Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.

Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 μM) and the more potent and specific P-gp inhibitor valspodar (5 μM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 μM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.

Médecines complémentaires: vers un consensus evidence- based à l'hôpital universitaire [Complementary and alternative medicines (CAM): towards an evidence-based consensus in the university hospital].

While a popular vote supported a new article on complementary and alternative medicines (CAM) in the Swiss Constitution, this assessment in 14 wards of the University Hospital of Lausanne, Switzerland, attempted at answering the question: How can CAM use be better taken into account and patients informed with more rigor and respect for their choices? Confronted with a review of the literature (> 2000 publications in "Evidence-based complementary medicines" since 1998), respondents declared their ignorance of the clinical data presently available on CAM. All were in favour of more teaching and information on the subject, plus an official statement from the Hospital direction, ensuring production and diffusion of rigorous and clinically significant information on CAM.

Inhibition of bicarbonate transport protects embryonic heart against reoxygenation-induced dysfunction.

It has not been well established whether the mechanisms participating in pH regulation in the anoxic-reoxygenated developing myocardium resemble those operating in the adult. We have specially examined the importance of Na+/H+ exchange (NHE) and HCO3-dependent transports in cardiac activity after changes in extracellular pH (pHo). Spontaneously contracting hearts isolated from 4-day-old chick embryos were submitted to single or repeated anoxia (1 min) followed by reoxygenation (10 min). The chronotropic, dromotropic and inotropic responses of the hearts were determined in standard HCO3- buffer at pHo 7.4 and at pHo 6.5 (hypercapnic acidosis). In distinct experiments, acidotic anoxia preceded reoxygenation at pHo 7.4. NHE was blocked with amiloride derivative HMA (1 micro mol/l) and HCO3-dependent transports were inactivated by replacement of HCO3 or blockade with stilbene derivative DIDS (100 micro mol/l). Anoxia caused transient tachycardia, depressed mechanical function and induced contracture. Reoxygenation temporarily provoked cardiac arrest, atrio-ventricular (AV) block, arrhythmias and depression of contractility. Addition of DIDS or substitution of HCO3 at pHo 7.4 had the same effects as acidosis per se, i.e. shortened contractile activity and increased incidence of arrhythmias during anoxia, prolonged cardioplegia and provoked arrhythmias at reoxygenation. Under anoxia at pHo 6.5/reoxygenation at pHo 7.4, cardioplegia, AV block and arrhythmias were all markedly prolonged. Interestingly, in the latter protocol, DIDS suppressed AV block and arrhythmias during reoxygenation, whereas HMA had no effect. Thus, intracellular pH regulation in the anoxic-reoxygenated embryonic heart appears to depend predominantly on HCO3 availability and transport. Furthermore, pharmacological inhibition of anion transport can protect against reoxygenation-induced dysfunction.

The environmental effectiviness of alternative agri-environmental policy reforms : theoretical and empirical analysis

Selostus: Maatalouden ympäristöpolitiikan reformien tehokkuus ravinnepäästöjen vähentämisessä - teoreettinen ja empiirinen analyysi

Entitat Metropolitana del Transport. Centre Operatiu d'Autobusos del Prat

El projecte contempla la resolució d’un Centre Operatiu d’Autobusos Metropolitans amb un programa que ha de donar cabuda a un mínim de 300 places d’aparcament de diferents mesures, tallers de manteniment, túnels de neteja, sortidors de repostatge, vestuaris, administració, oficines i serveis generals. L’emplaçament se situa en el barri de Sant Cosme del Prat de Llobregat, en un solar que esdevé la façana d’aquesta població a l’entrada a Barcelona des de l’aeroport. L’entorn el conformen els espais de protecció de les pistes que es perllonguen fins a tocar el Parc Natural del Delta del Llobregat, una zona humida protegida d’àmbit europeu. Al mateix temps, els requeriments del concurs sol•liciten mantenir un 50% de la superfície del solar com a parc urbà. Això comporta abordar la resolució d’un edifici extens, però de 3 alçades i mitja, per tal de poder encabir tot el programa. Tot i així, la proposta integra el gran volum de l’edificació en harmonia compositiva i cromàtica amb el canyissar i manté l’alçària en una cota similar a la dels edificis de l’entorn. L’àrea verda es concentra en la part de la parcel•la que té continuïtat directe amb el pati del nou Esplai del barri, per tal de optimitzar-ne l’ús. Al mateix temps, les àrees de circulació, neteja i manteniment dels autobusos se situen a la part posterior del solar, per fer-les compatibles amb la resta de requeriments funcionals i perquè la volumetria principal doni front a les vies d’entrada a l’àrea metropolitana. La cotxera està continguda en un únic volum lleugerament soterrat, per limitar l’alçària total. La construcció principal, de 120 x 55 x 14,5 metres, es troba configurada per una estructura regular que respecta les mesures i moviments dels autobusos, i per una pell consistent en una gelosia oberta en tres cares, i tancada en l’alçat nord. Aquest tancament es realitza amb prismes verticals de colors similars a la vegetació del entorn, separats harmònicament per tal de dissoldre lleument els contorns del volum. Com a contrapunt a la gran peça principal, es proposa un petit edifici vidriat que indica l’entrada a les oficines i conté les activitats administratives.Les àrees de funcionament es resumeixen en les següents:1. La circulació dels autobusos: el conjunt disposa de tres vies simultànies, una d’accés i dues de sortida, situades en línia amb dos punts de repostatge, aspiració interior i traspàs de dades i recaptacions, aptes per a ser utilitzades per tres vehicles alhora. També es disposen tres túnels de rentat previs a l’entrada a l’interior de la cotxera, amb pas per a tres carrils en by-pass. Es preveu una quarta via especial d’accés i sortida directes al taller, per situacions extraordinàries.2. La circulació dels vehicles de personal: tenen un accés i un recorregut independent al dels autobusos, amb control informatitzat. 3. La entrada peatonal de visites o personal: l’edifici disposa també d’una entrada peatonal que es produeix des de la porta principal, situada en el front del edifici administratiu.4. El edifici principal: consta de diferents nivells. El Nivell 0, a cota –1,3 m. es troba ocupat per la zona d’aparcament de vehicles privats (98 uts), l’aparcament de minibusos (20 uts), el taller d’autobusos (23 uts standard amb ITV, 2 uts articulats, 1 ut pintura articulat, 2 uts reparcions sostres), i l’àrea d’explotació i de dependències per conductors (vestidors, àrea de descans, cafeteria i espais habitables).El Nivell 1, a cota 2,4 m. està ocupat per l’aparcament de 47 autobusos de 13 m. de llarg i per 20 autobusos de 15 m.El Nivell 2, a cota 4,8 m. l’ocupen 22 places d’autobusos de 15 m., 6 places d’articulats i 37 de 13 m.El Nivell 3, a cota 7,2 m. és idèntic al Nivell 1.El Nivell 4, és idèntic al Nivell 2 i permet que la rampa continuï fins a un Nivell 5 de coberta, que excepcionalment pot convertir-se en aparcament descobert de 67 autobusos de més.La proposta contempla amb fermesa criteris de Sostenibilitat. Aquests es centren en primer lloc en la sobrietat del projecte que garanteix una organització clara en quan a circulacions i rendiment del espai i que, per tant, no malbarata més recursos dels necessaris. En segon lloc, s’aprofiten al màxim la llum i la ventilació naturals i, al mateix temps, es genera la pròpia energia per millorar la eficiència. També es resol el re-processament dels residus generats pel complex, es re-aprofiten les aigües utilitzades en els vestuaris i oficines pel rentat dels vehicles, i s’emmagatzemen les aigües pluvials per tal de complementar la generació d’energia i per escalfar amb el sol aigua calenta de neteja. En tercer lloc, es té especial cura en l’impacte ambiental del edifici, procurant adequar-lo a l’estructura urbana tant en alineacions com el alçària. També s’evita la contaminació acústica apantallant el so intern per tal de no enviar-lo a les àrees habitades, s’endrecen els accessos dels autobusos des de la rotonda de la via pública per alterar el mínim el trànsit dels veïns, i es concentra l’àrea verda en la zona on es té més contacte amb l’activitat veïnal comunitària: l’Esplai del barri.

Quantum transport phenomena and shallow impurity states in CdSb

This work is dedicated to investigation of the energy spectrum of one of the most anisotropic narrow-gap semiconductors, CdSb. At the beginning of the present studies even the model of its energy band structure was not clear. Measurements of galvanomagnetic effects in wide temperature range (1.6 - 300 K) and in magnetic fields up to 30 T were chosen for clarifying of the energy spectrum in the intentionally undoped CdSb single crystals and doped with shallow impurities (In, Ag). Detection of the Shubnikov - de Haas oscillations allowed estimating the fundamental energy spectrum parameters. The shapes of the Fermi surfaces of electrons (sphere) and holes (ellipsoid), the number of the equivalent extremums for valence band (2) and their positions in the Brillouin zone were determined for the first time in this work. Also anisotropy coefficients, components of the tensor of effective masses of carriers, effective masses of density of states, nonparabolicity of the conduction and valence bands, g-factor and its anisotropy for n- and p-CdSb were estimated for the first time during these studies. All the results obtained are compared with the cyclotron resonance data and the corresponding theoretical calculations for p-CdSb. This is basic information for the analyses of the complex transport properties of CdSb and for working out the energy spectrum model of the shallow energy levels of defects and impurities in this semiconductor. It was found out existence of different mechanisms of hopping conductivity in the presence of metal - insulator transition induced by magnetic field in n- and p-CdSb. Quite unusual feature opened in CdSb is that different types of hopping conductivity may take place in the same crystal depending on temperature, magnetic field or even orientation of crystal in magnetic field. Transport properties of undoped p-CdSb samples show that the anisotropy of the resistivity in weak and strong magnetic fields is determined completely by the anisotropy of the effective mass of the holes. Temperature and magnetic field dependence of the Hall coefficient and magnetoresistance is attributed to presence of two groups of holes with different concentrations and mobilities. The analysis demonstrates that below Tcr ~ 20 K and down to ~ 6 - 7 K the low-mobile carriers are itinerant holes with energy E2 ≈ 6 meV. The high-mobile carriers, at all temperatures T < Tcr, are holes activated thermally from a deeper acceptor band to itinerant states of a shallower acceptor band with energy E1 ≈ 3 meV. Analysis of temperature dependences of mobilities confirms the existence of the heavy-hole band or a non-equivalent maximum and two equivalent maxima of the light-hole valence band. Galvanomagnetic effects in n-CdSb reveal the existence of two groups of carriers. These are the electrons of a single minimum in isotropic conduction band and the itinerant electrons of the narrow impurity band, having at low temperatures the energies above the bottom of the conduction band. It is found that above this impurity band exists second impurity band of only localized states and the energy of both impurity bands depend on temperature so that they sink into the band gap when temperature is increased. The bands are splitted by the spin, and in strong magnetic fields the energy difference between them decreases and redistribution of the electrons between the two impurity bands takes place. Mobility of the conduction band carriers demonstrates that scattering in n-CdSb at low temperatures is strongly anisotropic. This is because of domination from scattering on the neutral impurity centers and increasing of the contribution to mobility from scattering by acoustic phonons when temperature increases. Metallic conductivity in zero or weak magnetic field is changed to activated conductivity with increasing of magnetic field. This exhibits a metal-insulator transition (MIT) induced by the magnetic field due to shift of the Fermi level from the interval of extended states to that of the localized states of the electron spectrum near the edge of the conduction band. The Mott variablerange hopping conductivity is observed in the low- and high-field intervals on the insulating side of the MIT. The results yield information about the density of states, the localization radius of the resonant impurity band with completely localized states and about the donor band. In high magnetic fields this band is separated from the conduction band and lies below the resonant impurity bands.

The origins, evolution, and functional potential of alternative splicing in vertebrates.

Alternative splicing (AS) has the potential to greatly expand the functional repertoire of mammalian transcriptomes. However, few variant transcripts have been characterized functionally, making it difficult to assess the contribution of AS to the generation of phenotypic complexity and to study the evolution of splicing patterns. We have compared the AS of 309 protein-coding genes in the human ENCODE pilot regions against their mouse orthologs in unprecedented detail, utilizing traditional transcriptomic and RNAseq data. The conservation status of every transcript has been investigated, and each functionally categorized as coding (separated into coding sequence [CDS] or nonsense-mediated decay [NMD] linked) or noncoding. In total, 36.7% of human and 19.3% of mouse coding transcripts are species specific, and we observe a 3.6 times excess of human NMD transcripts compared with mouse; in contrast to previous studies, the majority of species-specific AS is unlinked to transposable elements. We observe one conserved CDS variant and one conserved NMD variant per 2.3 and 11.4 genes, respectively. Subsequently, we identify and characterize equivalent AS patterns for 22.9% of these CDS or NMD-linked events in nonmammalian vertebrate genomes, and our data indicate that functional NMD-linked AS is more widespread and ancient than previously thought. Furthermore, although we observe an association between conserved AS and elevated sequence conservation, as previously reported, we emphasize that 30% of conserved AS exons display sequence conservation below the average score for constitutive exons. In conclusion, we demonstrate the value of detailed comparative annotation in generating a comprehensive set of AS transcripts, increasing our understanding of AS evolution in vertebrates. Our data supports a model whereby the acquisition of functional AS has occurred throughout vertebrate evolution and is considered alongside amino acid change as a key mechanism in gene evolution.

Mulching as an alternative technique for weed management in mandarine orchard tree rows

Peer reviewed

Alternative tests for correct specification of conditional predictive densities

We propose new methods for evaluating predictive densities that focus on the models' actual predictive ability in finite samples. The tests offer a simple way of evaluatingthe correct specification of predictive densities, either parametric or non-parametric.The results indicate that our tests are well sized and have good power in detecting mis-specification in predictive densities. An empirical application to the Survey ofProfessional Forecasters and a baseline Dynamic Stochastic General Equilibrium modelshows the usefulness of our methodology.

Evaluation of a piezoelectric system as an alternative to electroencephalogram/ electromyogram recordings in mouse sleep studies.

STUDY OBJECTIVES: Traditionally, sleep studies in mammals are performed using electroencephalogram/electromyogram (EEG/EMG) recordings to determine sleep-wake state. In laboratory animals, this requires surgery and recovery time and causes discomfort to the animal. In this study, we evaluated the performance of an alternative, noninvasive approach utilizing piezoelectric films to determine sleep and wakefulness in mice by simultaneous EEG/EMG recordings. The piezoelectric films detect the animal's movements with high sensitivity and the regularity of the piezo output signal, related to the regular breathing movements characteristic of sleep, serves to automatically determine sleep. Although the system is commercially available (Signal Solutions LLC, Lexington, KY), this is the first statistical validation of various aspects of sleep. DESIGN: EEG/EMG and piezo signals were recorded simultaneously during 48 h. SETTING: Mouse sleep laboratory. PARTICIPANTS: Nine male and nine female CFW outbred mice. INTERVENTIONS: EEG/EMG surgery. MEASUREMENTS AND RESULTS: The results showed a high correspondence between EEG/EMG-determined and piezo-determined total sleep time and the distribution of sleep over a 48-h baseline recording with 18 mice. Moreover, the piezo system was capable of assessing sleep quality (i.e., sleep consolidation) and interesting observations at transitions to and from rapid eye movement sleep were made that could be exploited in the future to also distinguish the two sleep states. CONCLUSIONS: The piezo system proved to be a reliable alternative to electroencephalogram/electromyogram recording in the mouse and will be useful for first-pass, large-scale sleep screens for genetic or pharmacological studies. CITATION: Mang GM, Nicod J, Emmenegger Y, Donohue KD, O'Hara BF, Franken P. Evaluation of a piezoelectric system as an alternative to electroencephalogram/electromyogram recordings in mouse sleep studies.

Volcanic debris avalanche deposits of the upper Maronne valley (Cantal Volcano, France): evidence for contrasted formation and transport mechanisms

The deposits of two volcanic debris avalanches (VDA I and II) that occur in the upper Maronne valley, northwest sector of Cantal Volcano, France, were studied to establish their mechanisms of formation, transport and deposition. These two volcanic debris avalanches that clearly differ with regard to their structures, textures and extensions, exemplify the wide spectrum of events associated with large-scale sector collapse. VDA I is voluminous (similar to1 km(3) in the upper Maronne valley) and widespread. The deposits comprise two distinct facies: the block facies that forms the intermediate and upper part of the unit and the mixed facies that crops out essentially at the base of the unit. The block facies consists of more or less brecciated lava, block-and-ash-flow breccia and pumice-flow tuff megablocks set in breccias resulting from block disaggregation. Mixing and differential movements are almost absent in this part of the VDA. The mixed facies consists of breccias rich in fine particles that originate from block disagregation, as well as being picked up from the substratum during movement. Mixing and differential movements are predominant in this zone. Analysis of fractures on lava megablocks suggests that shear stress during the initial sliding is the principal cause of fracture. These data strongly indicate that VDA I is purely gravitational and argue for a model in which the initial sliding mass transforms into a flow due to differential in situ fragmentation caused by the shear stress. VDA II is restricted to low-topography areas. Its volume, in the studied area, is about 0.3 km(3). The deposits consist of brecciated, rounded blocks and megablocks set in a fine-grained matrix composed essentially of volcanic glass. This unit is stratified, with a massive layer that contains all the megablocks at the base and in the intermediate part, and in the upper part a normally graded layer that contains only blocks <1 m in size. The different lithologies present are totally mixed. These observations suggest that VDA II may be of the Bezymianny-type and that it underwent a flow transformation from a turbulent to a stratified flow consisting of a basal hyperconcentrated laminar body overlain by a dilute layer. (C) 2000 Elsevier Science B.V. All rights reserved.

Plutonium and americium isotopes as alternative chronostratigraphic markers in tropical regions: An application in the Havana Bay (Cuba)

The low 137Cs activity observed in marine sediments of tropical regions often precludes its use as chronostratigraphic marker. Here we present a study on the use of Pu and Am radioisotopes as alternative markers to constrain the 210Pb ages in a sediment core of the Havana Bay (Cuba). Mean activity ratios of 238Pu/239,240Pu, 241Am/239,240Pu and 241Pu/239,240Pu indicated that the nuclear weapon tests fallout is the main source of the anthropogenic radionuclides. While the inventory of 137Cs in the sediments is lower than the expected fallout inventory, 239,240Pu accumulates in the sediments with inventories higher than the expected fallout inventory. The high fluxes of 239,240Pu are nevertheless corroborated here through use of 210Pb, and confirm that focusing of solid particles is of great importance in the investigated site. 239,240Pu showed to be a useful time tracer in marine sites where the 137Cs signal is very low.

Kaasukäyttöisen jäteauton toiminnan tutkiminen ja soveltuvuuden selvittäminen pääkaupunkiseudun jätteenkuljetuksiin

Kaasunkäyttö liikennepolttoaineena on Suomessa vielä melko vähäistä. Maa- ja biokaasun käyttöä pyritään kuitenkin lisäämään, sillä EU:n jäsenvaltioiden tulee korvatavuoteen 2010 mennessä 5,75 % nykyisistä liikenteen polttoaineista biopolttoaineilla ja vuoteen 2020 mennessä jopa 20 %:a. Tässä työssä tutkittiin kaasukäyttöisen (CNG) jäteauton vahvuuksia ja heikkouksia dieseljäteautoon verrattuna. Ensimmäinen CNG-jäteauto aloitti liikennöinnin Pääkaupunkiseudun yhteistyövaltuuskunnan alueella joulukuussa 2005. Kaasujäteautolle suoritettujen melu- ja pakokaasupäästömittausten perusteella selvisi, että CNG-jäteauto on ympäristön kannalta dieseljäteautoa puhtaampi vaihtoehto. Kaasujäteautolla on myös yrityksen imagoon positiivinen vaikutus. Jäteautojen kustannuslaskelmat osoittivat, että kaasujäteauto tulee kokonaiskustannuksiltaan kalliimmaksi kuin dieseljäteauto. Ainoastaan CNG-jäteauton polttoainekustannukset ovat toistaiseksi edullisemmat kuin dieseljäteauton. Kaasujäteautokannan lisääntyminen edellyttää kaasun liikennepolttoainekäytön tukemista esimerkiksi antamalla lisäpisteitä urakkatarjouskilpailuissa. Tällöin eri polttoainevaihtoehtojen välillesyntyy kilpailua, millä voi tulevaisuudessa olla vaikutusta CNG-jäteauton kokonaiskustannusten alenemiseen ja kaasun käytön lisäämiseen taloudellisesti kannattavasti. Myös edistämällä biokaasun hyötykäyttöä liikennepolttoaineena saavutetaan maakaasua paremmat ympäristöhyödyt ja saadaan kaatopaikoilla muodostuva metaani talteen. Biokaasu on hiilidioksidineutraali polttoaine, joten sen poltosta ei synny kasvihuonekaasupäästöjä.