Population pharmacokinetics in chronic myeloid leukaemia patients: observations under field-conditions

Introduction: Therapeutic drug monitoring (TDM) of imatinib has been increasingly proposed for chronic myeloid leukaemia (CML) patients, as several studies have found a correlation between trough concentrations (Cmin) >=1000ng/ml and improved response. The pharmacological monitoring project of EUTOS (European Treatment and Outcome Study) was launched to increase the availability of imatinib TDM, standardize labs, and validate proposed Cmin thresholds. Using the collected data, the objective of this analysis was to characterize imatinib Population pharmacokinetics (Pop-PK) in a large cohort of European patients, to quantify its variability and the influence of demographic factors and comedications, and to derive individual exposure variables suitable for further concentration-effect analyses.¦Methods: 4095 PK samples from 2478 adult patients were analyzed between 2006 and 2010 by LC-MS-MS and considered for Pop-PK analysis by NONMEM®. Model building used data from 973 patients with >=2 samples available (2590 samples). A sensitivity analysis was performed using all data. Available comedications (27%) were classified into inducers or inhibitors of P-glycoprotein, CYP3A4/5 and organic-cation-transporter-1 (hOCT-1).¦Results: A one-compartment model with linear elimination, zero-order absorption fitted the data best. Estimated Pop-PK parameters (interindividual variability, IIV %CV) for a 40-year old male patient were: clearance CL = 17.3 L/h (37.7%), volume V = 429L (51.1%), duration of absorption D1 = 3.2h. Outliers, reflecting potential compliance and time recording errors, were taken into account by estimating an IIV on the residual error (35.4%). Intra-individual residuals were 29.1% (proportional) plus ± 84.6 ng/mL (additive). Female patients had a 15.2% lower CL (14.6 L/h). A piece-wise linear effect of age estimated a CL of 18.7 L/h at 20 years, 17.3 L/h at 40 and 13.8 L/h at 60 years. These covariates explained 2% (CL) and 4.5% (V) of IIV variability. No effect of comedication was found. The sensitivity analysis expectedly estimated increased IIV, but similar fixed effect parameters.¦Conclusion: Imatinib PK was well described in a large cohort of CML patients under field conditions and results were concordant with previous studies. Patient characteristics explain only little IIV, confirming limited utility of prior dosage adjustment. As intra-variability is smaller than inter-patient variability, dose adjustment guided by TDM could however be beneficial in order to bring Cmin into a given therapeutic target.

J2EE: Inter Golf

TFC de la carrera d'ETIS, que pretén mostrar els passos i pautes que es tenen que seguir per desenvolupar l'aplicació Inter Golf en l'arquitectura J2EE. Inter Golf serà una pàgina web destinada a la gestió dels tornejos realitzats en un camp de golf, fent servir J2EE, MVC, Struts2, Hibernate i Tiles.

Estudo da dinâmica espaço-temporal do bioma Pantanal por meio de imagens MODIS

O objetivo deste trabalho foi avaliar dados multitemporais, obtidos pelo sensor "moderate resolution imaging spectroradiometer" (MODIS), para o estudo da dinâmica espaço-temporal de duas sub-regiões do bioma Pantanal. Foram utilizadas 139 imagens "enhanced vegetation index" (EVI), do produto MOD13 "vegetation index", dados de altimetria oriundos do "shuttle radar topography mission" (SRTM) e dados de precipitação do "tropical rainfall measuring mission" (TRMM). Para a redução da dimensionalidade dos dados, as imagens MODIS-EVI foram amostradas com base nas curvas de nível espaçadas em 10 m. Foram aplicadas as técnicas de análise de autocorrelação e análise de agrupamentos aos dados das amostras, e a análise de componentes principais na área total da imagem. Houve dependência tanto temporal quanto espacial da resposta espectral com a precipitação. A análise de agrupamentos apontou a presença de dois grupos, o que indicou a necessidade da análise completa da área. A análise de componentes principais permitiu diferenciar quatro comportamentos distintos: as áreas permanentemente alagadas; as áreas não inundáveis, compostas por vegetação; as áreas inundáveis com maior resposta de vegetação; e áreas com vegetação ripária.

Modelo autologístico espaço-temporal com aplicação à análise de padrões espaciais da leprose-dos-citros

O objetivo deste trabalho foi propor estratégias de modelagem aplicadas aos dados de incidência de leprose-dos-citros, por meio do uso de um modelo autologístico espaço-temporal. A adequação do modelo autologístico foi avaliada quanto à: análise de dados provenientes de avaliações feitas em diferentes momentos; detecção de padrões espaciais da doença, pela avaliação de diferentes estruturas de vizinhança; consideração do efeito defasado no tempo de covariáveis de vizinhança; e ao efeito do ácaro transmissor na probabilidade de nova infecção. O modelo autologístico espaço-temporal adotado estendeu o modelo logístico usual, em que a estrutura de vizinhança é descrita por meio da construção de covariáveis, a partir da resposta observada em plantas vizinhas à planta avaliada, na mesma avaliação, ou em avaliações anteriores. Os dados de incidência de leprose nas plantas de citros foram coletados em pontos referenciados no espaço, durante aproximadamente dois anos. Os modelos detectam o efeito da presença do vetor e os padrões espaciais na ocorrência de novas infecções, tanto para covariáveis de vizinhança da mesma avaliação, quanto para covariáveis de vizinhança da avaliação anterior. Além disso, os modelos considerados permitem quantificar as variações na probabilidade de ocorrência da doença de acordo com o estado da doença e com a incidência do ácaro transmissor.

Geoport Estadistic: aplicación web para el desarrollo de herramientas de análisis y consulta de la información estadística del Port de Barcelona, incluyendo la componente temporal

El següent projecte mostra la creació d’una aplicació web-map per a la realització de consultes sobre l’informació estadística relacionada amb el port de Barcelona. Aquesta aplicació integra les eines d'anàlisi estadística de Google Fusion Tables, i les llibreries per realitzar un visor geogràfic-temporal que són Timemap i Google Earth

Temporal changes of an alfalfa succession and related soil physical properties on the Loess Plateau, China

The objective of this work was to investigate the relationship between changes in the plant community and changes in soil physical properties and water availability, during a succession from alfalfa (Medicago sativa L.) to natural vegetation on the Loess Plateau, China. Data from a succession sere spanning 32 years were collated, and vegetative indexes were compared to changes related to soil bulk density and soil water storage. The alfalfa yield increased for approximately 7 years, then it declined and the alfalfa was replaced by a natural community dominated by Stipa bungeana that began to thrive about 10 years after alfalfa seeding. Soil bulk density increased over time, but the deterioration of the alfalfa was mainly ascribed to a severe reduction in soil water storage, which was lowest around the time when degradation commenced. The results indicated that water consumption by alfalfa could be reduced by reducing plant density. The analysis of the data also suggested that soil water recharge could be facilitated by rotating the alfalfa with other crops, natural vegetation, or bare soil.

Variação temporal de propriedades físicas do solo e crescimento radicular de feijoeiro em quatro sistemas de manejo

Os objetivos deste trabalho foram determinar a variação temporal da porosidade, da densidade e da resistência à penetração do solo, em quatro sistemas de manejo, e estudar seus efeitos sobre o crescimento radicular do feijoeiro (Phaseolus vulgaris). O experimento foi conduzido em Argissolo, em delineamento experimental de blocos ao acaso, com três repetições. Os tratamentos foram: plantio direto há 10 anos, preparo convencional, plantio em solo escarificado recentemente (Esc. recente) e plantio direto sobre área escarificada há 1 ano (Esc. 1 ano). A escarificação reduziu a densidade média do solo e aumentou a porosidade total durante o ciclo do feijoeiro. A maior densidade ocorreu na camada de 0,10-0,15 m dos sistemas plantio direto e Esc. 1 ano. A resistência à penetração foi a propriedade que melhor caracterizou e diferenciou os sistemas de manejo, as camadas com impedimento e o efeito do tempo de amostragem, porém não afetou o crescimento radicular do feijoeiro. Os efeitos da escarificação sobre a densidade e a resistência à penetração desapareceram um ano após a escarificação, o que indica a reconsolidação do solo.

Dépistage du cancer de la prostate: utilité, buts et perspectives en 2010 [Prostate cancer screening: utility, goals and perspectives in 2010].

According to recent results of a sub-group of 20,000 patients from the ERSPC study, prostate cancer screening significantly increases disease specific survival for men with a life expectancy of 15 years. However presently, only 20% of prostate biopsies lead to the diagnosis of cancer. This low yield may be increased by using new tools on their way to validation, such as the blood and urinary markers p2-PSA and PCA3, so as MRI and tridimensional computerized echography. Finally, the tumours detected must be managed with subtlety, since a third of them are not overtly aggressive clinically. Hence, a significant proportion of such tumours may not need immediate curative intent treatment, and can be followed up in an active surveillance protocol.

Partisan targeting of inter-governmental transfers & state interference in local elections: evidence from Spain

[spa] En este trabajo examinamos si, en la asignación de transferencias, los gobernantes regionales discriminan a favor de los gobiernos locales controlados por el mismo partido político, y si las perspectivas electorales de los gobiernos locales mejoran si están políticamente alineados con el gobierno regional. Con una nueva base de datos que considera 3.000 municipios españoles durante el período 2000-07 y un diseño de discontinuidad en la regresión, documentamos un efecto robusto de importante magnitud: en elecciones ajustadas, los municipios alineados con el gobierno regional reciben, en media, un 83% más de transferencias per cápita y su gobernante obtiene un 10% más de votos en las elecciones locales. También demostramos que el efecto de la alineación política es mayor: (i) si las elecciones regionales y locales se celebran el mismo día, (ii) en regiones donde las elecciones regionales son menos competidas, y (iii) en regiones con más recursos presupuestarios.

Partisan targeting of inter-governmental transfers & state interference in local elections: evidence from Spain

[spa] En este trabajo examinamos si, en la asignación de transferencias, los gobernantes regionales discriminan a favor de los gobiernos locales controlados por el mismo partido político, y si las perspectivas electorales de los gobiernos locales mejoran si están políticamente alineados con el gobierno regional. Con una nueva base de datos que considera 3.000 municipios españoles durante el período 2000-07 y un diseño de discontinuidad en la regresión, documentamos un efecto robusto de importante magnitud: en elecciones ajustadas, los municipios alineados con el gobierno regional reciben, en media, un 83% más de transferencias per cápita y su gobernante obtiene un 10% más de votos en las elecciones locales. También demostramos que el efecto de la alineación política es mayor: (i) si las elecciones regionales y locales se celebran el mismo día, (ii) en regiones donde las elecciones regionales son menos competidas, y (iii) en regiones con más recursos presupuestarios.

Estimating soybean crop areas using spectral-temporal surfaces derived from MODIS images in Mato Grosso, Brazil

The objective of this work was to evaluate the application of the spectral-temporal response surface (STRS) classification method on Moderate Resolution Imaging Spectroradiometer (MODIS, 250 m) sensor images in order to estimate soybean areas in Mato Grosso state, Brazil. The classification was carried out using the maximum likelihood algorithm (MLA) adapted to the STRS method. Thirty segments of 30x30 km were chosen along the main agricultural regions of Mato Grosso state, using data from the summer season of 2005/2006 (from October to March), and were mapped based on fieldwork data, TM/Landsat-5 and CCD/CBERS-2 images. Five thematic classes were considered: Soybean, Forest, Cerrado, Pasture and Bare Soil. The classification by the STRS method was done over an area intersected with a subset of 30x30-km segments. In regions with soybean predominance, STRS classification overestimated in 21.31% of the reference values. In regions where soybean fields were less prevalent, the classifier overestimated 132.37% in the acreage of the reference. The overall classification accuracy was 80%. MODIS sensor images and the STRS algorithm showed to be promising for the classification of soybean areas in regions with the predominance of large farms. However, the results for fragmented areas and smaller farms were less efficient, overestimating soybean areas.

Spatio-temporal sequence of cross-regulatory events in root meristem growth.

A central question in developmental biology is how multicellular organisms coordinate cell division and differentiation to determine organ size. In Arabidopsis roots, this balance is controlled by cytokinin-induced expression of SHORT HYPOCOTYL 2 (SHY2) in the so-called transition zone of the meristem, where SHY2 negatively regulates auxin response factors (ARFs) by protein-protein interaction. The resulting down-regulation of PIN-FORMED (PIN) auxin efflux carriers is considered the key event in promoting differentiation of meristematic cells. Here we show that this regulation involves additional, intermediary factors and is spatio-temporally constrained. We found that the described cytokinin-auxin crosstalk antagonizes BREVIS RADIX (BRX) activity in the developing protophloem. BRX is an auxin-responsive target of the prototypical ARF MONOPTEROS (MP), a key promoter of vascular development, and transiently enhances PIN3 expression to promote meristem growth in young roots. At later stages, cytokinin induction of SHY2 in the vascular transition zone restricts BRX expression to down-regulate PIN3 and thus limit meristem growth. Interestingly, proper SHY2 expression requires BRX, which could reflect feedback on the auxin responsiveness of SHY2 because BRX protein can directly interact with MP, likely acting as a cofactor. Thus, cross-regulatory antagonism between BRX and SHY2 could determine ARF activity in the protophloem. Our data suggest a model in which the regulatory interactions favor BRX expression in the early proximal meristem and SHY2 prevails because of supplementary cytokinin induction in the later distal meristem. The complex equilibrium of this regulatory module might represent a universal switch in the transition toward differentiation in various developmental contexts.

Temporal evolution of MR perfusion in neonatal hypoxic-ischemic encephalopathy

PURPOSE: To illustrate the evolution of brain perfusion-weighted magnetic resonance imaging (PWI-MRI) in severe neonatal hypoxic-ischemic (HI) encephalopathy, and its possible relation to further neurodevelopmental outcome. MATERIALS AND METHODS: Two term neonates with HI encephalopathy underwent an early and a late MRI, including PWI. They were followed until eight months of age. A total of three "normal controls" were also included. Perfusion maps were obtained, and relative cerebral blood flow (rCBF) and cerebral blood volume (rCBV) values were measured. RESULTS: Compared to normal neonates, a hyperperfusion (increased rCBF and rCBV) was present on early scans in the whole brain. On late scans, hyperperfusion persisted in cortical gray matter (normalization of rCBF and rCBV ratios in white matter and basal ganglia, but not in cortical gray matter). Diffusion-weighted imaging (DWI) was normalized, and extensive lesions became visible on T2-weighted images. Both patients displayed very abnormal outcome: Patient 2 with the more abnormal early and late hyperperfusion being the worst. CONCLUSION: PWI in HI encephalopathy did not have the same temporal evolution as DWI, and remained abnormal for more than one week after injury. This could be a marker of an ongoing mechanism underlying severe neonatal HI encephalopathy. Evolution of PWI might help to predict further neurodevelopmental outcome.