Malfunction of the system which regulates the bloodflow in the brain is a major cause of stroke and dementia, costing many lives and many billions of pounds each year in the UK alone. This regulatory system, known as cerebral autoregulation, has been the subject of much experimental and mathematical investigation yet our understanding of it is still quite limited. One area in which our understanding is particularly lacking is that of the role of nitric oxide, understood to be a potent vasodilator. The interactions of nitric oxide with the better understood myogenic response remain un-modelled and poorly understood. In this thesis we present a novel model of the arteriolar control mechanism, comprising a mixture of well-established and new models of individual processes, brought together for the first time. We show that this model is capable of reproducing experimentally observed behaviour very closely and go on to investigate its stability in the context of the vasculature of the whole brain. In conclusion we find that nitric oxide, although it plays a central role in determining equilibrium vessel radius, is unimportant to the dynamics of the system and its responses to variation in arterial blood pressure. We also find that the stability of the system is very sensitive to the dynamics of Ca²⁺ within the muscle cell, and that self-sustaining Ca2+ waves are not necessary to cause whole-vessel radius oscillations consistent with vasomotion.

Newly created software is presented in magister degree thesis. The software was created for the innovative non–invasive cerebral blood flow autoregulation monitor which has no analogy in the global high tech market. It will be possible at first time to get diagnostic information about the cerebral blood flow autoregulation status of patient with severe brain injuries using such non–invasive monitoring technology in clinical practice. That will help with the individual treatment decision making. Clinical studies were conducted in neurosurgical intensive care units using created software. It has been shown that non–invasive and invasive cerebrovascular blood flow autoregulation monitoring technologies provide the same diagnostic information about the patient status. That conclusion is statistically significant and evidence based. Some R & D projects were performed using non–invasive cerebrovascular blood flow autoregulation monitor with implemented new software. The results of such projects were used in order to formulate the metrological – technological requirements for the final design and development of the innovative non–invasive blood flow autoregulation monitor. Such device is under creation in Telematics Scientific Laboratory which works together with Vittamed Technologijos Ltd and conducts 6.015 million Lt project (BPD04-ERPF-3.1.7-03-05/0020).

Outcome after traumatic brain injury (TBI) depends on the extent of primary cell death and on the development of secondary brain injury. The general aim of this thesis was to find strategies and quality systems to minimize the extent of secondary insults in neurointensive care (NIC). An established standardized management protocol system, multimodality monitoring and computerized data collection, and analysis systems were used. The Uppsala TBI register was established for regular monitoring of NIC quality indexes. For 2008-2010 the proportion of patients improving during NIC was 60-80%, whereas 10% deteriorated. The percentage of ‘talk and die’ cases was < 1%. The occurrences of secondary insults were less than 5% of good monitoring time (GMT) for intracranial pressure (ICP) > 25 mmHg, cerebral perfusion pressure (CPP) < 50 mmHg and systolic blood pressure < 100 mmHg. Favorable outcome was achieved by 64% of adults. Nurse checklists of secondary insult occurrence were introduced. Evaluation of the use of nursing checklists showed that the nurses documented their assessments in 84-85% of the shifts and duration of monitoring time at insult level was significantly longer when secondary insults were reported regarding ICP, CPP and temperature. The use of nurse checklist was found to be feasible and accurate.  A clinical tool to avoid secondary insults related to nursing interventions was developed. Secondary brain insults occurred in about 10% of nursing interventions. There were substantial variations between patients. The risk ratios of developing an ICP insult were 4.7 when baseline ICP ≥ 15 mmHg, 2.9 when ICP amplitude ≥ 6 mmHg and 1.7 when pressure autoregulation ≥ 0.3. Hyperthermia, which is a known frequent secondary insult, was studied. Hyperthermia was most common on Day 7 after admission and 90% of the TBI patients had hyperthermia during the first 10 days at the NIC unit. The effects of hyperthermia on intracranial dynamics (ICP, brain energy metabolism and BtipO2) were small but individual differences were observed. Hyperthermia increased ICP slightly more when temperature increased in the groups with low compliance and impaired pressure autoregulation. Ischemic pattern was never observed in the microdialysis samples. The treatment of hyperthermia may be individualized and guided by multimodality monitoring.

Ischaemic stroke is a major cause of death and disability worldwide. Cerebral autoregulation, which can be impaired during acute stroke, and collateral flow to brain tissue through the circle of Willis, both play a role in preventing tissue infarction. The configuration of the arterial circle varies between individuals. Thus, personalised modelling of the cerebral arterial network, to determine the potential for collateral flow, can be of significant value in the clinical context of stroke. The interaction between autoregulation and collateral flow remains poorly understood. In this study, steady-state physiological models of the cerebral arterial network, including several common variants of the circle of Willis, were coupled to a spatially variable mathematical representation of cerebral autoregulation. The resulting model was used to simulate various arterial occlusions, as well as bilateral and unilateral impairment of autoregulation, in each structural variant. The work identified few circle of Willis variants that present either particularly high-risk or particularly low-risk of cerebral ischaemia. Instead it was found that most variants are dependent upon the bilateral function of autoregulation to facilitate collateral flow and preserve cerebral blood flows. When autoregulation was impaired unilaterally, downstream of an occlusion, blood flows in the contralateral hemisphere were preserved at the expense of the ipsilateral tissue at risk. Arterial network models have in the past been personalised using structural, rather than functional, angiography measurements. This thesis presents a novel model-based method for absolute blood volume flow rate quantification in short arterial segments using dynamic magnetic resonance angiography data. The work also investigated the additional information that can be obtained from such functional angiography. The flow quantification technique was found to accurately estimate flows in shorter arterial segments than an existing technique. However, improvements to noise performance, and strategies for rejection of contaminating signals from overlapping vessels within the imaging plane, are required before the technique can be applied to personalised cerebral arterial network modelling.

Summary<p>Brain dysfunction is a frequent complication of sepsis and is usually defined as “sepsis-associated encephalopathy” (SAE). Its pathophysiology is complex and related to a number of processes and pathways, while the exact mechanisms producing neurological impairment in septic patients have not been completely elucidated. Alterations in cerebral blood flow (CBF) have been suggested as a key component for the development of SAE. Reduction of CBF may be caused by cerebral vasoconstriction, induced either by inflammation or hypocapnia. More importantly, the natural mechanisms that protect the brain from reduced/inadequate CBF can be impaired in septic patients, especially in those with shock, and this further contributes to cerebral ischemia if blood pressure drops below a critical threshold. Hypercapnia is associated with a narrower autoregulatory plateau, which may potentially results in large CBF variations when mean arterial pressure (MAP) varies within usual targets. However, few data are available on the role of PaCO2 on cerebral autoregulation (CA). Finally, as SAE occurs also in patients without hemodynamic instability, alterations in brain tissue perfusion could occur independently from hypotension; thus, alterations in cerebral microcirculation, which largely regulates regional flow and blood-cellular nutrients exchanges, could contribute to SAE. In septic animals, these microcirculatory abnormalities could be implicated in the development of electrophysiological abnormalities observed during sepsis and contribute to neurological alterations. However, these findings were limited by several factors, including the technique used to assess the microcirculation, the short time of observation and the limited amount of fluid resuscitation used in those models. <p>In the first part of this work, I evaluated CA and the potential influence of PaCO2 on CA in patients with septic shock. In 21 mechanically ventilated patients, I observed that 14 of them had impaired CA. All the 7 patients with a PaCO2 ≥ 40 mmHg but only 7 of the 14 patients with a PaCO2 <40 mmHg had an impaired CA (p=0.046). Specifically, 4/9 (44%) patients with PaCO2 < 35 mmHg, 7/9 (77%) with PaCO2 between 35 and 42 mmHg, and 3/3 (100%) with PaCO2 > 42 mmHg had impaired CA. The Receiver Operating Characteristic (ROC) analysis showed that a PaCO2 threshold of 38 mmHg had a sensitivity of 50% and a specificity of 100% for the prediction of impaired CA, with an area under the ROC curve of 0.76 (95% confidence interval: 0.52–0.91).<p>In the second part of this work, I hypothesized that altered cerebral microcirculation may occur in the early phase of sepsis and contribute to brain hypoxia. In a clinically relevant model of ovine fecal peritonitis, I showed that there was a progressive deterioration of cerebral microvascular flow in septic animals (n=10) when compared to sham animals (n=5), starting already after 6 hours from sepsis induction and becoming significant at 12 hours thereafter. Moreover, changes in the cerebral microcirculation were not related to changes in MAP, cardiac output or blood lactate levels, suggesting that these alterations in the brain may occur even when global perfusion pressure is maintained, i.e. in non-hypotensive conditions. In a second study, including 10 septic and 5 sham animals, I found that cortical microvascular alterations were associated with decreased cerebral oxygenation. Furthermore, cerebral metabolic disturbances compatible with tissue hypoxia (i.e. increased brain lactate/pyruvate ratio, LPR) occurred mostly during shock, suggesting that hypotension is a critical factor in the development of anaerobic metabolism in the septic brain. Nevertheless, I showed in a third study (n=8) that the reversal of hypotension using vasopressor agents, although increased cerebral oxygenation and slightly reduced LPR, did not significantly influence the alterations of cerebral microcirculation and was associated with an increase in glutamate and glycerol, suggesting ongoing excitotoxicity and cellular damage. These alterations in cerebral microcirculation, oxygenation and metabolism may then contribute to the pathogenesis of SAE.<p><p><p><p><p>Résumé<p>La dysfonction cérébrale est une complication fréquente du sepsis et elle est généralement identifiée comme « encéphalopathie associée au sepsis » (sepsis-associated encephalopathy, SAE). La physiopathologie de la SAE est complexe et liée à des nombreux processus et voies de signalisation, même si les mécanismes qui induisent cette dysfonction cérébrale chez les patients en sepsis n’ont pas été clairement élucidés. Des anomalies du débit sanguin cérébral (cerebral blood flow, CBF) ont été proposées comme une des déterminants pour le développement de l’SAE. La réduction du CBF pourrait être induite par une vasoconstriction cérébrale, élicitée pas l’inflammation ou par l’hypocapnie. De plus, les mécanismes qui naturellement règlent le CBF pour qu’il soit ni diminué ni inadéquat aux besoins cellulaires peuvent être altérés pendant le sepsis, particulièrement en cas de choc septique, et ceci pourrait davantage contribuer au développement de zones d’hypoperfusion cérébrale si la pression artérielle diminue au-dessous d’un seuil critique. Un autre point important est que l’hypercapnie est associée à une diminution du plateau d’autorégulation du CBF, ce qui pourrait potentiellement causer des larges variations du CBF endéans des valeurs de pression artérielle considérés comme normaux en pratique clinique; malheureusement, très peu de données sont disponibles sur le rôle de la PaCO2 sur l’autorégulation cérébrale (cerebral autoregulation, CA). Enfin, vu que l’SAE survient aussi chez des patients qui n’ont pas d’instabilité hémodynamique, des anomalies de la perfusion cérébrale régionale pourraient se produire en absence de toute hypotension artérielle ;en effet, des altérations de la microcirculation cérébrale, qui règle le débit sanguin au niveau des tissues et l’échange d’oxygène et nutriments entre la circulation sanguine et le cellules, peuvent aussi contribuer au développement de la SAE. Dans des modelés expérimentaux de sepsis, les altérations microcirculatoires ont été associées à des troubles électrophysiologies et à la présence d’anomalies « cliniques ». Cependant, ces données ont été biaisées par le type de technique utilisée pour évaluer la microcirculation, le temps d’observation très court et la quantité limitée de fluides administrés au cours de la réanimation liquidienne dans ces modelés. <p>Dans la première partie de ce travail, j’ai décrit les anomalies de la CA et l’impact de la PaCO2 sur la CA chez des patients en choc septique. En étudiant 21 patients en ventilation mécanique, j’ai pu observer que 14 d’entre eux avaient une CA altérée, y compris 7/14 avec une PaCO2 < 40 mmHg et 7/7 avec une PaCO2 ≥ 40 mmHg (p = 0.046). De plus, 4/9 (44%) avec PaCO2 < 35 mmHg, 7/9 (77%) avec PaCO2 between 35 and 42 mmHg, and 3/3 (100%) avec PaCO2 > 42 mmHg avaient une CA altérée. L’analyse selon la « Receiver Operating Characteristic » (ROC) montrait une sensibilité de 50% et une spécificité de 100% pour prédire une CA altérée, avec un seuil de PaCO2 de 38 mmHg (l’aire sous la courbe de l’analyse ROC était à 0.76 [95% ICs: 0.52–0.91]).<p>Dans la deuxième partie de ce travail, j’ai émis l’hypothèse que des anomalies de la microcirculation cérébrale peuvent survenir dans la phase précoce du sepsis et contribuer au développement d’une hypoxie tissulaire. Dans un modelé de péritonite fécale induite chez le mouton, très proche de la situation clinique, j’ai pu montrer que il existe une détérioration progressive de la microcirculation cérébrale chez les animaux septiques (n-=10) quand comparés aux animaux témoins (n=5) qui commence déjà a la sixième heure de l’induction du sepsis and devient significative après 12 heures. De plus, les changement de la microcirculation cérébrale n’étaient pas corrélés à ceux de la pression artérielle, du débit cardiaque ou des taux de lactate, ce qui suggère que ces anomalies peuvent se produire aussi en conditions de stabilité hémodynamique. Dans une deuxième étude comprenant 10 animaux septique et 5 témoins, j’ai observé que les anomalies microcirculatoires étaient associées à une diminution de l’oxygénation cérébrale tissulaire. Toutefois, les anomalies du métabolisme cérébral compatible avec une hypoxie tissulaire (des valeurs élevées du rapport lactate/pyruvate, LPR) se développaient que dans la phase du choc septique, indiquant que l’hypotension artérielle est le facteur déterminant pour ces anomalies métaboliques au cours du sepsis. Cependant, dans une troisième étude sur 8 animaux en sepsis, j’ai démontré que la correction de l’hypotension par administration de vasopresseurs, même si elle était associée à une augmentation de l’oxygénation cérébral et une diminution du LPR, n’améliorait pas de façon significative la microcirculation cérébrale et s’accompagnait par une augmentation des taux de glutamate et glycérol, ce qui plaidait plutôt pour un excitoxicité persistante et une progression des lésions cellulaires. Toutes ces anomalies de microcirculation, oxygénation et métabolisme cérébral pourraient contribuer à la pathogenèse de l’SAE.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Les flux nés de la libéralisation du secteur des médias ont suscité des interrogations quant à la maîtrise du traitement de l’information par des hommes dont la grande majorité n’avait aucune connaissance en matière de journalisme. De même, les impératifs de service public et une répartition équitable des ondes devenaient une préoccupation des politiques publiques en matière de communication. C’est dans ce contexte, qu’un nouveau paradigme, celui de la régulation, apparaît dans la reformulation des politiques des médias. Appliquée au secteur des médias, la régulation devait non seulement protéger et garantir le bon fonctionnement du système mais aussi en assurer en cas de besoin une répartition équitable de son domaine d’action. Les instances de régulation en Afrique sont confrontées à de nouveaux défis auxquels elles sont désarmées. Il s’agit de l’évolution exponentielle de la technologie de l’information et de la communication (Tics). Elle se traduit en termes de la gestion des flots d’information véhiculés par les médias ligne et la problématique de la transition vers la télévision numérique terrestre. Pour les Sciences de l’information et de la communication, il s’avère important de comprendre la pertinence de la régulation des médias, d’en analyser les moyens et le champ. Notre question principale pourrait donc être formulée comme suit : Dans quelle mesure la régulation des médias peut-elle être un moyen de consolidation de la démocratie ? Cette question nous semble pertinente quand on voit les conflits d’intérêts entre les acteurs du débat public qu’ils soient du pouvoir politique, qu’ils soient inscrits dans des mouvements politiques ou dans la société civile. L’hypothèse qui se dégage est que la régulation médiatique peut être un outil de consolidation de la démocratie. Le mode de régulation étant tributaire du contexte de chaque pays, le champ de notre recherche se circonscrit au Burkina Faso. / Large flows stemming from the liberalization of the media sector arose questions related to the mastery of information processing by men among whom a large majority didn’t have any knowledge of journalism. Besides, the requirements of public services and a fair distribution of broadcasting systems constituted a major concern for public policies in connection with communication. This context has brought about a new paradigm that has urged the inclusion of media regulation in the reformulation of the media policies. The regulation process which is applied in the media sector should not only protect and guarantee the appropriate operation of the system but also ensure, in case of need, a fair distribution of its action scope. Regulations systems in Africa are confronted with new challenges which they face desperately. For instance, we can cite the rapid surge of information and communication technology (ICT). It is occurring in terms of managing information flows conveyed by line media and tackling the issue of turning the process into land digital television. In the field of information and communication sciences, it is important to understand the relevance of the media regulation and conduct an analysis of its means and scope. Therefore, our main question could be raised as follows: To what extent can media regulation constitute a means to consolidate democracy? This question seems to be relevant to us when one notice conflicts of interest arising between actors of the public debate whether they belong to the public power or they are registered in political movements or in civil society. With regard to this situation, we can assume that media regulation can be considered as a proper tool for the consolidation of democracy. Owing to the fact that the regulation mode depends on the context of each country, our research scope is limited within Burkina Faso.

This master's thesis deals with interpreter's self-training. The aim of this theoretical-empirical study is to give an overview of the interpreting students' attitude towards interpreter's self- training as well as of the techniques students use when they perform their self-training. Another aim is to describe the role of teachers in interpreter's self-training, i.e. to what extent they motivate and support their students when it comes to self-training. The research part of the study was conducted at the Institute of Translation Studies, Charles University, and at the Department of Translation Studies, University of Graz, with the aim to compare the situation at those two institutes taking into account the abovementioned criteria. The theoretical part of the thesis discusses interpreter's self-training in the context of deliberate practice and focuses also on group practice as well as on the teachers' role. It also presents methods, techniques and e-learning tools which students may find useful during their self-training. The empirical part consists of an analysis of the data collected by means of questionnaires at the abovementioned institutes. Collected data suggest that both institutes support students' self-training, be it to different extents, and offer them all the necessary tools and...

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Functional hyperaemia is an important mechanism by which increased neuronal activity is matched by a rapid and regional increase in blood supply. This mechanism is facilitated by a process known as “neurovascular coupling” – the orchestrated communication system involving the cells that comprise the neurovascular unit (neurons, astrocytes and the smooth muscle and endothelial cells lining arterioles). Blood flow regulation and neurovascular coupling are altered in several pathological states including hypertension, diabetes, Alzheimer’s disease, cortical spreading depression and stroke. By adapting and extending other models found in the literature, we create, for the first time, a mathematical model of the entire neurovascular unit that is capable of simulating two separate neurovascular coupling mechanisms: a potassium- and EET-based and a NO-based mechanism. These models successfully account for several observations seen in experiment. The potassium/EET-based mechanism can achieve arteriolar dilations similar in magnitude (3%) to those observed during a 60-second neuronal activation (modelled as a release of potassium and glutamate into the synaptic cleft). This model also successfully emulates the paradoxical experimental finding that vasoconstriction follows vasodilation when the astrocytic calcium concentration (or perivascular potassium concentration) is increased further. We suggest that the interaction of the changing smooth muscle cell membrane potential and the changing potassium-dependent resting potential of the inwardly rectifying potassium channel are responsible for this effect. Furthermore, our simulations demonstrate that the arteriolar behaviour is profoundly affected by depolarization of the astrocytic cell membrane, and by changes in the rate of perivascular potassium clearance or the volume ratio between the perivascular space and astrocyte. In the modelled NO-based neurovascular coupling mechanism, NO exerts its vasodilatory effects via neuronal and endothelial cell sources. With both sources included, the model achieves a 1% dilation due to a 60-second neuronal activation. When the endothelial contribution to NO production is omitted, the arteriole is more constricted at baseline. Without the endothelial NO contribution, the arteriolar change in diameter during neuronal activity is greater (6%). We hypothesize that NO has a dual purpose in neurovascular coupling: 1) it dixxxvi rectly mediates neurovascular coupling through release by neuronal sources, and 2) it indirectly modulates the size of the neurovascular coupling response by determining the baseline tone. Our physiological models of neurovascular coupling have allowed us to replicate, and explain, some of the phenomena seen in both neurovascular coupling-oriented and clinicallyoriented experimental research. This project highlights the fact that physiological modelling can be used as a tool to understand biological processes in a way that physical experiment cannot always do, and most importantly, can help to elucidate the cellular processes that induce or accompany our most debilitating diseases.

Les accords environnementaux sont des conventions entre les entreprises et les autorités publiques utilisées comme des alternatives à la réglementation environnementale. Ces instruments ont été créés par les administrations nationales dans les années 1980 pour négocier la régulation de l'impact environnemental des entreprises et de leurs produits. L'utilisation de ces instruments s'est ensuite répandue dans tous les pays de l'OCDE et en particulier dans les États membres de l'Union européenne. Puisque les administrations nationales sont chargées de l'exécution du droit communautaire, la migration des accords environnementaux des ordres juridiques nationaux au système juridique de l'Union européenne n'était qu'une question de temps. Ainsi, malgré le silence des Traités institutifs à leur sujet, les accords environnementaux sont devenus des instruments de l'administration européenne composée, utilisés au niveau national et au niveau communautaire. Cependant, ce nouvel instrument, intégré sans modification des Traités, soulève des questions juridiques multiples et complexes. Les auteurs des accords les utilisent-ils dans le respect du système juridique de l'Union ? Quel est l'impact de ces instruments sur l'évolution de l'administration européenne et au-delà, sur l'ordre juridique communautaire ? Quelle est leur nature juridique ? Quelle est leur portée ? Comment sont-ils adoptés et contrôlés ? / Environmental agreements are legal arrangements between undertakings and public authorities, used as alternative instruments to environmental regulation. Environmental agreements were created by national administrations around the 1980s to negotiate the reduction of the environmental impact of companies or products. The use of these instruments spread in all OECD countries and especially in the Member States of the European Union. As the administrations of the Member States are responsible for the implementation of European law, the migration of environmental agreements from national legal orders to the European legal order was only a matter of time. Indeed, despite the silence of the European treaties, environmental agreements became instruments of the European administration, both at national and at European level. However, this new instrument, used without a modification of the European Treaties raises complex legal issues. Do the authors of environmental agreements respect the European legal order when using them? What is the impact of these instruments on European administration and beyond, on the European legal order? What are their legal nature and effects? How are they adopted, monitored and reviewed? This study, the first monograph focused on environmental agreements in the European legal order, finds answers to these questions by analyzing the relevant provisions, which restrain the leeway of environmental agreements authors but, at the same time, are interpreted by them to maintain their discretion as much as possible