Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

La plupart des composés volatils connus et impliqués dans les mécanismes de l’expression fruitée des vins rouges sont présents à des teneurs inférieures ou proches de leurs seuils de perception individuels. Compte tenu de phénomènes d’interactions perceptives entre eux, il est très complexe de déterminer leur impact réel sur l’arôme du vin. Au vu des difficultés rencontrées pour reconstituer fidèlement l’arôme des vins à partir uniquement de composés purs, nous avons développé une méthodologie permettant d’aborder cette reconstitution aromatique à partir de fractions issues du vin lui-même, afin de pouvoir évaluer l’importance relative de ces différentes fractions aromatiques vis-à-vis de l’arôme global du vin. Grâce à l’analyse sensorielle, et en s’attachant à quelques descripteurs particuliers, nous avons pu mettre en évidence, quelques interactions perceptives particulières comme des effets de contributions marquées ou de masquage. La caractérisation des composés présents dans les fractions concernées et à l’origine de ces effets notables a été mise en œuvre. Nos résultats soulignent le rôle indirect du 2-hydroxy-4-méthylpentanoate d’éthyle, un ester éthylique élué dans la fraction à l’origine d’une contribution marquée aux notes de fruits noirs frais qui, en provoquant la diminution du "seuil de perception" du pool fruité des vins rouges et l’augmentation de l’intensité de leurs notes de fruits noirs et de fruits frais, agit comme un exhausteur naturel de ces notes fruitées. Nous sommes aussi parvenus à mettre en évidence, le rôle direct du diacétyle, mais aussi le rôle indirect de l’acétoïne, de l’acide acétique et de la γ-butyrolactone, malgré leurs concentrations infraliminaires, sur la diminution de l’intensité globale et l’intensité du caractère de fruits frais. Ces résultats soulignent leur fort caractère, seuls ou en mélanges, de "réducteurs" de l’intensité de ces notes, et ce, même à des concentrations infraliminaires. Enfin, le comportement particulier, au sein d’un mélange fruité, du 3-hydroxybutanoate d’éthyle, de l’acétate de 2-méthylpropyle, du propanoate d’éthyle et de l’acétate de butyle, présents à des concentrations infraliminaires a été mis en évidence. La présence en mélange des deux premiers provoque la baisse notable du "seuil de perception" du pool fruité et celle des trois derniers augmente l’intensité des notes de fruits frais et fruits noirs traduisant l’effet exhausteur d’arômes dû à ces composés, effet comparable de celui du 2-hydroxy-4-méthylpentanoate d’éthyle qui présente quelques analogies structurales avec ces composés. / Most of volatiles involved in red wines’ fruity expression are present at levels below or close to their individual perception thresholds. Given the existence of perceptive interactions between them, it is very difficult to determine their real impact on wine aroma. Rather than assessing the olfactive behavior of mixtures prepared from pure products, the main goal of this work was to highlight and study the impact of perceptive interactions on wine fruity aroma expression using various aromatic reconstitutions prepared from wine fractions. Sensory profile analyses identified significant differences among aromatic reconstitutions for the intensity of some descriptors, as particular "additive" or "masking" effects. The composition of the involved fractions was then studied by instrumental methods. The final target was to investigate the impact of fraction components on fruity aroma by preparing aromatic reconstitutions and using sensory reconstitution tests, to assess the role of these compounds on the perceptive interactions previously observed. Further analysis revealed that ethyl 2-hydroxy-4-methylpentanoate, eluted in fraction which had an "additive" effect on the black-berry and fresh fruity aroma, does not play a direct role as a key compound in red wine aroma. In contrast, our findings highlighted its indirect contribution to wine aroma, showing that this ester contributed to a synergistic effect, enhancing the perception of fruity character. Finally, it was clearly demonstrated that this compound acts as a natural enhancer for black-berry and fresh fruit notes in red wine. It was also established that diacetyl, acetoin, acetic acid and γ-butyrolactone together played the same hypo-additive role as fractions of which they were eluted, presenting a "masking" effect on fresh fruity aroma. The impact of the last three compounds was demonstrated conclusively, even at subthreshold concentrations. These findings highlighted the existence of new remarkable perceptual interactions impacting overall and fresh-fruit aroma perception. The particular behavior, in a fruity mixture, of ethyl-propanoate, ethyl-3-hydroxybutanoate, butyl acetate and 2-methylpropyl acetate, present at subthreshold concentrations, was demonstrated. The presence of ethyl-3-hydroxybutanoate and 2-methylpropyl acetate in mixture led to a significant decrease of the olfactory threshold of fruity pool confirming their synergistic effect in the overall increase intensity. These compounds with close chemical structures, participate, both quantitatively and qualitatively, in the modulation of red wines’ fruity aromas acting as natural enhancers of black-berry and fresh-fruit aromas.

The trend in the electronic and electrical equipment industry towards denser and more powerful product requires a higher level of performance from cooling devices. In this context, passive cooling techniques such as latent heat storage systems have attracted considerable attention in recent years. Phase change materials (PCMs) have turned out to be extremely advantageous in this regard as they absorb high amount of latent heat without much rise of temperature. But unfortunately, nearly all phase change materials (PCMs) with high latent heat storage capacity have unacceptably low thermal conductivity, which makes heating and cooling processes slow during melting and solidification of PCMs. Augmentation of heat transfer in a PCM is achieved by inserting a high thermal conductivity material, known as thermal conductivity enhancer (TCE), into the PCM. The conglomeration of PCM and TCE is known as a thermal storage unit (TSU). In this thesis, detailed and systematic analyses are presented on the thermal performance of TSUs subjected to two types of thermal loading- (a) constant power loading in which a constant power level is supplied to the chip (heater) for a limited duration of time, and (b) cyclic loading. Eicosane is used as the PCM, while aluminium pin or plate fins are used as TCEs. First, a 1-D analytical model is developed to obtain a closed-form temperature distribution for a simple PCM domain (without TCE) heated uniformly from the bottom. The entire heating process is divided into three stages, viz. (a) sensible heating period before melting, during which heat is stored in the solid PCM in the form of specific heat, (b) melting period, during which a melt front progresses from the bottom to the top layer of the PCM and heat is stored in latent as well as in sensible forms, and (c) post melting period, during which energy is stored again in the form of sensible heat. For each stage, conduction energy equation is solved with a set of initial and boundary conditions. Subsequently, a resistance capacitance model of phase change process is developed for further analysis. For transient performance under constant thermal loading, experimental investigations are carried out for TSUs with different percentages of TCE. A numerical model is developed to interpret the experimental results. The thermal performance of a TSU is found to depend on a number of geometrical parameters and boundary conditions. Hence, a systematic approach is desirable for finding the best TSU design for which the chip can be operated for a longer period of time before it reaches a critical temperature (defined as the temperature above which the chip starts malfunctioning). As a first step of the approach, it is required to identify the parameters which can affect the transient process. It is found that the convective heat transfer coefficient, ‘h’ and the exposed area for heat transfer have little effect on the chip temperature during the constant power operation. A randomized search technique, Genetic Algorithm (GA), is coupled with the CFD code to find an optimum combination of geometrical parameters of TSUs based on the design criteria. First, the optimization is carried out without considering melt convection within the PCM. It is found that the optimum half-fin width remains fixed for a given heat flux and temperature difference. Assuming a quasi steady process, the results of optimization are then explained by constructing and analyzing a resistance network model. The resistance network model is then extended to include the effect of melt convection, and it is shown that the optimum pitch changes with the strength of convection. Accordingly, numerical analysis is carried out by considering the effect of melt convection, and a correlation for optimum pitch is developed. Having established the role of melt convection on the thermal performance of TSUs, rigorous computational and experimental studies are performed in order to develop correlations among different non-dimensional numbers, such as Nusselt number, Rayleigh number, Stefan number and Fourier number, based on a characteristic length scale for convection. The enclosures are classified into three types, depending on the aspect ratio of cavity, viz. shallow, rectangular and tall enclosures. For a shallow enclosure, the characteristic length is the height of cavity whereas for a tall enclosure, the characteristic length is the fin pitch. In case of rectangular enclosure, both pitch and height are the important characteristic lengths. For cyclic operation, it is required that the fraction of the PCM melting during the heating cycle should completely solidify back during the cooling period, in order that that TSU can be operated for an unlimited number of cycles. If solidification is not complete during the cooling period, the TSU temperature will tend to rise with every cycle, thus making it un-operational after some cycles. It is found that the solidification process during the cooling period depends strongly on the heat transfer coefficient and the cooling surface area. However, heat transfer coefficient does not play any significant role during the heating period; hence a TSU optimized for transient operation may not be ideal for cyclic loading. Accordingly, studies are carried out to find the parameters which could influence the behaviour of PCM under cyclic loading. A number of parameters are identified in the process, viz. cycle period and heat transfer coefficient. It is found that the required heat transfer coefficient for infinite cyclic operation is very high and unrealistic with air cooling from the surface of the TSU. Otherwise, the required cooling period for complete re-solidification will be very high, which may not be suitable for most applications. In an effort to bring down the cooling period to a duration that is comparable to the heating period, a new design is proposed where both ‘h’ and area exposed to heat transfer can be controlled. In this new design, the gaps between the fins in a plate-fin TSU are alternately filled with PCM, such that only one side of a fin is in contact with PCM and the other side is exposed to the coolant (air). In this arrangement, the same heat flow path through the fin which is used for heating the PCM (during the heating stage) can also be used for cooling and solidifying the PCM during the cooling part of the cycle. Natural or forced air cooling through the passages can be introduced to provide a wide range of heat transfer coefficient which can satisfy the cooling requirements. With this arrangement, the enhanced area provided for cooling keeps the ‘h’ requirement within a realistic limit. This cooling method developed is categorized as a combination of active and passive cooling techniques. Analytical and numerical investigations are carried out to evaluate the thermal performance of this modified PCM-based heat sink in comparison to the ones with conventional designs. It is found that, the performance of new PCM-based heat sink is superior to that of the conventional one. Experiments are performed on both the conventional and the new PCM-based heat sinks to validate the new findings.

No description available.

Le cœur des vertébrés est un organe modulaire qui requiert le " patterning " complexe des champs morphogénétiques cardiogènes et la convergence coordonnée des diverses sous-populations de progéniteurs cardiogéniques. Au moins 7 facteurs de transcription de la famille T-box coopèrent au sein de ces nombreuses sous-populations de progéniteurs cardiogéniques afin de réguler la morphogenèse et l’agencement de multiples structures le long de l’ébauche cardiaque, ce qui explique que les mutations humaines de ces gènes engendrent diverses malformations congénitales cardiaques (MCCs). L’un de ces gènes T-box, Tbx5, dont l’haploinsuffisance génère le syndrome de Holt-Oram (SHO), intervient dans une grande variété de réseaux de régulation géniques (RRGs) qui orchestrent la morphogenèse des oreillettes, du ventricule gauche, de la valve mitrale, des septums inter-auriculaire et inter-ventriculaire, ainsi que du système de conduction cardiaque. La diversité des RRGs impliqués dans la formation de ces structures cardiaques suggère que Tbx5 détient une profusion de fonctions qui ne seront identifiables qu’en répertoriant ses activités moléculaires dans chaque lignée cardiaque examinée isolément. Afin d’aborder cette problématique, une ablation génétique de Tbx5 dans l’endocarde a été réalisée. Cette expérience a démontré le rôle crucial de Tbx5 dans la survie des cellules endocardiques bordant le septum primum et des cardiomyocytes au sein de cette structure embryonnaire qui contribuera à la morphogenèse du septum inter-auriculaire. En outre, cette étude a révélé l’existence d’une communication croisée entre la sous-population de cellules endocardiques Tbx5+ et le myocarde au niveau du septum primum, afin d’assurer la survie des cardiomyocytes, et ultimement de garantir la maturation du septum inter-auriculaire. Nos résultats confirment aussi l’importance de l’interdépendance génétique (Tbx5 et Gata4 ainsi que Tbx5 et Nos3) entre différents loci dans la morphogenèse de la cloison inter-auriculaire, et particulièrement de l’influence que peut avoir l’environnement sur la pénétrance et l’expressivité des communications inter-auriculaires (CIAs) dans le SHO. En outre, puisque les fonctions d’un gène dépendent ordinairement des différents isoformes qu’il peut générer, une deuxième étude a focalisé davantage sur l’aspect transcriptionnel de Tbx5. Cette approche a mené à la découverte de 6 transcrits alternatifs exhibant des fonctions à la fois communes et divergentes. La caractérisation de 2 de ces isoformes a révélé le rôle de l’isoforme long (Tbx5_v1) dans la régulation de la croissance des cardiomyocytes durant la cardiogénèse, tandis que l’isoforme court (Tbx5_v2), préférentiellement exprimé dans le cœur mature, réprime la croissance cellulaire. Il est donc entièrement concevable que les mutations de TBX5 entraînant une troncation de la région C-terminale accroissent la concentration d’une protéine mutée qui, à l’instar de Tbx5_v2, interfère avec la croissance de certaines structures cardiaques. En revanche, la divergence de fonctions de ces isoformes, caractérisée par les disparités de localisation subcellulaire et de d’interaction avec d’autres cofacteurs cardiaques, suggère que les mutations affectant davantage un isoforme favoriseraient l’émergence d’un type particulier de MCC. Finalement, un dernier objectif était d’identifier le ou les mécanisme(s) moléculaire(s) par le(s)quel(s) Tbx5 régule son principal gène cible, Nppa, et d’en extraire les indices qui éclairciraient sa fonction transcriptionnelle. Cet objectif nécessitait dans un premier lieu d’identifier les différents modules cis-régulateurs (MCRs) coordonnant la régulation transcriptionnelle de Nppa et Nppb, deux gènes natriurétiques dont l’organisation en tandem et le profil d’expression durant la cardiogénèse sont conservés dans la majorité des vertébrés. L’approche d’empreinte phylogénétique employée pour scanner le locus Nppb/Nppa a permis d’identifier trois MCRs conservés entre diverses espèces de mammifères, dont un (US3) est spécifique aux euthériens. Cette étude a corroboré que la régulation de l’expression du tandem génique Nppb/Nppa requérait l’activité transcriptionnelle d’enhancers en complément aux promoteurs de Nppa et Nppb. La concordance quasiment parfaite entre les profils d’expression de Tbx5 et de ces deux gènes natriurétiques chez les mammifères, suggère que le gradient d’expression ventriculaire de Tbx5 est interprété par le recrutement de ce facteur au niveau des différents enhancers identifiés. En somme, les études présentées dans cette thèse ont permis de clarifier la profusion de fonctions cardiaques que possède Tbx5. Certaines de ces fonctions émanent de l’épissage alternatif de Tbx5, qui favorise la synthèse d’isoformes dotés de propriétés spécifiques. Les diverses interactions combinatoires entre ces isoformes et d’autres facteurs cardiaques au sein des diverses sous-populations de progéniteurs cardiogènes contribuent à l’émergence de RRGs cardiaques divergents. / The vertebrate heart is a modular organ, which requires the complex patterning of the morphogenetic heart fields and the coordinated convergence of the diverse subpopulations of cardiogenic progenitors. At least 7 transcription factors of the T-box family cooperate within these numerous subpopulations of cardiogenic progenitors to regulate the morphogenesis and the layout of multiple structures along the primordial heart tube, which explains that the human mutations of these genes induce various congenital heart defects (CHDs). One of these T-box genes, Tbx5, whose haploinsufficiency generates the Holt-Oram syndrome (HOS), intervenes in a wide variety of gene regulatory networks (GRNs) that orchestrate the morphogenesis of the atria, the left ventricle, the mitral valve, the inter-atrial and inter-ventricular septa, as well as the cardiac conduction system. The diversity of GRNs involved in the formation of these cardiac structures suggests that Tbx5 holds a profusion of functions which will be identifiable only by indexing its molecular activities in each separately examined cardiac lineage. To address this problem, a conditional knockout of Tbx5 in the endocardium was generated. This experiment demonstrated a crucial role of Tbx5 in the survival of the endocardial cells lining the septum primum and the cardiomyocytes within this embryonic structure, which will contribute to the morphogenesis of the inter-atrial septum. Moreover, this study revealed a crosstalk between the Tbx5-positive endocardial cells subpopulation and the myocardium at the level of the septum primum to ensure the survival of cardiomyocytes, and ultimately to guarantee the maturation of the inter-atrial septum. Our results also confirmed the importance of genetic interdependence (Tbx5 and Gata4 as well as Tbx5 and Nos3) between different loci in the morphogenesis of the inter-atrial septum, and particularly the influence that the environment can have on the penetrance and the expressivity of atrial septal defects (ASDs) in the HOS. Besides, since the functions of a gene usually depend on the different isoforms it can generate, a second study focused more on the transcriptional aspect of Tbx5. This approach led to the discovery of 6 alternative transcripts exhibiting both common and specific functions. The characterization of 2 of these isoforms revealed the role of the long isoform (Tbx5_v1) in the regulation of cardiomyocytes growth during cardiogenesis, whereas the short isoform (Tbx5_v2), preferentially expressed in the mature heart, represses cell growth. It is thus entirely conceivable that TBX5 mutations leading to a C-terminal truncation increase the concentration of a mutated protein, which, like Tbx5_v2, interferes with the growth of certain cardiac structures. On the other hand, the divergence of functions of these isoforms, characterized by the disparities of subcellular localization and interaction with other cardiac cofactors, suggests that mutations affecting more one isoform would favor the emergence of a particular type of CHD. Finally, a last objective was to identify one or several molecular mechanism(s) by which Tbx5 regulates its main target gene, Nppa, and to extract clues that might clarify its transcriptional function. This objective required in a first place to identify the various cis-regulatory modules (CRMs) coordinating the transcriptional regulation of Nppa and Nppb, two natriuretic genes whose tandem organization and expression pattern during cardiogenesis are preserved in most vertebrates. The phylogenetic footprint approach employed to scan the Nppb/Nppa locus allowed the identification of three CRMs evolutionary conserved between different mammals species, one of which (US3) is specific to eutherians. This study confirmed that the regulation of the tandem genes Nppb/Nppa required the transcriptional activity of enhancers in complement to Nppa and Nppb promoters. The almost perfect concordance between the expression profiles of Tbx5 and these two natriuretic genes in mammals, suggests that the ventricular expression gradient of Tbx5 is interpreted by the recruitment of this factor to the identified enhancers. Altogether, the studies presented in this thesis allowed clarifying the profusion of Tbx5 cardiac functions. Some of these functions emanate from the alternative splicing of Tbx5, which favors the synthesis of isoforms endowed with specific properties. The diverse combinatorial interactions between these isoforms and other cardiac factors within the various cardiogenic progenitor subpopulations contribute to the emergence of distinct cardiac RRGs.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

5 Abstract Definitive diagnosis of inherited metabolic disorders commonly depends on the measurement of enzyme activity (which is often complicated) and/or molecular genetic testing. Yet even the standard mutation analysis can bring false negative results in the case of gross chromosomal rearrangements or incorrect regulation of gene expression due to the mutations in regulatory regions. In the present study I focused on characterization of complex mutations affecting the gene encoding ornithin transcarbamylase (OTC) followed by studies of regulatory regions of OTC and GBA (the gene encoding β-glucocerebrosidase). In the first study we identified 14 novel mutations including three large deletions in a cohort of 37 patients with OTC deficiency (OTCD). Subsequently we evaluated clinical significance of all these mutations. We also found a heterozygote carrying a hypomorphic mutation and manifesting OTCD most likely due to unfavorable X-inactivation which was observed independently in three different peripheral tissues. In order to evaluate the clinical significance of a promoter variation c.-366A>G found in a family with mild OTCD we identified three alternative transcription start sites (TSSs) of human OTC and delimited the promoter. We also found a distal enhancer and performed functional analysis of both...

Abstract Intracellular signalling cascades regulate cardiomyocyte hypertrophic response. Initially hypertrophy of individual myocytes occurs as an adaptive response to increased demands for cardiac work, e.g. during hypertension or after myocardial infarction, but a prolonged hypertrophic response, accompanied by accelerated fibrosis and apoptosis, predisposes the heart to impaired performance and the syndrome of heart failure. The goal of this work was to elucidate some of the main signalling pathways in experimental models of the cardiac hypertrophic response. Mechanical stretching of cultured neonatal rat cardiomyocytes in vitro activates the B-type natriuretic peptide (BNP) gene, a well-established marker of the hypertrophic response, through intracellular signalling cascades mitogen-activated protein kinases (MAPKs) and protein kinase A (PKA) -pathway. Further, transcription factors transcriptional enhancer factor-1 (TEF-1) and activating transcription factor 3 (ATF3) were induced during stretch, and TEF-1 activation was shown to be regulated by extracellular signal-regulated kinase (ERK), while ATF3 activation was modulated by PKA. The BNP gene was also activated by the adenoviral overexpression of the p38 MAPK isoforms p38α and p38β in vitro. Importantly, p38α–induced activation was mediated through activator protein-1 (AP-1) while p38β mediated BNP transcription through GATA-4, which suggests distinct physiological roles for different p38 isoforms. This was further confirmed by quantitative PCR, which demonstrated pro-fibrotic role for the p38α isoform and a pro-hypertrophic role for the p38β isoform. Finally, adenoviral overexpression of ATF3 in vitro and in vivo resulted in activation of cardiac survival factors nuclear factor-κВ and Nkx-2.5, and attenuation of central pro-inflammatory and pro-fibrotic mediators. Together these data suggest a protective role for ATF3 in the heart. Overall this study provides new insights into the role of several signalling molecules involved in cardiac hypertrophic process and suggests potential therapeutic strategies for the diagnosis and treatment of heart failure. / Tiivistelmä Sydämen kammioiden seinämät paksuuntuvat kuormituksen lisääntyessä mm. verenpainetaudissa tai sydäninfarktin jälkeen. Lisääntynyt kuormitus aiheuttaa sydänlihassolujen koon kasvun (hypertrofioitumisen) ohella sidekudoksen kertymistä (fibroosia) ja solukuolemaa. Nämä solutason muutokset lopulta vioittavat sydämen rakennetta niin, että sen toiminta pettää, ja sydän ajautuu vajaatoimintaan. Tätä taudin etenemistä säätelevät molekyylitasolla lukuisat solunsisäiset signaalinvälitysjärjestelmät, joita tässä väitöskirjatyössä tutkittiin eri koemalleissa. Sydämen täyttöpaineen nousun aiheuttama sydänlihassolujen mekaaninen venytys aktivoi natriureettisten peptidien (eteispeptidi, ANP ja B-tyypin natriureettinen peptidi, BNP) synteesiä ja vapautumista verenkiertoon. BNP geenin säätelyä mekaanisen venytyksen aikana tutkittiin rotan sydänlihassoluviljelmissä. Mitogeeni-aktivoituvat proteiinikinaasit (MAPK) sekä proteiinikinaasi A (PKA) säätelivät mekaanisen ärsykkeen aiheuttamaa BNP geenin ekspressiota. Venytys aktivoi myös transkriptiotekijöitä TEF-1 (transcriptional enhancer factor-1) ja ATF3 (activating transcription factor 3). TEF-1 sääteli venytyksen aiheuttamaa BNP:n aktivaatiota ERK:n (extracellular signal-regulated kinase) välityksellä BNP geenin säätelyalueella olevan sitoutumispaikkansa (M-CAT elementti) kautta. ATF3:n säätelyssä PKA:lla oli keskeinen merkitys. Tutkimus osoitti myös, että p38 MAPK:n alatyypeistä p38α lisäsi fibroosiin liittyvien geenien aktiivisuutta, kun taas p38β aiheutti solujen hypertrofioitumista lisäävien geenien ekspressiota. Molemmat alatyypit aktivoivat BNP geenin ekspressiota, mutta aktivaatio tapahtui eri transkriptiotekijöiden kautta. Tutkimuksessa havaittiin myös, että ATF3:n yliekspressio adenovirusvälitteisellä geeninsiirrolla lisäsi kahden sydäntä suojaavan transkriptiotekijän (nuclear factor-κВ ja Nkx-2.5) aktiivisuutta, sekä vähensi sydämen tulehdusvastetta ja fibroosia lisäävien tekijöiden (interleukiini-6 ja plasminogeeniaktivaattorin inhibiittori-1) ekspressiota. Väitöskirjatutkimus antaa uutta tietoa solunsisäisistä signaalinvälitys-järjestelmistä, jotka säätelevät sydänlihaksen kuormitusvastetta sydän- ja verenkiertoelimistön sairauksissa. Näiden solutason mekanismien tunteminen osaltaan edesauttaa jatkossa uusien menetelmien kehittämistä sydämen vajaatoiminnan ehkäisyyn ja hoitoon.