Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers.

OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic characteristics of angiotensin II receptor antagonists as a therapeutic class. DESIGN: Population pharmacokinetic-pharmacodynamic modelling study. METHODS: The data of 14 phase I studies with 10 different drugs were analysed. A common population pharmacokinetic model (two compartments, mixed zero- and first-order absorption, two metabolite compartments) was applied to the 2685 drug and 900 metabolite concentration measurements. A standard nonlinear mixed effect modelling approach was used to estimate the drug-specific parameters and their variabilities. Similarly, a pharmacodynamic model was applied to the 7360 effect measurements, i.e. the decrease of peak blood pressure response to intravenous angiotensin challenge recorded by finger photoplethysmography. The concentration of drug and metabolite in an effect compartment was assumed to translate into receptor blockade [maximum effect (Emax) model with first-order link]. RESULTS: A general pharmacokinetic-pharmacodynamic (PK-PD) model for angiotensin antagonism in healthy individuals was successfully built up for the 10 drugs studied. Representatives of this class share different pharmacokinetic and pharmacodynamic profiles. Their effects on blood pressure are dose-dependent, but the time course of the effect varies between the drugs. CONCLUSIONS: The characterisation of PK-PD relationships for these drugs gives the opportunity to optimise therapeutic regimens and to suggest dosage adjustments in specific conditions. Such a model can be used to further refine the use of this class of drugs.

Modelling structural zeros in compositional data

This analysis was stimulated by the real data analysis problem of householdexpenditure data. The full dataset contains expenditure data for a sample of 1224 households. The expenditure is broken down at 2 hierarchical levels: 9 major levels (e.g. housing, food, utilities etc.) and 92 minor levels. There are also 5 factors and 5 covariates at the household level. Not surprisingly, there are a small number of zeros at the major level, but many zeros at the minor level. The question is how best to model the zeros. Clearly, models that tryto add a small amount to the zero terms are not appropriate in general as at least some of the zeros are clearly structural, e.g. alcohol/tobacco for households that are teetotal. The key question then is how to build suitable conditional models. For example, is the sub-composition of spendingexcluding alcohol/tobacco similar for teetotal and non-teetotal households?In other words, we are looking for sub-compositional independence. Also, what determines whether a household is teetotal? Can we assume that it is independent of the composition? In general, whether teetotal will clearly depend on the household level variables, so we need to be able to model this dependence. The other tricky question is that with zeros on more than onecomponent, we need to be able to model dependence and independence of zeros on the different components. Lastly, while some zeros are structural, others may not be, for example, for expenditure on durables, it may be chance as to whether a particular household spends money on durableswithin the sample period. This would clearly be distinguishable if we had longitudinal data, but may still be distinguishable by looking at the distribution, on the assumption that random zeros will usually be for situations where any non-zero expenditure is not small.While this analysis is based on around economic data, the ideas carry over tomany other situations, including geological data, where minerals may be missing for structural reasons (similar to alcohol), or missing because they occur only in random regions which may be missed in a sample (similar to the durables)

Animal dispersal modelling: handling landscape features and related animal choices

Animal dispersal in a fragmented landscape depends on the complex interaction between landscape structure and animal behavior. To better understand how individuals disperse, it is important to explicitly represent the properties of organisms and the landscape in which they move. A common approach to modelling dispersal includes representing the landscape as a grid of equal sized cells and then simulating individual movement as a correlated random walk. This approach uses a priori scale of resolution, which limits the representation of all landscape features and how different dispersal abilities are modelled. We develop a vector-based landscape model coupled with an object-oriented model for animal dispersal. In this spatially explicit dispersal model, landscape features are defined based on their geographic and thematic properties and dispersal is modelled through consideration of an organism's behavior, movement rules and searching strategies (such as visual cues). We present the model's underlying concepts, its ability to adequately represent landscape features and provide simulation of dispersal according to different dispersal abilities. We demonstrate the potential of the model by simulating two virtual species in a real Swiss landscape. This illustrates the model's ability to simulate complex dispersal processes and provides information about dispersal such as colonization probability and spatial distribution of the organism's path.

The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling.

The resistance of mosquitoes to chemical insecticides is threatening vector control programmes worldwide. Cytochrome P450 monooxygenases (CYPs) are known to play a major role in insecticide resistance, allowing resistant insects to metabolize insecticides at a higher rate. Among them, members of the mosquito CYP6Z subfamily, like Aedes aegypti CYP6Z8 and its Anopheles gambiae orthologue CYP6Z2, have been frequently associated with pyrethroid resistance. However, their role in the pyrethroid degradation pathway remains unclear. In the present study, we created a genetically modified yeast strain overexpressing Ae. aegypti cytochrome P450 reductase and CYP6Z8, thereby producing the first mosquito P450-CPR (NADPH-cytochrome P450-reductase) complex in a yeast recombinant system. The results of the present study show that: (i) CYP6Z8 metabolizes PBAlc (3-phenoxybenzoic alcohol) and PBAld (3-phenoxybenzaldehyde), common pyrethroid metabolites produced by carboxylesterases, producing PBA (3-phenoxybenzoic acid); (ii) CYP6Z8 transcription is induced by PBAlc, PBAld and PBA; (iii) An. gambiae CYP6Z2 metabolizes PBAlc and PBAld in the same way; (iv) PBA is the major metabolite produced in vivo and is excreted without further modification; and (v) in silico modelling of substrate-enzyme interactions supports a similar role of other mosquito CYP6Zs in pyrethroid degradation. By playing a pivotal role in the degradation of pyrethroid insecticides, mosquito CYP6Zs thus represent good targets for mosquito-resistance management strategies.

A unified approach for representing rows and columns in contingency tables

By using suitable parameters, we present a uni¯ed aproach for describing four methods for representing categorical data in a contingency table. These methods include:correspondence analysis (CA), the alternative approach using Hellinger distance (HD),the log-ratio (LR) alternative, which is appropriate for compositional data, and theso-called non-symmetrical correspondence analysis (NSCA). We then make an appropriate comparison among these four methods and some illustrative examples are given.Some approaches based on cumulative frequencies are also linked and studied usingmatrices.Key words: Correspondence analysis, Hellinger distance, Non-symmetrical correspondence analysis, log-ratio analysis, Taguchi inertia

Regional and hemispheric determinants of language laterality: Implications for preoperative fMRI.

Language is typically a function of the left hemisphere but the right hemisphere is also essential in some healthy individuals and patients. This inter-subject variability necessitates the localization of language function, at the individual level, prior to neurosurgical intervention. Such assessments are typically made by comparing left and right hemisphere language function to determine "language lateralization" using clinical tests or fMRI. Here, we show that language function needs to be assessed at the region and hemisphere specific level, because laterality measures can be misleading. Using fMRI data from 82 healthy participants, we investigated the degree to which activation for a semantic word matching task was lateralized in 50 different brain regions and across the entire cortex. This revealed two novel findings. First, the degree to which language is lateralized across brain regions and between subjects was primarily driven by differences in right hemisphere activation rather than differences in left hemisphere activation. Second, we found that healthy subjects who have relatively high left lateralization in the angular gyrus also have relatively low left lateralization in the ventral precentral gyrus. These findings illustrate spatial heterogeneity in language lateralization that is lost when global laterality measures are considered. It is likely that the complex spatial variability we observed in healthy controls is more exaggerated in patients with brain damage. We therefore highlight the importance of investigating within hemisphere regional variations in fMRI activation, prior to neuro-surgical intervention, to determine how each hemisphere and each region contributes to language processing. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc.

Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase (TM) Unified List Based on International Collaborative Work

BACKGROUND Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans. OBJECTIVE (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase). DATA SOURCES AND EXTRACTION (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, 'overall liver injury' and 'ALF'. EBGM of >or=2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of 'overall liver injury' and 'ALF' calculated from VigiBase. DATA SYNTHESIS After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of 'overall liver injury' and 83.1% were associated with at least one reported case of ALF. CONCLUSIONS This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.

The interactional space in CLIL (Content and Language Integrated Learning) and EFL (English as a Foreign Language) classrooms

Aquest estudi pretén investigar els intercanvis verbals mestre/a – aprenent(s) en dos contextos d'instrucció diferents: classes amb un enfocament AICLE (Aprenentatge Integrat de Continguts Curriculars i Llengua Estrangera) on s’aprenen continguts no lingüístics a través de l’anglès, per una banda, i classes 'tradicionals' d'anglès com a llengua estrangera, on l’anglès és alhora objecte d’estudi i vehicle de comunicació, per una altra banda. Més concretament, les preguntes que formula el/la mestre/a, la producció oral dels aprenents i el 'feedback' del/de la mestre/a en els episodis d’atenció a la forma s’han estudiat a la llum de les principals teories provinents del camp de l’Adquisició de Segones Llengües (SLA) per tal de demostrar el seu paper en l’aprenentatge de l’anglès. El corpus de dades prové de l’enregistrament de 7 sessions AICLE i d'11 sessions EFL enregistrades en format àudio i vídeo en dos centres públics d’Educació Primària (EP) de Catalunya. A cadascuna de les escoles, el/la mateix/a mestre/a és l’encarregat/da dels dos tipus d’instrucció amb el mateix grup d’aprenents (10-11 anys d’edat), fet que permet eliminar variables individuals com l'aptitud dels aprenents o l'estil del/de la mestre/a.Els resultats mostren un cert nombre de similituds discursives entre AICLE i EFL donat que ambdós enfocaments tenen lloc en el context-classe amb unes característiques ben definides. Tal com apunta la recerca realitzada en aquest camp, la instrucció AICLE reuneix un seguit de condicions idònies per un major desenvolupament dels nivells de llengua anglesa més enllà de les classes ‘tradicionals’ d’anglès. Malgrat això, aquest estudi sembla indicar que el potencial d'AICLE pel que fa a facilitar una exposició rica a l’anglès i una producció oral significativa no s’explota degudament. En aquest sentit, els resultats d’aquest estudi poden contribuir a la formació dels futurs professors d'AICLE si es busca l’assoliment d’una complementarietat d’ambdós contextos amb l’objectiu últim de millorar els nivells de domini de la llengua anglesa.

Universal complex structures in written language

Quantitative linguistics has provided us with a number of empirical laws that characterise the evolution of languages and competition amongst them. In terms of language usage, one of the most influential results is Zipf’s law of word frequencies. Zipf’s law appears to be universal, and may not even be unique to human language. However, there is ongoing controversy over whether Zipf’s law is a good indicator of complexity. Here we present an alternative approach that puts Zipf’s law in the context of critical phenomena (the cornerstone of complexity in physics) and establishes the presence of a large-scale “attraction” between successive repetitions of words. Moreover, this phenomenon is scale-invariant and universal – the pattern is independent of word frequency and is observed in texts by different authors and written in different languages. There is evidence, however, that the shape of the scaling relation changes for words that play a key role in the text, implying the existence of different “universality classes” in the repetition of words. These behaviours exhibit striking parallels with complex catastrophic phenomena.

Exploring Cross-layer power management for PGAS applications on the SCC platform

Technological limitations and power constraints are resulting in high-performance parallel computing architectures that are based on large numbers of high-core-count processors. Commercially available processors are now at 8 and 16 cores and experimental platforms, such as the many-core Intel Single-chip Cloud Computer (SCC) platform, provide much higher core counts. These trends are presenting new sets of challenges to HPC applications including programming complexity and the need for extreme energy efficiency.In this work, we first investigate the power behavior of scientific PGAS application kernels on the SCC platform, and explore opportunities and challenges for power management within the PGAS framework. Results obtained via empirical evaluation of Unified Parallel C (UPC) applications on the SCC platform under different constraints, show that, for specific operations, the potential for energy savings in PGAS is large; and power/performance trade-offs can be effectively managed using a cross-layerapproach. We investigate cross-layer power management using PGAS language extensions and runtime mechanisms that manipulate power/performance tradeoffs. Specifically, we present the design, implementation and evaluation of such a middleware for application-aware cross-layer power management of UPC applications on the SCC platform. Finally, based on our observations, we provide a set of recommendations and insights that can be used to support similar power management for PGAS applications on other many-core platforms.