Mathematical modeling and optimal control of malaria

Malaria continues to infect millions and kill hundreds of thousands of people worldwide each year, despite over a century of research and attempts to control and eliminate this infectious disease. Challenges such as the development and spread of drug resistant malaria parasites, insecticide resistance to mosquitoes, climate change, the presence of individuals with subpatent malaria infections which normally are asymptomatic and behavioral plasticity in the mosquito hinder the prospects of malaria control and elimination. In this thesis, mathematical models of malaria transmission and control that address the role of drug resistance, immunity, iron supplementation and anemia, immigration and visitation, and the presence of asymptomatic carriers in malaria transmission are developed. A within-host mathematical model of severe Plasmodium falciparum malaria is also developed. First, a deterministic mathematical model for transmission of antimalarial drug resistance parasites with superinfection is developed and analyzed. The possibility of increase in the risk of superinfection due to iron supplementation and fortification in malaria endemic areas is discussed. The model results calls upon stakeholders to weigh the pros and cons of iron supplementation to individuals living in malaria endemic regions. Second, a deterministic model of transmission of drug resistant malaria parasites, including the inflow of infective immigrants, is presented and analyzed. The optimal control theory is applied to this model to study the impact of various malaria and vector control strategies, such as screening of immigrants, treatment of drug-sensitive infections, treatment of drug-resistant infections, and the use of insecticide-treated bed nets and indoor spraying of mosquitoes. The results of the model emphasize the importance of using a combination of all four controls tools for effective malaria intervention. Next, a two-age-class mathematical model for malaria transmission with asymptomatic carriers is developed and analyzed. In development of this model, four possible control measures are analyzed: the use of long-lasting treated mosquito nets, indoor residual spraying, screening and treatment of symptomatic, and screening and treatment of asymptomatic individuals. The numerical results show that a disease-free equilibrium can be attained if all four control measures are used. A common pitfall for most epidemiological models is the absence of real data; model-based conclusions have to be drawn based on uncertain parameter values. In this thesis, an approach to study the robustness of optimal control solutions under such parameter uncertainty is presented. Numerical analysis of the optimal control problem in the presence of parameter uncertainty demonstrate the robustness of the optimal control approach that: when a comprehensive control strategy is used the main conclusions of the optimal control remain unchanged, even if inevitable variability remains in the control profiles. The results provide a promising framework for the design of cost-effective strategies for disease control with multiple interventions, even under considerable uncertainty of model parameters. Finally, a separate work modeling the within-host Plasmodium falciparum infection in humans is presented. The developed model allows re-infection of already-infected red blood cells. The model hypothesizes that in severe malaria due to parasite quest for survival and rapid multiplication, the Plasmodium falciparum can be absorbed in the already-infected red blood cells which accelerates the rupture rate and consequently cause anemia. Analysis of the model and parameter identifiability using Markov chain Monte Carlo methods is presented.

An experimental model of hemolysis-induced acute pancreatitis

The literature indicates that acute pancreatitis is a complication of massive hemolysis with a prevalence of about 20%. We describe an experimental model of hemolysis-induced acute pancreatitis. Hemolytic anemia was induced in rats by a single ip injection of 60 mg/kg of 20 mg/ml acetylphenylhydrazine (APH) in 20% (v/v) ethanol on the first experimental day (day 0). One hundred and fifty Wistar albino rats weighing 180-200 g were divided into three groups of 50 animals each: groups 1, 2 and 3 were injected ip with APH, 20% ethanol, and physiological saline, respectively. Ten rats from each group were sacrificed on study days 1, 2, 3, 4 and 5. Serum amylase, lipase levels and pancreatic tissue tumor necrosis factor-alpha (TNF-alpha) and platelet-activating factor (PAF) contents were determined and a histological examination of the pancreas was performed. No hemolysis or pancreatitis was observed in any of the rats in groups 2 and 3. In group 1, massive hemolysis was observed in 35 (70%) of 50 rats, moderate hemolysis in seven (14%), and no hemolysis in eight (16%). Thirty-three of 35 (94.2%) rats with massive hemolysis had hyperamylasemia, and 29 of these rats (82.8%) had histologically proven pancreatitis. The most severe pancreatitis occurred on day 3, as demonstrated by histology. Tissue TNF-alpha and PAF levels were statistically higher in group 1 than in groups 2 and 3. Acute massive hemolysis induced acute pancreatitis, as indicated by histology, in almost 80% of cases. Hemolysis may induce acute pancreatitis by triggering the release of proinflammatory and immunoregulatory cytokines.

Cytoskeletal and cellular adhesion proteins in zebrafish (Danio rerio) myogenesis

The current myogenesis and myofibrillogenesis model has been based mostly on in vitro cell culture studies, and, to a lesser extent, on in situ studies in avian and mammalian embryos. While the more isolated artificial conditions of cells in culture permitted careful structural analysis, the actual in situ cellular structures have not been described in detail because the embryos are more difficult to section and manipulate. To overcome these difficulties, we used the optically clear and easy to handle embryos of the zebrafish Danio rerio. We monitored the expression of cytoskeletal and cell-adhesion proteins (actin, myosin, desmin, alpha-actinin, troponin, titin, vimentin and vinculin) using immunofluorescence microscopy and video-enhanced, background-subtracted, differential interference contrast of 24- to 48-h zebrafish embryos. In the mature myotome, the mononucleated myoblasts displayed periodic striations for all sarcomeric proteins tested. The changes in desmin distribution from aggregates to perinuclear and striated forms, although following the same sequence, occurred much faster than in other models. All desmin-positive cells were also positive for myofibrillar proteins and striated, in contrast to that which occurs in cell cultures. Vimentin appeared to be striated in mature cells, while it is developmentally down-regulated in vitro. The whole connective tissue septum between the somites was positive for adhesion proteins such as vinculin, instead of the isolated adhesion plaques observed in cell cultures. The differences in the myogenesis of zebrafish in situ and in cell culture in vitro suggest that some of the previously observed structures and protein distributions in cultures could be methodological artifacts.

Stretch-induced nerve injury: a proposed technique for the study of nerve regeneration and evaluation of the influence of gabapentin on this model

The rat models currently employed for studies of nerve regeneration present distinct disadvantages. We propose a new technique of stretch-induced nerve injury, used here to evaluate the influence of gabapentin (GBP) on nerve regeneration. Male Wistar rats (300 g; n=36) underwent surgery and exposure of the median nerve in the right forelimbs, either with or without nerve injury. The technique was performed using distal and proximal clamps separated by a distance of 2 cm and a sliding distance of 3 mm. The nerve was compressed and stretched for 5 s until the bands of Fontana disappeared. The animals were evaluated in relation to functional, biochemical and histological parameters. Stretching of the median nerve led to complete loss of motor function up to 12 days after the lesion (P<0.001), compared to non-injured nerves, as assessed in the grasping test. Grasping force in the nerve-injured animals did not return to control values up to 30 days after surgery (P<0.05). Nerve injury also caused an increase in the time of sensory recovery, as well as in the electrical and mechanical stimulation tests. Treatment of the animals with GBP promoted an improvement in the morphometric analysis of median nerve cross-sections compared with the operated vehicle group, as observed in the area of myelinated fibers or connective tissue (P<0.001), in the density of myelinated fibers/mm2 (P<0.05) and in the degeneration fragments (P<0.01). Stretch-induced nerve injury seems to be a simple and relevant model for evaluating nerve regeneration.

Alpha-tocopherol and gamma-tocopherol concentration in vegetable oils

Vegetable oils are the richest dietary sources of vitamin E. Vitamin E determination levels in foods are of great importance to adjust the ingestion of nutrients by the population. The purpose of this paper is to determine the concentration of alpha-tocopherol and gamma-tocopherol in vegetable oils and compare the alpha-tocopherol value to the nutritional requirement of vitamin E. The analysis was performed using High Performance Liquid Chromatography. The values expressed as mg/kg for alpha and gamma-tocopherol were, respectively, 120.3±4.2 and 122.0±7.9 in canola oil; 432.3±86.6 and 92.3±9.5 in sunflower oil; 173.0±82.3 and 259.7±43.8 in corn oil; 71.3±6.4 and 273.3±11.1 in soybean oil. A significant difference was encountered between the alpha-tocopherol concentrations in vegetable oils. Similar results were found for gamma-tocopherol, except for corn and soybean oils. It was concluded that the soybean oil was not considered a source of vitamin E. The canola and corn oils were considered sources, and the sunflower oil was considered an excellent source.

The effect of 17-B estradiol therapy on bone mineral density and structure of alveolar bone in the ovariectomized rat model of postmenopausal osteoporosis

The ovariectomized (OVX) rat, a preclinical model for studying postmenopausal bone loss, may also be used to study differences in alveolar bone (AB). The objectives of this study were to quantify the differences in AB following estrogen replacement therapy (ERT), and to investigate the relationship between AB structure and density, and trabecular bone at the femoral neck (FN) and third lumbar vertebral body (LB3). Estrogen treated rats had a higher bone volume fraction (BV/TV) at the AB region (9.8% P < 0.0001), FN (12% P < 0.0001), and LB3 (11.5% P < 0.0001) compared to the OVX group. BV/TV of the AB was positively correlated with the BV/TV at the FN (r = 0.69 P < 0.0001) and the LB3 (r = 0.75 P < 0.0001). The trabecular number (Tb.N), trabecular separation (Tb.Sp), and structure model index (SMI) were also positively correlated (P < 0.05) between the AB and FN (r = 0.42, 0.49, and 0.73, respectfully) and between the AB and LB3 (r = 0.44, 0.63, and 0.69, respectfully). Given the capacity of AB to respond to ERT, future preclinical drug/nutritional intervention studies aimed at improving skeletal health should include the AB as a region of interest (ROI).

Genetic and Electrophysiological Correlates of Self-Regulation in Adolescence

Self-regulation is considered a powerful predictor of behavioral and mental health outcomes during adolescence and emerging adulthood. In this dissertation I address some electrophysiological and genetic correlates of this important skill set in a series of four studies. Across all studies event-related potentials (ERPs) were recorded as participants responded to tones presented in attended and unattended channels in an auditory selective attention task. In Study 1, examining these ERPs in relation to parental reports on the Behavior Rating Inventory of Executive Function (BRIEF) revealed that an early frontal positivity (EFP) elicited by to-be-ignored/unattended tones was larger in those with poorer self-regulation. As is traditionally found, N1 amplitudes were more negative for the to-be-attended rather than unattended tones. Additionally, N1 latencies to unattended tones correlated with parent-ratings on the BRIEF, where shorter latencies predicted better self-regulation. In Study 2 I tested a model of the associations between selfregulation scores and allelic variations in monoamine neurotransmitter genes, and their concurrent links to ERP markers of attentional control. Allelic variations in dopaminerelated genes predicted both my ERP markers and self-regulatory variables, and played a moderating role in the association between the two. In Study 3 I examined whether training in Integra Mindfulness Martial Arts, an intervention program which trains elements of self-regulation, would lead to improvement in ERP markers of attentional control and parent-report BRIEF scores in a group of adolescents with self-regulatory difficulties. I found that those in the treatment group amplified their processing of attended relative to unattended stimuli over time, and reduced their levels of problematic behaviour whereas those in the waitlist control group showed little to no change on both of these metrics. In Study 4 I examined potential associations between self-regulation and attentional control in a group of emerging adults. Both event-related spectral perturbations (ERSPs) and intertrial coherence (ITC) in the alpha and theta range predicted individual differences in self-regulation. Across the four studies I was able to conclude that real-world self-regulation is indeed associated with the neural markers of attentional control. Targeted interventions focusing on attentional control may improve self-regulation in those experiencing difficulties in this regard.

The role of transcription factor Pitx1 and its regulation by hypoxia in Adolescent Idiopathic Scoliosis

La scoliose idiopathique de l’adolescent (SIA) est définie comme une courbure de la colonne vertébrale supérieure à 10 degrés, qui est de cause inconnue et qui affecte de façon prépondérante les adolescents. Des études précédentes sur des modèles murins ont démontré une inactivation partielle du gène Pitx1. Cette inactivation partielle provoque une déformation spinale sévère lors du développement des souris Pitx1+/-, ce qui est grandement similaire au phénotype de la SIA. En se basant sur ces observations, nous postulons que la perte de fonction de Pitx1 pourrait avoir un rôle dans la SIA et pourrait être régulée par des mécanismes moléculaires spécifiques. En effet, des études faites sur l’expression de Pitx1 révèlent une perte de son expression dans les ostéoblastes dérivés de patients SIA au niveau de l’ARNm. Nous émettons l’hypothèse que la perte de Pitx1 dans la SIA pourrait être déclenchée par des facteurs hypoxiques puisqu’il est connu que Pitx1 est réprimé par l’hypoxie et que HIF-2 alpha est surexprimés dans les ostéoblastes des patients SIA même dans des conditions normoxiques. De plus, nous avons découvert une mutation dans le domaine ODD des HIF-1 alpha chez certains patients SIA (3,1%). Une fonction connue de ce domaine est de stabiliser et d’augmenter l’activité transcriptionnelle de HIF-1 alpha dans des conditions normoxiques. Nous avons confirmé, par la technique EMSA, l’existence d’un élément de réponse fonctionnel à l’hypoxie au niveau du promoteur de Pitx1. Cependant, des co-transfections avec des vecteurs d’expression pour HIF-1 alpha et HIF-2 alpha, en présence de leur sous-unité beta ARNT, ont conduit à une activation du promoteur de Pitx1 dans la lignée cellulaire MG-63 ainsi que dans les ostéoblastes des sujets contrôles. Il est intéressant de constater qu’aucune activité du promoteur de Pitx1 dans les ostéoblastes SIA n’a été observée, même après la co-expression de HIF-2 alpha et ARNT, confirmant le fait que l’expression de Pitx1 est abrogée dans la SIA. Dans l’ensemble, nos résultats démontrent un rôle important de Pitx1 dans la SIA et une possible régulation par des facteurs hypoxiques.

Essays on oil price fluctuations and macroeconomic activity

Dans cette thèse, je me suis intéressé aux effets des fluctuations du prix de pétrole sur l'activité macroéconomique selon la cause sous-jacente ces fluctuations. Les modèles économiques utilisés dans cette thèse sont principalement les modèles d'équilibre général dynamique stochastique (de l'anglais Dynamic Stochastic General Equilibrium, DSGE) et les modèles Vecteurs Autorégressifs, VAR. Plusieurs études ont examiné les effets des fluctuations du prix de pétrole sur les principaux variables macroéconomiques, mais très peu d'entre elles ont fait spécifiquement le lien entre les effets des fluctuations du prix du pétrole et la l'origine de ces fluctuations. Pourtant, il est largement admis dans les études plus récentes que les augmentations du prix du pétrole peuvent avoir des effets très différents en fonction de la cause sous-jacente de cette augmentation. Ma thèse, structurée en trois chapitres, porte une attention particulière aux sources de fluctuations du prix de pétrole et leurs impacts sur l'activité macroéconomique en général, et en particulier sur l'économie du Canada. Le premier chapitre examine comment les chocs d'offre de pétrole, de demande agrégée, et de demande de précaution de pétrole affectent l'économie du Canada, dans un Modèle d'équilibre Général Dynamique Stochastique estimé. L'estimation est réalisée par la méthode Bayésienne, en utilisant des données trimestrielles canadiennes sur la période 1983Q1 à 2010Q4. Les résultats montrent que les effets dynamiques des fluctuations du prix du pétrole sur les principaux agrégats macro-économiques canadiens varient en fonction de leurs sources. En particulier, une augmentation de 10% du prix réel du pétrole causée par des chocs positifs sur la demande globale étrangère a un effet positif significatif de l'ordre de 0,4% sur le PIB réel du Canada au moment de l'impact et l'effet reste positif sur tous les horizons. En revanche, une augmentation du prix réel du pétrole causée par des chocs négatifs sur l'offre de pétrole ou par des chocs positifs de la demande de pétrole de précaution a un effet négligeable sur le PIB réel du Canada au moment de l'impact, mais provoque une baisse légèrement significative après l'impact. En outre, parmi les chocs pétroliers identifiés, les chocs sur la demande globale étrangère ont été relativement plus important pour expliquer la fluctuation des principaux agrégats macroéconomiques du Canada au cours de la période d'estimation. Le deuxième chapitre utilise un modèle Structurel VAR en Panel pour examiner les liens entre les chocs de demande et d'offre de pétrole et les ajustements de la demande de travail et des salaires dans les industries manufacturières au Canada. Le modèle est estimé sur des données annuelles désagrégées au niveau industriel sur la période de 1975 à 2008. Les principaux résultats suggèrent qu'un choc positif de demande globale a un effet positif sur la demande de travail et les salaires, à court terme et à long terme. Un choc négatif sur l'offre de pétrole a un effet négatif relativement faible au moment de l'impact, mais l'effet devient positif après la première année. En revanche, un choc positif sur la demande précaution de pétrole a un impact négatif à tous les horizons. Les estimations industrie-par-industrie confirment les précédents résultats en panel. En outre, le papier examine comment les effets des différents chocs pétroliers sur la demande travail et les salaires varient en fonction du degré d'exposition commerciale et de l'intensité en énergie dans la production. Il ressort que les industries fortement exposées au commerce international et les industries fortement intensives en énergie sont plus vulnérables aux fluctuations du prix du pétrole causées par des chocs d'offre de pétrole ou des chocs de demande globale. Le dernier chapitre examine les implications en terme de bien-être social de l'introduction des inventaires en pétrole sur le marché mondial à l'aide d'un modèle DSGE de trois pays dont deux pays importateurs de pétrole et un pays exportateur de pétrole. Les gains de bien-être sont mesurés par la variation compensatoire de la consommation sous deux règles de politique monétaire. Les principaux résultats montrent que l'introduction des inventaires en pétrole a des effets négatifs sur le bien-être des consommateurs dans chacun des deux pays importateurs de pétrole, alors qu'il a des effets positifs sur le bien-être des consommateurs dans le pays exportateur de pétrole, quelle que soit la règle de politique monétaire. Par ailleurs, l'inclusion de la dépréciation du taux de change dans les règles de politique monétaire permet de réduire les coûts sociaux pour les pays importateurs de pétrole. Enfin, l'ampleur des effets de bien-être dépend du niveau d'inventaire en pétrole à l'état stationnaire et est principalement expliquée par les chocs sur les inventaires en pétrole.

Labor's shares - aggregate and industry: accounting for both in a model of unbalanced growth with induced innovation

The relative stability of aggregate labor's share constitutes one of the great macroeconomic ratios. However, relative stability at the aggregate level masks the unbalanced nature of industry labor's shares – the Kuznets stylized facts underlie those of Kaldor. We present a two-sector – one labor-only and the other using both capital and labor – model of unbalanced economic development with induced innovation that can rationalize these phenomena as well as several other empirical regularities of actual economies. Specifically, the model features (i) one sector ("goods" production) becoming increasingly capital-intensive over time; (ii) an increasing relative price and share in total output of the labor-only sector ("services"); and (iii) diverging sectoral labor's shares despite (iii) an aggregate labor's share that converges from above to a value between 0 and unity. Furthermore, the model (iv) supports either a neoclassical steadystate or long-run endogenous growth, giving it the potential to account for a wide range of real world development experiences.

Semantic-level Visual Content Descriptor combining visual and textual cues as collaterals

In this paper, we introduce a novel high-level visual content descriptor which is devised for performing semantic-based image classification and retrieval. The work can be treated as an attempt to bridge the so called “semantic gap”. The proposed image feature vector model is fundamentally underpinned by the image labelling framework, called Collaterally Confirmed Labelling (CCL), which incorporates the collateral knowledge extracted from the collateral texts of the images with the state-of-the-art low-level image processing and visual feature extraction techniques for automatically assigning linguistic keywords to image regions. Two different high-level image feature vector models are developed based on the CCL labelling of results for the purposes of image data clustering and retrieval respectively. A subset of the Corel image collection has been used for evaluating our proposed method. The experimental results to-date already indicates that our proposed semantic-based visual content descriptors outperform both traditional visual and textual image feature models.

A simple model for predicting soil temperature in snow-covered and seasonally frozen soil: model description and testing

Microbial processes in soil are moisture, nutrient and temperature dependent and, consequently, accurate calculation of soil temperature is important for modelling nitrogen processes. Microbial activity in soil occurs even at sub-zero temperatures so that, in northern latitudes, a method to calculate soil temperature under snow cover and in frozen soils is required. This paper describes a new and simple model to calculate daily values for soil temperature at various depths in both frozen and unfrozen soils. The model requires four parameters average soil thermal conductivity, specific beat capacity of soil, specific heat capacity due to freezing and thawing and an empirical snow parameter. Precipitation, air temperature and snow depth (measured or calculated) are needed as input variables. The proposed model was applied to five sites in different parts of Finland representing different climates and soil types. Observed soil temperatures at depths of 20 and 50 cm (September 1981-August 1990) were used for model calibration. The calibrated model was then tested using observed soil temperatures from September 1990 to August 2001. R-2-values of the calibration period varied between 0.87 and 0.96 at a depth of 20 cm and between 0.78 and 0.97 at 50 cm. R-2 -values of the testing period were between 0.87 and 0.94 at a depth of 20cm. and between 0.80 and 0.98 at 50cm. Thus, despite the simplifications made, the model was able to simulate soil temperature at these study sites. This simple model simulates soil temperature well in the uppermost soil layers where most of the nitrogen processes occur. The small number of parameters required means, that the model is suitable for addition to catchment scale models.

Impacts of forestry on nitrogen in upland and lowland catchments: a comparison of the River Severn at Plynlimon in mid-Wales and the Bedford Ouse in south-east England using the INCA Model

The impacts of afforestation at Plynlimon in the Severn catchment, mid-Wales. and in the Bedford Ouse catchment in south-east England are evaluated using the INCA model to simulate Nitrogen (N) fluxes and concentrations. The INCA model represents the key hydrological and N processes operating in catchments and simulates the daily dynamic behaviour as well as the annual fluxes. INCA has been applied to five years of data front the Hafren and Hore headwater sub-catchments (6.8 km(2) area in total) of the River Severn at Plytilimon and the model was calibrated and validated against field data. Simulation of afforestation is achieved by altering the uptake rate parameters in the model. INCA simulates the daily N behaviour in the catchments with good accuracy as well as reconstructing the annual budgets for N release following clearfelling a four-fold increase in N fluxes was followed by a slow recovery after re-afforestation. For comparison, INCA has been applied to the large (8380 km(2)) Bedford Ouse catchment to investigate the impact of replacing 20% arable land with forestry. The reduction in fertiliser inputs from arable farming and the N uptake by the forest are predicted to reduce the N flux reaching the main river system, leading to a 33% reduction in N-Nitrate concentrations in the river water.

The physical properties of the atmosphere in the new Hadley Centre Global Environmental Model (HadGEM1). Part II: Aspects of variability and regional climate

The performance of the atmospheric component of the new Hadley Centre Global Environmental Model (HadGEM1) is assessed in terms of its ability to represent a selection of key aspects of variability in the Tropics and extratropics. These include midlatitude storm tracks and blocking activity, synoptic variability over Europe, and the North Atlantic Oscillation together with tropical convection, the Madden-Julian oscillation, and the Asian summer monsoon. Comparisons with the previous model, the Third Hadley Centre Coupled Ocean-Atmosphere GCM (HadCM3), demonstrate that there has been a considerable increase in the transient eddy kinetic energy (EKE), bringing HadGEM1 into closer agreement with current reanalyses. This increase in EKE results from the increased horizontal resolution and, in combination with the improved physical parameterizations, leads to improvements in the representation of Northern Hemisphere storm tracks and blocking. The simulation of synoptic weather regimes over Europe is also greatly improved compared to HadCM3, again due to both increased resolution and other model developments. The variability of convection in the equatorial region is generally stronger and closer to observations than in HadCM3. There is, however, still limited convective variance coincident with several of the observed equatorial wave modes. Simulation of the Madden-Julian oscillation is improved in HadGEM1: both the activity and interannual variability are increased and the eastward propagation, although slower than observed, is much better simulated. While some aspects of the climatology of the Asian summer monsoon are improved in HadGEM1, the upper-level winds are too weak and the simulation of precipitation deteriorates. The dominant modes of monsoon interannual variability are similar in the two models, although in HadCM3 this is linked to SST forcing, while in HadGEM1 internal variability dominates. Overall, analysis of the phenomena considered here indicates that HadGEM1 performs well and, in many important respects, improves upon HadCM3. Together with the improved representation of the mean climate, this improvement in the simulation of atmospheric variability suggests that HadGEM1 provides a sound basis for future studies of climate and climate change.

North Atlantic Oscillation response to transient greenhouse gas forcing and the impact on European winter climate: a CMIP2 multi-model assessment

This study investigates the response of wintertime North Atlantic Oscillation (NAO) to increasing concentrations of atmospheric carbon dioxide (CO2) as simulated by 18 global coupled general circulation models that participated in phase 2 of the Coupled Model Intercomparison Project (CMIP2). NAO has been assessed in control and transient 80-year simulations produced by each model under constant forcing, and 1% per year increasing concentrations of CO2, respectively. Although generally able to simulate the main features of NAO, the majority of models overestimate the observed mean wintertime NAO index of 8 hPa by 5-10 hPa. Furthermore, none of the models, in either the control or perturbed simulations, are able to reproduce decadal trends as strong as that seen in the observed NAO index from 1970-1995. Of the 15 models able to simulate the NAO pressure dipole, 13 predict a positive increase in NAO with increasing CO2 concentrations. The magnitude of the response is generally small and highly model-dependent, which leads to large uncertainty in multi-model estimates such as the median estimate of 0.0061 +/- 0.0036 hPa per %CO2. Although an increase of 0.61 hPa in NAO for a doubling in CO2 represents only a relatively small shift of 0.18 standard deviations in the probability distribution of winter mean NAO, this can cause large relative increases in the probabilities of extreme values of NAO associated with damaging impacts. Despite the large differences in NAO responses, the models robustly predict similar statistically significant changes in winter mean temperature (warmer over most of Europe) and precipitation (an increase over Northern Europe). Although these changes present a pattern similar to that expected due to an increase in the NAO index, linear regression is used to show that the response is much greater than can be attributed to small increases in NAO. NAO trends are not the key contributor to model-predicted climate change in wintertime mean temperature and precipitation over Europe and the Mediterranean region. However, the models' inability to capture the observed decadal variability in NAO might also signify a major deficiency in their ability to simulate the NAO-related responses to climate change.