Spontaneous Speech and Emotional Response modeling based on One-class classifier oriented to Alzheimer Disease diagnosis

The purpose of our project is to contribute to earlier diagnosis of AD and better estimates of its severity by using automatic analysis performed through new biomarkers extracted from non-invasive intelligent methods. The methods selected in this case are speech biomarkers oriented to Sponta-neous Speech and Emotional Response Analysis. Thus the main goal of the present work is feature search in Spontaneous Speech oriented to pre-clinical evaluation for the definition of test for AD diagnosis by One-class classifier. One-class classifi-cation problem differs from multi-class classifier in one essen-tial aspect. In one-class classification it is assumed that only information of one of the classes, the target class, is available. In this work we explore the problem of imbalanced datasets that is particularly crucial in applications where the goal is to maximize recognition of the minority class as in medical diag-nosis. The use of information about outlier and Fractal Dimen-sion features improves the system performance.

Osakkeenomistajan suojaaminen vähemmistöosakkeiden hankinnassa - Oikeusvertaileva tarkastelu Suomen ja Delawaren käytännöistä

Tutkielmassa tarkastellaan osakkeenomistajien suojaamiskeinoja Suomessa ja Delawaressa. Oikeusvertailevaa metodia sovelletaan kolmella tasolla: lakien ja määräysten osalta, menettelyn osalta sekä suojaamiskeinojen osalta. Osakkeenomistajien katsotaan tarvitsevan suojaa vähemmistöosakkeiden hankinnan yhteydessä, sillä siinä osakkeiden vapaan vaihdettavuuden perusperiaate ja pakkolunastaminen kohtaavat. Suojaamiskeinot on jaettu etukäteisiin, menettelya koskeviin sekä hinnanmäärittelyyn liittyviin keinoihin. Etukäteisiin keinoihin voidaan laskea johdon vastuu, joka koostuu huolellisuus- ja lojaliteettivelvoitteista, ja yhtiöjärjestysmääräykset. Delawaressa johdon vastuu on määritelty Suomea tarkemmin. Yhtiöjärjestysmääräykset ovat ongelmallisia Suomessa, sillä ne saattavat olla arvopaperimarkkinalain vastaisia. Delawaressa niiden käyttö on runsasta. Menettelyyn liittyviaä suojakeinoja löytyi useita. Vähemmistönsuojaperiaatetta toteutetaan Suomessa yhdenvertaisuusperiaatetta noudattamalla sekä määräämällä lunastusoikeudesta tai -velvollisuudesta. Delawaressa vähemmistöllä on oikeus saada erityistuomioistuin Court of Chanceryn arviointi menettelyn oikeellisuudesta. Menettelyn oikeellisuutta pyritään kummassakin tutkimuskohteessa suojaamaan myös tiedonantovelvollisuudella. Lisäksi Delawaressa johdon on asetettava aina erikoiskomitea neuvottelemaan ostajan kanssa. Hinnanmäärittelyn osalta suojaa antavat käyvän hinnan vaatimus, sekä Suomessa taloudellisen yhdenvertaisuuden periaate ja Delawaressa vähemmistön oikeus saada Court of Chanceryn arviointi oikeasta hinnasta.

Omistus, kontrolli ja päämies-agentti- ongelmat osakeyhtiössä

Tutkielman tavoitteena on selvittää osakeyhtiön määräysvaltasuhteet ja miten päämies-agentti- ongelmat vaikeuttavat määräysvallan käyttöä. Tutkimusmetodi on lainopillinen ja lähestyminen aiheeseen tapahtuu sekä yhtiöoikeudellisesta, että oikeustaloustieteellisestä näkökulmasta. Aineistona tutkielmassa käytetään lähinnä voimassa olevaa lainsäädäntöä ja oikeuskirjallisuutta. Päämies-agentti- ongelmalla tarkoitetaan osakeyhtiössä määräysvallan osittaista luisumista omistajalta (päämies) yritysjohdolle (agentti) tai vähemmistöomistajalta (päämies) kontrolloivalle omistajalle (agentti). Tärkeimpiä ongelman lähteitä ovat epäsymmetrinen informaatio ja intressiristiriidat yhtiön johdon ja omistajien välillä tai toisaalta yhtiötä lähellä olevien omistajien ja muiden omistajien välillä. Epäsymmetrinen informaatio luo osaltaan puitteet agenttitahojen opportunistiselle käyttäytymiselle. Ratkaisuja päämies-agentti- ongelmiin ovat ennen kaikkea päämiestahoja suojaava lainsäädäntö ja ulkoiset yritysjohtajien käyttäytymistä ohjaavat keinot, kuten erilaiset kannustinjärjestelmät ja hyvät hallintotavat. Kontrolloivien omistajien käyttäytymistä on puolestaan vaikea ohjata ja erilaisilla määräysvaltaa keskittävillä omistusrakenteilla onkin taipumus voimistaa päämies-agentti- ongelmien vaikutusta. Erityisiä tilanteita osaltaan luovat myös luonteiltaan erilaiset omistajatahot, kuten institutionaaliset omistajat.

Proportionality and Party Success in Europe

This thesis consists of four articles and an introductory section. The main research questions in all the articles are about proportionality and party success in Europe, at European, national or district levels. Proportionality in this thesis denotes the proximity of seat shares parties receive compared to their respective vote shares, after the electoral system’s allocation process. This proportionality can be measured through numerous indices that illustrate either the overall proportionality of an electoral system or a particular election. The correspondence of a single party’s seat shares to its vote shares can also be measured. The overall proportionality is essential in three of the articles (1, 2 and 4), where the system’s performance is studied by means of plots. In article 3, minority party success is measured by advantage-ratios that reveal single party’s winnings or losses in the votes to seat allocation process. The first article asks how proportional are the European parliamentary (EP) electoral systems, how do they compare with results gained from earlier studies and how do the EP electoral systems treat different sized parties. The reasons for different outcomes are looked for in explanations given by traditional electoral studies i.e. electoral system variables. The countries studied (EU15) apply electoral systems that vary in many important aspects, even though a certain amount of uniformity has been aspired to for decades. Since the electoral systems of the EP elections closely resemble the national elections, the same kinds of profiles emerge as in the national elections. The electoral systems indeed treat the parties differentially and six different profile types can be found. The counting method seems to somewhat determine the profile group, but the strongest variables determining the shape of a countries’ profile appears to be the average district magnitude and number of seats allocated to each country. The second article also focuses on overall proportionality performance of an electoral system, but here the focus is on the impact of electoral system changes. I have developed a new method of visualizing some previously used indices and some new indices for this purpose. The aim is to draw a comparable picture of these electoral systems’ changes and their effects. The cases, which illustrate this method, are four elections systems, where a change has occurred in one of the system variables, while the rest remained unchanged. The studied cases include the French, Greek and British European parliamentary systems and the Swedish national parliamentary system. The changed variables are electoral type (plurality changed to PR in the UK), magnitude (France splitting the nationwide district into eight smaller districts), legal threshold (Greece introducing a three percent threshold) and counting method (d’Hondt was changed to modified Sainte-Laguë in Sweden). The radar plots from elections after and before the changes are drawn for all country cases. When quantifying the change, the change in the plots area that is created has also been calculated. Using these radar plots we can observe that the change in electoral system type, magnitude, and also to some extent legal threshold had an effect on overall proportionality and accessibility for small parties, while the change between the two highest averages counting method had none. The third article studies the success minority parties have had in nine electoral systems in European heterogeneous countries. This article aims to add more motivation as to why we should care how different sized parties are treated by the electoral systems. Since many of the parties that aspire to represent minorities in European countries are small, the possibilities for small parties are highlighted. The theory of consociational (or power-sharing) democracy suggests that, in heterogeneous societies, a proportional electoral system will provide the fairest treatment of minority parties. The OSCE Lund Recommendations propose a number of electoral system features, which would improve minority representation. In this article some party variables, namely the unity of the minority parties and the geographical concentration of the minorities were included among possible explanations. The conclusions are that the central points affecting minority success were indeed these non-electoral system variables rather than the electoral system itself. Moreover, the size of the party was a major factor governing success in all the systems investigated; large parties benefited in all the studied electoral systems. In the fourth article the proportionality profiles are again applied, but this time to district level results in Finnish parliamentary elections. The level of proportionality distortion is also studied by way of indices. The average magnitudes during the studied periodrange from 7.5 to 26.2 in the Finnish electoral districts and this opens up unequal opportunities for parties in different districts and affects the shape of the profiles. The intra-country case allows the focus to be placed on the effect of district magnitude, since all other electoral systems are kept constant in an intra-country study. The time span in the study is from 1962 to 2007, i.e. the time that the districts have largely been the same geographically. The plots and indices tell the same story, district magnitude and electoral alliances matter. The district magnitude is connected to the overall proportionality of the electoral districts according to both indices, and the profiles are, as expected, also closer to perfect proportionality in large districts. Alliances have helped some small parties to gain a much higher seat share than their respective vote share and these successes affect some of the profiles. The profiles also show a consistent pattern of benefits for the small parties who ally with the larger parties.

Osakeyhtiölain muutokset pienen osakeyhtiön toiminnassa

Osakeyhtiölain kokonaisuudistus astui voimaan 1.9.2006. Lain tavoitteeksi asetettiin yhtiöiden toimintaedellytysten hallittu lisääminen velkojain- tai vähemmistöosakkaiden suojaa heikentämättä. Erityisesti pienten yhtiöiden asemaan kiinnitettiin huomiota selventämällä lakia ja keventämällä muotomääräyksiä. Tämän tutkimuksen tavoitteena on selvittää, miten uudistukset vaikuttivat pienen osakeyhtiön toimintaan. Tutkimuksessa käydään läpi niitä osakeyhtiölain säädöksiä, jotka vaikuttavat pienyhtiön toimintaan sekä kirjallisuuden pohjalta että case-yhtiöiden avulla. Case-yhtiöinä tutkimuksessa on kaksi pientä osakeyhtiötä. Tutkimusmenetelmä on kvalitatiivinen ja osin deskriptiivinen tutkimus. Tutkimus osoitti, että osakeyhtiölain uudistuksen kokonaisvaikutus pienissä yhtiössä näkyy muotosäännösten kevenemisenä ja tahdonvaltaisuuden lisääntymisenä. Suurin haaste pienille yhtiöille on lain maksukykyisyysvaatimus varojenjakopäätöstä tehtäessä. Se, missä määrin lain suomia mahII dollisuuksia käytäntöjen keventämiseen yhtiöissä otetaan käyttöön, riippuu täysin yhtiön johdon aktiivisuudesta ja muutosvastarinnan voittamisesta.

Right heart ischemia in cases of sepsis.

Data from the literature suggest that cases of sepsis complicated by right ventricular (RV) dysfunction have poorer prognosis. In these cases progressive hypoperfusion associated to increasing, injury-related, pulmonary vascular resistance account for RV ischemia. In the present analysis, we wanted to evaluate whether prevalent RV cardiac ischemic damage could be detected in a series of fatal sepsis cases. We retrospectively investigated 20 cases of sepsis that underwent forensic autopsy (study group-11&#9792;, 9&#9794;, mean age 57 years) and compared them to a group of 20 cases of hanging (hanging group-4 &#9792;, 16 &#9794;, mean age 44 years) as well as to a group of 20 cases of myocardial infarction (MI group-9 &#9792;, 11 &#9794;, mean age 65 years), as examples of cardiac damage due to global hypoxia during agony and ischemic damage, respectively. We performed immunohistochemistry with the antibodies anti-fibronectin and C5b-9. The reactions were semiquantitively classified and the groups were compared. In 30% of the cases of sepsis prevalent RV ischemic damage could be detected with the antibody anti-fibronectin. This expression was significantly different from that observed in cases of MI (p=0.028) and hanging (p<0.001). Our study showed that, in cases of fatal sepsis, prevalent RV ischemic damage occurred in a substantial minority of cases.

Language extinction and linguistic fronts

Language diversity has become greatly endangered in the past centuries owing to processes of language shift from indigenous languages to other languages that are seen as socially and economically more advantageous, resulting in the death or doom of minority languages. In this paper, we define a new language competition model that can describe the historical decline of minority languages in competition with more advantageous languages. We then implement this non-spatial model as an interaction term in a reactiondiffusion system to model the evolution of the two competing languages. We use the results to estimate the speed at which the more advantageous language spreads geographically, resulting in the shrinkage of the area of dominance of the minority language. We compare the results from our model with the observed retreat in the area of influence of the Welsh language in the UK, obtaining a good agreement between the model and the observed data

Facteurs impliqués dans le développement et la progression de la maladie aLcoolique du foie [Factors influencing development and progression of alcoholic liver disease].

Only a minority ot excessive drinkers develop cirrhosis. The main cofactors implicated in the pathophysiology of alcoholic liver disease are obesity, diabetes or the metabolic syndrome. Several genetic polymorphisms have been associated with a higher risk of alcoholic cirrhosis. Recent data indicate that gut microbiota could play a role in the pathogenesis of alcoholic liver disease. The aim of this review is to summarize the factors that influence development and progression of alcoholic liver disease.

Ethnic Identity among Indigenous and Mestizos from Intercultural University of Chiapas = Identidad étnica entre los indígenas y los mestizos de la Universidad Intercultural de Chiapas

This study explored ethnic identity among 662 students (326 mestizos and 336 indigenous) from the Intercultural University of Chiapas (IUCh). Scholars suggest that ethnicity is more salient for ethnic minority adolescents than for adolescents who are members of the ethnic majority. The aims for this study were: 1) to determine the structure and validity of ethnic identity as measured by the Multigroup Ethnic Identity Measure in a sample of majority and minority ethnic groups from Intercultural University in Chiapas, and 2) to examine the variability of ethnic identity across ethnic groups. Specifically, it was hypothesized that the Multigroup Ethnic Identity Measure would show two factors, and that ethnic groups would differ on ethnic identity. The results supported the hypotheses

Identification and ethnic diversity underlie support for multicultural rights : a multilevel analysis in Bulgaria

Bulgaria is historically a multicultural society, composed of the Bulgarian (ethnic) majority and a number of ethnic minorities among which Bulgarian Turks and Roma are the largest. Both minority communities are stigmatized in contemporary Bulgaria, though to different degrees and for different reasons. Ethnic minorities' rights to preserve their culture, customs, and language are a topic of contentious debate. The purpose of this study was to examine individual- and context-level antecedents of the ethnic Bulgarian majority's support for multicultural rights of ethnic minorities. Multilevel regression analyses were conducted with International Social Survey Programme ISSP 2003 data (N = 920 in 28 Bulgarian districts). At the individual-level, an ethnic conception of the nation and anti-Roma symbolic prejudice were negatively related to support for multicultural rights, whereas national identification was positively related to the support of these rights. Over and above individual-level effects, and in line with recent extensions of intergroup contact theory, thepercentage ofBulgarianTurks withindistricts was positively related to support for multicultural rights. Importantly, support for multicultural rights was particularly high in districts characterized by ethnic diversity, that is, in districts with high proportions of both Bulgarian Turks and Roma. The beneficial effects of ethnic diversity and theoretical implications of findings are discussed.

Voting advice applications : impact on voting decisions in the 2011 Swiss national elections

In most democracies voting Advice Applications (VAAs) advising citizens which candidate or party they should vote for become more and more popular. It is therefore crucial to know more about the functioning and the effects of such tools. After some general remarks about the spread of these tools and their possible effects gathered so far in various studies, this paper presents the latest results from a research conducted in the course of the 2011 Swiss national elections. They confirm that VAAs can lead to better informed voters and are likely to have a positive impact on electoral turnout. Additionally it can be shown that the Swiss VAA smartvote made voters change their voting intention and that they voted for a different party. This was particularly advantageous for the Green Liberal Party. At the moment, only a minority of voters rely on the voting recommendation by smartvote. This might change dramatically with the introduction of e-voting. Once people can vote electronically, there are hardly any possibilities to prevent voters from transferring their selection of candidates based on the recommendation given by a VAA into the official electronic ballot paper. If this is possible, e-voting will become more popular than postal voting.

Characterization of local and systemic immune-modulation in melanoma patients

Le mélanome cutané est un des cancers les plus agressifs et dont l'incidence augmente le plus en Suisse. Une fois métastatique, le pronostic de survie moyenne avec les thérapies actuelles est d'environ huit mois, avec moins de 5% de survie à cinq ans. Les récents progrès effectués dans la compréhension de la biologie de la cellule tumorale mais surtout dans l'importance du système immunitaire dans le contrôle de ce cancer ont permis le développement de nouveaux traitements novateurs et prometteurs. Ces thérapies, appelées immunothérapies, reposent sur la stimulation et l'augmentation de la réponse immunitaire à la tumeur. Alors que les derniers essais cliniques ont démontré l'efficacité de ces traitements chez les patients avec des stades avancés de la maladie, le contrôle de la maladie à long- terme est seulement atteint chez une minorité des patients. La suppression locale et systémique de la réponse immunitaire spécifique anti-tumorale apparaitrait comme une des raisons expliquant la persistance d'un mauvais pronostic clinique chez ces patients. Des études sur les souris ont montré que les vaisseaux lymphatiques joueraient un rôle primordial dans ce processus en induisant une tolérance immune, ce qui permettrait à la tumeur d'échapper au contrôle du système immunitaire et métastatiser plus facilement. Ces excitantes découvertes n'ont pas encore été établi et prouvé chez l'homme. Dans cette thèse, nous montrons pour la première fois que les vaisseaux lymphatiques sont directement impliqués dans la modulation de la réponse immunitaire au niveau local et systémique dans le mélanome chez l'homme. Ces récentes découvertes montrent le potentiel de combiner des thérapies visant le système lymphatique avec les immunothérapies actuellement utilisées afin d'améliorer le pronostic des patients atteint du mélanome. -- Cutaneous melanoma is one of the most invasive and metastatic human cancers and causes 75% of skin cancer mortality. Current therapies such as surgery and chemotherapy fail to control metastatic disease, and relapse occurs frequently due to microscopic residual lesions. It is, thus, essential to develop and optimize novel therapeutic strategies to improve curative responses in these patients. In recent decades, tumor immunologists have revealed the development of spontaneous adaptive immune responses in melanoma patients, leading to the accumulation of highly differentiated tumor-specific T cells at the tumor site. This remains one of the most powerful prognostic markers to date. Immunotherapies that augment the natural function of these tumor-specific T cells have since emerged as highly attractive therapeutic approaches to eliminate melanoma cells. While recent clinical trials have demonstrated great progress in the treatment of advanced stage melanoma, long-term disease control is still only achieved in a minority of patients. Local and systemic immune suppression by the tumor appears to be responsible, in part, for this poor clinical evolution. These facts underscore the need for a better analysis and characterization of immune- related pathways within the tumor microenvironment (TME), as well as at the systemic level. The overall goal of this thesis is, thus, to obtain greater insight into the complexity and heterogeneity of the TME in human melanoma, as well as to investigate immune modulation beyond the TME, which ultimately influences the immune system throughout the whole body. To achieve this, we established two main objectives: to precisely characterize local and systemic immune modulation (i) in untreated melanoma patients and (ii) in patients undergoing peptide vaccination or checkpoint blockade therapy with anti-cytotoxic T- lymphocyte-asisctaed protein-4 (CTLA-4) antibody. In the first and main part of this thesis, we analyzed lymphatic vessels in relation to anti-tumor immune responses in tissues from vaccinated patients using a combination of immunohistochemistry (IHC) techniques, whole slide scanning/analysis, and an automatic quantification system. Strikingly, we found that increased lymphatic vessel density was associated with high expression of immune suppressive molecules, low functionality of tumor-infiltrating CD8+ T cells and decreased cytokine production by tumor-antigen specific CD8+ T cells in the blood. These data revealed a previously unappreciated local and systemic role of lymphangiogenesis in modulating T cell responses in human cancer and support the use of therapies that target lymphatic vessels combined with existing and future T cell based therapies. In the second objective, we describe a metastatic melanoma patient who developed pulmonary sarcoid-like granulomatosis following repetitive vaccination with peptides and CpG. We demonstrated that the onset of this pulmonary autoimmune adverse event was related to the development of a strong and long-lasting tumor-specific CD8+ T cell response. This constitutes the first demonstration that a new generation tumor vaccine can induce the development of autoimmune adverse events. In the third objective, we assessed the use of Fourier Transform Infrared (FTIR) imaging to identify melanoma cells and lymphocyte subpopulations in lymph node (LN) metastasis tissues, thanks to a fruitful collaboration with researchers in Brussels. We demonstrated that the different cell types in metastatic LNs have different infrared spectral features allowing automated identification of these cells. This technic is therefore capable of distinguishing known and novel biological features in human tissues and has, therefore, significant potential as a tool for histopathological diagnosis and biomarker assessment. Finally, in the fourth objective, we investigated the role of colony- stimulating factor-1 (CSF-1) in modulating the anti-tumor response in ipilimumab-treated patients using IHC and in vitro co-cultures, revealing that melanoma cells produce CSF-1 via CTL-derived cytokines when attacked by cytotoxic T lymphocytes (CTLs), resulting in the recruitment of immunosuppressive monocytes. These findings support the combined use of CSF-1R blockade with T cell based immunotherapy for melanoma patients. Taken together, our results reveal the existence of novel mechanisms of immune modulation and thus promote the optimization of combination immunotherapies against melanoma. -- Le mélanome cutané est un des cancers humains les plus invasifs et métastatiques et est responsable de 75% de la mortalité liée aux cancers de la peau. Les thérapies comme la chirurgie et la chimiothérapie ont échoué à contrôler le mélanome métastatique, par ailleurs les rechutes sous ces traitements ont été montrées fréquentes. Il est donc essentiel de développer et d'optimiser de nouvelles stratégies thérapeutiques pour améliorer les réponses thérapeutiques de ces patients. Durant les dernières décennies, les immunologistes spécialisés dans les tumeurs ont démontré qu'un patient atteint du mélanome pouvait développer spontanément une réponse immune adaptative à sa tumeur et que l'accumulation de cellules T spécifiques tumorales au sein même de la tumeur était un des plus puissants facteurs pronostiques. Les immunothérapies qui ont pour but d'augmenter les fonctions naturelles de ces cellules T spécifiques tumorales ont donc émergé comme des approches thérapeutiques très attractives pour éliminer les cellules du mélanome. Alors que les derniers essais cliniques ont démontré un progrès important dans le traitement des formes avancées du mélanome, le contrôle de la maladie à long-terme est seulement atteint chez une minorité des patients. La suppression immune locale et systémique apparaitrait comme une des raisons expliquant la persistance d'un mauvais pronostic clinique chez ces patients. Ces considérations soulignent la nécessité de mieux analyser et caractériser les voies immunitaires non seulement au niveau local dans le microenvironement tumoral mais aussi au niveau systémique dans le sang des patients. Le but de cette thèse est d'obtenir une plus grande connaissance de la complexité et de l'hétérogénéité du microenvironement tumoral dans les mélanomes mais aussi d'investiguer la modulation immunitaire au delà du microenvironement tumoral au niveau systémique. Afin d'atteindre ce but, nous avons établi deux objectifs principaux : caractériser précisément la modulation locale et systémique du système immunitaire (i) chez les patients atteints du mélanome qui n'ont pas reçu de traitement et (ii) chez les patients qui ont été traités soit par des vaccins soit par des thérapies qui bloquent les points de contrôles. Dans la première et majeure partie de cette thèse, nous avons analysé les vaisseaux lymphatiques en relation avec la réponse immunitaire anti-tumorale dans les tissus des patients vaccinés grâce à des techniques d'immunohistochimie et de quantification informatisé et automatique des marquages. Nous avons trouvé qu'une densité élevée de vaisseaux lymphatiques dans la tumeur était associée à une plus grande expression de molécules immunosuppressives ainsi qu'à une diminution de la fonctionnalité des cellules T spécifiques tumoral dans la tumeur et dans le sang des patients. Ces résultats révèlent un rôle jusqu'à là inconnu des vaisseaux lymphatiques dans la modulation directe du système immunitaire au niveau local et systémique dans les cancers de l'homme. Cette recherche apporte finalement des preuves du potentiel de combiner des thérapies visant le système lymphatique avec des autres immunothérapies déjà utilisées en clinique. Dans le second objectif, nous rapportons le cas d'un patient atteint d'un mélanome avec de multiples métastases qui a développé à la suite de plusieurs vaccinations répétées et consécutives avec des peptides et du CpG, un évènement indésirable sous la forme d'une granulomatose pulmonaire sarcoid-like. Nous avons démontré que l'apparition de cet évènement était intimement liée au développement d'une réponse immunitaire durable et spécifique contre les antigènes de la tumeur. Par là- même, nous prouvons pour la première fois que la nouvelle génération de vaccins est aussi capable d'induire des effets indésirables auto-immuns. Pour le troisième objectif, nous avons voulu savoir si l'utilisation de la spectroscopie infrarouge à transformée de Fourier (IRTF) était capable d'identifier les cellules du mélanome ainsi que les différents sous-types cellulaires dans les ganglions métastatiques. Grâce à nos collaborateurs de Bruxelles, nous avons pu établir que les diverses composantes cellulaires des ganglions atteints par des métastases du mélanome présentaient des spectres infrarouges différents et qu'elles pouvaient être identifiées d'une façon automatique. Cette nouvelle technique permettrait donc de distinguer des caractéristiques biologiques connues ou nouvelles dans les tissus humains qui auraient des retombées pratiques importantes dans le diagnostic histopathologique et dans l'évaluation des biomarqueurs. Finalement dans le dernier objectif, nous avons investigué le rôle du facteur de stimulation des colonies (CSF-1) dans la modulation de la réponse immunitaire anti-tumorale chez les patients qui ont été traités par l'Ipilimumab. Nos expériences in vivo au niveau des tissus tumoraux et nos co-cultures in vitro nous ont permis de démontrer que les cytokines secrétées par les cellules T spécifiques anti-tumorales induisaient la sécrétion de CSF-1 dans les cellules du mélanome ce qui résultait en un recrutement de monocytes immunosuppresseurs. Dans son ensemble, cette thèse révèle donc l'existence de nouveaux mécanismes de modulation de la réponse immunitaire anti-tumorale et propose de nouvelles optimisations de combinaison d'immunothérapies contre le mélanome.

Simultaneous acute pulmonary embolism and isolated septal myocardial infarction in a young patient

While the overall incidence of myocardial infarction (MI) has been decreasing since 2000 [1], there is an increasing number of younger patients presenting with MI [2]. Few studies have focused on MI in very young patients, aged 35 years or less, as they only account for a minority of all patients with myocardial infarction [3]. According to the age category, MI differs in presentation, treatment and outcome, as illustrated in table 1. Echocardiography is considered mandatory according to scientific guidelines in the management and diagnosis of MI [4,5,6]. However, new imaging techniques such as cardiac magnetic resonance (CMR) and computed tomography (CT) are increasingly performed and enable further refinement of the diagnosis of MI. These techniques allow, in particular, precise location and quantification of MI. In this case, MI was located to the septum, which is an unusual presentation of MI. The incidence of pulmonary embolism (PE) has also increased in young patients over the past years [7]. Since symptoms and signs of PE may be non-specific, establishing its diagnosis remains a challenge [8]. Therefore, PE is one of the most frequently missed diagnosis in clinical medicine. Because of the widespread use of CT and its improved visualization of pulmonary arteries, PE may be discovered incidentally [9]. In the absence of a congenital disorder, multiple and/or simultaneous disease presentation is uncommon in the young. We report the rare case of a 35 year old male with isolated septal MI and simultaneous PE. The diagnosis of this rare clinical entity was only possible by means of newer imaging techniques.

A matter of scale: apparent niche differentiation of diploid and tetraploid plants may depend on extent and grain of analysis

Aim: Emerging polyploids may depend on environmental niche shifts for successful establishment. Using the alpine plant Ranunculus kuepferi as a model system, we explore the niche shift hypothesis at different spatial resolutions and in contrasting parts of the species range. Location: European Alps. Methods: We sampled 12 individuals from each of 102 populations of R. kuepferi across the Alps, determined their ploidy levels, derived coarse-grain (100x100m) environmental descriptors for all sampling sites by downscaling WorldClim maps, and calculated fine-scale environmental descriptors (2x2m) from indicator values of the vegetation accompanying the sampled individuals. Both coarse and fine-scale variables were further computed for 8239 vegetation plots from across the Alps. Subsequently, we compared niche optima and breadths of diploid and tetraploid cytotypes by combining principal components analysis and kernel smoothing procedures. Comparisons were done separately for coarse and fine-grain data sets and for sympatric, allopatric and the total set of populations. Results: All comparisons indicate that the niches of the two cytotypes differ in optima and/or breadths, but results vary in important details. The whole-range analysis suggests differentiation along the temperature gradient to be most important. However, sympatric comparisons indicate that this climatic shift was not a direct response to competition with diploid ancestors. Moreover, fine-grained analyses demonstrate niche contraction of tetraploids, especially in the sympatric range, that goes undetected with coarse-grained data. Main conclusions: Although the niche optima of the two cytotypes differ, separation along ecological gradients was probably less decisive for polyploid establishment than a shift towards facultative apomixis, a particularly effective strategy to avoid minority cytotype exclusion. In addition, our results suggest that coarse-grained analyses overestimate niche breadths of widely distributed taxa. Niche comparison analyses should hence be conducted at environmental data resolutions appropriate for the organism and question under study.