Characterization of the angiotensin II receptor antagonist TCV-116 in healthy volunteers.

The purpose of this study was to assess the inhibitory effect of TCV-116, an orally active angiotensin II (Ang II) antagonist, on the pressor action of exogenous Ang II and to determine the compensatory rise in plasma renin activity and Ang II levels. Twenty-three male volunteers were treated for 8 days in a double-blind fashion with either placebo or TCV-116 (1, 2, or 4 mg PO daily) and challenged on the first, fourth, and eighth days with repeated bolus injections of Ang II. An additional 4 subjects received 8 mg PO daily in a single-blind fashion. The inhibitory effect on the systolic blood pressure response to Ang II was long lasting and clearly dose related. Six hours after 4 mg TCV-116, the systolic blood pressure response to a given dose of Ang II was reduced to 40 +/- 4% and 35 +/- 8% of baseline value on days 1 and 8, respectively. TCV-116 induced a dose-related increase in plasma renin activity and Ang II levels that was more pronounced on the eighth than on the first day of drug administration. Despite this compensatory mechanism, the relation between the time-integrated systolic blood pressure response to Ang II and the time-integrated CV-11974 levels, the active metabolite of TCV-116, was not different between days 1 and 8. In conclusion, TCV-116 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of Ang II in men.

Glucose sensing by the hepatoportal sensor is GLUT2-dependent: in vivo analysis in GLUT2-null mice.

In the preceding article, we demonstrated that activation of the hepatoportal glucose sensor led to a paradoxical development of hypoglycemia that was associated with increased glucose utilization by a subset of tissues. In this study, we tested whether GLUT2 plays a role in the portal glucose-sensing system that is similar to its involvement in pancreatic beta-cells. Awake RIPGLUT1 x GLUT2-/- and control mice were infused with glucose through the portal (Po-) or the femoral (Fe-) vein for 3 h at a rate equivalent to the endogenous glucose production rate. Blood glucose and plasma insulin concentrations were continuously monitored. Glucose turnover, glycolysis, and glycogen synthesis rates were determined by the 3H-glucose infusion technique. We showed that portal glucose infusion in RIPGLUT1 x GLUT24-/- mice did not induce the hypoglycemia observed in control mice but, in contrast, led to a transient hyperglycemic state followed by a return to normoglycemia; this glycemic pattern was similar to that observed in control Fe-mice and RIPGLUT1 x GLUT2-/- Fe-mice. Plasma insulin profiles during the infusion period were similar in control and RIPGLUT1 x GLUT2-/- Po- and Fe-mice. The lack of hypoglycemia development in RIPGLUT1 x GLUT2-/- mice was not due to the absence of GLUT2 in the liver. Indeed, reexpression by transgenesis of this transporter in hepatocytes did not restore the development of hypoglycemia after initiating portal vein glucose infusion. In the absence of GLUT2, glucose turnover increased in Po-mice to the same extent as that in RIPGLUT1 x GLUT2-/- or control Fe-mice. Finally, co-infusion of somatostatin with glucose prevented development of hypoglycemia in control Po-mice, but it did not affect the glycemia or insulinemia of RIPGLUT1 x GLUT2-/- Po-mice. Together, our data demonstrate that GLUT2 is required for the function of the hepatoportal glucose sensor and that somatostatin could inhibit the glucose signal by interfering with GLUT2-expressing sensing units.

Mudanças na Imigração

Os da dos es ta tís ti cos so bre o re cen te cres ci men to da imi gra ção, com a emer gên cia de no vos flu xos (Les te) e a in ten si fi ca ção dos tra di ci o na is (PALOP e, so bre tu do, Bra sil), são ana li sa dos ten do em con ta o fac to de Por tu gal ser hoje, no con tex to eu ro peu, um dos pa í ses com me nor pro por ção de es tran ge i ros na po pu la ção re si den te e, si mul ta ne a men te, com um ma i or es go ta men to das re ser vas do seu mer ca do de tra ba lho in ter no.

High-dose sequential chemotherapy (ICE) under circulating progenitor cells (CPC) protection in patients with small cell lung carcinoma (SCLC). Preliminary report on a multicentric study

Starting in February 1994, 20 patients (pt) with a median age of 50 years(range 41-63) from 7 European centers have been included. Completedata were obtained in 16 patients so far. CPC were mobilized with chemo(Epirubicine 75 mg/m2 /d, 01 + 02) followed by G-CSF 5 p.gfkg/d for14 days. HD chemo consisted in 3 sequential courses of ICE regimen(UOs. 10 g/m2 , Carbo. 1200 mg/m2 and Etop. 1200 mg/m2 ) underCPC protection and G-CSF 5 p.g/kg/d. Out of the 16 pt, 12 completedfull program (3 cycles). One pt died of septic shock before receivingany ICE course. One pt died during the first ICE of renal insufficiency.Two pt had only 2 courses because of toxicity. Among the 16 pt, responserate (RR) was: 7 CR, 6 PR, 1 PO; 3 pt are not evaluable dueto early withdrawal (overall RR: 13/16 = 81 %). Thirty-nine cycles ofHD chemo were given with a median hematological recovery of 9 days(range 7-12) until neutro. counts> 1.0 x 109 /1 and 9 days (range 717)until thrombo. > 20 x 109 /1. No cumulative, hematological toxicitywas seen. Accrual of patients is still ongoing and updated results will bepresented.

Functions of peroxisome proliferator-activated receptors (PPAR) in skin homeostasis.

The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the nuclear hormone receptor family. Three isotypes (PPAR alpha, PPAR beta or delta, and PPAR gamma) with distinct tissue distributions and cellular functions have been found in vertebrates. All three PPAR isotypes are expressed in rodent and human skin. They were initially investigated for a possible function in the establishment of the permeability barrier in skin because of their known function in lipid metabolism in other cell types. In vitro studies using specific PPAR agonists and in vivo gene disruption approaches in mice indeed suggest an important contribution of PPAR alpha in the formation of the epidermal barrier and in sebocyte differentiation. The PPAR gamma isotype plays a role in stimulating sebocyte development and lipogenesis, but does not appear to contribute to epidermal tissue differentiation. The third isotype, PPAR beta, regulates the late stages of sebaceous cell differentiation, and is the most effective isotype in stimulating lipid production in these cells, both in rodents and in humans. In addition, PPAR beta activation has pro-differentiating effects in keratinocytes under normal and inflammatory conditions. Finally, preliminary studies also point to a potential role of PPAR in hair follicle growth and in melanocyte differentiation. By their diverse biological effects on cell proliferation and differentiation in the skin, PPAR agonists or antagonists may offer interesting opportunities for the treatment of various skin disorders characterized by inflammation, cell hyperproliferation, and aberrant differentiation.

Biomasa desovante 1995 del stock norte - centro de la anchoveta peruana, engraulis ringens. Estimada por el método de producción de huevos.

Se estimó la biomasa desovante del stock norte-centro de la anchoveta peruana (Engraulis ringens) por el Método de Producción de Huevos en 5,9 millones de toneladas, con límites de confianza al 95% de +/- 1,9 millones de toneladas, que equivale al 32,14%. El crucero se realizó durante el invierno de 1995 y abarcó el área comprendida entre Tambo de Mora y Punta Falsa. Se analizan parámetros tales como frecuencia del desove (F) y la producción diaria de huevos (Po) y las posibles causas de su variación en relación a los encontrados en 1994.

Estimación de la biomasa desovante del stock norte centro de la anchoveta por el método de producción de huevos durante el invierno 1996

La biomasa desovante de la anchoveta peruana Engraulis ringens en el área comprendida entre Tambo de Mora (13°30 'S) y Punta Falsa (06° S), fue estimada en 4,02 millones de toneladas. En esta oportunidad, a diferencia de las anteriores, se hicieron ajustes en la determinación de la producción diaria de huevos (Po) así como en la fecundidad. En el primer caso, por efectos de la dispersión de los huevos en un área de desove mayor; y en el segundo, por no cubrir todo el rango de tamaños. El crucero se llevó a cabo del 11 de agosto al 27 de setiembre de 1996 a bordo del BIC Humboldt. Los valores promedio de los parámetros involucrados en la estimación fueron: proporción de hembras, 0,52; producción diaria de huevos, 10.14E+13; peso promedio de hembras, 29,79 g; fecundidad parcial, 18 495 huevos por hembra y frecuencia de desove, 7,8%. Los parámetros que presentaron mayor variación con respecto a 1995 fueron: la fecundidad parcial, producción diaria de huevos y frecuencia de desove.

iLOGP: A Simple, Robust, and Efficient Description of n-Octanol/Water Partition Coefficient for Drug Design Using the GB/SA Approach.

The n-octanol/water partition coefficient (log Po/w) is a key physicochemical parameter for drug discovery, design, and development. Here, we present a physics-based approach that shows a strong linear correlation between the computed solvation free energy in implicit solvents and the experimental log Po/w on a cleansed data set of more than 17,500 molecules. After internal validation by five-fold cross-validation and data randomization, the predictive power of the most interesting multiple linear model, based on two GB/SA parameters solely, was tested on two different external sets of molecules. On the Martel druglike test set, the predictive power of the best model (N = 706, r = 0.64, MAE = 1.18, and RMSE = 1.40) is similar to six well-established empirical methods. On the 17-drug test set, our model outperformed all compared empirical methodologies (N = 17, r = 0.94, MAE = 0.38, and RMSE = 0.52). The physical basis of our original GB/SA approach together with its predictive capacity, computational efficiency (1 to 2 s per molecule), and tridimensional molecular graphics capability lay the foundations for a promising predictor, the implicit log P method (iLOGP), to complement the portfolio of drug design tools developed and provided by the SIB Swiss Institute of Bioinformatics.

El Advergaming en el digital signage: actores que determinan la obtención del "flow experience" de acuerdo a la ubicación de un dispositivo de emisión de contenido digital, dinámico e interactivo con videojuegos de marca

En la recerca d’eines que suposen la interactivitat com a punt clau en el model de comunicació, la present investi- gació aborda l’ús de videojocs amb contingut publicitari o “advergaming” com a punt central d’estudi i pretén es- tablir els factors que determinen una experiència de joc òptima a través de l’ús de pantalles digitals com a mitjà difusor d’aquest tipus de contingut. Parlarem de “flow experience” o teoria de la psicologia po- sitiva segons el seu creador i precursor Mihály Csíkszent- mihályi, i serà la perspectiva des de la qual pretenem desenvolupar aquest estudi, entenent el “flow experience” com l’estat òptim o nivell més alt d’experiència d’usuari que es pot assolir durant una activitat

Frações fosfatadas em mudas de Eucalyptus

Com o objetivo de avaliar os teores e o efeito do tempo de omissão de fósforo nas frações de P em diferentes espécies de eucalipto, instalou-se um experimento em condições controladas no Departamento de Solos da Universidade Federal de Viçosa - UFV, no período de fevereiro a julho de 1993. Avaliou-se, em câmara de crescimento, o comportamento das frações fosfatadas em mudas das seguintes espécies de eucalipto: E. clöeziana ,E. grandis ,E. pellita ,E. pilularis e E. urophylla, quando submetidas à omissão de P. Foi fornecida às plantas uma solução nutritiva com elevado teor de P (8 mg L-1 de P) por vinte e quatro horas. Após esse período, eliminou-se o P da solução nutritiva e analisaram-se as frações de P total solúvel em ácido (Pts), fósforo inorgânico (Pi) e fósforo orgânico (Po), nos tempos de 0, 10 e 20 dias após a omissão do nutriente. Os compartimentos analisados foram as partes apicais e basais de folhas e raízes. A omissão do P da solução nutritiva causou queda no conteúdo de Pts e Pi em todas as espécies, embora em diferente magnitude. E. clöeziana apresentou o maior conteúdo de Pts. Com o aumento do tempo de omissão, as espécies de eucalipto apresentaram redução no percentual de participação do Pi em relação ao Pts, seguido de maior participação relativa do Po nos diversos compartimentos analisados. E. pellita e E. grandis apresentaram um padrão mais homogêneo de comportamento das frações fosfatadas com o tempo de omissão, quando comparadas às outras espécies. Entretanto, essas espécies apresentaram baixos teores de Pi já aos 10 dias de omissão de P, indicativo de um baixo "poder tampão interno de Pi" em relação às outras espécies avaliadas.

Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway.

Apoptosis, differentiation, and proliferation are cellular responses which play a pivotal role in wound healing. During this process PPARbeta translates inflammatory signals into prompt keratinocyte responses. We show herein that PPARbeta modulates Akt1 activation via transcriptional upregulation of ILK and PDK1, revealing a mechanism for the control of Akt1 signaling. The resulting higher Akt1 activity leads to increased keratinocyte survival following growth factor deprivation or anoikis. PPARbeta also potentiates NF-kappaB activity and MMP-9 production, which can regulate keratinocyte migration. Together, these results provide a molecular mechanism by which PPARbeta protects keratinocytes against apoptosis and may contribute to the process of skin wound closure.