Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors.

Angio-oedema (AE) is a known adverse effect of angiotensin converting enzyme inhibitor (ACE-I) therapy. Over the past several decades, evidence of failure to diagnose this important and potentially fatal reaction is commonly found in the literature. Because this reaction is often seen first in the primary care setting, a review was undertaken to analyse and document the keys to both diagnostic criteria as well as to investigate potential risk factors for ACE-I AE occurrence. A general review of published literature was conducted through Medline, EMBASE, and the Cochrane Database, targeting ACE-I-related AE pathomechanism, diagnosis, epidemiology, risk factors, and clinical decision making and treatment. The incidence and severity of AE appears to be on the rise and there is evidence of considerable delay in diagnosis contributing to significant morbidity and mortality for patients. The mechanism of AE due to ACE-I drugs is not fully understood, but some genomic and metabolomic information has been correlated. Additional epidemiologic data and clinical treatment outcome predictors have been evaluated, creating a basis for future work on the development of clinical prediction tools to aid in risk identification and diagnostic differentiation. Accurate recognition of AE by the primary care provider is essential to limit the rising morbidity associated with ACE-I treatment-related AE. Research findings on the phenotypic indicators relevant to this group of patients as well as basic research into the pathomechanism of AE are available, and should be used in the construction of better risk analysis and clinical diagnostic tools for ACE-I AE.

From e-voting to smart-voting : e-Tools in and for elections and direct democracy in Switzerland

To what extent do and could e-tools contribute to a democracy like Switzerland? This paper puts forward experiences and visions concerning the application of e-tools for the most traditional democratic processes- elections and, of special importance in Switzerland, direct-democratic votes.Having the particular voting behaviour of the Swiss electorate in mind (low voter turnout - especially among the youngest age group, low political knowledge, etc.) we believe that e-tools which provide information in the forefront of elections or direct-democratic votes offer an enormous service to the voter. As soon as e-voting will be possible in Switzerland (as planned by the government), those e-tools for gathering information online will become indispensable and will gain power enormously. Therefore political scientists should not only focus on potential effects of e-voting itself but rather on the combination of (connected)e-tools of the pre-voting and the voting sphere. In the case of Switzerland, we argue in this paper, the offer of VAAs such as smartvote for elections and direct-democratic votes can provide the voter with more balanced and qualitatively higher information and thereby make a valuable contribution to the Swiss democracy.

Benchmarking therapeutic drug monitoring software: A review of available computer tools

Therapeutic drug monitoring (TDM) aims to optimize treatments by individualizing dosage regimens based on the measurement of blood concentrations. Dosage individualization to maintain concentrations within a target range requires pharmacokinetic and clinical capabilities. Bayesian calculations currently represent the gold standard TDM approach but require computation assistance. In recent decades computer programs have been developed to assist clinicians in this assignment. The aim of this survey was to assess and compare computer tools designed to support TDM clinical activities. The literature and the Internet were searched to identify software. All programs were tested on personal computers. Each program was scored against a standardized grid covering pharmacokinetic relevance, user friendliness, computing aspects, interfacing and storage. A weighting factor was applied to each criterion of the grid to account for its relative importance. To assess the robustness of the software, six representative clinical vignettes were processed through each of them. Altogether, 12 software tools were identified, tested and ranked, representing a comprehensive review of the available software. Numbers of drugs handled by the software vary widely (from two to 180), and eight programs offer users the possibility of adding new drug models based on population pharmacokinetic analyses. Bayesian computation to predict dosage adaptation from blood concentration (a posteriori adjustment) is performed by ten tools, while nine are also able to propose a priori dosage regimens, based only on individual patient covariates such as age, sex and bodyweight. Among those applying Bayesian calculation, MM-USC*PACK© uses the non-parametric approach. The top two programs emerging from this benchmark were MwPharm© and TCIWorks. Most other programs evaluated had good potential while being less sophisticated or less user friendly. Programs vary in complexity and might not fit all healthcare settings. Each software tool must therefore be regarded with respect to the individual needs of hospitals or clinicians. Programs should be easy and fast for routine activities, including for non-experienced users. Computer-assisted TDM is gaining growing interest and should further improve, especially in terms of information system interfacing, user friendliness, data storage capability and report generation.

The clinical application of converting enzyme inhibitors.

Chronic blockade of the renin angiotensin system became possible when orally active inhibitors of angiotensin converting enzyme, the enzyme which catalyzes the transformation of angiotensin I into angiotensin II, were synthetized. Two compounds, captopril and enalapril, have been investigated in clinical studies. The decrease of the pressor response to exogenous angiotensin I and of the circulating levels of angiotensin II following administration of these inhibitors has been demonstrated to be directly related to the degree of suppression of plasma angiotensin converting enzyme activity. These inhibitors have been shown to normalize blood pressure alone in some hypertensive patients whereas in many others, satisfactory blood pressure control can be achieved only after the addition of a diuretic. Captopril and enalapril also markedly improve cardiac function of patients with chronic congestive heart failure. Chronic blockade of the renin angiotensin system has therefore provided an interesting new approach to the treatment of clinical hypertension and heart failure.

Effect of angiotensin converting enzyme inhibition in renovascular hypertension.

The unique ability of angiotensin converting enzyme (ACE) inhibitors to inhibit the generation of angiotensin II has made them very useful agents for treating patients with renovascular hypertension. Their efficacy in lowering blood pressure in this type of secondary hypertension is now well established. However, episodes of acute renal failure may occur during ACE inhibition, particularly when renal perfusion is compromised. This is often the case in patients with renal artery stenosis and a single kidney or with bilateral renal artery stenosis. In recent years, investigators have shown concern at the long-term fate of the stenotic kidney in patients with unilateral renal artery stenosis who are treated with ACE inhibitors. Although overall renal function remained stable, a decrease in glomerular filtration was demonstrated in the stenotic kidney under ACE inhibition. The long-term implications of this observation merit further investigations.

Experimental design for acquiring relevant data to address the issue of comparing consecutively manufactured tools and firearms

The comparison of consecutively manufactured tools and firearms has provided much, but not all, of the basis for the profession of firearm and toolmark examination. The authors accept the fundamental soundness of this approach but appeal to the experimental community to close two minor gaps in the experimental procedure. We suggest that "blinding" and attention to appropriateness of other experimental conditions that would consolidate the foundations of our profession. We do not suggest that previous work is unsound.

Angiotensin-converting enzyme inhibitor versus calcium antagonist in the treatment of hypertension.

Sixteen patients with essential hypertension were treated for 2 consecutive 6-week periods with either the angiotensin-converting enzyme (ACE) inhibitor enalapril (20 mg once daily) or the calcium antagonist diltiazem (120 mg twice daily). The sequence of the treatment phases was randomly allocated. Blood pressure decreased from 154/102 +/- 5/2 mm Hg (mean +/- SEM) to 135/96 +/- 4/2 and 140/98 +/- 3/2 mm Hg during treatment with enalapril and diltiazem, respectively. It was impossible in the individual hypertensive patient to predict the long-term blood pressure response to one of the agents studied based on the long-term blood pressure response to the other agent.

Angiotensin-converting enzyme inhibition by hydroxamic zinc-binding idrapril in humans.

The new angiotensin-converting enzyme (ACE) inhibitor idrapril acts by binding the catalytically important zinc ion to a hydroxamic group. We investigated its pharmacodynamic and pharmacokinetic properties in 8 healthy men: Increasing doses of 1, 5, and 25 mg idrapril as well as placebo or 5 mg captopril were administered intravenously (i.v.) at 1-week intervals. Six of the subjects received 100 mg idrapril orally (p.o.) last, and two ingested oral placebo as a double-blind control. Blood pressure (BP) and heart rate (HR) remained unchanged. No serious side effects were observed. ACE inhibition in vivo was evaluated by changes in the ratio of specifically measured plasma angiotensin II (AngII) and AngI concentrations determined by high-performance liquid chromatography/radioimmunoassay (HPLC/RIA) techniques. Plasma ACE activity in vitro was estimated by radioenzymatic assay; it was suppressed by > or = 93% at 15 min after injection of 25 mg idrapril or 5 mg captopril and by 96% 2 h after idrapril intake. Mean AngII levels were decreased dose dependently at 15 min after idrapril injections. At the same time, plasma renin activity (PRA) and AngI increased according to the doses. The AngII/AngI ratio was clearly related to plasma idrapril levels (r = -0.88, n = 60). Oral idrapril inhibited ACE maximally at 1-4 h after dosing, when < 7% of initial ACE activity was observed in vitro and in vivo. Idrapril is a safe and efficient ACE inhibitor in human subjects. It is well absorbed orally. Besides having a slightly slower onset of action, idrapril has pharmacodynamic effects comparable to those of captopril.

Pharmacokinetics of angiotensin converting enzyme inhibitors.

1. The pharmacokinetics of most ACE inhibitors have been evaluated indirectly by the measurements of plasma ACE activity and circulating levels of angiotensin I and II. 2. Although plasma ACE activity is very useful to study the degree and the time-course of ACE inhibition, one has to be aware that very different results can be obtained depending on the substrate employed in the assay. It is therefore impossible to compare the results of different inhibitors unless an identical methodology is used. 3. A clear dissociation between plasma angiotensin II levels and the antihypertensive effects of ACE inhibitors has been reported. This observation is in part linked to problems with the measurement of angiotensin II. New methods of determination of plasma angiotensin II have now allowed demonstration of the complete disappearance of plasma angiotensin II following acute ACE inhibition. During chronic treatment, however, angiotensin II generation is effectively blocked only during part of the day, but blood pressure remains controlled permanently. 4. Among the different pharmacokinetic characteristics of ACE inhibitors presently available, the route of excretion and to a lesser degree the half-life appear to be the most clinically relevant. However, the importance of the ability of ACE inhibitors to inhibit tissue renin-angiotensin systems remains to be defined.

Species distribution models for conservation-oriented studies in Switzerland : filling data and tools gaps

SUMMARYSpecies distribution models (SDMs) represent nowadays an essential tool in the research fields of ecology and conservation biology. By combining observations of species occurrence or abundance with information on the environmental characteristic of the observation sites, they can provide information on the ecology of species, predict their distributions across the landscape or extrapolate them to other spatial or time frames. The advent of SDMs, supported by geographic information systems (GIS), new developments in statistical models and constantly increasing computational capacities, has revolutionized the way ecologists can comprehend species distributions in their environment. SDMs have brought the tool that allows describing species realized niches across a multivariate environmental space and predict their spatial distribution. Predictions, in the form of probabilistic maps showing the potential distribution of the species, are an irreplaceable mean to inform every single unit of a territory about its biodiversity potential. SDMs and the corresponding spatial predictions can be used to plan conservation actions for particular species, to design field surveys, to assess the risks related to the spread of invasive species, to select reserve locations and design reserve networks, and ultimately, to forecast distributional changes according to scenarios of climate and/or land use change.By assessing the effect of several factors on model performance and on the accuracy of spatial predictions, this thesis aims at improving techniques and data available for distribution modelling and at providing the best possible information to conservation managers to support their decisions and action plans for the conservation of biodiversity in Switzerland and beyond. Several monitoring programs have been put in place from the national to the global scale, and different sources of data now exist and start to be available to researchers who want to model species distribution. However, because of the lack of means, data are often not gathered at an appropriate resolution, are sampled only over limited areas, are not spatially explicit or do not provide a sound biological information. A typical example of this is data on 'habitat' (sensu biota). Even though this is essential information for an effective conservation planning, it often has to be approximated from land use, the closest available information. Moreover, data are often not sampled according to an established sampling design, which can lead to biased samples and consequently to spurious modelling results. Understanding the sources of variability linked to the different phases of the modelling process and their importance is crucial in order to evaluate the final distribution maps that are to be used for conservation purposes.The research presented in this thesis was essentially conducted within the framework of the Landspot Project, a project supported by the Swiss National Science Foundation. The main goal of the project was to assess the possible contribution of pre-modelled 'habitat' units to model the distribution of animal species, in particular butterfly species, across Switzerland. While pursuing this goal, different aspects of data quality, sampling design and modelling process were addressed and improved, and implications for conservation discussed. The main 'habitat' units considered in this thesis are grassland and forest communities of natural and anthropogenic origin as defined in the typology of habitats for Switzerland. These communities are mainly defined at the phytosociological level of the alliance. For the time being, no comprehensive map of such communities is available at the national scale and at fine resolution. As a first step, it was therefore necessary to create distribution models and maps for these communities across Switzerland and thus to gather and collect the necessary data. In order to reach this first objective, several new developments were necessary such as the definition of expert models, the classification of the Swiss territory in environmental domains, the design of an environmentally stratified sampling of the target vegetation units across Switzerland, the development of a database integrating a decision-support system assisting in the classification of the relevés, and the downscaling of the land use/cover data from 100 m to 25 m resolution.The main contributions of this thesis to the discipline of species distribution modelling (SDM) are assembled in four main scientific papers. In the first, published in Journal of Riogeography different issues related to the modelling process itself are investigated. First is assessed the effect of five different stepwise selection methods on model performance, stability and parsimony, using data of the forest inventory of State of Vaud. In the same paper are also assessed: the effect of weighting absences to ensure a prevalence of 0.5 prior to model calibration; the effect of limiting absences beyond the environmental envelope defined by presences; four different methods for incorporating spatial autocorrelation; and finally, the effect of integrating predictor interactions. Results allowed to specifically enhance the GRASP tool (Generalized Regression Analysis and Spatial Predictions) that now incorporates new selection methods and the possibility of dealing with interactions among predictors as well as spatial autocorrelation. The contribution of different sources of remotely sensed information to species distribution models was also assessed. The second paper (to be submitted) explores the combined effects of sample size and data post-stratification on the accuracy of models using data on grassland distribution across Switzerland collected within the framework of the Landspot project and supplemented with other important vegetation databases. For the stratification of the data, different spatial frameworks were compared. In particular, environmental stratification by Swiss Environmental Domains was compared to geographical stratification either by biogeographic regions or political states (cantons). The third paper (to be submitted) assesses the contribution of pre- modelled vegetation communities to the modelling of fauna. It is a two-steps approach that combines the disciplines of community ecology and spatial ecology and integrates their corresponding concepts of habitat. First are modelled vegetation communities per se and then these 'habitat' units are used in order to model animal species habitat. A case study is presented with grassland communities and butterfly species. Different ways of integrating vegetation information in the models of butterfly distribution were also evaluated. Finally, a glimpse to climate change is given in the fourth paper, recently published in Ecological Modelling. This paper proposes a conceptual framework for analysing range shifts, namely a catalogue of the possible patterns of change in the distribution of a species along elevational or other environmental gradients and an improved quantitative methodology to identify and objectively describe these patterns. The methodology was developed using data from the Swiss national common breeding bird survey and the article presents results concerning the observed shifts in the elevational distribution of breeding birds in Switzerland.The overall objective of this thesis is to improve species distribution models as potential inputs for different conservation tools (e.g. red lists, ecological networks, risk assessment of the spread of invasive species, vulnerability assessment in the context of climate change). While no conservation issues or tools are directly tested in this thesis, the importance of the proposed improvements made in species distribution modelling is discussed in the context of the selection of reserve networks.RESUMELes modèles de distribution d'espèces (SDMs) représentent aujourd'hui un outil essentiel dans les domaines de recherche de l'écologie et de la biologie de la conservation. En combinant les observations de la présence des espèces ou de leur abondance avec des informations sur les caractéristiques environnementales des sites d'observation, ces modèles peuvent fournir des informations sur l'écologie des espèces, prédire leur distribution à travers le paysage ou l'extrapoler dans l'espace et le temps. Le déploiement des SDMs, soutenu par les systèmes d'information géographique (SIG), les nouveaux développements dans les modèles statistiques, ainsi que la constante augmentation des capacités de calcul, a révolutionné la façon dont les écologistes peuvent comprendre la distribution des espèces dans leur environnement. Les SDMs ont apporté l'outil qui permet de décrire la niche réalisée des espèces dans un espace environnemental multivarié et prédire leur distribution spatiale. Les prédictions, sous forme de carte probabilistes montrant la distribution potentielle de l'espèce, sont un moyen irremplaçable d'informer chaque unité du territoire de sa biodiversité potentielle. Les SDMs et les prédictions spatiales correspondantes peuvent être utilisés pour planifier des mesures de conservation pour des espèces particulières, pour concevoir des plans d'échantillonnage, pour évaluer les risques liés à la propagation d'espèces envahissantes, pour choisir l'emplacement de réserves et les mettre en réseau, et finalement, pour prévoir les changements de répartition en fonction de scénarios de changement climatique et/ou d'utilisation du sol. En évaluant l'effet de plusieurs facteurs sur la performance des modèles et sur la précision des prédictions spatiales, cette thèse vise à améliorer les techniques et les données disponibles pour la modélisation de la distribution des espèces et à fournir la meilleure information possible aux gestionnaires pour appuyer leurs décisions et leurs plans d'action pour la conservation de la biodiversité en Suisse et au-delà. Plusieurs programmes de surveillance ont été mis en place de l'échelle nationale à l'échelle globale, et différentes sources de données sont désormais disponibles pour les chercheurs qui veulent modéliser la distribution des espèces. Toutefois, en raison du manque de moyens, les données sont souvent collectées à une résolution inappropriée, sont échantillonnées sur des zones limitées, ne sont pas spatialement explicites ou ne fournissent pas une information écologique suffisante. Un exemple typique est fourni par les données sur 'l'habitat' (sensu biota). Même s'il s'agit d'une information essentielle pour des mesures de conservation efficaces, elle est souvent approximée par l'utilisation du sol, l'information qui s'en approche le plus. En outre, les données ne sont souvent pas échantillonnées selon un plan d'échantillonnage établi, ce qui biaise les échantillons et par conséquent les résultats de la modélisation. Comprendre les sources de variabilité liées aux différentes phases du processus de modélisation s'avère crucial afin d'évaluer l'utilisation des cartes de distribution prédites à des fins de conservation.La recherche présentée dans cette thèse a été essentiellement menée dans le cadre du projet Landspot, un projet soutenu par le Fond National Suisse pour la Recherche. L'objectif principal de ce projet était d'évaluer la contribution d'unités 'd'habitat' pré-modélisées pour modéliser la répartition des espèces animales, notamment de papillons, à travers la Suisse. Tout en poursuivant cet objectif, différents aspects touchant à la qualité des données, au plan d'échantillonnage et au processus de modélisation sont abordés et améliorés, et leurs implications pour la conservation des espèces discutées. Les principaux 'habitats' considérés dans cette thèse sont des communautés de prairie et de forêt d'origine naturelle et anthropique telles que définies dans la typologie des habitats de Suisse. Ces communautés sont principalement définies au niveau phytosociologique de l'alliance. Pour l'instant aucune carte de la distribution de ces communautés n'est disponible à l'échelle nationale et à résolution fine. Dans un premier temps, il a donc été nécessaire de créer des modèles de distribution de ces communautés à travers la Suisse et par conséquent de recueillir les données nécessaires. Afin d'atteindre ce premier objectif, plusieurs nouveaux développements ont été nécessaires, tels que la définition de modèles experts, la classification du territoire suisse en domaines environnementaux, la conception d'un échantillonnage environnementalement stratifié des unités de végétation cibles dans toute la Suisse, la création d'une base de données intégrant un système d'aide à la décision pour la classification des relevés, et le « downscaling » des données de couverture du sol de 100 m à 25 m de résolution. Les principales contributions de cette thèse à la discipline de la modélisation de la distribution d'espèces (SDM) sont rassemblées dans quatre articles scientifiques. Dans le premier article, publié dans le Journal of Biogeography, différentes questions liées au processus de modélisation sont étudiées en utilisant les données de l'inventaire forestier de l'Etat de Vaud. Tout d'abord sont évalués les effets de cinq méthodes de sélection pas-à-pas sur la performance, la stabilité et la parcimonie des modèles. Dans le même article sont également évalués: l'effet de la pondération des absences afin d'assurer une prévalence de 0.5 lors de la calibration du modèle; l'effet de limiter les absences au-delà de l'enveloppe définie par les présences; quatre méthodes différentes pour l'intégration de l'autocorrélation spatiale; et enfin, l'effet de l'intégration d'interactions entre facteurs. Les résultats présentés dans cet article ont permis d'améliorer l'outil GRASP qui intègre désonnais de nouvelles méthodes de sélection et la possibilité de traiter les interactions entre variables explicatives, ainsi que l'autocorrélation spatiale. La contribution de différentes sources de données issues de la télédétection a également été évaluée. Le deuxième article (en voie de soumission) explore les effets combinés de la taille de l'échantillon et de la post-stratification sur le la précision des modèles. Les données utilisées ici sont celles concernant la répartition des prairies de Suisse recueillies dans le cadre du projet Landspot et complétées par d'autres sources. Pour la stratification des données, différents cadres spatiaux ont été comparés. En particulier, la stratification environnementale par les domaines environnementaux de Suisse a été comparée à la stratification géographique par les régions biogéographiques ou par les cantons. Le troisième article (en voie de soumission) évalue la contribution de communautés végétales pré-modélisées à la modélisation de la faune. C'est une approche en deux étapes qui combine les disciplines de l'écologie des communautés et de l'écologie spatiale en intégrant leurs concepts de 'habitat' respectifs. Les communautés végétales sont modélisées d'abord, puis ces unités de 'habitat' sont utilisées pour modéliser les espèces animales. Une étude de cas est présentée avec des communautés prairiales et des espèces de papillons. Différentes façons d'intégrer l'information sur la végétation dans les modèles de répartition des papillons sont évaluées. Enfin, un clin d'oeil aux changements climatiques dans le dernier article, publié dans Ecological Modelling. Cet article propose un cadre conceptuel pour l'analyse des changements dans la distribution des espèces qui comprend notamment un catalogue des différentes formes possibles de changement le long d'un gradient d'élévation ou autre gradient environnemental, et une méthode quantitative améliorée pour identifier et décrire ces déplacements. Cette méthodologie a été développée en utilisant des données issues du monitoring des oiseaux nicheurs répandus et l'article présente les résultats concernant les déplacements observés dans la distribution altitudinale des oiseaux nicheurs en Suisse.L'objectif général de cette thèse est d'améliorer les modèles de distribution des espèces en tant que source d'information possible pour les différents outils de conservation (par exemple, listes rouges, réseaux écologiques, évaluation des risques de propagation d'espèces envahissantes, évaluation de la vulnérabilité des espèces dans le contexte de changement climatique). Bien que ces questions de conservation ne soient pas directement testées dans cette thèse, l'importance des améliorations proposées pour la modélisation de la distribution des espèces est discutée à la fin de ce travail dans le contexte de la sélection de réseaux de réserves.

Acute antihypertensive effect of angiotensin converting enzyme inhibition and calcium entry blockade.

The acute blood pressure response to an angiotensin converting enzyme inhibitor (enalaprilat) was compared in patients with uncomplicated essential hypertension with that obtained under similar conditions with a calcium entry blocker (nifedipine). The patients were studied after a 3 week washout period. At a 48 h interval, each patient received in randomized order either enalaprilat (5 mg i.v.) or nifedipine (10 mg p.o.). Enalaprilat and nifedipine were equally effective in acutely lowering blood pressure. However, good responders to one agent were not necessarily good responders to the other.