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京都大学 / 新制・論文博士 / 博士(医学) / 乙第13481号 / 論医博第2256号 / 新制||医||1059(附属図書館) / (主査)教授 平井 豊博, 教授 岩田 想, 教授 秋山 芳展 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

In the last decade, the potential of β-glucan, a fungal cell wall component, to induce epigenetic and functional modification of innate immune cells, signified as trained innate immunity (TII) has been demonstrated in several pre-clinical and clinical studies. Parenteral administration of β-glucan has resulted in centrally induced TII in the bone marrow/circulating monocytes. Such trained innate immune cells play a critical role in protection against secondary infections. However, there are now indications that inducing local long-lasting immunity at mucosal barrier tissues such as the lung is warranted for protective immunity against respiratory pathogens. Currently, it remains unclear whether respiratory mucosal administration of β-glucan will induce long-lasting resident-memory macrophages and TII and if so, what are the underlying mechanisms of development and maintenance of memory macrophages at respiratory mucosa. To address this, and kinetics of immune responses in the lung were studied. Profound changes in airway macrophage (AM) pools were observed starting from 3 days post-exposure, which was associated with monocyte recruitment, and this was followed by a series of phenotypic shifts in AMs. The altered AM phenotype profile persisted for up to 8 weeks post-exposure. Importantly, β-glucan-trained AMs demonstrated heightened MHC II expression, enhanced responses to secondary stimulation and improved capacity to perform bacterial phagocytosis. Furthermore, mice with, β-glucan-trained AMs displayed higher rates of survival and improved bacterial control, in the lung and periphery, following a lethal S. pneumoniae infection. Our findings together indicate that a single intranasal delivery of β-glucan is able to train AMs. Further work into epigenetics, metabolism, and the contribution of AMs in protection is needed. / Thesis / Master of Health Sciences (MSc) / The immune system has been classically divided into two major compartments known as the innate and adaptive immune system. For decades, the predominant consensus amongst the field was that only the adaptive immune system can form memory against any pathogens encountered. It has been well established that plants and invertebrates only possess an innate immune system and still show boosted responses and enhanced protection against previously encountered as well as new pathogens. Recently, such capacity for innate immune memory has also been demonstrated in humans and pre-clinical animal models. Innate immune memory provides non-specific, broad- spectrum protection whereas adaptive memory is specific to a singular pathogen. Inducing broad-spectrum protection can be crucial for the future of human medicine. Activation of both adaptive and innate immune arms could prove to be extremely beneficial in vaccination strategies. Through the use of a pre-clinical model, we have found that administering β-glucan, a component of fungal cell wall, directly into the lung significantly alters the phenotype and functionality of lung immune cells, and also provides enhanced protection against a heterologous infection.

Pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) is the leading cause of infectious disease-related death worldwide. The critical role of adaptive immunity in anti-TB host defence has been firmly established; thus, current efforts in developing novel vaccination strategies against TB are primarily focused on generating protective adaptive immunity at the infection site, the lungs. Innate immunity has not been a target for vaccination strategies against TB due to the belief that innate immune cells cannot exhibit memory-like characteristics which are known to be central to the long-lasting immunity created by vaccines. Also, the importance of innate immunity in anti-TB immunity has been overlooked. However, over 25% of individuals that are heavily exposed to M.tb clear infection without any detectable conventional T cell immune responses, suggesting a crucial role for innate immune cells in bacterial clearance. Interestingly, the early protection in these individuals is associated with their Bacillus Calmette-Guerin (BCG) vaccination status. Epidemiological studies have shown that BCG is capable of providing protection against numerous infections unrelated to TB in an innate-immune dependent manner. Such observations suggest that the innate immune system exhibits memory-like characteristics, capable of remembering the exposure to the vaccine and thereby responding in an augmented manner to future systemic infections. Nonetheless, it still remains unknown whether parenteral BCG immunization modulates the innate immune cells in the lung and airways, and if so, what role the trained innate immune cells play in early protection against pulmonary TB. Using a subcutaneous BCG immunization and pulmonary TB challenge murine model, we show that early protection against M.tb is independent of adaptive responses in the BCG immunized host. Our data suggest that enhanced early protection is mediated by the BCG-trained memory alveolar macrophages that we have shown to be functionally, phenotypically, metabolically, and transcriptionally altered following immunization. These novel findings suggest a significant anti-TB immune role for the innate immune memory established in the lung following parenteral BCG immunization and have important implications for the development of novel vaccination strategies against TB. / Thesis / Master of Science (MSc) / Pulmonary tuberculosis (TB) is a disease of the lung and is now one of the leading causes of human mortality worldwide. For more than eight decades, parenterally administered Bacillus Calmette–Guérin (BCG) vaccine has been globally used as the only approved vaccine against TB. Recently, it has also been observed that BCG vaccination provides protection against other diseases unrelated to TB and reduces childhood mortality in many developing countries where it is routinely administered to children shortly after birth. The mechanisms underlying the off-target protective effects of BCG vaccine remains largely under-investigated. In this project, we investigated how BCG vaccination enhances the immune system responses against TB and other unrelated infectious diseases. A better understanding of how the BCG vaccination modulates our immune system will provide us with the knowledge that will be useful in the development of more effective vaccination strategies against infectious diseases.

There are limited methods of assessing pulmonary function in horses at rest. In this study, we developed clinical techniques to measure gas exchange efficiency in horses. These techniques were then used to evaluate horses with varying degrees of lower respiratory disease. Three groups of horses (Group 1: asymptomatic, n=6; Group 2: symptomatic only with rebreathing, n=11; Group 3: symptomatic at rest, n=9) were selected based on physical exam, transtracheal aspirate, and thoracic radiographs. Blood samples were obtained from the transverse facial artery and jugular vein. Maximal end-tidal CO₂ tension (E_TCO₂) was measured by an infrared capnograph through a facemask. Alveolar O, tension, alveolar dead space fraction (V_DB/V_T), and physiologic shunt fraction (Q_S/Q_T) were calculated using standard formulas. Horses with both mild and severe signs of lower respiratory disease had significant (p<0.05) differences in gas exchange indices at rest compared to asymptomatic horses. Albuterol was administered to seven of the Group 2 horses from a metered-dose inhaler through an equine facemask at a dose of 90 μg per 100 kg. Blood samples and tidal gas samples were obtained 15 minutes post-treatment, and Q_S/Q_T and (V_DB/V_T) were calculated. Albuterol caused significant (p<0.05) hypoxemia 15 minutes following inhaled administration. This was accompanied by a significant increase in Q_S/Q_T, suggesting that the hypoxemia was due to increases in which the ratios of ventilation to perfusion were decreased. / Master of Science

[EN] Hollow core slab is a prestressed precast concrete structural element very commonly used in the industrial construction context. It is manufactured in highly industrialized precast factories where its design parameters are under control. Hollow core slab optimization takes particular advantage of this aspect. Moreover, up to now there are no other works related to this topic where clear conclusions about optimal hollow core slab design had been obtained. Therefore, the main aim of this research work is to obtain significant conclusions related to the optimal design of hollow core slab series through a multi-objective approach. Hollow core slab series are formed by several elements which share the same concrete geometry and have different reinforcement. The optimization carried out is constrained, due to the fact that several geometrical and mechanical constrains have been identified. Heuristic algorithms have been used in order to solve this optimization problem. Specifically the Simulated Annealing algorithm has been used to solve the mono-objective and multi-objective optimization problem. Besides, geometrical and mechanical models to reproduce hollow core behaviour have been performed by the author to use heuristic algorithms and obtain optimal solutions along its life cycle. From the optimization results new hollow core optimal designs have found out, obtaining important economical savings (15-17% lower than current commercial design). Finally, a new hollow design based on three different parts has been performed to be used in practice. Several useful design rules for the hollow core slab manufacture from an optimal approach have been provided. / [ES] La placa alveolar pretensada es un elemento estructural prefabricado de hormigón pretensado empleado muy profusamente en el ámbito de la construcción industrial. Su producción está altamente industrializada en plantas de producción específica, con un elevado grado de control sobre sus variables de diseño. Este último aspecto la hace especialmente interesante en el campo de la optimización estructural. Además debe sumarse a este hecho el que no se hayan desarrollado hasta la fecha otros trabajos de investigación significativos que deduzcan conclusiones claras sobre el diseño óptimo de la placa alveolar. Por tanto, el presente trabajo tiene como objetivo fundamental aplicar criterios de optimización multiobjetivo al diseño de series completas de placa alveolar, entendiendo éstas como un conjunto de placas alveolares que comparten un diseño de molde de hormigón y se diferencian en el diseño de las armaduras interpuestas. La optimización desarrollada es de tipo condicionada, ya que se establecen múltiples restricciones de tipo geométrico y mecánico. Para la resolución del problema se han implementado técnicas heurísticas, muy desarrolladas en el ámbito de la investigación operativa, empleadas para la resolución de problemas de optimización combinatoria. Concretamente se han adaptado en este problema diversos algoritmos del tipo Simulated Annealing tanto monoobjetivo como multiobjetivo. Para la resolución del problema, además de la construcción de las diversas heurísticas necesarias como herramienta de optimización, se han diseñado los modelos matemáticos tanto geométricos como mecánicos a efecto de evaluar la idoneidad de las soluciones alcanzadas a lo largo de todo su ciclo de vida. De los resultados obtenidos se han podido deducir interesantes conclusiones en relación con el diseño óptimo de series de placa alveolar, alcanzando unos ahorros en términos económicos del entorno del 15-17 % con respecto a los diseños comerciales actuales. Por último, dándole un importante carácter aplicado al presente estudio, se ha propuesto un novedoso diseño de alveolo triple óptimo para la fabricación de las series de placa alveolar pretensada así como diversas recomendaciones útiles de diseño. / [CA] Les plaques alveolars pretesades son un element estructural prefabricat de formigó pretesat utilitzat de manera profusa a l'àmbit de la construcció industrial. La seua producció està altament industrialitzada en plantes de producció específica. Amb elevat grau de control sobre les seues variables de disseny. Aquest últim aspecte la fa especialment interessant al camp de l'optimització estructural. A més a més ha d'afegir-se a aquest fet el que no s'hagen desenvolupat fins ara altres treballs d'investigació significatius que dedueixen conclusions clares sobre el disseny òptim de la placa alveolar. Per tant, aquest treball té com objectiu fonamental aplicar criteris d'optimització multi objectiu al disseny de sèries completes de placa alveolar, entenent estes com un conjunt de plaques alveolars que comparteixen el disseny del mole es diferencien en el disseny de les armadures. L'optimització desenvolupada es de tipus condicionat, ja que s'estableixen múltiples restriccions de tipus geomètric i mecànic. Per a la resolució del problema s'han implementat tècniques heurístiques, molt desenvolupades en l'àmbit de la investigació operativa, empleades per a la resolució de problemes d'optimització combinatòria. Concretament s'han adaptat en aquest problema diversos algoritmes del tipus Simmulated Annealing, tant monobjectius como multi objectius. Per a la resolució del problema, a més a més de la construcció de les diverses heurístiques necessàries como a ferramenta d'optimització, s'han dissenyat els models matemàtics tant geomètric como mecànics per a avaluar la idoneïtat de les solucions obtingudes al llar del seu cicle de vida útil. Des resultat obtinguts es poden deduir interesants resultats en relació amb el disseny òptim de sèries de placa alveolar, arribant fins a uns estalvis econòmics del 15-17 % en comparació amb els dissenys comercials actuals. Per últim, donant-li una important vessant aplicada al present estudi, un nou disseny d'alveol triple òptim ha sigut proposat per a la fabricació de sèries de placa alveolar pretesades així como diverses recomanacions útils de disseny. / Albero Gabarda, V. (2016). OPTIMIZACIÓN MULTIOBJETIVO DE LA PLACA ALVEOLAR PRETENSADA [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/73145

AIM: To evaluate marginal bone loss around dental implants at the 2nd stage abutment surgery and retrospectively evaluate the association of pre-surgical variables. MATERIAL AND METHODS: Eighty-seven subjects (41 Males and 46 females) were enrolled in this cohort. The subjects' ages ranged from 23 to 80 years. Two endosseous implant brands were utilized: Nobel Biocare and Straumann Bone Level . Clinical measurements (mesial, distal, buccal, and lingual) were recorded from the coronal margin of the implant platform to the bone margin with a periodontal probe (Williams periodontal probe, Hu-Friedy) at the time of implant placement and at the 2nd stage abutment surgery. The pre-surgical variables (medication intake, implant site, bone graft volume, membrane type, and smoking) were evaluated using Chi-square test. RESULTS: The marginal bone loss (MBL) difference was calculated. The Mean clinical MBL: Mesial = 0.71 mm, Distal = 0.56mm, Buccal/Labial = 0.65 mm, and Lingual/Palatal = 0.56 mm. The test showed no statistically significant difference between test and control subjects in each of the variables, with the exception of thyroid medication. A statistically significant (P value = 0.011) association was found between levothyroxine and MBL at the mesial measurement. CONCLUSION: This limited cohort study suggests that medication-controlled hypothyroidism patients may experience an increased risk of marginal alveolar bone loss around dental implants at the 2nd stage abutment surgery. The final determination will be recalculated when the study population reaches the estimated requirement of 200 subjects.

A doença periodontal é caracterizada por alterações inflamatórias, como vermelhidão e edema da margem gengival, sangramento provocado, alterações no contorno gengival e perda óssea alveolar. Evidências recentes sugerem que o fator de crescimento endotelial vascular (VEGF) pode ser um mediador importante na doença periodontal inflamatória. Portanto, este trabalho teve como objetivos avaliar durante a progressão da doença periodontal inflamatória induzida experimentalmente em ratos: 1) o efeito do meloxicam, inibidor preferencial da COX-2, na perda óssea alveolar; 2) a cinética de expressão de RNAm para COX-2, VEGF, VEGFR-1 e VEGFR-2; e 3) a cinética de expressão da proteína VEGF. Cento e vinte (120) ratos foram aleatoriamente divididos em: grupo 1 (sem tratamento com meloxicam) e grupo 2 (tratados com meloxicam). Ligaduras de fio de seda foram colocadas na margem gengival do primeiro molar inferior direito de todos os ratos. O grupo 2 foi tratado por 3, 7, 14 e 30 dias com meloxicam (3 mg/kg/dia, via intraperitoneal) e o grupo 1 foi usado como controle. As técnicas utilizadas para as análises foram: análise microscópica, RT-PCR, Western Blot e imunohistoquímica. Os resultados foram submetidos à análise de Correlação de Pearson, Análise de Variância (ANOVA), seguida do teste de Tukey, sendo adotado nível de significância de 5%. Observou-se, neste estudo, que o meloxicam foi efetivo em diminuir a perda óssea alveolar nos tecidos periodontais em todos os períodos de indução da doença periodontal. Experimentos de RT-PCR revelaram correlação positiva da cinética de expressão de RNAm para COX-2 e VEGF nos tecidos gengivais afetados pela doença periodontal inflamatória (R=0,80). A expressão de RNAm para VEGF na doença periodontal inflamatória, no período de 14 dias, diminuiu no grupo de animais tratados com meloxicam, mostrando diferença estatisticamente significativa quando comparado com os animais não tratados (p=0,023). Não houve diferença significativa na expressão de RNAm para os receptores VEGFR-1 e VEGFR-2 no tecido gengival em nenhum dos períodos de indução da doença periodontal. Nos experimentos de Western Blot houve tendência de menor expressão da proteína VEGF na doença periodontal inflamatória no período de 14 dias nos animais tratados com meloxicam (p=0,08). Em experimentos de imunohistoquímica foi detectado aumento da expressão da proteína VEGF nos tecidos afetados pela doença periodontal em todos os períodos estudados, bem como diminuição da expressão desta proteína nos tecidos periodontais dos animais tratados com meloxicam. Portanto, a análise conjunta dos dados sugere importante participação do VEGF na doença periodontal inflamatória induzida experimentalmente em ratos e o meloxicam, inibidor preferencial da COX-2, pode modificar a progressão da doença periodontal neste modelo experimental por diminuir a perda óssea e a expressão de VEGF. / Inflammatory periodontal disease is characterized by alveolar bone loss and inflammatory changes in the periodontal tissues, which become hemorrhagic and edematous. However, there is little information concerning the biologic mechanisms which may produce these changes. Vascular endothelial growth factor (VEGF) is a macromolecule of importance in inflammation. The aims of this study were to investigate the presence of VEGF during progression of periodontal disease, and to evaluate the effect of a preferential COX-2 inhibitor, meloxicam, on the alveolar bone loss and VEGF expression in experimentally induced periodontitis. One hundred and twenty (120) Wistar rats were randomly separated into two groups [group 1 (no treatment with meloxicam) and group 2 (treatment with meloxicam)]. Silk ligatures were placed at the gingival margin level of the lower right first molar of all rats. Group 2 was treated for 3, 7, 14 and 30 days with meloxicam (3 mg/kg/day, intraperitoneal) and the group 1 was used as control. The expression of VEGF was assessed by RT-PCR, Western Blot and immunohistochemical analysis. Alveolar bone loss was determined by microscopic analysis. The results were submitted to the analysis of Correlation Coefficient by Pearson, Analysis of Variance (ANOVA), and Tukey\'s post test (p<0.05). A reduction of the alveolar bone resorption was observed in the meloxicam treated group (2), as compared with the control group (1) in all periods studied. There was a positive correlation between COX- 2 mRNA and VEGF mRNA in the gingival tissue with periodontal disease (R=0.80). VEGF mRNA expression was significantly lower in rats treated with meloxiam after 14 days (p=0.023). No difference in the expression of VEGFR-1 mRNA and VEGFR-2 mRNA was observed for all the periods studied. VEGF protein expression was significantly higher in diseased sites as compared with healthy sites (p<0.05). After 14 days lower VEGF protein expression in rats treated with meloxicam was detected (p=0.08). Altogether these data suggest an important participation of VEGF in the progression of periodontal disease, and the systemic therapy with meloxicam, preferential COX-2 inhibitor, can modify the progression of experimentally induced periodontitis in rats by reducing the alveolar bone loss and the VEGF expression.