Die Kopf-Hals-Region ist eine der anatomisch kompliziertesten Regionen und enthält et- wa 300 Lymphknoten, die innerhalb eines komplexen Lymphgefäßsystems miteinander in Verbindung stehen. Die meisten Plattenepithelkarzinome der oberen Luft- und Speise- wege sind potentiell heilbar, aber sie metastasieren früh in die regionalen zervikalen Lymphknoten. Der Status dieser Lymphknoten ist der signifikanteste prognostische Faktor in der Therapie der Kopf-Hals-Tumoren. Die Neck Dissection, englisch für „Halsausräu- mung“, wird auch im deutschsprachigen Raum so genannt und ist der Standard der chir- urgischen Behandlung. Die vorliegende monozentrische Studie untersucht erstmals mittels Workflowanalyse ei- ne Serie von Neck dissections (ND) im Interoperateur-Vergleich und zielt auf die quali- tätsrelevante Erfassung der Operationssystematik ab. Von Januar bis Dezember 2011 wurden an einer onkologisch ausgerichteten HNO-Univer- sitätsklinik 42 selektive NDs (SND) und modifiziert radikale NDs (MRND) bei 5 unter- schiedlichen Operateuren mit der Workflowaufnahmesoftware s.w.an-Editor systemati- siert kodiert und vergleichend ausgewertet. Die Operateure variierten in ihrer Operationserfahrung mit Neck dissections zwischen 1- 17 Jahren und führten im Untersuchungszeitraum 19-76 NDs durch. Die Gesamtpräpara- tionszeit (15min. (2-48)) korrelierte negativ mit der Anzahl der jährlich durchgeführten NDs (p<.033). Bei der Dauer der Entfernung der einzelnen Lymphknotenpakete (33min. (10-81)) ergab sich eine negative Korrelation mit der jeweiligen Erfahrung des Opera- teurs (p<.001). 63 Als bevorzugte Reihenfolge der entfernten Level zeigte sich die Chronologie: 3-2A-(2B)- 5-4-(1). Diese variierte trotz „Schule des Hauses“ signifikant. Bei SNDs ergab sich eine Korrelation (p<.038) zwischen Erfahrung und Befolgung dieser Reihenfolge. Die Summe der entfernten Lymphknoten im histopathologischen Präparat gesamt (17 (0- 29)) sowie pro Level (3,8 (0-11)) zeigte keinen signifikanten Unterschied in Abhängigkeit von Erfahrung, Anzahl der 2011 durchgeführten NDs, befolgter Chronologie und Dauer der Operation. Trotz signifikanter Unterschiede bei den Operateuren im operativen Vorgehen fanden sich keine signifikanten Unterschiede in Gesamtsumme der entnommenen Lymphknoten- zahl. Die Workflowanalyse hilft, die Operationssystematik zu erfassen und damit bei wechselnden Operateuren einen Standard zu definieren.:1.1. KOPF-HALS-TUMOREN 1.2. ÄTIOLOGIE UND RISIKOFAKTOREN 1.3. EPIDEMIOLOGIE 1.4. KLINIK 1.5. DIAGNOSTIK 1.6. HISTORISCHER ÜBERBLICK 1.6.1. ANFÄNGE DER CHIRURGIE 1.6.2. ENTWICKLUNG DER STRAHLENTHERAPIE 1.6.3. RADIKALE NECK DISSECTION 1.6.4. FUNKTIONELLE ODER MODIFIZIERT RADIKALE NECK DISSECTION 1.6.5. SELEKTIVE NECK DISSECTION 1.6.6. NOMENKLATUR DER LYMPHKNOTEN-LEVEL 1.6.7. NOMENKLATUR DER NECK DISSECTION 1.7. THERAPIE 1.7.1. STRAHLENTHERAPIE 1.7.2. NECK DISSECTION 1.7.3. CHEMOTHERAPIE 1.8. AKTUELLEENTWICKLUNGEN 1.8.1. ENTWICKLUNGEN IN DER DIAGNOSTIK 1.8.2. ENTWICKLUNGEN DES CHIRURGISCHEN VORGEHENS 1.9. KOMPLIKATIONEN 1.10. PROGNOSE 2. AUFGABENSTELLUNG 3. MATERIAL UND METHODEN 3.1. PATIENTEN 3.2. DATENERHEBUNG 3.3. EIN- UND AUSSCHLUSSKRITERIEN DER ERHOBENEN DATEN 3.4. STATISTISCHE METHODEN II 4. ERGEBNISSE 4.1. GESAMTKOLLEKTIV 4.1.1. PATIENTENGUT 4.1.2. EINTEILUNG DER OPERATION IN PHASEN 4.1.3. EINTEILUNG DER DATEN NACH KOMPLEXITÄT DER OPERATION 4.2. OPERATEURE IM VERGLEICH 4.2.1. ERFAHRUNG UND ROUTINE DER OPERATEURE 4.2.2. GESAMTDAUER DER OPERATION 4.2.3. ANZAHL DER DURCHGEFÜHRTEN ARBEITSSCHRITTE 4.2.4. KORRELATION ZWISCHEN ERFAHRUNG SOWIE ROUTINE DER OPERATEURE UND DAUER DER OPERATION 4.3. LYMPHKNOTEN IM FOKUS 4.3.1. CHRONOLOGIE DER LYMPHKNOTENENTNAHME 4.3.2. HISTOPATHOLOGIE 5. DISKUSSION 5.1. GESAMTKOLLEKTIV 5.1.1. PATIENTENGUT 5.1.2. EINTEILUNG DER OPERATION IN PHASEN 5.1.3. EINTEILUNG DER DATEN NACH KOMPLEXITÄT DER OPERATION 5.2. OPERATEURE IM VERGLEICH 5.2.1. ERFAHRUNG UND ROUTINE DER OPERATEURE 5.2.2. GESAMTDAUER DER OPERATION 5.2.3. ANZAHL DER DURCHGEFÜHRTEN ARBEITSSCHRITTE 5.2.4. KORRELATION ZWISCHEN ERFAHRUNG SOWIE ROUTINE DER OPERATEURE UND DAUER DER OPERATION 5.3. LYMPHKNOTEN IM FOKUS 5.3.1. CHRONOLOGIE DER LYMPHKNOTENENTNAHME 5.3.2. HISTOPATHOLOGIE 5.4. SCHLUSSFOLGERUNG 6. BIBLIOGRAFIE

Indiana University-Purdue University Indianapolis (IUPUI) / Shoulder pain was constantly reported as a problematic symptom causing dysfunction and quality of life interference after neck dissection in head and neck cancer patients. Due to a lack of conceptual framework and inconsistency of instrument selection, a comparison among previous studies was almost impossible, making it difficult to understand the phenomenon. The current study applied the University of California, San Francisco School of Nursing Symptom Management Model. The purposes of the study were to (a) describe the symptom experience of shoulder pain at 1 month after neck dissection, (b) describe the relationships among symptom experience of shoulder pain, functional status, and quality of life, and (c) identify the contextual variables, concurrent symptoms, and/or adherence predicting symptom experience of shoulder pain, functional status, and/or quality of life. This was a descriptive study with a convenience sample of head and neck cancer patients. The data were collected via a medical record review, a self-administered survey, and a physical examination. The data from 29 patients were entered for descriptive statistics, Pearson correlations, and multiple regressions. At 1 month after surgery, 62% of patients reported they had shoulder pain at some point within a week. Their shoulder pain was from mild to moderate. Fifty-nine percent complained that shoulder pain bothered them about the moderated level. In the final model, symptom experience, shoulder pain, was significantly correlated with one outcome, active shoulder abduction, but not the other, total quality of life, generic quality of life, and head and neck quality of life. Active shoulder abduction was significantly correlated with three quality of life measures. Adding significant predictors of symptom experience and outcomes into the final model, there is a potential that the model would be useful to guide treatment strategies. Treatment for myofascial pain of the levator scapulae could relieve shoulder pain after neck dissection and improve head and neck quality of life. Those with level V dissection were high risk populations of developing shoulder pain. Risk factors of quality of life, which were depression, loss of sensation, and radiation would describe how an intervention could change or unchange the patient’s life.

<p><i>Chlamydophila pneumoniae</i> (<i>C. pneumoniae</i>) has been suggested as a stimulator of chronic inflammation in atherosclerosis. <i>C. pneumoniae</i> DNA was demonstrated in aortic biopsies in 50% of patients with stable angina pectoris or acute coronary syndrome undergoing coronary artery bypass grafting. <i>C. pneumoniae</i> mRNA, a marker of replicating bacteria, was demonstrated in 18% of the aortic biopsies. </p><p>Inflammation may have a role in the pathogenesis of thoracic aortic aneurysm, aortic dissection and aortic valve stenosis. <i>C. pneumoniae </i>DNA was demonstrated in aortic biopsies in 26% of thoracic aortic aneurysm patients and in 11% of aortic dissection patients undergoing thoracic surgery and in 22% of stenotic aortic heart valves from patients undergoing aortic valve replacement. No bacterial mRNA was demonstrated in these aortic biopsies, nor in the valves, suggesting that the infection has passed into a persistent state. <i>C. pneumoniae</i> DNA was demonstrated in peripheral blood mononuclear cells in only 5% of aortic valve stenosis patients and not in thoracic aortic aneurysm or aortic dissection patients, suggesting that the bacterium disseminated to the cardiovascular tissue long before the patient required surgery. The copper/zinc ratio in serum, a marker of infection/inflammation, was significantly elevated in thoracic aortic aneurysm patients, supporting an inflammatory pathogenesis. Patients positive for <i>C. pneumoniae</i> in the aortic valve had more advanced coronary atherosclerosis, further supporting a possible role for <i>C. pneumoniae</i> in atherosclerosis. </p><p>Mice were infected with <i>C. pneumoniae</i> that disseminated to all organs investigated (i.e. lungs, heart, aorta, liver and spleen). Trace element concentrations were altered in infected animals with an increased copper/zinc ratio in serum, a progressively increased iron concentration in the liver and a progressively decreased iron concentration in serum. Iron is important for <i>C. pneumoniae</i> metabolism, and a changed iron homeostasis was noted in infected mice by alterations in iron-regulating proteins, such as DMT1 and hepcidin.</p>

Background: Thoracic aortic aneurysms and dissections (TAAD) have a genetic component with an estimated 20-25% of the patients having a positive family history. An aneurysm often precedes a dissection. Acute aortic dissections are associated with high mortality and morbidity, even when operated on. Complications due to prophylactic surgery are considerably fewer. Therefore, patients at risk for dissection should be identified, followed-up and evaluated for prophylactic intervention. Aims: 1. To establish reference values for ascending (AoA) and descending aortic (AoD) diameters measured by computed tomography. 2. To study the effectiveness of phenotypic cascade screening in families with an inherited form of thoracic aortic aneurysms and dissections (FTAAD) and to address questions that arise when screening for a genetic disorder is applied. 3. To study the agreement of aortic diameters obtained by TTE and MRI and to study aortic stiffness in individuals from families with FTAAD. 4. To perform exome sequencing in order to identify pathogenic sequence variants causing FTAAD, to characterize the phenotype, and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers. Results: Paper I: The diameter of the thoracic aorta increased by 0.17 mm (0.12 – 0.20 mm) per year. The mean sex-related difference in diameter was 1.99 mm (1.28 – 2.60 mm) with men having larger aortas than women. The mean difference in aortic diameter per unit BMI was 0.27 mm (0.14 – 0.44 mm). Upper normal limits for the AoA can be calculated by the formula D (mm)=31+0.16*age and for the AoD by D (mm)=21+0.16*age. Paper II: Of 106 individuals from families with FTAAD but without known thoracic aortic disease, 19 individuals (18%) were identified to have a dilated AoA. The expected number of individuals in this group with an autosomal dominant disease would have been 40 (p&lt;0.0001). In first-degree relatives younger than 40, we found only one individual with a dilated aorta although the expected number of individuals with disease causing mutation would have been 10. Paper III: Of 116 individuals investigated, 21 were identified with thoracic aortic dilatation and 95 individuals with normal thoracic aortic diameter. Aortic stiffness increased with age and diameter. The individuals with aortic dilatation were older than those without (49 vs. 37 years, p=0.001) and showed lower aortic elastic properties. The diameters measured by TTE and MRI correlated strongly (r2=0.93). The mean difference in diameters between the two methods was 0.72 mm (95% CI 0.41-1.02) with TTE giving larger diameters than MRI. Paper IV: From exome sequencing and segregation analysis, a 2-bp deletion in the MYLK gene (c.3272_3273del) was identified to cause FTAAD. The age and the aortic diameter at dissection or rupture varied in the family members. We did not find any differences in aortic diameter, aortic stiffness, or pulse wave velocity between carriers and non-carriers. Conclusions: Thoracic aortic diameter increases with age, and sex and body size are also associated with the diameter. In FTAAD, screening identifies family members with a previously unknown aortic dilatation. However, a normal aortic diameter does not exclude an individual from being a carrier of FTAAD. TTE can be used in follow-up for the ascending aorta. Individuals identified to have a dilated thoracic aorta have increased aortic stiffness compared to individuals with normal thoracic aortic diameter. The MYLK mutation (c.3272_3273del) causes thoracic aortic dissections with variable clinical expression. No differences in aortic stiffness were identified between MYLK mutation carriers and non-carriers.

Ce mémoire est divisé en quatre chapitres. D’abord, une introduction initie le lecteur au domaine des neurosciences. Ensuite, le chapitre 1 décrit les étapes de la dissection virtuelle par tractographie, à partir du phénomène physique de la diffusion jusqu’aux mesures statistiques des structures de la matière blanche. Le chapitre 2 présentera une nouvelle méthode d’assurance qualité, basée sur l’analyse volumique des faisceaux de la matière blanche, la contribution principale de ce mémoire. Finalement, la conclusion contient une discussion des problématiques non résolues ainsi que des perspectives d’avenir pour la tractographie.

O esvaziamento cervical faz parte do tratamento oncológico de pacientes portadores de neoplasias da cabeça e pescoço, onde o ombro está sob risco de alterações relacionadas ao procedimento. A morbidade pós-operatória está diretamente relacionada com a extensão cirúrgica, na qual podem estar associados deslocamentos de retalhos e ressecções de tecidos e estruturas neuromusculares. Sendo assim, a doença nesta região apresenta potencial suficiente para afetar a função e a qualidade de vida relacionada ao ombro dos pacientes. Altos índices de complicações funcionais são encontrados após o esvaziamento cervical, os quais variam de 18 a 77% nas cirurgias com a preservação do nervo acessório. As seqüelas mais comumente encontradas são a dor, disfunção na amplitude de movimento e força muscular do ombro, déficit funcional e piora da qualidade de vida. Este estudo teve por objetivo avaliar a função do ombro, a dor e a qualidade de vida em pacientes portadores de câncer de cabeça e pescoço submetidos a esvaziamento cervical, bem como avaliar os resultados do protocolo de reabilitação fisioterápica proposto. Foram avaliados prospectivamente 88 pacientes (120 ombros) no pré-operatório, 1º mês e no 3º mês após o procedimento, os quais foram submetidos a esvaziamento cervical unilateral ou bilateral por doença maligna na região da cabeça e pescoço. A maioria dos pacientes foi do sexo masculino e com idade média de 56,7 anos (mediana de 56,5 anos). Destes 120 ombros, o nervo acessório foi preservado em 108. Observou-se que a função do ombro apresentou-se significativamente afetada após o esvaziamento cervical, sendo o esvaziamento cervical seletivo, o estadiamento clínico inicial (I/II), a não realização de rotação de retalho miocutâneo de peitoral maior e a não realização de radioterapia os fatores relacionados a uma menor perda relativa para os movimentos do ombro bem como das forças musculares, principalmente de trapézio. Especificamente, o esvaziamento cervical seletivo foi associado a uma menor perda relativa nos movimentos de extensão (p=0,004) e rotação interna (p=0,043) no 1º mês e flexão (p=0,027) e rotação externa (p=0,008) no 3º mês; o estadiamento clínico I/II à abdução (p=0,045), força de trapézio médio (p=0,005), trapézio inferior (p=0,007) e rombóides (p<0,001) no 3º mês; a não realização de rotação de retalho de peitoral maior à flexão (p=0,003) no 1º mês e rotação externa (p=0,006) no 3º mês; e a não realização de radioterapia à abdução (p=0,007) no 3º mês. Verificou-se também que após a cirurgia, os movimentos de flexão e abdução, as forças de trapézio médio, trapézio inferior e rombóides e o Escore de Constant são os principais fatores relacionados à dor; assim como a flexão, extensão, rotação interna e rotação externa, forças de trapézio médio, serrátil anterior e rombóides são os fatores relacionados a qualidade de vida (domínios dor, atividade, recreação e ombro). Observou-se ainda que o protocolo de reabilitação fisioterápica, quando realizado de forma completa, pode ser benéfico para os pacientes, minimizando a perda da função pós-operatória e reduzindo no 3º mês após a cirurgia a seqüela instalada no 1º mês nos movimentos de flexão e abdução, bem como na força de trapézio, estes que são os movimentos e força muscular principalmente limitados após o esvaziamento cervical / Neck dissection is the treatment of head and neck cancer patient in whom the shoulder is at risk for changes related to the procedure. The postoperative morbidity is directly related with the surgery, which can be associated with displacement of flaps and resection of tissue and neuromuscular structures. The disease in this region has sufficient potential to affect the function and quality of life related to the shoulder of these patients. High rates of functional complications are found after neck dissection, which vary from 18 to 77% in surgery sparing the accessory nerve. The most common sequels found are pain and changes on range of motion and muscle strength in shoulder function, functional deficits and worsening quality of life. This study aimed to evaluate the shoulder function, pain and quality of life in head and neck cancer patients undergone neck dissection, and evaluate the results of the protocol physiotherapy rehabilitation proposed. We prospectively evaluated 88 patients (120 shoulders) preoperatively, 1st month and 3rd months after the unilateral or bilateral neck dissection due to malignancy in the head and neck region. Most of the patients were male and mean age was 56.7 years (median 56.5 years). Of 120 shoulders, the accessory nerve was preserved in 108. It was observed that the shoulder function had to be significantly affected after neck dissection, being the selective neck dissection, the initial clinical staging (I/II), not undergone the pectoral myocutaneos flap and not submitted to postoperative radiotherapy were the factors related to a lower relative loss on the shoulder movements and the muscle strength, especially considering the trapezius muscle. Specifically, the selective neck dissection was associated with a lower relative loss on the extension (p=0.004) and internal rotation (p=0.043) at 1st month and flexion (p=0.027) and external rotation (p=0.008) in the 3rd month; the clinical staging I / II for abduction (p=0.045), strength of middle trapezius (p=0.005), lower trapezius (p=0.007) and rhomboid (p<0.001) at 3rd month, patients not undergone pectoral myocutaneos flap showed lower losses for flexion (p=0.003) at 1st month and external rotation (p=0.006) at 3rd monts, and patients not submitted to postoperative radiotherapy were at lower risk for losses at abduction (p=0.007) in the 3rd month. It was found that after surgery, the movement of flexion and abduction, the strength of middle trapezius, lower trapezius and rhomboid and the Constant Score were the main factors related to pain, as well as flexion, extension, internal rotation and external rotation, strength the middle trapezius, serratus anterior and rhomboid are the factors related to quality of life (domains pain, activity, recreation and shoulder). Considering the protocol of physiotherapy rehabilitation it was observed that, if done in full, it might be beneficial to patients, minimizing the loss of function and reducing postoperative at 3rd months after surgery the sequel installed at 1st month in the movements of flexion and abduction, as well as the muscle strength of trapezius, which are the movements and muscle strength mainly affected after neck dissection

Introdução: A dissecção endoscópica submucosa (ESD) de neoplasias superficiais extensas de esôfago pode evoluir com altas taxas de estenose pós operatória, resultando em uma importante piora na qualidade de vida. Diversas terapias estão disponíveis para prevenir essa complicação. Entretanto, até o momento, nenhuma revisão sistemática e metanálise foram realizadas para avaliar esses resultados. Métodos: Uma revisão sistemática e metanálise foram realizadas utilizando as bases de dados eletrônicas Medline, Embase, Cochrane, LILACS, Scopus e CINAHL. Ensaios clínicos e estudos observacionais foram pesquisados de março de 2014 a fevereiro de 2015. Os termos pesquisados foram: endoscopy, ESD, esophageal stenosis, e esophageal stricture. Três estudos retrospectivos e quatro prospectivos (três randomizados) foram selecionados. Um total de 249 pacientes com diagnóstico de neoplasia superficial de esôfago, submetidos a ESD de pelo menos dois terços da circunferência do órgão foram incluídos. Foram selecionados estudos comparando diversas técnicas para prevenir a estenose de esôfago após extensa ESD. Resultados: Foram realizadas diferentes metanálises com ensaios clínicos randomizados (RCT), ensaios clínicos não randomizados (non- RCT) e uma análise global. Nos RCT (três estudos, n=85), a terapia preventiva diminuiu o risco de estenose (diferença de risco = - 0,36, IC 95% - 0,55 a - 0,18, p = 0,0001). Dois estudos (um randomizado e um não randomizado, n = 55) demonstraram que a terapia preventiva diminui o número médio de dilatações (diferença média = - 8,57, IC 95% - 13,88 a - 3,25, p < 0,002). Não houve diferenças significativas em três RCT em relação à taxa de complicações entre pacientes submetidos à terapia preventiva e aqueles não submetidos (diferença de risco = 0,002, IC 95% -0,09 a 0,14, p = 0,68). Conclusão: O uso da terapia preventiva após extensa ESD no esôfago, reduz o risco de estenose e o número de dilatações endoscópicas para resolução da estenose, sem aumentar o número de complicações / Background: Endoscopic submucosal dissection (ESD) of extensive superficial cancers of the esophagus may progress with high rates of postoperative stenosis, resulting in significant decrease in quality of life. Several therapies are performed to prevent this complication. However, they have not yet been compared in a systematic review. Methods: A systematic review of the literature and meta-analysis were performed using the Medline, Embase, Cochrane, LILACS, Scopus, and CINAHL databases. Clinical trials and observational studies were searched from March 2014 to February 2015. Search terms included: endoscopy, endoscopic submucosal dissection, esophageal stenosis, and esophageal stricture. Three retrospective and four prospective (3 randomized) cohort studies were selected. They involved 249 patients with superficial esophageal neoplasia who underwent ESD of at least two-thirds of the circumference. We grouped trials comparing different techniques to prevent esophageal stenosis post-ESD. Results: Were realized different meta-analyses on randomized clinical trials (RCT), non-RCT, and global analysis. In RCT (3 studies, n=85), preventive therapies decreased the risk of stenosis (risk difference = -0.36, 95% CI= -0.55 to -0.18, p = 0.0001). Two studies (1 randomized, 1 non-randomized, n = 55) showed that preventive therapies lowered the average number of endoscopy dilatations (mean difference = -8.57, 95% CI = -13.88 to -3.25, p < 0,002). There were no significant differences in the 3 RCT studies (n=85) with regards to complication rates between patients with preventive therapies and those without (risk difference = 0.02, 95% CI = -0.09 to 0.14, p = 0.68). Conclusion: The use of preventive therapies after extensive ESD of the esophagus reduces the risk of stenosis and the number of endoscopic dilatations for resolution of stenosis without increasing the number of complications

La réponse immunitaire innée est induite par des infections microbiennes ou des lésions tissulaires. L’étude de sa régulation est l'un des aspects les plus étudiés actuellement en immunologie, et porte notamment sur divers aspects du contrôle des agents pathogènes, du développement de vaccins et de la thérapie contre les maladies inflammatoires chroniques. L’ADN peut jouer le rôle de ligand endogène et induire une réaction immunitaire forte chez les animaux. Des souris déficientes pour la DNaseII lysosomiale accumulent de l’ADN dans leurs macrophages, notamment celui provenant des noyaux expulsés des érythroblastes lors de leur maturation en érythrocytes. Elles n’arrivent pas à les dégrader. Elles produisent en réponse de grandes quantités d’interférons de type I. Les souris meurent d'anémie au stade embryonnaire. Ce phénomène m’a amenée à poser une question importante: Comment les cellules reconnaissentelles l'ADN et comment y répondentelles? Pour savoir comment les cellules reconnaissent et répondent à l'ADN, nous avons visé trois objectifs spécifiques: I. Mise au point un modèle in vivo de drosophile pour étudier la réponse immunitaire innée contre l'ADN II. Dissection génétique de la réponse immunitaire induite par l'ADN III. Trouver des récepteurs de l’AND A l’issu de mon travail de thèse, je peux proposer que (i) la réponse immunitaire induite par l’ADN repose sur la voie IMD chez la drosophile, (ii) IK2 (TBK1), CG1667 (TMEM173), et EYA (EYA4) sont des molécules clés dans la cascade de signalisation en aval de la détection de l'ADN chez la drosophile, (iii) EYA est liée à la voie IMD au niveau de RELISH ou IKKβ, (iv) Orthologue drosophile LRRFIP1 de l'ADN des mammifères capteur est responsable de la détection de l'ADN dans le modèle DNaseII mouche déficiente (v) chez la drosophile CG3800 (CNBP) est un candidat pour la détection d'AND dans les insectes et les mammifères. / Innate immune responses are initiated during infections and tissue damage, and largely impact on various human diseases. DNA has been shown to be a strong innate immune stimulator in animals. For example, DNaseII deficient mice accumulate undigested DNA in macrophages from the expelled nuclei of erythroid progenitor cells, produce large amounts of type I Interferons in DNA-accumulated cells, and die from anemia at the embryonic stage. This phenomenon brought us an important question: How does cells recognize DNA and respond to it? To answer the question, we took three approaches: (1) Establishing in vivo model to study the innate immune response against DNA (2) Genetic dissection of the DNA-mediated immune response (3) Finding DNA sensors In my thesis project, we provide (1) DNA-mediated immune responses relies on the IMD pathway in Drosophila, (2) IK2(TBK1), CG1667(TMEM173, STING), and EYA(EYA4) are key molecules in the downstream signaling cascade of DNA sensing in Drosophila, (3) EYA is linked to the IMD pathway at the level of RELISH or IKKβ, (4) Drosophila orthologue of mammalian DNA sensor LRRFIP1 is responsible for DNA sensing in DNaseII deficient fly model, (5) Drosophila CG3800(CNBP) is a candidate for DNA sensing in both insects and mammals.

A solução fixadora a partir do formaldeído permanece ate os dias de hoje como o composto fixador \"padrão ouro\" para trabalho de rotina. Porém, este é classificado como cancerígeno para os seres humanos e , portanto, representa um risco para qualquer pessoa manusear. Assim, a busca por substitutos tem sido motivada, e, mais recentemente, surgiram algumas soluções alternativas com potencial para substituí-lo. A maioria destas soluções alternativas são à base de álcool , e a maior parte delas são apenas para amostras microscópicas. A partir do conhecimento de ácido tânico para estabilizar a elastina e o colágeno, diluído em glutaraldeído, para microscopia eletrônica, bem como para próteses biológicas, emerge a ideia de uma nova solução fixadora alcoólica, contendo ácido tânico como componente principal. Em análises microscópicas coração, cérebro, intestino e rins foram coletados e preservados sendo armazenados em diferentes soluções fixadoras (10 % de formalina v/v, 70 % de álcool e solução alcoólica de ácido tânico), e preparado para procedimentos histológicos de rotina. Adicionalmente, ratos wistar inteiros foram fixados com a solução alcoólica de ácido tânico ou formalina e estudantes de medicina que praticam dissecção há pelo menos 2 anos ou mais, dissecaram estes espécimes durante o curso de dissecação, como uma alternativa para adquirir habilidades básicas de cirurgia e responderam a um questionário detalhado que inferia sobre a qualidade da peça a ser dissecada. A toxicidade do composto foi analisada por ensaio \"in silico\" para o sistema respiratório e a cutis. A análise microscópica mostrou que solução à base de ácido tânico pode ser melhor que os outros fixadores comuns testados diversos parâmetros, e houve diferença entre os tecidos analisados. Entretanto, o resultado microscópico mais importante foi que esta nova solução possui forte capacidade de preservar e estabilizar a elastina e o colágeno, demonstrando resultados melhores em relação aos outros fixadores. Os resultados macroscópicos revelaram também uma superioridade da solução de ácido tânico em diversos parâmetros analisados, como odor, textura e flexibilidade durante dissecção. A toxicidade da solução de ácido tânico para cútis e sistema respiratório foi considerada moderada em relação à formalina que é considerada altamente tóxica. Concluímos que a solução fixadora de ácido tânico é eficaz para macro e para microscopia, é menos tóxica do que o formaldeído e inodora. Portanto, pode ser uma alternativa real para a evitar a utilização de formol, diminuindo os fatores de risco durante a manipulação de cadáveres e tecidos fixados. / The fixative solution from the formaldehyde remains until nowadays as the \"gold standard\" for routine work fixative compounds. Nevertheless, it is classified as carcinogenic to humans and, therefore, represents a risk to anyone handling the solution. Thus, the search for formaldehyde substitutes has been motivated, and more recently, some alternative solutions with potential to replace it have appeared. Most of these alternative solutions are alcohol-based, and most of them are only for microscopic specimens. From the knowledge that tannic acid diluted in glutaraldehyde can stabilize elastin and collagen for electron microscopy as well as for bioprotheses, emerge the idea for a new alcoholic fixative solution, containing tanic acid as the main component. For microscopical analyses heart, brain, intestine and kidneys were collected and preserved in different fixative solutions (10% v/v regular formalin, 70% alcohol and tannic acid alcoholic solution), and prepared for routine histology procedures. Additionally, whole wistar rats were fixed in the tanic acid alcohol-based solution or formalin and medicine students, who practice dissection for at least 2 or more years, dissected the rats during the dissection course, as an alternative to acquire basic surgery skills and answered a detailed questionnaire about the quality of dissected specimen. The toxicity of the compound was analyzed by in silico tests for cutais and respiratory system. The microscopial analysis showed that tannic acid based solution could be better than others common fixatives as tested in several parameters, and there are differences among tissues. Moreover, the most important microscopic result was that this new solution showed a strong capability to preserve and stabilize elastin and collagen, shppwing better results in relation to other analysed fixatives. The macroscopial analyses also showed better results of tannic acid solution for several parameters, as odor, texture and flexibility during dissection. The toxicity of tannic acid solution for skin and respiratory system was considered moderate in relation to formaldehyde, which is considered highly toxic. We conclude that tanic acid solution is efficient to preserve tissues for macroand microscopical studies, is less toxic than formaldehyde and odorless. Therefore, it could be a real alternative to avoid the regular use of formalin, decreasing risk factors to the ones manipulating fixed corpses and tissues.

Introdução: o status dos linfonodos axilares permanece um dos mais importantes fatores prognósticos no carcinoma de mama em estágios iniciais, além de definir o uso de terapias complementares. A biópsia de linfonodo sentinela (BLNS) surgiu com a finalidade de estadiar a axila com o mínimo de morbidade, tendo como objetivo a identificação e o estudo patológico do primeiro linfonodo axilar proveniente da drenagem linfática da mama. Pacientes com axila clinicamente negativa têm indicação de biópsia de linfonodo sentinela como método de estadiamento da axila, e quando o resultado era positivo para metástase recomendava-se o esvaziamento axilar. Por recomendação do ACOSOG Z0011, o esvaziamento axilar (EA) após uma biópsia de linfonodo sentinela positivo não é necessário. Esse estudo demonstrou não haver benefício em realizar o EA na presença de LNS positivo na sobrevida global ou na sobrevida livre de doença. Objetivos: Avaliar a taxa de recidiva e morte em pacientes submetidas à cirurgia conservadora de mama e BLNS positiva com posterior esvaziamento axilar no Hospital de Clínicas de Porto Alegre; e, como objetivo secundário, avaliar as características clínicas e patológicas dessa população. Método: foi realizado um estudo de coorte retrospectiva, incluindo pacientes com diagnóstico de carcinoma de mama invasor submetidas à cirurgia conservadora da mama e BLNS, cujo resultado foi positivo para presença de metástases, e foram submetidas ao EA o período de janeiro de 2004 a dezembro de 2008. Resultados: foram incluídas 144 pacientes submetidas à biópsia de linfonodo sentinela e CCM; 33 tiveram o achado de biópsia de linfonodo sentinela positivo para metástase, e dessas 33 pacientes restaram 27 para análise dos dados. A taxa de sucesso na identificação do LNS foi de 0,96. A idade média das pacientes foi de 53,8 anos, o número de LNS ressecados foi de 1,6 por paciente; a média do tamanho tumoral foi de 2,3 cm. Seis pacientes apresentaram doença axilar residual correspondendo a 22,2% da amostra e tiveram um risco relativo de morte de 3 vezes mais para aquelas sem doença axilar residual e 50% a mais de desenvolvimento de metástases. Conclusão: O comprometimento axilar é importante fator no prognóstico das pacientes com câncer de mama, quanto maior o comprometimento da axilar pior será o desfecho de sobrevida livre de doença e de morte. Acreditamos que se pode aplicar a conduta do ACOSOG Z0011 também nas pacientes do HCPA devido à alta sensibilidade do método no nosso meio. / Introduction: The status of axillary lymph nodes remains one of the most important prognostic factors in breast carcinoma in the early stages, in addition it helps to defining the use of complementary therapies. Sentinel lymph node biopsy (SLNB) was developed with the purpose of staging the axilla with minimal morbidity, aiming at the identification and pathological study of the first axillary lymph node from the lymphatic drainage of the breast. Patients with clinically negative lymph node have indication of SLNB as a method of axillary staging, and with a positive finde for metastasis the axilar clereance was performed. Nowadays, due to the ACOSOG Z0011 Study, the axillary dissection (AD) after a positive SLNB for metastasis was put in check. This estudy have as a result no difference in global survive ou disease free survive if ALND was not performed in a positive SLNB. In the present study, we intend to evaluate the clinical and histopathological characteristics of patients submitted to breast conservative surgery and sentinel lymph node biopsy with a positive result for metastasis. Main objective: Evaluate the rate of recurrence and death in patients submitted to conservative breast surgery and BLNS with posterior axillary emptying at Hospital de Clínicas, Porto Alegre. It is a secondary objective to evaluate the clinical and pathological characteristics of this population. Material and Methods: A retrospective cohort study was performed, including 144 patients diagnosed with invasive breast carcinoma submitted to conservative breast surgery and SLNB, whose results were positive for metastases, and were submitted to AD, at the Mastology Unit of the Hospital de Clinicas de Porto Alegre (HCPA), from January 2004 to December 2008. Results: Of 144 patients submitted to SLNB and BCS, 33 had SLNB positive for metastasis, of these 33 patients remained 27 for data analysis. The success rate in LNS identification was 0.96. The mean age of the patients was 53.8 years, the number of resected SLN was 1.6 per patient; The mean tumor size was 2.3 cm. Six patients had residual axillary disease corresponding to 22.2% of the sample and had a relative risk of death of 3 times more for those without residual axillary disease and 50% more for the development of metastases. Conclusion: Axillary involvement is an important factor in the prognosis of patients with breast cancer, and the greater the axillary impairment, the worse the diseasefree survival outcome and death. We believe that the ACOSOG Z0011 trial can also be applied to HCPA patients who meet the inclusion criteria for this purpose, due to the high sensitivity of the method in our environment.