L’action du système nerveux périphérique sympathique sur le métabolisme osseux, via la sécrétion de neurotransmetteurs, comme le VIP, est clairement établie. Réciproquement, les cellules osseuses expriment des molécules possédant des propriétés chémo-attractives (NGF) ou répulsives (Sémaphorine 3a) suggérant que l’os est capable de contrôler sa propre innervation. Afin de mieux comprendre les relations entre système nerveux et cellules osseuses, notre travail s’est déroulé en deux étapes.Dans un premier temps, nous avons montré que la sympathectomie chimique à la guanéthidine monosulfatée, au niveau du périoste mandibulaire, modulait le ratio OPG/RANKL par l’intermédiaire de la voie cholinergique du système nerveux sympathique. Le traitement par du VIP des rats sympathectomisés a permis de rétablir le potentiel résorbant du système sympathique et ainsi confirmé le rôle prépondérant du VIP dans la modulation du métabolisme osseux au niveau du périoste mandibulaire. Dans un deuxième temps, nous avons évalué les variations d’expression du NGF et de la Séma3a, en fonction de la disponibilité locale en VIP. La sympathectomie, dans le compartiment ostéogène du périoste mandibulaire, a épuisé les réserves en proNGF et en Sema 3a et provoqué une migration de fibres sensorielles immunoréactives au CGRP où physiologiquement elles sont absentes. Dans compartiment non-ostéogène, la sympathectomie a induit une dégranulation des mastocytes et la libération de βNGF (forme mature) et le développement de fibres CGRP-IR.. Le traitement par le VIP10-28, un antagoniste des récepteurs du VIP, a provoqué des effets similaires à la sympathectomie. In vitro, le VIP n’a pas modifié l’expression relative des ARNm codant pour le NGF et la Séma 3a, augmenté celle de RANKL et diminué celle d’OPG. Le VIP10-28 a permis d’augmenter l’expression d’OPG, et de diminuer celle de Séma3a et de CGRP. L’ensemble de ce travail a permis de montrer que le système sympathique cholinergique, via le VIP, module à la fois le rapport OPG/RANKL et l’expression de NGF et de Sema3a au niveau des ostéoblastes et du périoste mandibulaire et renforce l’hypothèse d’une communication bidirectionnelle entre les cellules nerveuses et osseuses. / The action of the sympathetic nervous system on bone metabolism, via the secretion of neurotransmitters such as VIP, is clearly established. Conversely, bone cells express molecules with chemo-attractive properties (NGF) or -repulsive (Semaphorin3a), suggesting that bone can control its own innervation. To better understand the relationship between the nervous system and the bone cells, our work takes place in two stages. As a first step, we have shown that chemical monosulfate guanethidine sympathectomy, modulates in the mandible periosteum the OPG/RANKL ratio through the cholinergic nervous system. VIP treatment of sympathectomized rats restored to controls the resorption potential of the sympathetic system and thus confirmed the leading role of VIP in the modulation of bone metabolism in this bone envelope. In a second step, we evaluated, the variations in NGF and Sema3a expressions, according to the local availability in VIP. Sympathectomy, exhausted proNGF and Sema 3a stores in the osteogenic compartment of the periosteum and caused its invasion by CGRP immunoreactive sensory fibers, where they are physiologically absent. In the non-osteogenic compartment, sympathectomy induced mast cell degranulation and release of βNGF (the mature form) and sprouting of CGRP-IR fibers Treatment with VIP10-28, a VIP receptors antagonist, had effects similar to sympathectomy. In vitro, VIP did not alter the relative expression of mRNA encoding NGF and Sema 3a, increased RANKL and decreased OPG mRNAs. VIP10-28 increased OPG mRNA expression and decreased that of Sema3a and CGRP.In conclusion, this work showed that the cholinergic sympathetic system, via VIP, modulates the OPG/RANKL ratio and NGF and Sema3a expression in periosteal osteoblasts and strengthens the hypothesis of a bi-directional communication between nerve and bone cells.

Orientadores: Gustavo Pereira Fraga, Elcio Shiyoiti Hirano / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T11:34:02Z (GMT). No. of bitstreams: 1 Calderan_ThiagoRodriguesAraujo_M.pdf: 1173071 bytes, checksum: 565643da6ec1a5d82f9b31566a9fe7fa (MD5) Previous issue date: 2014 / Resumo: A lesão de cólon, que ocorre em 25% a 41% dos ferimentos por projétil de arma de fogo (FPAF) e em 5% a 20% dos ferimentos por arma branca (FAB) que acometem o abdome, apesar de possuir baixa mortalidade, apresenta uma alta morbidade. O presente estudo teve como objetivo analisar quais os fatores prognósticos envolvidos no aumento da morbidade e da mortalidade no trauma penetrante do cólon. Foi realizado um estudo retrospectivo de 21 anos, em que 462 pacientes foram admitidos com trauma de cólon, excluindo os traumas contusos e lesões grau I, sendo incluídos neste estudo 324 pacientes. Destes, 90,7% eram do sexo masculino, com média de idade de 28,9 anos, sendo que 59,6% encontravam entre 14 e 29 anos. Os FPAF foram responsáveis em 82,4% dos casos. As médias dos escores de trauma foram: RTS de 7,3 (± 1,31), ISS de 16,9 (± 9) e ATI de 25,1 (± 12). Reparo primário foi realizado em 72,2% dos casos. A morbidade global foi de 39,8%, com infecção abdominal em 8% dos pacientes. A mortalidade foi de 13,6%. Fístula ou deiscência de anastomose aconteceu em 14 pacientes (4,3%), sem fator de risco específico para sua ocorrência. Lesões destrutivas do cólon e pacientes com RTS alterado na admissão apresentaram maior taxa de morbidade e mortalidade. Pacientes com hemoperitônio estimado em mais de 1000 mL, múltiplas lesões abdominais associadas e lesões torácicas associadas com o cólon também apresentaram aumento da morbidade. Aqueles pacientes com ISS maior ou igual a 25, que necessitaram de transfusão sanguínea ou apresentaram coagulopatia e com lesões de estômago associada ao cólon apresentaram maior taxa de mortalidade. Conclui-se que é possível predizer o risco de complicações em grupo selecionados de pacientes com trauma penetrante de cólon / Abstract: Colon injuries have a low morbidity, but a high mortality. They occur in 25 to 41% of gunshot and 5 to 20% of stab wound injuries in the abdomen. The present study aims to determine the prognostic factors involved in increased morbidity and mortality rates for penetrating colon trauma. The present study is a retrospective analysis over the last 21 years, were 462 patients were admitted with colon trauma. Patients with blunt trauma and with grade I injuries were excluded. A total of 324 patients were included in the study. Of these patients, 90.7% were male, with a mean age of 28.9 years, with 59,6% of patients between 14 and 29 years old. The gunshot injuries were observed in 82.4% of cases. The trauma scores means were: RTS of 7.3 (± 1.31), ISS of 16.9 (± 9) and ATI of 25.1 (± 12). Primary repair was performed in 72.2% of cases. The overall morbidity rate was 39.8 %, abdominal infections were observed in 8% of the. The mortality rate was 13.6%. Fistula or anastomotic leak was present in 14 patients (4.3%), but not associated with specific risk factors. Destructive lesions of the colon and patient presented with an altered RTS score have a higher morbidity and mortality rates. The presence of hemoperitoneum greater than 1000ml, multiple abdominal injuries or thoracic injuries associates with the colon also had a higher morbidity rate. Those patients with ISS greater than or equal to 25, that required blood transfusions or presented coagulopathy, as well as those sustaining gastric lesions in association with the colon also had a higher mortality rate. In conclusion, it is possible to predict complications in selected group of patients with penetrating colon injury / Mestrado / Fisiopatologia Cirúrgica / Mestre em Ciências

Parâmetros morfométricos do tubo digestório são necessários para o conhecimento dos processos digestivos dos alimentos no organismo animal além de indicar a preferência alimentar de uma espécie. Este trabalho visou descrever morfologicamente os intestinos delgado e grosso, órgãos do sistema digestório de representantes da ordem Xenarthra a fim de fornecer subsídios para a avaliação da dieta e realização de procedimentos clínicos nestes animais, sejam de vida livre ou de cativeiro. Foram utilizados no total 7 espécimes entre preguiças-de-coleira (Bradypus torquatus), tatu-verdadeiro (Dasypus novemcinctus) e tamanduá-bandeira (Myrmecophaga tridactyla). Todas as amostras foram processadas seguindo procedimentos de rotina para a macroscopia, e microscopia de luz e varredura. Os intestinos de B. torquatus se apresentaram curtos e simples, já em D. novemcintus e M. tridactyla notamos intestino longo e com algumas peculiaridades. No duodeno de todos os espécimes notamos presença de glândulas de Brünner, que aumentam a superfície de absorção. Apenas em B. torquatus, o mesentério mantinha o jejuno preso à parede dorsal da cavidade abdominal. O íleo representou a menor porção do intestino em todos os espécimes estudados, exceto M. tridactyla. O ceco em D. novemcinctus e M. tridactyla apresentava tamanho considerável e glândulas na mucosa, indicando a funcionalidade do órgão. Na mucosa do cólon de todos os espécimes, havia criptas de Lieberkühn, sendo mais numerosas em D. novemcinctus e M. tridactyla. Apenas em B. torquatus, o reto apresentou maior diâmetro e rigidez em relação ao cólon. No reto de todas as espécies estudadas, notamos a superfície glandular numerosa e grande quantidade de células caliciformes, que produzem muco para facilitar a defecação. Por fim, neste estudo notamos que os intestinos dos exemplares estudados têm algumas semelhanças entre si, principalmente entre D. novemcintus e M. tridactyla, provavelmente por serem ambos insetívoros, mas diferem em muitos aspectos, por vezes apresentando-se mais próximos aos intestinos de espécies de outras famílias do que dentro da família dos Xenarthras, possívelmente devido à alimentação semelhante / Morphometric parameters of the digestive tract are required for an understanding of the digestive processes of the food in the animal organism, besides indicating the feeding preference of specie. This study aimed to describe morphologically the small and large intestines, organs of the digestive system of representatives of Xenarthra order to provide data for the evaluation of diet and conduct clinical procedures in these animals, whether free-living or captive. At this research, were used in total 7 specimens from three-toed sloths (Bradypus torquatus), nine-banded armadillo (Dasypus novemcinctus) and giant anteater (Myrmecophaga tridactyla). All samples were processed following routine procedures for macroscopic, and light and scanning electron microscopy. The intestines of B. torquatus were short and simple, but at the specimens of D. novemcintus and M. tridactyla the intestines were long and had some peculiarities. We notice the presence of Brunner\'s glands and structures to increase the surface absorption at the duodenum of all specimens. Only in B. torquatus, we notice that the mesentery remains the jejune attached to the dorsal wall of the abdominal cavity. The ileum represented the lower portion of the intestines in all studied specimens except in M.tridactyla. The cecum in D. novemcinctus and M. tridactyla showed considerable size, glands at the mucosa and was full of food debris, indicating that it is functional. In the mucosa of the colon of all specimens had crypts of Lieberkühn, being more numerous in D. novemcinctus and M. tridactyla. Only in B. torquatus, the rectum showed greater diameter and stiffness compared to the colon. In all species studied, we notice a large glandular surface and lots of goblet cells that produce mucus to facilitate defecation. In summary, this study noted that the intestines of the studied has some similarities between them, especially among D. novemcintus and M. tridactyla, probably because they are both insectivores, but differ in many ways, presenting sometimes the intestines more assimilated with species of other families than within the family of Xenarthras, especially among animals with similar feed habits

Le renouvellement de l’épithélium intestinal repose sur la prolifération incessante de cellules souches intestinales (CSI) capables de régénérer l’intégralité de l’épithélium en 3 à 5 jours. Des altérations de ces dernières sont à l’origine de la transformation tumorale. L’étude des mécanismes impliqués dans la protection des CSI face à différents stress est donc essentielle pour mieux comprendre l’homéostasie et les pathologies intestinales. Dans un modèle de souris prédisposées à développer des tumeurs suite à la perte du gène Apc, notre équipe a pu précédemment démontrer une activation de l’autophagie nécessaire à la croissance tumorale. Nos travaux visent à étudier le rôle de ce processus catabolique dans l’homéostasie des CSI. Pour ce faire, nous utilisons des modèles murins génétiquement modifiés et des cultures d’organoïdes afin d’étudier les effets de l’inhibition de l’autophagie dans l’homéostasie intestinale et en particulier dans les CSI.Nos travaux indiquent que l’inhibition de l’autophagie par l’invalidation du gène Atg7 conduit à une activation de p53 et de l’apoptose spécifique des CSI. L’invalidation simultanée du gène Tp53 empêche la mort des CSI déficientes en autophagie. De plus, au long terme, ces souris développent des tumeurs, contrairement aux souris invalidées uniquement pour les gènes Atg7 ou Tp53. Nous avons donc émis l’hypothèse que l’inhibition de l’autophagie sensibilisait les CSI à l’apoptose suite à une accumulation de dommages cytotoxiques. Par une analyse d’expressions géniques des CSI issues de cryptes contrôles et invalidées pour le gène Atg7, nous avons mis en évidence une altération des réponses associées au stress oxydant et à la réparation de l’ADN. Confirmant ces signatures, nous avons observé des dommages de l’ADN dans les cryptes déficientes en autophagie et un défaut de réparation de ces dommages suite à une irradiation. Nous observons également une accumulation d’espèces réactives de l’oxygène dans les CSI déficientes en autophagie associée à une atténuation de la réponse antioxidante médiée par NRF2. Des traitements antibiotiques à large-spectre ou antioxydants améliorent la survie des CSI déficientes en autophagie et soutiennent l’influence des espèces réactives de l’oxygène et de la flore intestinale sur la mort des CSI. Nos travaux indiquent donc un rôle important de l’autophagie dans la protection et le maintien des CSI, de par son contrôle des espèces réactives de l’oxygène, du microenvironnement bactérien et des voies de réparation de l’ADN. / The renewal of the intestinal epithelium relies on the continuous proliferation of stem cells capable of regenerating the entire epithelium every 3 to 5 days. These intestinal stem cells (ISC) are thought to be the cell of origin for colorectal cancer. Thus, characterizing the mechanisms involved the protection of ISC against different stresses is key to understanding both intestinal homeostasis and tumor development. In tumoral tissue from mice predisposed to intestinal tumor development following the loss of the tumor suppressor gene Apc, our laboratory previously showed an upregulation of autophagy required for tumor growth. Our work aims to understand the role this catabolic mechanism in the homeostasis of ISC. To this end, we use genetically modified mouse models and intestinal organoid culture to study the effects of autophagy inhibition in intestinal homeostasis and in particular in ISC.We found that the inhibition of autophagy upon deletion of the gene Atg7 results in p53 activation and apoptosis of ISC specifically. The simultaneous deletion of Tp53 prevents the death of autophagy-deficient ISC. Moreover, over time, mice deficient for both Atg7 and Tp53 develop tumors, contrary to those deficient for either Atg7 or Tp53 alone. We therefore hypothesized that the inhibition of autophagy sensitizes ISC to p53-mediated apoptosis as a result of accumulated pro-tumorigenic damages. Transcriptomic analysis on sorted control or Atg7-deficient ISC revealed aterations in oxidative stress and DNA damage responses. Confirming these signatures, we observed DNA damages in autophagy-deficient crypts along with a defect in the repair of induced damages following irradiation. We additionally observed an accumulation of reactive oxygen species in autophagy-deficient ISC linked to a downregulation of the NRF2-mediated antioxidant response. Wide-spectrum antibiotic or antioxidant treatments improve the survival of autophagy-deficient ISC and support the contribution of both reactive oxygen species and the intestinal microbiota to the death of ISC. Our work therefore reveals we find an important function of autophagy in the integrity and maintenance of ISC by controlling reactive oxygen species, the microbial microenvironment and DNA repair pathways.

This study evaluated the changes in body composition, glycogen tissue reserves, visceral organ growth, and small intestine morphology in the young pig. A total of 96 crossbred pigs were euthanized at birth (pre-suckle), days 1, 2, 3, 5, 7, 14 postpartum, weaning at day 21, and days 1, 2, 3, 5, 7, 14, 28, and 42 post-weaning. Body composition of the pig had increasing dry matter and fat, decreasing ash, calcium and phosphorus, and relatively static protein percentage over the course of the study. Liver and muscle glycogen was greatest at birth. Following birth and weaning there was a distinct decrease in the amount of liver glycogen, while there was only a clear decrease in muscle glycogen at birth. Absolute measures of the visceral organs increased in a variety of manners (linear, quadratic and/or cubic); relative measures of visceral organs responded in different manners to increasing age. In the suckling period, villous height, villous height:crypt depth ratio, and goblet cell count was greater than in the post-weaning period. Crypt depth continued to increase through the entire study. Villi measurements of the middle and distal portion of the small intestine taken via scanning electron microscope, revealed different responses to increasing age, but numerically, villi width increased, villi density, enterocyte width, and microvilli density decreased, and microvilli diameter was relatively static. Villi, on average, increased the absorptive area of the small intestine 18 fold and microvilli increased the surface area on average 400 fold. This study provided a vast amount of biometric information on the development of the young pig from birth to 42 d post weaning.

No description available.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12978号 / 論医博第2104号 / 新制||医||1012(附属図書館) / 32448 / 京都大学大学院医学研究科医学専攻 / (主査)教授 三森 経世, 教授 椛島 健治, 教授 生田 宏一 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

No description available.

As one of the most common medications, it is reasonable to assume that the adverse effects from nonsteroidal anti-inflammatory drugs (NSAIDs) are well understood. While this is the case for NSAID-induced gastropathy, NSAID-induced enteropathy is often clinically overlooked and has a pathogenesis that is incompletely understood. The goal of this study was to determine how alterations in the microbiota impact NSAID-induced intestinal injury. Initial studies explore how gastric acid secretion suppression substantially decreases Bifidobacteria in the small intestine, and emphasize how replenishment of these bacteria results in an amelioration of NSAID-induced enteropathy. Follow-up studies involved pretreating rats with specific bacteria that have conferred protection in other models of small intestinal injury. We examined the role that acetate may play in reducing the damage by evaluating bacteria that had an acetate production gene knocked out via homologous recombination. Protection levels were similar between wildtype and knockout bacteria, and it did not appear that acetate had a key role in damage reduction. Moreover, we found that changes in intestinal damage were dependent not only on the strain of bacteria used but also on the NSAID administered. None of the bacterial pretreatments tested protected against indomethacin- or diclofenac-induced small intestinal injury, and pretreatment with one specific bacterial strain resulted in a significant worsening of damage. To gain further insight as to the potential role of the microbiota in exacerbation of injury, we conducted studies using single antibiotics and antibiotic cocktails. No single antibiotic treatment conferred protection against naproxen-induced small intestinal injury, but an antibiotic cocktail decreased damage scores by ~46%. Furthermore we explored the effects of L-lactic acid supplementation of drinking water but this was unable to reduce naproxen-induced intestinal damage. Collectively, the work presented in this thesis provides novel insights on the relationship between alterations in the microbiota and susceptibility to NSAID-induced enteropathy. / Dissertation / Doctor of Philosophy (Medical Science)