Das vom endonasalen Neuroepithel der Rima olfactoria entstandenen Aesthesioneuroblastom gehört zu den seltenen malignen Tumoren der Rhinobasis. Eine generelle Therapieempfehlung für die Behandlung dieses Tumors gibt es nicht, da bis heute etablierte, durch umfassende onkologische Studien untermauerte diagnostische und therapeutische Standards fehlen und der klinische Verlauf oft unberechenbar ist. Die Aufgabe der vorliegenden Arbeit bestand in der Überprüfung des chirurgischen Konzeptes bei der Therapie von Aesthesioneuroblastomen und in der erstmaligen molekularzytogenetischen Charakterisierung von Aesthesioneuroblastomen. Dazu wurden 18 Patienten mit Aesthesioneuroblastomen, die im Zeitraum zwischen 1988 und 2001 in der HNO-Klinik (17 Patienten) sowie in der Neurochirurgischen Klinik des Klinikums Fulda operiert wurden, untersucht. Die daraus resultierenden 22 Aesthesioneuroblastome wurden alle mit Hilfe der Vergleichenden Genomischen Hybridisierung (CGH) analysiert. Nach derzeitigem Kenntnisstand besteht die optimale Therapie der Aesthesioneuroblastome in der chirurgischen Resektion des Tumors mit nachfolgender stereotaktischer Bestrahlung. Für die operative Sanierung der Aesthesioneuroblastome und auch anderer Malignome der vorderen Schädelbasis ist das nachfolgende neue Fuldaer Konzept empfehlenswert: 1) Endonasale Resektion, wenn keine intrakranielle bzw. orbitale Tumorinfiltration vorliegt; 2) Subfrontaler Zugang, bei Infiltration des Gehirns; 3) Midfacial degloving, bei weit lateraler Tumorausbreitung; 4) Laterale Rhinotomie nur bei der Notwendigkeit der simultanen Exenteratio orbitae (bei orbitaler Tumorinfiltration). Aesthesioneuroblastomen sind durch ein typisches genetisches Muster charakterisiert, das Deletionen im Bereich der chromosomalen Arme 1p, 2q, 3p/q, 4p/q, 5p/q, 6q, 8p/q, 9p, 10p/q, 11p, 12q, 13q, 18q und 21q sowie Amplifikationen der Chromosomen 1p, 7q, 9q, 11q, 14q, 16p/q, 17p/q, 19p/q, 20p/q und 22p/q umfasst. Die beim Aesthesioneuroblastom häufigen DNA-Verluste im Bereich der chromosomalen Banden 1p21-p31 scheinen mit der Prognose dieser Tumoren assoziiert zu sein. Die Tumoren aller in der vorliegenden Studie am Malignom verstorbenen Patienten zeigten eine Kombination aus 1p21-p31-Deletion, dem Vorliegen des klinischen Stadiums C oder D sowie gleichzeitig einer schlechten Differenzierung (Grad III oder IV). Vermittels der CGH ist es möglich, eine klonale Zuordnung von Metastasen bzw. auch Rezidiven zu ihren primären Aesthesioneuroblastomen vorzunehmen. Die vorliegende Arbeit zeigt nicht nur neue Ansätze in der chirurgischen Therapie von Aesthesioneuroblastomen sondern auch die erste umfassende molekularzytogenetische Analyse dieser Tumorentität, auf dem Weg, das biologische Verhalten dieser Malignome genauer charakterisieren zu können. / Esthesioneuroblastoma (ENB) is a very rare malignant neoplasm arising from the olfactory epithelium which is recognized for its propensity for local recurrence and distant dissemination. Therapeutic management approaches for this neoplasm lack uniformity. The present study describes therapeutic management in ENB: Complete surgical resection combined with adjuvant stereotactic radiation therapy. Thereby, a new surgical concept is recommended: 1) Endonasal approach in cases without tumor infiltration of the orbit and/or the brain; 2) Subfrontal approach in cases with extended tumor infiltration of the intradural space or of the brain; 3) Midfacial degloving in cases with far lateral tumor spread, particularly fossa pterygoidea or pterygopalatina; 3) Lateral rhinotomy in all cases where an exenteratio orbitae is needed. Secondarily, the study characterizes the specific chromosomal alterations of ENB analyzed using Comparative Genomic Hybridization (CGH). ENB show frequently deletions of chromosoms 1p, 2q, 3p/q, 4p/q, 5p/q, 6q, 8p/q, 9p, 10p/q, 11p, 12q, 13q, 18q and 21q as well as DNA gains of chromosoms 1p, 7q, 9q, 11q, 14q, 16p/q, 17p/q, 19p/q, 20p/q and 22p/q. Deletions of the chromosomal region 1p21-p31 could be associated with bad prognosis since the tumors of all patients who died were of stage C or D and grade III or IV, and showed 1p21-p31 deletions. The analysis of primary ENB and their corresponding metastases shows clonality by a high concordance of alterations between the tumor pairs. For the first time, this study presents the specific chromosomal alterations of ENB pathogenesis and progression.

Made available in DSpace on 2016-04-26T18:16:49Z (GMT). No. of bitstreams: 1 Jose Rodrigo Paulino Fontanari.pdf: 1160818 bytes, checksum: 4eeaf8c3a0d6645e434d1ff24228b14f (MD5) Previous issue date: 2008-02-25 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / The current research approaches the comunicative modality we name: olfactory communication . We understand the perfume as a media form. We have investigated the history of the perfume in several civilizations and its use in the rituals. We have inserted some discoveries regarding the smell in the communication of the human being since their early age. As the contemporary civilization has privileged the senses of distance (the sight and the hearing) to detriment of the proximity senses (the smell and the taste), we have attempted to verify the translation of the perfume for the visual code. In such a way, therefore executives advertising propagated in the feminine magazines Claude, Elle, Marie Claire and Nova in the period of 1993 the 2004 are analaysed. The work is supported in the concepts of ecology of the communication proposed by Vicente Romano, of the ethology of the communication by Boris Cyrulnik, as well the concepts of primary, secondary and tertiary media of Harry Pross. In the same proportion of the suffering of the proximity senses, we observe of the bonds of the affection. To carry out of this research, Semiotics of the Culture was chosen, wich understands the body, the perfume and the smell as cultural possessing texts of great informative capacity in ample direction. Through this semiotics, the paradigms will be constituted as object of study object and to tack the three spheres of the research (body, perfume and smell). This triad shows as one of the possible ways to keep the interpersonal communicative bonds of proximity / A presente pesquisa aborda a modalidade comunicativa que denominamos comunicação olfativa . Compreendemos o perfume como forma de mídia. Investigamos a história do perfume em diversas civilizações e seu uso nos rituais. Inserimos algumas descobertas a respeito do olfato na comunicação do ser humano desde seus primeiros anos de vida. Uma vez que a civilização contemporânea tem privilegiado os sentidos de distância (a visão e a audição) em detrimento dos sentidos de proximidade (o olfato e o paladar), procuramos verificar como se dá a tradução do perfume para o código visual. Para tanto, são analisadas peças publicitárias veiculadas nas revistas femininas Claudia, Elle, Marie Claire e Nova no período de 1993 a 2004. O trabalho apóia-se nos conceitos de ecologia da comunicação proposto por Vicente Romano, de etologia da comunicação de Boris Cyrulnik e também de mídia primária, secundária e terciária de Harry Pross. Na mesma proporção do padecimento dos sentidos de proximidade, observa-se o esmaecimento dos vínculos do afeto. Para a elaboração desta pesquisa, elegeu-se a Semiótica da Cultura, que entende o corpo, o perfume e o olfato como textos da cultura possuidores de grande capacidade informativa em sentido amplo. Por meio dessa semiótica, serão constituídos os paradigmas para focar o objeto de estudo e alinhavar as três esferas de pesquisa (corpo, perfume e olfato). Essa tríade revela-se como uma das possíveis maneiras de manter os vínculos comunicativos interpessoais de proximidade

A diferença da percepção álgica entre homens e mulheres é, há muito, conhecida e documentada na literatura. Sabe-se também que a sensibilidade feminina varia durante o ciclo menstrual, o que levou à hipótese de que os hormônios ovarianos poderiam estar envolvidosnesse processo. Assim, este estudo teve como objetivo investigar os limiares de sensibilidade somestésica (térmica, dolorosa, tátil, vibratória e elétrica), gustativa e olfativa durante o ciclo menstrual de mulheres saudáveis e a sua relação com as concentrações dos hormônios estrógeno e progesterona na saliva. Foram avaliadas 39 mulheres com idade entre 19 e 47 anos, com ciclos menstruais regulares e sem morbidades associadas à dor. Todas as mulheres foram orientadas quanto aos propósitos desta pesquisa, e somente participaram do estudo aquelas que preencheram os critérios de inclusão e assinaram o termo de consentimento livre e esclarecido. A avaliação foi realizada em três momentos do ciclo menstrual: fase menstrual, fase folicular e fase lútea. Em cada uma dessas fases foram utilizados os seguintes métodos: coleta da saliva no início de cada sessão, para avaliação dos níveis hormonais; avaliação de fluxo salivar; avaliação sensitiva superficial (dor, tato - IITC Woodland Hills, EUA; frio, calor - MSA II e vibratórios - Somedic, Suécia) aplicada na região do ramo maxilar do nervo trigêmeo e na região do antebraço, ambas no lado direito da paciente; e avaliação das sensibilidades gustativa (doce - glicose, salgado - cloreto de sódio, azedo - ácido cítrico e amargo - ureia) e olfativa (isopropanol em diferentes concentrações). Foram observadas oscilações sensitivas em todas as modalidades de acordo com o momento do ciclo menstrual das mulheres avaliadas, sendo que níveis baixos de estrógeno se associaram a altos limiares de dor de profundidade no braço (p=0,008) e na face (p=0,041), altos limiares táteis (p=0,001) e álgicos superficiais (p=0,006) na face. Em contrapartida, altos níveis de progesterona se associaram a altos limiares de dor de profundidade na face (p=0,033) e altos limiares do sabor salgado (p < 0,001). Concluímos que o estrógeno e a progesterona estão envolvidos na neuromodulação da sensibilidade somestésica, gustativa e olfativa de mulheres, durante o ciclo menstrual / There is a sexual difference on pain perception that is supported by the scientific literature. Moreover, sexual hormones seem to be involved in the modulation of sensory detection and there is evidence of sensory variation during the menstrual cycle. Thus, the aim of this study was to investigate the somatosensory (thermal, painful, tactile, vibratory and electric), gustatory (salty, bitter, sweet, sour) and olfactory thresholds during the menstrual cycle in healthy women and verify association with saliva concentration of estradiol and progesterone. We evaluated 39 women aged between 19 and 47 years, with regular menstrual cycles and with no comorbidities related to pain.All women were instructed about the purposes of the study and only those that signed the informed consent were included. The evaluation wasperformed in three moments of the cycle: menstrual phase, follicular phase and luteal phase. In each of these stages, the following methods were used: saliva collection at the beginning of each session, to assess hormone levels; salivary flow measurement; somatosensory evaluation with quantitative sensory testing (pain, tactile - IITC Woodland Hills, USA; cold and warm - MSA II; and vibration - Somedic, Sweden) applied to the right maxillary branch region of the trigeminal nerve and right forearm region; and gustative (sweet - glucose, salt - sodium chloride, sour - citric acid and bitter - urea) and olfactory (isopropanol at different concentrations) thresholds. All sensory thresholds showed fluctuation during the menstrual cycle. Lower estrogen levels were correlated tohigher deep pain thresholds at the forearm (p=0.008) and face (p=0.041); they were also associated with higher tactile thresholds (p=0.001) and higher superficial pain (p=0.006) thresholds at face.High levels of progesterone were associated with high deep pain threshold at the face and high salty threshold (p < 0.001). In conclusion, estrogen and progesterone seems to be involved in sensory neuromodulation in women, during the menstrual cycle

L’olfaction est importante pour de nombreuses fonctions vitales comme la reproduction, les interactions sociales, la détection des aliments et le comportement alimentaire. Toutefois, l'impact nutritionnel sur le système olfactif n'a pas été précisément décrit. Dans ce contexte, le sujet de cette thèse consistait en l’étude des effets du jeûne sur la représentation spatiotemporelle des odeurs dans le bulbe olfactif principal (BO), une structure assurant la première étape du codage de l'information olfactive dans le cerveau.Dans le BO, les caractéristiques des molécules odorantes sont représentées sous forme d’activitéspatiale et temporelle respectivement dans la couche glomérulaire et celles des cellules mitrales et granulaires. Pour étudier le codage spatial au niveau glomérulaire, nous avons utilisé l’imagerie optique du signal intrinsèque qui permet de cartographier l’activité évoquée sur la surface du BO en réponse à des odeurs. Pour étudier le codage temporel des odeurs, nous avons enregistré les variations spécifiques de l'activité oscillatoire du potentiel de champ local (LFP) dans les couches profondes.Nous avons testé les réponses aux odeurs chez des rats mis à jeun pendant 17 heures par rapport aux rats nourris ad libitum. Nous avons utilisé deux stimuli olfactifs à des concentrations différentes: la première (odeur commerciale d’arôme d'amande) est associée à la nourriture car elle est préalablement incorporée dans une pâte sucrée présentée aux rats quotidiennement ; le second (hexanal), est une molécule odorante pure, nouvelle et neutre pour eux. L'utilisation de ces odeurs dans une gamme de concentrations faibles nous a permis d’étudier les modifications de seuil d’activation du BO. Nous avons analysé les deux types de représentation spatiale et temporelle chez des rats anesthésiés, à jeun versus nourris. Nous avons observé que les cartes spatiales et les changements des profils oscillatoires évoqués dans le BO sont présents pour les deux types de stimuli à de faibles concentrations chez tous les rats à jeun mais pas chez tous les animaux nourris. Par contre, pour les fortes concentrations d'odeurs, nous avons observé plus de réponses chez les animaux nourris. Nous avons conclu que le jeûne affecte profondément le seuil d’activation spatiotemporelle du BO.Nous avons alors cherché à identifier les candidats moléculaires qui pourraient déclencher cetteplasticité olfactive à jeun. Nous avons analysé dans le BO la variation de l'expression des récepteurs à deux hormones satiétogènes, la leptine et l'insuline, mais n'avons pas trouvé de changement significatif entre les deux groupes de rats. En outre, l'injection intrapéritonéale de leptine n'a pas inversé le profil oscillatoire induit chez des rats à jeun. Nous avons conclu que la leptine n'agit pas à elle seule dans la signalisation de l'état nutritionnel qui induit la plasticité bulbaire. Nous avons également cherché des modifications spécifiques des circuits du BO pendant le jeûne et avons obtenu des données préliminaires intéressantes sur la plasticité astrocytaire. Enfin, nous avons mené un nouveau projet sur le rôle des endocannabinoïdes dans la prise alimentaire. Le THC est un agoniste des récepteurs CB1 aux endocannabinoïdes qui induit une hyperphagie. Les CB1 étant présents dans le BO, nous avons testé ses effets sur l'activité oscillatoire chez des souris à jeun. Nous avons trouvé que le THC inhibe la désensibilisation olfactive qui est déclenchée chez les souris contrôle par la présentation d'odeurs répétées. / Olfactory cues are important for many vital functions as reproduction, social interactions, fooddetection and feeding behavior. However, the nutritional impact on the olfactory system has not been precisely described. Here we studied the effects of fasting on the spatiotemporal activities in the main olfactory bulb (OB), a structure supporting the first step of odor coding in the brain.Odorant signals undergo a complex processing that starts in the Main Olfactory Epithelium where the olfactory sensitive neurons (OSN) are located. OSN project into the OB where odorant features (among them identity and concentration) evoke spatiotemporal patterns of activities located respectively at the glomerular and mitral/granule cells levels. The spatial coding at the glomerular level is classically studied by optical imaging of odor-evoked activities on the surface of the MOB in response to different odors at different concentrations. The temporal coding is characterized by specific variations in the oscillatory activity of the Local Field Potential (LFP) in deeper layers.We tested odor responses in the OB in 17 hours-fasted rats compared to ad libitum-fed rats. We used two olfactory stimuli at different concentrations: the first one (almond aroma odor) is associated to food since it is incorporated into a homemade cake that rats love to eat; the second is the pure odorant hexanal which is new and neutral for them. Using these odorants at low concentrations to probe threshold modifications, we analyzed both types of OB coding (spatial and temporal) at the levels where they occur (glomerular layer and mitral/granule cell layers respectively) in anesthetized rats.Using intrinsic optical signals imaging and local field potential recording, we observed that odor maps and changes in oscillatory patterns of activity in the OB are present for both types of stimuli at low concentrations in all fasted rats but not in all fed animals. For higher odor concentrations, further fed animals responded. We conclude that fasting deeply impacts the overall odor threshold detection in the OB.Then, we sought to identify putative molecular candidates that could trigger this olfactory plasticity in fasted conditions. We have checked the variation of receptor expression for leptin and insulin, two anorexigen hormones, in the OB but did not find any significant changes between the two groups. In addition, i.p. injection of leptin did not reverse the oscillatory profile induced in fasted rats. We concluded that leptin does not act solely in signalling the nutritional state that induces the OB plasticity. We are still looking for specific modifications of OB circuits during fasting and we present interesting preliminary data about astrocytic plasticity in this manuscript. Finally, we have also run a new and exciting project dealing with the role of endocannabinoids in food intake: since THC, a potent agonist of endocannabinoids CB1 receptors which are expressed in the OB, selectively increases food intake when injected at low doses, we tested its effects on the OB oscillatory activity in fasted mice. We found that THC inhibits olfactory desensitization that is triggered in control mice by repeated odor presentation.

<p>The blood-brain barrier restricts the access of many compounds, including therapeutic agents, to the brain. Several human studies indicate that nasal administration of hydrophilic compounds, such as peptides, can bypass the blood-brain barrier. The aims of this thesis were to develop and refine models for this direct nose-to-brain transfer.</p><p>In a mouse model, [³H]-dopamine was given as a unilateral nasal dose. The resulting radioactivity in the ipsilateral olfactory bulb was significantly higher than that in the contralateral bulb and peaked at 4 h. Tape section autoradiography showed that the radioactivity was concentrated in the olfactory nerve layer and the glomerular layer of the olfactory bulb. The olfactory transfer of dopamine was also studied <i>in vitro</i>. At a lower donor concentration, the mucosal-to-serosal dopamine permeability was higher than the serosal-to-mucosal permeability, but at a higher concentration, the permeability coefficients were similar. Together, these results suggest that the olfactory transfer of dopamine has an active component.</p><p>Olfactory transfer of fluorescein-labeled dextran through the epithelium and deeper tissues was studied in a rat model, which enabled visualization of the transfer using fluorescence microscopy. Although the epithelial transfer appeared to be mainly intracellular, transfer in the following deeper tissues was extracellular. Without altering the route of uptake, a gellan gum formulation enhanced the uptake of fluorescein dextran. The enhancing effect was considered likely to be the result of an increased residence time in the nasal cavity.</p><p>In conclusion, dopamine and fluorescein-labeled dextran were identified as suitable model compounds for the study of olfactory drug transfer mechanisms and the influence of drug formulation. Two new <i>in vitro</i> models of olfactory transfer were compared. Also, a rat model, which enabled the visualization of the entire nose-to-brain transfer, was developed.</p>

The blood-brain barrier restricts the access of many compounds, including therapeutic agents, to the brain. Several human studies indicate that nasal administration of hydrophilic compounds, such as peptides, can bypass the blood-brain barrier. The aims of this thesis were to develop and refine models for this direct nose-to-brain transfer. In a mouse model, [3H]-dopamine was given as a unilateral nasal dose. The resulting radioactivity in the ipsilateral olfactory bulb was significantly higher than that in the contralateral bulb and peaked at 4 h. Tape section autoradiography showed that the radioactivity was concentrated in the olfactory nerve layer and the glomerular layer of the olfactory bulb. The olfactory transfer of dopamine was also studied in vitro. At a lower donor concentration, the mucosal-to-serosal dopamine permeability was higher than the serosal-to-mucosal permeability, but at a higher concentration, the permeability coefficients were similar. Together, these results suggest that the olfactory transfer of dopamine has an active component. Olfactory transfer of fluorescein-labeled dextran through the epithelium and deeper tissues was studied in a rat model, which enabled visualization of the transfer using fluorescence microscopy. Although the epithelial transfer appeared to be mainly intracellular, transfer in the following deeper tissues was extracellular. Without altering the route of uptake, a gellan gum formulation enhanced the uptake of fluorescein dextran. The enhancing effect was considered likely to be the result of an increased residence time in the nasal cavity. In conclusion, dopamine and fluorescein-labeled dextran were identified as suitable model compounds for the study of olfactory drug transfer mechanisms and the influence of drug formulation. Two new in vitro models of olfactory transfer were compared. Also, a rat model, which enabled the visualization of the entire nose-to-brain transfer, was developed.

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