京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18856号 / 医博第3967号 / 新制||医||1007(附属図書館) / 31807 / 京都大学大学院医学研究科医学専攻 / (主査)教授 野田 亮, 教授 小川 誠司, 教授 松田 道行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Surgical castration of young male piglets is an extremely common husbandry procedure in the United States swine industry, with nearly 100% of males castrated. The procedure is performed primarily to prevent the occurrence of boar taint in the meat and to reduce aggression as the animals age. No research has investigated the impact of surgical castration on the long-term mood states – also known as the affective state – of piglets, but it has been proven to cause both acute and chronic pain that can last up to 4 days, modify piglet behavior, and reduce weight gain. Because of this, feasible approaches for pain alleviation are needed. A hinderance to this is that currently no analgesics are approved for piglets. In addition, we need validated, practical methods to recognize pain in piglets in order to help researchers, veterinarians, and caretakers to identify the need for analgesics. One useful tool for this could be the Piglet Grimace Scale, which has previously been validated in this context, but is not widely applied. The current lack of analgesic use during castration may be cause for concern for consumers, however little is known about the public's knowledge on the industry's practices. Therefore, the thesis' objectives are to (1) assess the impact of surgical castration on pain and affective states, (2) determine people's ability to recognize pain expression after surgical castration, and (3) get insights into public perception of swine industry practices. In Chapter 3, we assessed the impact of surgical castration and practical pain alleviation methods during and after castration on piglets' short and long-term affective states and activity levels. Piglets were surgically castrated, castrated with analgesics, or sham-handled at 3 days of age. Data on piglets' activity (using accelerometers), tails (affective states), and grimaces (pain expression) were collected for 1, 6, and 24 hours after castration treatments while piglets were in their home pens. An attention bias test was then performed in week 1 and 12 to assess anxiety (an affective state). Home pen activity after castration treatments suggested that there was a positive impact of using analgesics. The piglets' behavior (eating) and activity during the attention bias test at week 1 suggest a negative impact of castration on affective states. The differences observed in week 1 were no longer found in week 12, suggesting that any impact of surgical castration at 3 days of age on affective states are no longer detectable at 12 weeks of age. In Chapter 4, through an online survey we investigated the validity and reliability of Piglet Grimace Scale ratings applied by swine industry professionals and the general public, to assess its potential utility in non-research settings. The survey contained a training, followed by 9 piglet images showing facial expressions immediately after castration or sham-handling. Both response groups were able to recognize pain in castrated piglets. However, both response groups overestimated pain experience compared to trained experts, suggesting more training may be necessary. Nevertheless, overall, the scale can be widely applied by veterinarians, industry professionals and even members of the public. In Chapter 5, a survey provided initial insights into public knowledge and perceptions on castration and analgesia use and compared this to industry stakeholders. The results show that knowledge on industry practices was especially lacking for public respondents, but also for a minority of industry respondents, indicating opportunities for education and further research on the topic. / Master of Science / Surgical castration is performed on nearly every male piglet in the United States swine industry. Males are castrated to prevent the occurrence of boar taint and to reduce aggression. Boar taint is the unpleasant odor produced by the skatole and androsterone in the fat when the meat is prepared. It is unclear how this practice impacts piglet's long-term mood states (affective states), but we do know it causes pain, changes in behavior, and reduced productivity. Thus, we need feasible approaches for pain relief. However, there are currently no pain relievers approved for piglets. In addition, we need validated, practical methods to quantify pain in piglets in order to identify the need for pain relief. One useful tool is the Piglet Grimace Scale, which is validated but is not widely applied. The current lack of pain relief use during castration may concern consumers, yet no data is collected on this. Therefore, the thesis' objectives are to (1) assess the impact of surgical castration on pain and affective states, (2) determine people's ability to recognize pain expression after surgical castration, and (3) get insights into public perception of swine industry practices. In Chapter 3, we assessed the impact of surgical castration and practical pain alleviation methods during and after castration on piglets' short and long-term affective states and activity levels. Piglets were surgically castrated, castrated with analgesics, or sham-handled at 3 days of age. Home pen activity after castration treatments showed a positive impact of using analgesics. The piglets' behavior and activity during an attention bias test at week 1 suggest that piglets were experiencing a negative emotional state after castration. The differences seen in week 1 were no longer found in week 12. This suggests that any potential impact of surgical castration on affective states are no longer detectable at 12 weeks of age. In Chapter 4, an online survey was used to investigate the Piglet Grimace Scale ratings applied by swine industry professionals and the general public. After training, respondents scored 9 images showing facial expressions of piglets after castration or sham-handling. Both public and industry people were able to recognize pain in castrated piglets. However, both response groups overestimated the pain experience compared to trained experts, suggesting more training may be necessary. Nevertheless, overall findings suggest that the scale can be widely applied. In Chapter 5, a survey provided insights into public knowledge and perceptions on castration and pain relief use in the industry, and compared this to industry stakeholders. The results showed that knowledge on industry practices was especially lacking for public respondents, but also for a minority of industry respondents, indicating opportunities for education and further research on the topic.

By Her Own Hand: Female Agency Through Self-Castration in Nineteenth-Century British Fiction explores the intentional methods of self-castration that lead to authorial empowerment. The project relies on the following self-castration formula: the author’s recognition of herself as a being defined by lack. This lack refers to the inability to signify within the phallocentric system of language. In addition to this initial recognition, the female author realizes writing for public consumption emulates the process of castration but, nevertheless, initiates the writing process as a way to resituate the origin of castration—placing it in her own hand. The female writer also recognizes her production as feminine and, therefore works to castrate her own femininity in her pursuit to create texts that are liberated from the critical assignation of “feminine productions.” Female self-castration is a violent act of displacement. As the author gains empowerment through the writing process, she creates characters that bear the mark of castration. The text opens a field of play in which the author utilizes the page as a way to cut, disfigure, or erase the feminine sexual body. On the authorial level, the feminine writer works through her self-castration process through the process of writing, editing, and publication. Within the text, her characters demonstrate a will toward liberation from authorial productive hegemony by carrying the mark of their creator’s castration and by taking on the power the process allocates to the writer.

Cette thèse, La représentation féminine chez Alain Robbe-Grillet, a pour objectif d’étudier la place primordiale occupée par la femme dans les œuvres de cet auteur. La femme joue bien évidemment un rôle essentiel dans la vie des hommes. Elle représente le noyau de la vie. Depuis des siècles, elle est source d’inspiration artistique et lieu de controverse. Pour cette raison, la femme a retenu notre attention. [...] / This thesis, which deals with the representation of women in Alain Robbe-Grillet’s work, aims at studying the essential place occupied by women in in his different novels. Naturally, women play an essential part in the life of men. They represent the essence of life. For centuries, she is artistic source of inspiration and place of controversy. That is why the role played by women in Alain Robbe-Grillet’s work seems to us particularly important. [...]

Ce travail de thèse propose d’approfondir la compréhension de l’anorexie de l’adolescente à partir d’une méthodologie projective (Rorschach et T.A.T.).Il révèle notamment la présence d’une instabilité des frontières du Moi et un dépassement insuffisant des conflits prégénitaux venant influer sur la construction du féminin et favoriser le recours à des défenses de type phalliques narcissiques permettant d’éviter tout autant le vécu de séparation que celui de dépendance.Ce travail met par ailleurs en évidence un traitement singulier des fantasmes de séduction marqué par un renversement de la construction hystérique, l’insuffisance du refoulement et l’impossibilité à investir une position passive venant entraîner un vécu spécifique marqué par une exacerbation des angoisses persécutives qui paraît liée au caractère insuffisamment sécurisé des frontières propres et à la difficulté de régulation de l’excitation pulsionnelle.Dans son approche différentielle, ce travail révèle également chez les patientes présentant un profil restrictif une plus grande efficience des défenses narcissiques en comparaison des patientes présentant un tableau d’anorexie-boulimie où la problématique de porosité des enveloppes et les difficultés de maniement pulsionnel se dévoilent davantage. Les problématiques mobilisées paraissent néanmoins semblables. L’apport de cette recherche se situe davantage dans la mise en évidence de mouvements de clivage au Moi pouvant conduire à deux types d’aménagements distincts venant s’exercer soit sur un mode persécutif, soit sur un mode adhésif, avec une influence sur le type de structuration psychique de ces adolescentes se révélant indépendante des formes symptomatiques tout en pouvant correspondre à deux temps distincts de la maladie. / This paper attempts to go further into female teen anorexia from the perspective of a projective methodology. It brings particularly to light the presence of a blurred frontier of the Ego and an insufficient expansion of pregenital conflicts which affects the construction of the feminine and facilitates resorting to a narcissistic phallic type of defense which helps avoid the experience of separation as much as that of dependency.This paper brings further to light a particular handling of seduction fantasies marked by a reversal of hysterical construction, insufficient repression and the impossibility to invest a passive position. This leads to a specific real life experience marked by an exacerbation of persecution anxiety which seem to be linked to both the insufficiently secured nature of instinctive excitation and the difficulty to regulate it. From its differential approach, this paper also highlights a better efficiency of narcissist defense in those female patients presenting a restrictive profile compared with those presenting anorexia-bulimia stigmas where porosity of envelopes and difficulty of handling drive are more apparent. However, the issues raised appear to be similar.This research paper brings brings further highlight to the cleavage process phenomenon in the Ego leading of anorectic patients to two distinctive types of psychic adjustments which expresses itself either on a persecution mode or adhesive one. This in turn has an influence on the type of psychic structures in female teens which turn out to be independent from symptomatic forms while they may at the same time correspond to two different stages of the illness.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This study aimed to evaluate performance, behavior as well as meat and carcass characteristics of beef cattle with different sexual conditions, finished at 18 months, raised on Aruana (Panicum maximum Jacq cv. Aruana) pasture, receiving energy supplementation. The treatments consisted of surgically castrated, immunocastrated or non-castrated animals. The experiment consisted of 39 contemporary male bovine animals with initial body weight of 284.1 ± 31.4 kg and average age of 14 months. Chemical composition analysis and patterns of pasture production did not differ among treatments. Average daily gain, final weight and live weight gain per hectare, were not influenced by the sexual condition. In assessing the agonistic behavior of the animals, non-castrated animals more often displayed aggressive activities such as threats and fights when compared to immunocastrated animals. Feeding behavior, grazing time, rumination and idleness were not affected by treatments. Non-castrated animals spent more time at the feeder (56.20 minutes) than either surgically castrated (41.43 minutes) or immunocastrated, (32.38 minutes).. As for carcass attributes, no difference was found for slaughter weight, hot and cold carcass weight and their respective yields. Regarding Muscle and fat yield per 100 kg of cold casting, non-castrated animals had higher muscle ratio (67.9%) vs. castrated calves (65.1%) or immunocastrated (64,1%) in detriment of the greater proportion of fat found in castrated animals. Regarding meat characteristics, meat from immunocastrated and surgically castrated animals demonstrated color with greater intensity of red and yellow hues. The characteristics evaluated by the taste panel did not differ for any of the evaluated sexual conditions and were classified as "slightly above average". The combination of the correct handling of Aruana grazing and the use of supplementation was promising for finishing cattle with different sexual conditions at 18 months of age, considering that there was no difference in average daily gain, final weight and gain liveweight per hectare. Castrates both surgically as immunocastrated obtained higher yield of fat in the carcass while uncastrated animals have higher muscle performance. In the flesh, there was difference in the color, and steers (surgically or immunocastrated) produced meat prone to lighter red color compared to uncastrated cattle. In choosing the method recommended castration this latter, to be a less invasive method for cattle, which determines greater preservation of animal welfare. / Objetivou-se, mensurar o desempenho, o comportamento e as características de carcaça e carne de bovinos de corte com diferentes condições sexuais, terminados aos 18 meses em pastagem de Aruana, recebendo suplementação energética. Os tratamentos consistiram em novilhos castrados cirurgicamente, imunocastrados ou não castrados. Foram utilizados, para o experimento, 39 bovinos machos, contemporâneos, com peso corporal e idade inicial média de 284,1 ± 31,4 kg e 14 meses, respectivamente. Os resultados referentes à análise da composição bromatológica e os parâmetros produtivos da pastagem não diferiram para os tratamentos. As variáveis, ganho médio diário, peso final e ganho de peso vivo por hectare, não sofreram influência da condição sexual. Ao avaliar o comportamento agonístico dos novilhos verifica-se que os não castrados apresentaram maior número de atividades como ameaças e brigas em relação aos imunocastrados. No comportamento ingestivo, os tempos de pastejo, ócio e ruminação não foram influenciados pelos tratamentos. O tempo de permanência no comedouro dos animais não castrados, 56,20 minutos, foi superior ao detectado para castrados cirurgicamente ou imunocastrados, 41,43 e 32,38 minutos. Nos atributos de carcaça, não foi encontrada diferença para peso de abate, peso de carcaça quente e fria, bem como para seus respectivos rendimentos. No que se refere aos rendimentos de músculo e gordura por 100 kg de carcaça fria, os novilhos não castrados obtiveram maior proporção de músculo (67,9%) ao comparar com novilhos castrados cirurgicamente (65,1%) ou imunocastrados (64,1%), em detrimento da maior proporção de gordura dos animais castrados. Para as características de carne, os novilhos castrados cirurgicamente e imunocastrados dispuseram de carnes com maior intensidade de vermelho e amarelo. As características avaliadas pelo painel de degustadores não diferiram para nenhuma das condições sexuais trabalhadas neste ensaio, sendo classificadas como levemente acima da média . A combinação entre o correto manejo da pastagem de Aruana e o uso de suplementação se mostrou promissora para a terminação de bovinos com diferentes condições sexuais aos 18 meses de idade, considerando-se que não houve diferença para ganho médio diário, peso final e ganho de peso vivo por hectare. Animais castrados tanto cirurgicamente quanto imunocastrados obtiveram maior rendimento de gordura na carcaça, enquanto, animais não castrados apresentam maior rendimento de músculo. Na carne, observou-se diferença para a cor, sendo que novilhos castrados (cirurgicamente ou imunocastrados) produziram carne com tendência a coloração vermelho mais claro, comparado aos bovinos não castrados. Na escolha do método de castração se recomenda essa última, por ser um método menos invasivo para o bovino, o que determina maior preservação do bem- estar animal.

Le cancer de la prostate représente actuellement un problème majeur de santé publique. L’hormonothérapie, par privation de l’axe androgénique, constitue aujourd’hui la seule arme thérapeutique efficace pour les formes avancées. Malgré un taux important de réponse initiale, une forme de résistance survient inéluctablement, conduisant pour la plupart au décès du patient. La progression tumorale vers la résistance à la castration est un processus multifactoriel. Elle peut être associée à une dérégulation de l’axe du récepteur des androgènes, l’activation de voies de survie cellulaire, et favoriser une différenciation cellulaire vers l’acquisition d’un phénotype neuroendocrine androgéno-indépendant. L’objectif de la recherche actuelle repose donc sur l’identification de nouveaux biomarqueurs de résistance thérapeutique afin de proposer de nouvelles cibles permettant de contrecarrer la résistance à la castration. La caractérisation d’une signature moléculaire associée à l’émergence d’une différenciation neuroendocrine du cancer de la prostate résistant à la castration a permis d’identifier la Neuropiline-1, une glycoprotéine transmembranaire impliquée dans le développement neuronal et vasculaire. La répression de la voie du récepteur des androgènes au cours de l’hormonothérapie régule dynamiquement l’expression de la Neuropiline-1 et favorise la résistance à la castration associée à une différenciation neuroendocrine. La Neuropiline-1 joue donc un rôle important dans la résistance thérapeutique puisqu’elle favorise la neuro-transdifférenciation, l’activation de voie de survie cellulaire et altère la sensibilité des cellules cancéreuses à la chimiothérapie. L’étude des voies de signalisation associées à la Neuropiline-1 a permis d’identifier la voie des PKCs, impliquée dans la régulation de la différenciation neuroendocrine du cancer de la prostate. Par conséquent, nous montrons pour la première fois que le ciblage de cette voie activée par la Neuropiline-1 bloque l’évolution tumorale vers la résistance à la castration et augmente l’efficacité d’une chimiothérapie à base de docétaxel sur des modèles précliniques in vivo. Parallèlement, la caractérisation des ligands de la Neuropiline a permis d’identifier de nouveaux partenaires dont la Pléiotrophine, comme nouveau ligand associé aux activités biologiques de la Neuropiline-1 dans la carcinogenèse prostatique. L’ensemble de ces travaux apporte de nouvelles connaissances sur la caractérisation de la résistance thérapeutique du cancer de la prostate, et fournit un réel intérêt clinique porteur d’espoir dans la prise en charge de la maladie neuroendocrine résistante à la castration. / Prostate cancer currently represents a major public health problem. Hormone therapy, by deprivation of androgen signaling axis represents the only efficient treatment for advanced forms. Despite effective initial response, a form of resistance inevitably occurs, leading mostly to patient's death. Tumor progression to castration resistance is a multifactorial process. It can be associated to dysregulation of the androgen receptor axis and activation of cell survival pathways, and thus promotes cell differentiation towards the acquisition of an androgen-independent neuroendocrine phenotype. Therefore, the goal of current research is based on the identification of new biomarkers of therapeutic resistance to propose new targets to counteract the castration resistance. The characterization of a molecular signature associated with the emergence of a neuroendocrine castration-resistant prostate cancer identified Neuropilin-1, a transmembrane glycoprotein involved in vascular and neuronal development. Down-regulation of androgen receptor axis during hormone therapy dynamically regulates the expression of Neuropilin-1 and promotes resistance to castration associated with neuroendocrine differentiation. Thus, Neuropilin-1 plays an important role in the therapeutic resistance since it favors the neuro-transdifferentiation, activation of cell survival pathway and alters the sensitivity of cancer cells to chemotherapy. Moreover, the study of signaling pathways associated with Neuropilin-1 and involved in the regulation of the neuroendocrine differentiation of prostate cancer has identified the PKCs pathway. We show for the first time that targeting this pathway activated by Neuropilin-1 blocks tumor evolution towards resistance to castration and increases the efficacy of docetaxel-based chemotherapy in preclinical models in vivo. In parallel, the characterization of Neuropilin’s ligands identified new partners, including Pleiotrophin, as a new ligand associated with Neuropilin-1 biological activities in prostate carcinogenesis. All this work provides new knowledge in the characterization of therapeutic resistance in prostate cancer, and supports a real promising clinical value in the treatment of neuroendocrine castration-resistant form of the disease.

Maladie de l'homme mûr, le cancer de la prostate nécessite des traitements qui rendent le patient impuissant, parfois de manière irréversible. Cela fait écho psychiquement à l'appréhension d'une castration qui n'a pas attendu l'avènement de cette quasi-réalité pour s'avérer l'un des moteurs psychiques de l'angoisse des hommes et de leur dynamique identificatoire, narcissique et objectale. Le cancer de la prostate se révélant être tabou dans notre société, ces hommes sont sommés de souffrir en silence. À l'appui d'une double méthodologie composée d'entretiens et d'épreuves projectives auprès de 17 patients atteints d'un cancer de la prostate (et, dans une visée comparative, de 2 patients atteints d'un cancer du rein et de 2 patients venant pour un simple dépistage), nous nous sommes proposée de discerner comment cette détresse interdite pouvait expliquer en partie la mise en avant d'une position hyper phallique ("même pas peur, même pas triste, même pas mal"). Revendiquer de n'être ni touché ni ébranlé par ce qui arrive permettrait ainsi à ces hommes de pallier une décompensation dépressive, peut-être pire que tout pour eux, car "anti-virile", dans le sens où un homme n'est censé ni chuter, ni s'effondrer, ni se plaindre. C'est pourquoi, dans la filiation des travaux de C. Chabert et de F. Neau, nous avons proposé l'idée d'un "masculin hypomane" ; il serait une défense contre le mouvement mélancolique (à entendre comme traitement narcissique de la perte) insupportable et comme retournement de la passivité en activité contre l'être pénétré (par la maladie, les explorations médicales), l'être traversé (par l'angoisse, le temps qui passe) et l'être excité (par l'autre, son désir). Portée par un faux masculin abritant le genre neutre dans le latent et durcie par un hyperinvestissement narcissique, cette solution serait à la fois coûteuse et mortifère, mais aussi salvatrice et trophique pour le sujet, déplaçant alors les frontières entre normal et pathologique. En effet, elle protégerait le sujet contre les affres de l'effondrement dépressif dans le manifeste, soutiendrait son identité virile déjà bien malmenée. Elle lui permettrait de se défendre contre le mouvement mélancolique qui infiltre le latent et, enfin, elle contiendrait l'excitation désorganisatrice de la pulsion sexuelle derrière les remparts de la pulsion de mort dans sa valence anarchiste. La dimension performative de la virilité nous a ainsi permis d'envisager la clinique de la passation (mais également la relation clinique et les mouvements transférentiels pendant les entretiens) comme un espace potentiellement traumatique (car elle peut, certes, mettre en lumière et révéler une sensibilité à la castration à travers l'implicite de performance) mais aussi, comme un espace transitionnel et thérapeutique. Ce qui semble très important pour la construction future de projets thérapeutiques concernant ces patients. / A disease affecting older men, prostrate cancer requires treatment that renders patients impotent, sometimes permanently. Psychically speaking, this resonates with the fear of castration, which does not await the advent of this quasi-reality to emerge as one of the psychic driving forces of men's anxiety and of their identity-related, narcissistic and objectal dynamic. In today's society, prostrate cancer is a taboo subject; men suffering from the condition are thus forced to suffer in silence. We met 17 patients with prostate cancer and, in a comparative way, 2 patients with kidney cancer and 2 healthy patients. Using projective methods and semi-directive interviews, we attempted to discern how this forbidden distress could partly explain why patients chose to adopt a hyperphallic stance ("Ain't scared, ain't sad, doing just fine !"). Claiming to be neither affected nor shaken by unfolding events would allow these men to mitigate depressive decompensation, which might be the worst thing for them because it would be unmanly insofar as a man must never fall, collapse or complain. Drawing from the studies undertaken by C. Chabert and F. Neau, we thus put forward the notion of "masculine hypomania". This would not only be a defense against unbearable melancholia (construed as the narcissistic treatment of loss), but would also be the reversal of passivity into action against the penetrated being (by disease and medical explorations), the permeated being (by anxiety and the passing of time) and the excited being (by the other and his desire). Driven by narcissistic hyperinvestment, this solution would be costly and mortifying on the one hand, and life-saving and nourishing on the other, moving boards between normality and pathology. Indeed, it would enable patients to defend themselves against depressive decompensation, to support shaken male identity, to defend themselves against melancholic movement and, at last, to contain excitation of the sexual drive through the death instinct in its anarchist valency. The performative dimension of manhood allowed to consider the clinical perspective of test administration (but also clinical relationship and transference during interviews) as a potentially traumatic space (because it could reveal a sensitivity to castration behind the implicit of performance), but also as a transitional and therapeutic space, which seems very important for the construction of therapeutic projects for these patients in the future.