independence from Portugal. The younger Vandelli followed their footsteps but soon engaged in a multiple career, at first in Portugal and later in Brazil, of which little is known and is here presented for the first time.

Comptes de l'église Saint-Sauveur de Blois (1400 et 1449).

Contient : « Compte de messire Jehan Viet, prebstre, chappelain et boursier de la grant bourse de l'esglise de Saint Saulveur ou chasteau de Bloys, de la recepte des deniers et autres rentes venant à la grant bourse de la dicte esglise,... depuis la vigille de saint Bartholomy appoustre mil CCCC quarante-neuf inclus, jusques à la vigille de ladicte feste mil IIIIe cinquante exclus » ; « Compotus Bartholomei Baudrici, ecclesie Sancti Salvatoris Blesensis canonici, ac Petri de Montigniaco, capellani perpetui ipsius ecclesie, presbiterorum censuariorum, de recepta censuum querendorum..., a vigilia beati Andree apostoli anni quadringentesimi usque ad dictam vigiliam anni quadringentesimi primi »

Self-presentational motives in eating disorders : a known groups difference approach

Self-presentation reflects the processes by which individuals attempt to monitor and control the impressions others form of them (Schlenker & Leary, 1982). Concerns over impressions conveyed have been linked to numerous health behaviors (Crawford & Eklund, 1994; Martin, Leary, & O'Brien, 2001). The present study investigated the role of cognitive manifestations of dispositional and situational self presentational motivation (SPM) in 131 females with known groups differences on a measure of eating disorders. Participants were classified as in-treatment (IN = 39); at risk (AT = 46); and not at risk (NOT = 46) for eating disordered behaviour. Each participant completed The Brief Fear of Negative Evaluation Scale (FNE; Leary, 1983), the Public Self-Consciousness Scale (PSC; Fenigstein, Sheier, & Buss, 1975), and the Social Physique Anxiety Scale (SPA; Hart, Leary, & Rejeski, 1989), as measures of dispositional SPM. Situational SPM was assessed through Self-Presentational Efficacy (SPE; Gammage, Hall, & Martin, 2004), and the Exercise Motivation Inventory-2 (Markland & Ingeldew, 1997). Significant differences emerged on the measure of eating disorder behaviour between AT and NOT. To determine if group differences existed on measures of trait SPM an ANOVA was conducted. Results indicated that the NOT group experienced less FNE, PSC and SPA than the IN and AT groups, and the AT group experienced less FNE and PSC than the IN group. Pearson bivariate correlations were conducted on measures of trait SPM and EMI-2 subscales theoretically linked to SPM. It was found that FNE, PSC and SPA were all positively correlated with weight management for the NOT group. To determine if group differences existed on selfpresentational exercise motives independent samples I-tests were conducted. Results revealed that the AT group was more motivated to exercise for weight management, and appearance, and social recognition than the NOT group. To determine if group differences existed on the state measure of self-presentational efficacy a series of ANOVA's were conducted. Results revealed that the NOT group experienced significantly greater self-presentational efficacy expectancy and self-presentational outcome value than the AT group. Finally, a discriminant function analysis was conducted to determine if trait SPM would predict group membership. Results revealed that 63.4% of participants were correctly classified, with SPA, PSC, and FNE differentiating the NOT group from the AT and IN groups and FNE and PSC differentiating the AT group from the IN group. Thus self-presentation motivation appears to have an influence on females who have an eating disorder and those at risk for an eating disorder. Potential applications of the influence of self-presentational motives on eating disorders and future research directions are discussed.

Note that John Brown has done grading in the section between Geneva Street and Slabtown [known as Merritton prior to amalgamation with St. Catharines in 1961]

Note that John Brown has done grading in the section between Geneva Street and Slabtown [known as Merritton prior to amalgamation with St. Catharines in 1961]. This document is badly stained and faded. It is signed by S.D. Woodruff, 1855.

Letter of agreement to Welland D. Woodruff to pay Hamilton K. Woodruff $27, 500 for the property known as DeVeaux Hall

Letter of agreement to Welland D. Woodruff to pay Hamilton K. Woodruff $27, 500 for the property known as DeVeaux Hall.

Memoria histórica, técnica y administrativa de las obras del desague del Valle de México, 1449-1900

UANL

Memoria histórica, técnica y administrativa de las obras del desague del Valle de México, 1449-1900

UANL

Esprit du don, dispositifs et reconnaissance : de "Diaries, Notes and Sketches : Also Known as Walden" (1969) à "The First Forty" (2006) de Jonas Mekas.

Après avoir passé plus de 4 ans dans des camps de travail forcé, Jonas Mekas, lituanien, est déporté avec son frère par les Nations-Unies en 1949 aux États-Unis. Les deux rescapés de la seconde guerre mondiale dédient alors leur temps au cinéma. Dès leur arrivée, ils se procurent une caméra 16 mm bolex et se tournent vers le cinéma expérimental, grâce, entre autre, à une de ces cinéastes pionnières américaine Maya Deren. En marge de l'industrie cinématographique hollywoodienne, Jonas Mekas participe à l'édification de structures - coopératives, associations, magazines, journaux - afin de rendre accessible ce genre filmique, de lui obtenir une reconnaissance publique et de, ultimement, le préserver. En 1969, il réalise un film intitulé "Diaries, Notes and Sketches : Also Known as Walden". Mekas réalise ensuite des films qui réemploient des séquences qui se trouvent dans cette première ébauche filmique. Ce processus se retrace au sein de son « premier essai » numérique qu'il réalise à l'ère cybériste intitulé "The First Forty" (2006), composé de vidéos et de descriptions textuelles. Tout comme il l’avait fait avec Walden, Mekas présente explicitement celui-ci à un public, en l’occurrence son nouveau public d'internautes, qui en prend connaissance sur son site web officiel. La présentation numérique et la table des matières papier accompagnant "Diaries, Notes and Sketches : Also Known as Walden" rédigée par l'artiste en 1969 ont une fonction similaire au sens où, par elles, Jonas Mekas donne ces deux créations aux spectateurs. Nous avons choisi d'employer le terme de dispositif pour parler de ces « objets » qui font appel à diverses formes énonciatives afin de créer un effet spécifique chez le spectateur. En explorant la théorie sociologique moderne du don développée par Jacques T. Godbout, notre projet a été de relever « l'esprit de don » qui se retrace au sein de ces dispositifs. Cette étude nous permet de constater que les dispositifs audiovisuels / cinématographiques que développa Mekas sont des « objets » qui peuvent être reçus tel des dons suscitant le désir de donner chez les spectateurs. Ils sont le ciment symbolique personnel et collectif nécessaire à l’accomplissement du processus de « reconnaissance » qu’implique le don.

Respuestas de elección durante el contraste negativo sucesivo consumatorio en ratas

En ratas, el cambio de una solución preferida (agua azucarada al 32%) por otra menos preferida (agua azucarada al 4%) produce una caída del consumo por debajo de un grupo control no devaluado, el cual siempre recibe acceso a la solución de valor bajo. Este fenómeno denominado contraste negativo sucesivo consumatorio ocurre incluso cuando la devaluación coincide con cambios en las claves ambientales o gustativas y cuando hay múltiples opciones de respuesta (con el reforzador de valor bajo disponible en varios lugares). En este artículo se presenta un experimento donde un grupo de ratas se entrenó en la fase pre-cambio con una solución preferida con sabor a almendra (32%A) y otro con una menos preferida (4%A). La fase post-cambio se realizó en un contexto distinto y novedoso, donde todos los animales pudieron elegir entre consumir 4% o 4%A. Se observó un efecto de contraste negativo en los animales que experimentaron la devaluación y una preferencia por la solución con el sabor a almendra utilizado durante la fase precambio en los sujetos de ambos grupos.

The elements : a visual exploration of every known atom in the universe.

Las imágenes de esta publicación constituyen la representación visual más completa de cada átomo del universo. Organizada por orden de aparición en la tabla periódica, de cada elemento de los ciento dieciocho que la componen se facilitan datos, cifras, propiedades incluyendo el peso atómico, densidad, punto de ebullición y de fusión, valencia, electronegatividad, y el año y lugar en que se descubrió. Fotografías adicionales muestran cada elemento en formas ligeramente alteradas y sus aplicaciones.

The known unknowns and the unknown unknowns of the EMU. Bruegel Policy Contribution 2012/18, October 2012

Extensive prior research on the economics of European monetary union highlighted some potential risks (the known unknowns) but overlooked others (the unknown unknowns). Asymmetries among participating countries, the potentially destabilising character of a one-size-fits all monetary policy, the weakness of adjustment mechanisms, the lack of incentives for fiscal discipline, the possibility of sovereign solvency crises and their adverse consequences were all known and understood. But policymakers often relied on a complacent reading of the evidence. • The potential for financial disruption was vastly underestimated. Economists generally did not consider, or underestimated, the possibility of balance of payment crises such as those experienced by southern European countries, or the risk of a feedback loop between banks and sovereigns. • Remedying EMU’s systemic deficiencies is on the policy agenda. Banking union would go a long way towards addressing the fault lines. The urgent question for economists is if it is going to be enough and, if not, what else should complement the ‘bare-bones’ EMU of Maastricht.