Caenorhabditis elegans is a powerful tool to study cellular migration and morphogenesis during organ development. During pharynx development, the dorsal gland cell, g1p, is born in the anterior aspect of the pharyngeal primordium and undergoes a form of morphogenesis called retrograde extension. egl-15, the single Fibroblast Growth Factor Receptor (FGFR) in C. elegans and ina-1, one of two α-integrin receptors, are both required for the proper extension or migration of g1p cell. Mutations in either egl-15 or ina-1 show similar gland cell over-migration defects where the gland cell body migrates past the terminal bulb and is located in proximity of the intestine. The kinase domain of EGL-15 was found to be required for migration and transgenic rescue strategies were used to determine the tissue of EGL-15 function. RNA interference was used to determine if egl-15 and ina-1 are functioning in the same pathway to regulate gland cell migration. / February 2015

Objetivos: As fissuras labiopalatinas constituem a malformação congênita de maior prevalência na espécie humana. O fechamento cirúrgico do lábio e do palato, que visa restaurar a forma e a função, paradoxalmente impacta negativamente sobre o crescimento maxilar e, consequentemente, sobre a morfofisiologia nasal, levando à deformidades como desvio de septo e hipertrofia das conchas nasais. Estas alterações reduzem as dimensões internas da cavidade nasal e aumentam a resistência ao fluxo aéreo respiratório. Assim, foi objetivo do presente estudo avaliar tridimensionalmente o espaço aéreo faríngeo dos pacientes com fissura labiopalatina unilateral completa por meio de tomografia computadorizada de feixe cônico. Material e Métodos: Foram avaliados exames tomográficos de dois grupos de pacientes: 1) Grupo Controle (GC): 30 tomografias de pacientes sem FLP + discrepância maxilomandibular do tipo classe III de Angle, e, 2) Grupo Fissura (GF): 30 tomografias de pacientes com FLP unilateral completa + discrepância maxilomandibular do tipo classe III de Angle. Dois avaliadores treinados e calibrados avaliaram, em dois tempos distintos, as imagens por meio do software Dolphin Imaging 11.0, no qual foram obtidos valores de volume (V) faríngeo e da área seccional mínima faríngea (ASM). Os valores médios da ASM e do V, obtidos nas duas medições do avaliador 1, foram considerados para análise. A reprodutibilidade intra e interexaminador foram calculadas pelo oeficiente de Correlação Intraclasse. A significância das diferenças entre os grupos foram avaliadas pelo teste t de Student para amostras independentes. A correlação entre as variáveis foi aferida pelo Coeficiente de correlação de Pearson. Valores de p<0.05 foram considerados significantes. Resultados: Os valores médios de V (mm3) do GF (20,9±5,0) foram significantemente menores que os do GC (26,9±9,6) (p=0,004). Apesar de estatisticamente não significante, os indivíduos do GF apresentam as ASMs dimensionalmente menores (158,6±99,1) que as do GC (188,8±110,2). Constatou-se forte correlação positiva entre as variáveis ASM e V, nos grupos GC e GF (p<0.001) e forte correlação negativa entre as variáveis ASM e idade, apenas no grupo GF (p=0.017). Conclusão: A faringe do paciente com fissura labiopalatina unilateral completa com discrepância dento-esquelética classe III de Angle é volumetricamente menor que a de indivíduos sem fissura labiopalatina com o mesmo tipo de discrepância dento-esquelética. Este resultado sugere maior chance de colapsabilidade da faringe, e, consequentemente, maior risco para apneia obstrutiva do sono nesta população. / Objective: Cleft lip and palate (CLP) is the most prevalent congenital malformation in humans. Primary plastic surgeries, which main objective is to repair the anatomy and the function of the lip and palate, paradoxically, impair maxillary growth and, consequently, impact negatively on the nasal morphophysiology, leading to deformities such as septal deviation and turbinate hypertrophy. These changes reduce the internal nasal dimensions and increase the resistance to respiratory airflow. The aim of the present study was to evaluate three-dimensionally the pharyngeal airway space of individuals with complete unilateral cleft lip and palate by means of cone beam computed tomography. Materials and Methods: Two groups were evaluated: 1) Control group (CoG): 30 CT scans of individuals without CLP + Angle class III malocclusion, and 2) Cleft group (ClG): 30 CT scans of individuals with CLP + Angle class III malocclusion. Two trained and calibrated examiners assessed the images, in two different moments, by means of Dolphin Imaging 11.0 software. Mean values of pharyngeal volumes (V) and minimal cross-sectional areas (CSA) obtained by examiner 1 were considered for analysis. Intra and inter-examiner reproducibility were assessed by Intraclass correlation coeficiente test. The significance of differences between groups was evaluated by Student \"t\" test for independent samples. The correlation between variables was assessed using Pearson\'s correlation coefficient. P values <0.05 were considered significant. Results: Mean values of V (mm3) for the ClG (20,9±5,0) were significantly lower than for the CoG (26,9±9,6) (p=0,004). Although not statistically significant, individuals from the ClG presented with lower ASMs (158,6±99,1) than the CG individuals (188.8±110,2). A strong positive correlation was observed between the ASM and V variables in both groups (p <0.001) and a strong negative correlation was observed between the variables ASM and age, only for the ClG (p = 0.017). Conclusion: The pharynx of the patients with complete unilateral cleft lip and palate and with Angle Class III malocclusion is volumetrically smaller than that of individuals without cleft lip and palate and with the same type of skeletal discrepancy. This result suggests a greater chance for pharyngeal collapsibility in individuals with cleft lip and palate and, consequently, a greater risk for obstructive sleep apnea in this population.

A determinação da morfologia e dimensões da traqueia são imprescindíveis para o diagnóstico de hipoplasia e definição do tamanho de stent e escolha de sonda endotraqueal apropriada. O buldogue inglês é o principal representante da hipoplasia traqueal e também da síndrome obstrutiva respiratória do cão braquicefálico (SORB). Assim, o conhecimento dos parâmetros da normalidade nesta raça é essencial para o auxílio diagnóstico destas afecções. O exame radiográfico tem sido a modalidade de eleição, entretanto, com a facilidade de acesso à tomografia computadorizada (TC) e melhor resolução espacial, a padronização dos parâmetros da TC se tornou igualmente importante. A presente pesquisa teve como objetivos revisar a literatura quanto as principais modalidades de diagnóstico por imagem para avaliação da traqueia, aplicar de métodos de mensuração traqueal já descritos por meio do exame radiográfico, sugerir o estudo da avaliação morfológica e morfométrica da traqueia e da faringe em cães buldogue inglês por meio da (TC), comparar os achados obtidos pela TC com os radiográficos, e correlacioná-los com as manifestações clínicas da SORB. Incluíram-se cães da raça buldogue inglês com graus I e II da SORB, os quais foram submetidos ao exame de TC (n=31) e de radiografia computadorizada (n=37) da faringe e traqueia. Ao exame radiográfico, avaliouse a traqueia pelo uso de métodos morfométricos previamente estabelecidos pela literatura, e pela análise morfológica. Pela TC e pelo exame radiográfico, avaliou-se o diâmetro e área transversal da traqueia, assim como sua morfologia. Ainda, avaliou-se pela TC e pelo exame radiográfico, o diâmetro e área transversal da nasofaringe e a espessura e comprimento do palato mole. Por meio do método de Bland-Altman, analisou-se a comparação estatística entre as modalidades de imagem, e por meio do coeficiente de correlação de Spearman, testou-se a correlação entre os achados morfométricos com as manifestações clínicas da SORB. Para tanto, esta pesquisa foi dividida em quatro capítulos, e a metodologia detalhada, resultados, discussões e conclusões estão apresentados individualmente em cada capítulo / Determination of the morphology and dimensions of the trachea are essential for the hypoplasia diagnosis, for stent size definition and appropriate endotracheal tube selection. The English Bulldog is the most affected breed with the tracheal hypoplasia and also brachycephalic obstructive airway syndrome (BOAS). Thus, knowledge of the normal range in this breed is essential to aid diagnosis of these diseases. Radiographic analysis has been the method of choice, however, the increased access to computed tomography (CT) and better spatial resolution, the standardization of CT parameters became equally important. This study aimed to review the literature of the main modalities of diagnostic imaging for evaluation of the trachea, apply tracheal measurement methods already described by radiographic examination, suggest the study of morphological and morphometric evaluation of the trachea and pharynx in English Bulldog by (CT), compare the CT and radiographic results, and correlate them with the clinical manifestations of BOAS. English Bulldog classified as BOAS grade I and II were included and underwent to CT scan (n = 31) and computed radiography (n = 37) of the pharynx and trachea. Radiographic examination evaluated the trachea with morphometric methods previously established in the literature, and with morphological analysis. Diameter and cross-sectional area of the trachea, as well as their morphology was evaluated by CT and the radiograph. Also, the diameter and crosssectional area of the nasopharynx, as well as the thickness and length of the soft palate was evaluated by CT and radiographic examination. Bland-Altman method, was used to analyzed the statistical comparison between imaging modalities, and the Spearman correlation coefficient was used to test morphometric findings with the clinical signs of SORB. Therefore, this study was divided into four chapters, and detailed methodology, results, discussion and conclusions are presented individually in each chapter

Zusammenfassung: Ziel dieser retrospektiven vergleichenden Studie war die Untersuchung der metrischen und volumetrischen Veränderungen des pharyngealen Atemweges („posterior airway space“, PAS) nach uni- und bimaxillärer Umstellungsosteotomie einer großen Patientengruppe mit einer Dysgnathie der Angle Klasse III anhand von Daten der digitalen Volumentomographie (DVT). In dieser Arbeit wurden prä- und postoperative DVT-Daten (1 Woche vor der OP und 4-5 Wochen nach der OP erstellt) von insgesamt 80 nach Abschluss des Wachstums kombiniert kieferorthopädisch-kieferchirurgisch behandelten Patienten der Angle-Klasse III (40 unimaxillär – Gruppe 1, 40 bimaxillär therapiert – Gruppe 2) mittels der Software Mimics Innovation Suite 14.1® (Materialise, Leuven, Belgien) dreidimensional visualisiert und analysiert. Ausgeschlossen waren Patienten mit kraniofazialen Syndromen, Lippenkiefergaumensegelspalten und fazialen Asymmetrien. Nach kephalometrischer Auswertung von aus den DVT-Daten generierten Fernröntgenseitenbildern (= FRS) konnten Korrelationen zwischen dreidimensionalen PAS-Parametern und sagittalen Parametern des Gesichtsskeletts hergestellt werden. Die operationsbedingten dreidimensionalen Veränderungen des PAS (Form und Volumen) zeigten in beiden Gruppen keine klinisch relevanten Korrelationen zu den skelettalen Veränderungen aus den kephalometrischen Auswertungen. Sowohl in Gruppe 1 als auch in Gruppe 2 führte die Operation zu keinen signifikanten Volumenänderungen. Durch bimaxilläre Umstellungsosteotomie veränderten sich die pharyngealen Maße Querschnitt, anteroposteriorer und lateraler Durchmesser weniger als durch unimaxilläre Osteotomie. Durch unimaxilläre Osteotomie verringerte sich die engste Stelle signifikant. / Abstract: The aim of this retrospective study was to determine the metric and volumetric changes in pharyngeal airway space (PAS) after orthodontic surgery of a large cohort of patients with Class III dysgnathia by CBCT. Pre- and postoperative CBCT scans of 80 patients with Class III dysgnathia (40 mandibular setback surgery – Group 1, 40 bimaxillary surgery – Group 2) were three-dimensional visualized and analyzed by using the software Mimics Innovation Suite 14.1® (Materialise, Leuven, Belgium). After cephalometric analysis of cephalograms from each 3D record, this datas were to investigate correlations between 3D PAS parameters and sagittal craniofacial parameters. There were no clinical significant correlations between changes of 3D parameters of the PAS and skelettal cephalometric changes in both groups. Neither mandibular setback surgery nor bimaxillary surgery showed significant changes in volumetric parameters. Bimaxillary surgery caused less modification of the pharyngeal parameters cross sectional area, anteroposterior and lateral ratio than mandibular setback surgery. Smallest cross sectional area decreased significantly in the group of patients with mandibular setback surgery.

Obstructive sleep apnea syndrome (OSAS) is characterized by snoring, apneas and excessive daytime sleepiness (EDS). Obesity is a risk factor for snoring and sleep apnea, but data on other factors in relation to obesity are ambiguous. Symptoms of sleep apnea in women have not been fully elucidated. OSAS is an important risk factor for cardiovascular disease (CVD). A common feature in patients with CVD and sleep apnea is an increase in systemic inflammation. From the general population 7,051 women ≥ 20 years answered a questionnaire on snoring and sleep disturbances. Habitual snoring was found in 8% of the total population, and influenced by age, obesity and smoking. The highest prevalence (14%) was found in women 50-59 years. In lean women, alcohol dependence was associated with snoring, while physical inactivity was a risk factor for snoring in obese women. Further, 230 snoring women and 170 women regardless of snoring status were investigated with polysomnography, blood sampling and anthropometric measurements. Of these, 132 participants underwent an ocular and endoscopic examination of their upper airways. Several findings in the upper airways characterised normal-weight women with an apnea-hypopnea index (AHI) ≥ 10. In women with BMI of &gt; 25, no pharyngeal characteristics predicted sleep apnea. When adjusting for age, obesity, smoking, AHI and sleep parameters, several aspects of daytime sleepiness correlated to snoring independently of AHI (EDS, falling asleep involuntarily during day, waking up unrefreshed and fatigue). No symptoms correlated to AHI independently of snoring. Blood samples were analysed for systemic inflammation (CRP, TNFα, IL-6, myeloperoxidase (MPO) and lysozyme). Strong correlations were found between obesity and inflammatory markers. AHI and nocturnal hypoxia correlated to all markers except MPO. When adjusting for age, obesity and smoking, only IL-6 and TNFα were independently associated with nocturnal hypoxia. In conclusion, age and obesity influence the prevalence of snoring and sleep apnea in women from the general population. Other risk factors differ according to BMI. Daytime symptoms are independently related to snoring per se. Despite a strong correlation between obesity and inflammation, an independent relationship between sleep apnea and inflammatory markers was found.

FoxA transcription factors are central regulators of gut development in all species. In C. elegans, pha-4/FoxA is necessary to generate cells of the foregut, or pharynx. FoxA factors need to be precisely regulated for proper development, yet we know very little about FoxA regulation. To look for potential genes that act as pha-4 regulators, the Mango lab previously conducted two screens for suppressors of the lethality associated with a partial loss of pha-4 activity. Both screens uncovered smg-8, a novel gene that is highly conserved amongst metazoans. Interestingly, the human homolog of smg-8 is amplified in some breast cancers, which also depend on FoxA1. This observation makes smg-8 a very exciting gene to investigate. The goal of my thesis is to analyze smg-8 to better understand its function and potential role as a candidate regulator of pha-4/FoxA, using C. elegans as a model system. In this thesis, I show that C. elegans smg-8 does not have a role in the Nonsense Mediated Decay pathway. I find that smg-8 modulates pha-4 protein levels during embryonic development. This work is the first direct evidence that smg-8 is a modulator of pha-4. I used biochemical and bioinformatic approaches to uncover possible partners of smg-8. These approaches identified several interesting candidates that will help place C. elegans smg-8 in a functional pathway. This work has expanded our understanding of smg-8 function and lays the foundation for further investigation of the role of this novel gene as a regulator of pha-4/FoxA in C. elegans.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Thesis (M.Sc.)--University of Alberta, 2010. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Speech-Language Pathology, Department of Speech Pathology and Audiology. Title from pdf file main screen (viewed on July 25, 2010). Includes bibliographical references.

Introdução: O sinal da aspiração faríngea (SAF) e o sinal do pigarrear (SPIG), manifestações clínicas em geral relacionadas, respectivamente, a doenças de vias aéreas superiores e inferiores, são expressões de mecanismos de defesa de natureza mecânica que atuam na limpeza do trato respiratório, e com freqüência encontram-se associados à tosse crônica. Repercutem especialmente em nível faríngeo, com as correspondentes modificações estruturais desse compartimento. Objetivo: Descrever e analisar as modificações anatômicas e características fisiológicas que servem de base para a ocorrência do SAF e do SPIG. Métodos: Estudo clínico observacional onde, foram selecionados 30 indivíduos adultos de ambos os sexos, portadores de rinussinusite crônica, fora de agudização, os quais foram submetidos a exames de imagem, estáticos (radiográficos) e dinâmicos (fluoroscópicos), de modo a ser possível estudar as alterações anatômicas nos momentos mencionados (SAF, SPIG), e durante a situação de repouso (REP). Os pacientes eram colocados em posição ortostática, de perfil, buscando-se, com isto, reduzir os efeitos da sobreposição de tecidos, objetivando tornar as mensurações mais acuradas. Cada um dos 30 indivíduos foi estudado nas três situações: em repouso (REP), em manobra de aspiração faríngea (SAF), e durante o ato do pigarrear SPIG). Usaram-se testes de média para comparações entre as mensurações (teste T e ANOVA), intervalos de confiança de 95,0 %, adotando-se nível de significância de 5,0 %. Resultados: Encontrou-se a área transversa da faringe medindo 4,13±1,339 cm² na posição de repouso, 1,879±0,950 cm² durante a manobra de aspiração, e 5,280±1,421 cm² durante o pigarrear. Esses três valores foram todos significativamente diferentes entre si (p<0,001). A maior variação com relação ao repouso ocorreu no SAF (120,0% menor), enquanto que no SPIG foi em torno de 30,0% maior. Os valores foram menores entre as mulheres, mas a variabilidade foi similar em ambos os sexos. Conclusão: A área da secção transversa da faringe, mensurada no nível da primeira vértebra cervical de indivíduos adultos, mostrou-se significativamente menor durante a manobra inspiratória (SAF), em comparação com a situação de repouso (REP), enquanto que a do pigarrear (SPIG) foi significativamente maior. As modificações do calibre da faringe, em especial o acentuado estreitamento durante o SAF, associadas a movimentos vibratórios das estruturas locais, devem conferir a esse compartimento maior eficiência na remoção das secreções do trato respiratório. / Introduction: The signs of both pharyngeal aspiration (SPA) and phlegm in the throat (SPT), clinical manifestations generally related, respectively, to either upper or lower diseases of the airways, are expressions of mechanic defense mechanisms for respiratory tract cleaning, frequently associated to chronic cough. They have repercussion mainly at pharyngeal level, with the correspondent structural modifications of that compartment. Objective: To describe the anatomic modifications and physiologic characteristics in which are based the grounds for the SPA and SPT occurrence. Methods: Clinical and observational study in which were selected 30 of both sex adult individuals, all with inflammatory upper airways disease, with the purpose to specially study the alterations in morphology of the pharynx, which occurs during the SPA and SPT expression. For that, the individuals in orthostatic position were submitted to static (radiographic) and dynamic (fluoroscopy) image exams, in profile projections, aiming with this to reduce the tissue superposition and to obtain more accurate measurements. Each of the 30 individuals were studied in three situations: at rest (RST), in SPA and SPT. Tests of media (T, ANOVA) were used for comparisons between measurements, adopting a 5.0% significance level. Results: It was found the transverse area of pharynx measuring 4.133±1.339 cm2 in the rest (RST) position, 1.879±0.950 cm2 during pharyngeal aspiration (SPA), and 5.280±1.421 cm2 in SPT – values that were significantly different (P<0.001). In relation to the rest situation, the most accented variation occurred in SPA (120.0% smaller), whereas in SPT it was 30.0% greater. The values were smaller among females, but their variability was similar in both sexes in all the three situations. Conclusions: In comparison to the rest situation (RST), the transverse section of the pharynx, measured at the first cervical vertebra, was significantly smaller during the aspiration (SPA), and greater on the SPT maneuver. The modifications of the pharynx caliber, specially its accented narrowing associated to vibratory movements of the local anatomic structures, should be confer to that compartment a better efficiency for secretion removal from the respiratory tract.

Introdução: O sinal da aspiração faríngea (SAF) e o sinal do pigarrear (SPIG), manifestações clínicas em geral relacionadas, respectivamente, a doenças de vias aéreas superiores e inferiores, são expressões de mecanismos de defesa de natureza mecânica que atuam na limpeza do trato respiratório, e com freqüência encontram-se associados à tosse crônica. Repercutem especialmente em nível faríngeo, com as correspondentes modificações estruturais desse compartimento. Objetivo: Descrever e analisar as modificações anatômicas e características fisiológicas que servem de base para a ocorrência do SAF e do SPIG. Métodos: Estudo clínico observacional onde, foram selecionados 30 indivíduos adultos de ambos os sexos, portadores de rinussinusite crônica, fora de agudização, os quais foram submetidos a exames de imagem, estáticos (radiográficos) e dinâmicos (fluoroscópicos), de modo a ser possível estudar as alterações anatômicas nos momentos mencionados (SAF, SPIG), e durante a situação de repouso (REP). Os pacientes eram colocados em posição ortostática, de perfil, buscando-se, com isto, reduzir os efeitos da sobreposição de tecidos, objetivando tornar as mensurações mais acuradas. Cada um dos 30 indivíduos foi estudado nas três situações: em repouso (REP), em manobra de aspiração faríngea (SAF), e durante o ato do pigarrear SPIG). Usaram-se testes de média para comparações entre as mensurações (teste T e ANOVA), intervalos de confiança de 95,0 %, adotando-se nível de significância de 5,0 %. Resultados: Encontrou-se a área transversa da faringe medindo 4,13±1,339 cm² na posição de repouso, 1,879±0,950 cm² durante a manobra de aspiração, e 5,280±1,421 cm² durante o pigarrear. Esses três valores foram todos significativamente diferentes entre si (p<0,001). A maior variação com relação ao repouso ocorreu no SAF (120,0% menor), enquanto que no SPIG foi em torno de 30,0% maior. Os valores foram menores entre as mulheres, mas a variabilidade foi similar em ambos os sexos. Conclusão: A área da secção transversa da faringe, mensurada no nível da primeira vértebra cervical de indivíduos adultos, mostrou-se significativamente menor durante a manobra inspiratória (SAF), em comparação com a situação de repouso (REP), enquanto que a do pigarrear (SPIG) foi significativamente maior. As modificações do calibre da faringe, em especial o acentuado estreitamento durante o SAF, associadas a movimentos vibratórios das estruturas locais, devem conferir a esse compartimento maior eficiência na remoção das secreções do trato respiratório. / Introduction: The signs of both pharyngeal aspiration (SPA) and phlegm in the throat (SPT), clinical manifestations generally related, respectively, to either upper or lower diseases of the airways, are expressions of mechanic defense mechanisms for respiratory tract cleaning, frequently associated to chronic cough. They have repercussion mainly at pharyngeal level, with the correspondent structural modifications of that compartment. Objective: To describe the anatomic modifications and physiologic characteristics in which are based the grounds for the SPA and SPT occurrence. Methods: Clinical and observational study in which were selected 30 of both sex adult individuals, all with inflammatory upper airways disease, with the purpose to specially study the alterations in morphology of the pharynx, which occurs during the SPA and SPT expression. For that, the individuals in orthostatic position were submitted to static (radiographic) and dynamic (fluoroscopy) image exams, in profile projections, aiming with this to reduce the tissue superposition and to obtain more accurate measurements. Each of the 30 individuals were studied in three situations: at rest (RST), in SPA and SPT. Tests of media (T, ANOVA) were used for comparisons between measurements, adopting a 5.0% significance level. Results: It was found the transverse area of pharynx measuring 4.133±1.339 cm2 in the rest (RST) position, 1.879±0.950 cm2 during pharyngeal aspiration (SPA), and 5.280±1.421 cm2 in SPT – values that were significantly different (P<0.001). In relation to the rest situation, the most accented variation occurred in SPA (120.0% smaller), whereas in SPT it was 30.0% greater. The values were smaller among females, but their variability was similar in both sexes in all the three situations. Conclusions: In comparison to the rest situation (RST), the transverse section of the pharynx, measured at the first cervical vertebra, was significantly smaller during the aspiration (SPA), and greater on the SPT maneuver. The modifications of the pharynx caliber, specially its accented narrowing associated to vibratory movements of the local anatomic structures, should be confer to that compartment a better efficiency for secretion removal from the respiratory tract.