Objetivos: Investigar a ocorrência de queixa respiratória nos pacientes com sinais clínicos da Síndrome Velocardiofacial (SVCF) submetidos à cirurgia para a correção da Disfunção Velofaríngea (DVF), comparativamente àqueles com fissura isolada de palato sem sinais da SVCF, além de verificar se a condição respiratória pré-cirúrgica interfere na escolha do tratamento cirúrgico para correção da DVF. Material e Método: Estudo retrospectivo e prospectivo com 30 indivíduos de ambos os sexos, que realizaram procedimento cirúrgico para a correção da DVF (veloplastia intravelar ou retalho faríngeo), sendo 15 com sinais clínicos da SVCF (grupo estudo) e 15 com fissura isolada de palato sem sinais clínicos da SVCF, pareado por sexo e idade (grupo controle). Um levantamento de sintomas respiratórias foi realizado utilizando-se três questionários, um aplicado antes e após a cirurgia (Caouette-Laberge et al 1992) e dois aplicados apenas após a cirurgia (Petry et al 2008, Berlin, proposto por Netzer et al 1999). As comparações foram realizadas por meio do Teste Exato de Fisher, considerando-se nível de significância de 5%. Resultados: Sintomas como respiração oral e ronco estavam presentes nos períodos pré e pós-cirúrgico em ambos os grupos estudados, não sendo detectada diferença entre esses períodos quanto à presença desses sintomas, nos dois grupos. Diferença entre os grupos não foram constatadas em relação à presença de sonolência diurna excessiva, ronco, apneia, sono/fadiga, histórico de obesidade ou hipertensão arterial e risco potencial para SAOS. No grupo estudo houve semelhante distribuição entre a realização de veloplastia intravelar e retalho faríngeo, diferentemente do grupo controle em que prevaleceu a veloplastia intravelar, não havendo relação entre a frequência de sintomas respiratórios e o tipo de cirurgia, para ambos os grupos. Conclusão: Nos pacientes com sinais clínicos da SVCF, sintomas de respiração oral e ronco estão presentes antes e após a correção cirúrgica da DVF; não há diferença quanto aos sintomas respiratórios entre indivíduos com sinais clínicos da SVCF e indivíduos com fissura isolada de palato sem sinais da SVCF; a condição respiratória antes da cirurgia não interferiu na escolha do tipo de procedimento cirúrgico para correção da DVF. / Objectives: To investigate the occurrence of respiratory complaint in individuals with clinical signs of Velocardiofacial Syndrome (VCFS) submitted to surgery for correction of Velopharyngeal Dysfunction (VPD), compared to individuals without signs of VCFS, and analyzed if the preoperative respiratory condition interferes with surgical treatment planning for correction of VPD. Material and method: Retrospective and prospective study of 30 individuals of both genders, who were submitted to surgery for correction of VPD (intravelar veloplasty or pharyngeal flap), being 15 with clinical signs of VCFS (study group) and 15 with isolated cleft palate without clinical signs of VCFS, matched for gender and age (control group). A survey of respiratory complaints was performed using three questionnaires, one applied before and after surgery (Caouette-Laberge et al 1992) and two applied only after surgery (Petry et al 2008, Berlin, proposed by Netzer et al 1999). Comparisons were performed by the exact Fisher test, at a significance level of 5%. Results: Symptoms as mouth breathing and snoring were present in pre- and postoperative periods in both groups, without difference between periods concerning the presence of these symptoms, in the two groups. No differences were observed between groups as to the presence of excessive somnolence during the day, snoring, apnea, sleep/fatigue, history of obesity or arterial hypertension and potential risk to OSA. The study group presented similar distribution of intravelar veloplasty and pharyngeal flap, different from the control group that presented predominance of intravelar veloplasty, without relationship between the frequency of respiratory symptons and type of surgery, for both groups. Conclusion: In patients with clinical signs of VCFS, complaints of mouth breathing and snoring are present before and after surgical correction of VPD; there is no difference in the complaints of respiratory symptoms between individuals with clinical signs of VCFS and individuals with isolated cleft palate without signs of VCFS; the respiratory condition before surgery did not interfere with selection of the type of surgical procedure for correction of VPD.

Introdução: O uso de biomassa como combustível para aquecimento e preparação de alimentos vem sendo considerado como um importante fator associado à prevalência aumentada de sintomas respiratórios e à perda de função pulmonar. No presente estudo apresentamos os efeitos respiratórios da exposição crônica à combustão de biomassa (BM) dentro (BMD) ou fora (BMF) do domicílio em uma população do interior do Brasil e comparamos os resultados aos de indivíduos da mesma população que utilizam gás liquefeito de petróleo (GLP). Métodos: Foram incluídos 1402 indivíduos em 260 domicílios divididos em três grupos de acordo com a exposição (GLP, BMD, BMF). Os sintomas respiratórios foram avaliados utilizando questionários validados. O índice de refletância de filtros de papel foi utilizado para avaliar a exposição à biomassa. Em 48 domicílios a concentração de material particulado PM2,5 também foi quantificada. Provas de função pulmonar (PFP) foram realizadas em 120 indivíduos. Resultados: O índice de refletância correlacionou-se diretamente com a concentração de PM2,5 (r=0,92, p<0,001) e foi portanto utilizado para estimar a exposição (ePM2,5). Demonstramos aumento significativo do ePM2,5 no grupo BMD e BMF em comparação com o grupo GLP (p<0,001). Houve ainda aumento significativo da razão de chances (OR) para tosse produtiva, chiado e dispnéia nos adultos expostos à BMD (OR=2,93, 2,33, 2,59, respectivamente) e BMF (OR=1,78, 1,78, 1,80, respectivamente) em comparação com o grupo GLP. As PFP demonstraram que tanto o grupo BM-nãotabagista como GLP-tabagista apresentaram redução no % do VEF1 predito e na relação VEF1/CVF quando comparado com GLP-não-tabagista (p=0,002), o mesmo ocorrendo para o grupo BM-tabagista, em relação a todos os demais (p<0,05). A prevalência de obstrução de vias aéreas encontrada no grupo BM-não-tabagista e GLP-tabagista foi semelhante (20%) e menor do que a observada no grupo BM-tabagista (33%). A PFP correlacionou-se inversamente com o tempo de exposição e a concentração de ePM2,5 (p<0,001). Conclusões: A exposição crônica à combustão de biomassa está associada com o aumento da prevalência de sintomas respiratórios, redução da função pulmonar e desenvolvimento de doença pulmonar obstrutiva crônica. Esses efeitos estão associados com a duração e magnitude da exposição e são potencializadas pelo tabagismo. / Introduction: The use of biomass fuels for cooking and heating is considered an important factor associated with respiratory symptoms and loss of pulmonary function. We report the respiratory effects of chronic exposure to biomass (BM) combustion in a Brazilian population and compared the results with those of individuals from the same community using Liquefied Petroleum Gas (LPG). Methods: 1,402 individuals in 260 residences were divided into three groups according to exposure (LPG, indoor-BM, outside-BM). Respiratory symptoms were assessed using questionnaires. Reflectance of paper filters was used to assess BM. In 48 residences the amount of PM2.5 was also quantified. Pulmonary function tests (PFT) were performed in 120 individuals. Results: Reflectance-index correlated directly with PM2.5 (r=0.92, p<0.001) and was used to estimate exposure (ePM2.5). There was a significant increase in ePM2.5 in Indoor-BM and Outside-BM, compared to LPG (p<0.001). There was a significantly increased odds ratio (OR) for cough with sputum, sneezing and dyspnea in adults exposed to Indoor-BM (OR=2.93, 2.33, 2.59, respectively) and Outside-BM (OR=1.78, 1.78, 1.80, respectively) compared to LPG. PFTs revealed both non-smoker-BM and smoker-LPG individuals to have decreased %predicted-FEV1 and FEV1/FVC as compared to non-smoker-LPG (p=0.022). Reduction was also observed in both parameters between smoker-BM and other groups (p<0.05). The prevalence of chronic obstructive pulmonary disease was 20% for both non-smoker-BM and smoker-LPG and smaller than that observed for smoker-BM (33%). PFT data was inversely correlated with duration and ePM2.5 (p<0.001). The prevalence of airway obstruction was 20% in both non-smoker-BM and smoker-LPG subjects. Conclusions: Chronic exposure to BM is associated with increased prevalence of respiratory symptoms, reduced lung function and development of chronic obstructive pulmonary disease. These effects are associated with the duration and magnitude of exposure and are exacerbated by tobacco smoke.

Introdução: O uso de biomassa como combustível para aquecimento e preparação de alimentos vem sendo considerado como um importante fator associado à prevalência aumentada de sintomas respiratórios e à perda de função pulmonar. No presente estudo apresentamos os efeitos respiratórios da exposição crônica à combustão de biomassa (BM) dentro (BMD) ou fora (BMF) do domicílio em uma população do interior do Brasil e comparamos os resultados aos de indivíduos da mesma população que utilizam gás liquefeito de petróleo (GLP). Métodos: Foram incluídos 1402 indivíduos em 260 domicílios divididos em três grupos de acordo com a exposição (GLP, BMD, BMF). Os sintomas respiratórios foram avaliados utilizando questionários validados. O índice de refletância de filtros de papel foi utilizado para avaliar a exposição à biomassa. Em 48 domicílios a concentração de material particulado PM2,5 também foi quantificada. Provas de função pulmonar (PFP) foram realizadas em 120 indivíduos. Resultados: O índice de refletância correlacionou-se diretamente com a concentração de PM2,5 (r=0,92, p<0,001) e foi portanto utilizado para estimar a exposição (ePM2,5). Demonstramos aumento significativo do ePM2,5 no grupo BMD e BMF em comparação com o grupo GLP (p<0,001). Houve ainda aumento significativo da razão de chances (OR) para tosse produtiva, chiado e dispnéia nos adultos expostos à BMD (OR=2,93, 2,33, 2,59, respectivamente) e BMF (OR=1,78, 1,78, 1,80, respectivamente) em comparação com o grupo GLP. As PFP demonstraram que tanto o grupo BM-nãotabagista como GLP-tabagista apresentaram redução no % do VEF1 predito e na relação VEF1/CVF quando comparado com GLP-não-tabagista (p=0,002), o mesmo ocorrendo para o grupo BM-tabagista, em relação a todos os demais (p<0,05). A prevalência de obstrução de vias aéreas encontrada no grupo BM-não-tabagista e GLP-tabagista foi semelhante (20%) e menor do que a observada no grupo BM-tabagista (33%). A PFP correlacionou-se inversamente com o tempo de exposição e a concentração de ePM2,5 (p<0,001). Conclusões: A exposição crônica à combustão de biomassa está associada com o aumento da prevalência de sintomas respiratórios, redução da função pulmonar e desenvolvimento de doença pulmonar obstrutiva crônica. Esses efeitos estão associados com a duração e magnitude da exposição e são potencializadas pelo tabagismo. / Introduction: The use of biomass fuels for cooking and heating is considered an important factor associated with respiratory symptoms and loss of pulmonary function. We report the respiratory effects of chronic exposure to biomass (BM) combustion in a Brazilian population and compared the results with those of individuals from the same community using Liquefied Petroleum Gas (LPG). Methods: 1,402 individuals in 260 residences were divided into three groups according to exposure (LPG, indoor-BM, outside-BM). Respiratory symptoms were assessed using questionnaires. Reflectance of paper filters was used to assess BM. In 48 residences the amount of PM2.5 was also quantified. Pulmonary function tests (PFT) were performed in 120 individuals. Results: Reflectance-index correlated directly with PM2.5 (r=0.92, p<0.001) and was used to estimate exposure (ePM2.5). There was a significant increase in ePM2.5 in Indoor-BM and Outside-BM, compared to LPG (p<0.001). There was a significantly increased odds ratio (OR) for cough with sputum, sneezing and dyspnea in adults exposed to Indoor-BM (OR=2.93, 2.33, 2.59, respectively) and Outside-BM (OR=1.78, 1.78, 1.80, respectively) compared to LPG. PFTs revealed both non-smoker-BM and smoker-LPG individuals to have decreased %predicted-FEV1 and FEV1/FVC as compared to non-smoker-LPG (p=0.022). Reduction was also observed in both parameters between smoker-BM and other groups (p<0.05). The prevalence of chronic obstructive pulmonary disease was 20% for both non-smoker-BM and smoker-LPG and smaller than that observed for smoker-BM (33%). PFT data was inversely correlated with duration and ePM2.5 (p<0.001). The prevalence of airway obstruction was 20% in both non-smoker-BM and smoker-LPG subjects. Conclusions: Chronic exposure to BM is associated with increased prevalence of respiratory symptoms, reduced lung function and development of chronic obstructive pulmonary disease. These effects are associated with the duration and magnitude of exposure and are exacerbated by tobacco smoke.

Periodontal disease affects 47% of Americans over 30 and is a growing global concern. Current treatments for periodontal disease focus on the mechanical elimination of periodontal biofilms. Very few treatments are available that target the rampant, unregulated host immune response that is ultimately responsible for tissue degradation. BET proteins have been shown to play critical roles in inflammatory gene regulation and are therefore potentially ideal therapeutic targets for treating periodontal disease. RVX-208 is a selective BET-inhibitor with a high affinity for Bromodomain 2 (BD2) as compared to BD1 in BET proteins. Our previous studies have shown that RVX-208 inhibits inflammatory cytokine production and suppresses osteoclast differentiation. Cell culture assays have provided proof of concept for RVX-208 and its feasibility as a treatment for periodontal disease. As such, our long term goal is to develop RVX-208 as a front-line treatment for periodontitis. The objectives of this study were to determine the ability of RVX-208 to reduce bone loss in a ligature-induced periodontitis model, and to further investigate the mechanisms through which RVX-208 mediates its anti-inflammatory and osteoclastogenesis-suppressive effects. The specific aims of this study were: 1) To further validate the in vivo effects of RVX-208 on a ligature-induced periodontitis model in rats, and 2) To determine the molecular mechanisms of RVX-208 on preventing alveolar bone loss in periodontal disease. To investigate, a ligature-induced periodontitis model was created in rodents. Those rodents were treated with increasing dosages of RVX-208 (0-2.5 mM) by subgingival injection every other day. After 2 weeks, the maxillae were harvested and analyzed via a micro-CT protocol that had been created and validated through statistical analyses. To study the ability of RVX-208 to suppress osteoclastogenesis, RAW264.7 cells were induced into osteoclasts by RANKL and then treated with RVX-208. To ensure RVX-208 was not species specific, THP-1 cells were challenged with either E. coli-LPS or P. gingivalis bacteria and then treated with RVX-208. Linear and volumetric micro-CT analysis showed that RVX-208 could significantly ameliorate bone loss in a ligature-induced periodontitis model. RVX-208 was shown to prevent osteoclast differentiation by suppressing the expression of genes closely associated with osteoclast differentiation and maturation. RVX-208 was found to not be species specific, as it was able to mediate its effects on a human cell line, and had consistent anti-inflammatory effects regardless of whole pathogen or LPS-induced inflammatory response. Therefore, RVX-208 is a promising therapeutic for treatment of periodontal diseases.

Dissertation (Ph.D.)--University of South Florida, 2008. / Includes vita. Includes bibliographical references.

Expansion of visceral adipose tissue correlates with the metabolic syndrome and increased cardiovascular risk. Hypertrophied visceral fat becomes inflamed, causing increased lipolysis, decreased triglyceride storage, and lipotoxicity in skeletal muscle and liver resulting in insulin resistance. Perivascular adipose tissue is a normal component of the adventitia of arteries in humans and animals. Whether or not perivascular adipose also becomes inflamed in obesity is an important question, as this may be an additional, direct mechanism by which obesity causes vascular inflammation and disease. Thus, for the first part of my thesis, we asked the question: does perivascular adipose in mice become inflamed with high fat feeding? In contrast to visceral adipose, macrophage gene expression was not increased in perivascular adipose in response to high fat diet, and this correlated with reduced F480 antigen positive cells as seen by immunohistochemistry and flow cytometry. Interestingly, perivascular adipose surrounding the thoracic aorta was similar to brown adipose tissue, a highly thermogenic fat depot, as shown by histology and DNA microarrays. Moreover, inter-scapular brown adipose was also resistant to diet induced inflammation in comparison to visceral adipose. These findings suggest that brown adipose in the perivascular niche may serve to protect the vasculature from diet induced inflammation, or from cold exposure, or both; whether or not brown perivascular adipose tissue exists in humans has yet to be determined. In the second part of my thesis, we evaluated the role of perivascular adipose tissue in the apolipoprotein E knockout mouse, which exhibits severe hyperlipidemia and atherosclerosis, but is resistant to diet induced obesity and glucose intolerance. We tested the hypothesis that in this model of severe atherosclerosis, inflammation of perivascular adipose does occur. However, we were surprised to find that macrophage specific gene expression, as determined by either microarray analysis or quantitative polymerase chain reaction, was not increased in either the perivascular or the visceral adipose of high fat diet fed apolipoprotein E knockout mice. While the visceral adipose of wild type mice had extensive alterations in gene expression in response to high fat diet, in particular, enrichment of inflammatory gene expression and broad down regulation of peroxisome proliferator activated receptor gamma target genes, apolipoprotein E knockout visceral adipose did not. Importantly, the apolipoprotein E knockout visceral adipose instead showed increased expression of genes encoding enzymes in fatty acid oxidation pathways. High fat diet fed apolipoprotein E knockout visceral adipose was also characterized by smaller adipocyte size. We conclude that, 1) inflammation in thoracic perivascular adipose does not occur in conjunction with diet induced obesity in normal animals nor with atherosclerosis in apolipoprotein E knockout mice, 2) thoracic perivascular adipose tissue is essentially identical to brown adipose tissue in mice, thus potentially protecting the vasculature from the cold, and 3) apolipoprotein E knockout mice remain lean on a high fat diet, despite hyperlipidemia and atherosclerosis, and the decreased adiposity correlates with decreased adipocyte size and adipose inflammation but increased oxidation of fatty acids. Consistent with previous work showing apolipoprotein E controls adipocyte uptake and deposition of triglyceride, its absence prevents adipocyte hypertrophy and resultant inflammation of visceral adipose tissue. Thus limiting adipocyte acquisition of fatty acids may be advantageous, provided that compensatory mechanisms to prevent sustained hyperlipidemia and peripheral organ lipotoxicity can be activated.

Orientador: Albina Rodrigues Torres / Resumo: Introdução: O transtorno obsessivo-compulsivo (TOC) apresenta expressiva heterogeneidade de sintomas. Análises fatoriais têm mostrado que obsessões e compulsões de simetria, ordenação, repetição e contagem se caracterizam como uma dimensão separada. Apesar de a dimensão de simetria ser manifestação comum do TOC, estudos sobre esta dimensão são escassos na literatura. Objetivo: investigar a prevalência, a gravidade e o perfil sociodemográfico e clínico de pacientes que apresentam sintomas da dimensão de simetria em uma amostra clínica de pacientes com TOC. Método: estudo transversal com 1001 pacientes do banco de dados do Consórcio Brasileiro de Pesquisa em Transtornos do Espectro Obsessivo-Compulsivo. Diversas variáveis independentes foram investigadas através de instrumentos estruturados, tais como: Questionário sobre história natural do TOC, Escalas de Yale-Brown (Y-BOCS) e Escala Dimensional de Sintomas Obsessivo-compulsivos (DY-BOCS), Escala de Fenômenos Sensoriais (USP-SPS), Inventário de Depressão de Beck (BDI), Escala de Crenças de Brown (BABS) e Entrevista Clínica Estruturada para Transtornos do Eixo I do DSM-IV (SCID-I). Após a análise descritiva, foram feitas análises bivariadas entre possíveis fatores associados à presença da dimensão de simetria através do teste de qui-quadrado ou exato de Fisher e o teste t de Student ou Mann-Whitney. Como medidas de tamanho de efeito, foram calculadas razões de chances (odds ratios-OR) com intervalos de confiança e D de Cohen. P... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Obsessive-compulsive disorder (OCD) presents an expressive heterogeneity of symptoms. Factorial analyses have shown that obsessions and compulsions of symmetry, ordering, repetition, and counting are characterized as a separate symptom dimension. Although the symmetry dimension is a common manifestation of OCD, studies on this dimension are scarce in the literature. Objective: to investigate the prevalence, severity, and the sociodemographic and clinical profile of patients with symmetry symptoms in a clinical sample of OCD patients. Method: a cross-sectional study with 1001 patients from the database of the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. Several independent variables were investigated through structured instruments, such as: OCD Natural History Questionnaire, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Dimensional Obsessive-Compulsive Scale (DY-BOCS), Sensory Phenomena Scale (USP-SPS), Beck Depression Inventory (BDI), Brown Assessment of Beliefs Scale (BABS), and Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). After the descriptive analysis, bivariate analyses were performed between possible factors associated with the presence of the symmetry dimension using the chi-square or Fisher's exact test and the Student's t-test or Mann-Whitney test. As measures of effect size, odds ratios (ORs) with confidence intervals and Cohen's D were calculated. Finally, a logistic regression was performed to cont... (Complete abstract click electronic access below) / Mestre

A common phenotype observed in most cancers is chromosomal instability. This includes both structural and numerical chromosomal aberrations, which can promote carcinogenesis. The fusion gene CBFB/MYH11 is created by the structural chromosomal inversion(16)(p13.1q22), resulting in the fusion protein CBFβ-SMMHC, which blocks differentiation in hematopoietic progenitor cells. This mutation alone, however, is not sufficient for transformation, and at least one additional cooperating mutation is necessary. The role of wildtype Cbfb in modulating the oncogenic function of the fusion protein Cbfβ-SMMHC in mice was examined. Transgenic mice expressing the fusion protein, but lacking a wild-type copy of Cbfb, were created to model the effects of these combined mutations. It was found that wild-type Cbfb is necessary for maintaining normal hematopoietic differentiation. Consequently, complete loss of wild-type Cbfb accelerates leukemogenesis in Cbfb/MYH11 mice compared to mice expressing both the fusion and wild-type proteins. While there is no evidence in human patient samples that loss of wild-type Cbfb expression cooperates with the fusion protein to cause transformation, it is apparent from these experiments that wild-type Cbfβ does play a role in maintaining genomic integrity in the presence of Cbfβ-SMMHC. Experiments have also shown that loss of Cbfb leads to accumulation of hematopoietic progenitor cells, which may acquire additional cooperating mutations. Not unlike CBFB/MYH11, the human papillomavirus (HPV) E6 and E7 proteins are not sufficient for cellular transformation. Instead, high risk HPV E7 causes numerical chromosomal aberrations, which can lead to accumulation of additional cooperating mutations. Expression of HPV-16 E7 and subsequent downregulation of the retinoblastoma protein (Rb) has been shown to induce polyploidy in human keratinocytes. Polyploidy predisposes cells to aneuploidy and can eventually lead to transformation in HPV positive cells. There are several possible mechanisms through which E7 may lead to polyploidization, including abrogation of the spindle assembly checkpoint, cleavage failure, abrogation of the postmitotic checkpoint, and re-replication. Rb-defective mouse and human cells were found to undergo normal mitosis and complete cytokinesis. Furthermore, DNA re-replication was not found to be a major mechanism to polyploidization in HPV-E7 cells upon microtubule disruption. Interestingly, upon prolonged mitotic arrest, cells were found to adapt to the spindle assembly checkpoint and halt in a G1-like state with 4C DNA content. This post-mitotic checkpoint is abrogated by E7-induced Rb-downregulation leading to S-phase induction and polyploidy. This dissertation explores two examples of the multi-step pathway in human cancers. While certain genes or genetic mutations are often characteristic of specific cancers, those mutations are often not sufficient for transformation. The genetic or chromosomal abnormalities that they produce often stimulate the additional mutations necessary for oncogenesis. The studies with Cbfb/MYH11 and HPV E7 further exemplify the significance of numerical and structural chromosomal aberrations in multi-step carcinogenesis.

Made available in DSpace on 2015-07-22T20:49:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-03-30 / Objetivos: Comparar a avaliação objetiva da obstrução nasal, mensurada por rinometria acústica (RnA) (volume dos cinco primeiros centímetros da cavidade nasal, V5) e rinomanometria anterior ativa (RMAA) (resistência nasal total, RNT), com a avaliação subjetiva dada pelo escore de obstrução (EO, escala de 0 a 10) em crianças e adolescentes com rinite alérgica e controles. Método: Trinta pacientes, entre sete e 18 anos, com rinite alérgica persistente e trinta controles participaram do estudo. As variáveis objetivas foram mensuradas em triplicata e de acordo com recomendações mais utilizadas. O EO foi referido para a cavidade nasal total e para as narinas em separado. RNT, V5 e EO foram mensurados nos momentos basal e após indução de obstrução nasal (100% aumento RNT após provocação nasal com histamina). Os pacientes com rinite alérgica foram tratados com corticosteroide tópico nasal (mometasona 100 mcg/dia por 15 dias) e avaliados 21 (±5) dias após. Resultados: Houve correlações significantes e negativas entre RNT e V5 em todos os grupos e situações de avaliação. Os valores de r encontrados variaram de -0,73 a -0,32, sendo a correlação encontrada no grupo rinite, no momento basal, na avaliação da narina mais obstruída a mais forte (r= -0,727). Para a cavidade nasal total não houve correlação significante entre EO e RNT e entre EO e V5 em todos os momentos estudados. Em relação à narina mais obstruída, verificamos correlação significante e negativa para EO e RNT (r= -0,51) e significante e positiva para EO e V5 (r= 0,29), avaliando-se o grupo total no momento basal. Não houve diferenças nítidas nos coeficientes de correlação encontrados nos paciente e nos controles. Os coeficientes de correlação não se alteraram após a indução de obstrução nasal e após tratamento com corticosteroide nasal. De forma semelhante, as crianças mais novas apresentaram coeficientes de correlação semelhantes aos dos adolescentes mais velhos. Conclusões: Assim como já fora descrito para adultos, a avaliação objetiva da obstrução nasal por RnA (V5) e RMAA (RNT) não apresentou correlação significativa em relação à avaliação subjetiva (escore de obstrução), em crianças e adolescentes, ao avaliar-se a cavidade nasal como um todo, fato que ocorreu na avaliação unilateral da cavidade nasal. Houve forte correlação entre as avaliações objetivas. A presença de doença nasal crônica (rinite alérgica) não interferiu na correlação entre as avaliações objetivas e subjetivas da obstrução nasal. A indução aguda de obstrução nasal, o tratamento com corticosteroide nasal e a idade também parecem não induzir alterações nessa correlação. Sugere-se, portanto, utilidade no acréscimo de um método objetivo para avaliação da obstrução nasal nas pesquisas em rinologia e, na sua impossibilidade, a avaliação das narinas em separado. / Objectives: Compare the objective assessment of nasal obstruction, measured by acoustic rhinometry (ARM) (volume of the first five centimeters of the nasal cavity, V5) and active anterior rhinomanometry (AARMM) (total nasal resistance, TNR), with the subjective evaluation given by obstruction scores (OS, scale from 0 to 10) in children and adolescents with allergic rhinitis and controls. Method: Thirty patients, aged 7 to 18 years, with persistent allergic rhinitis and thirty controls were enrolled. The objective variables were measured in triplicate and according to existing recommendations. The OS was reported for the total nasal cavity and nostrils separately. TNR, V5 and EO were measured at baseline and in the moments after the induction of nasal obstruction (100% increase in NTS after nasal challenge with histamine). Patients with allergic rhinitis were treated with topical nasal corticosteroids, mometasone 100mcg/day for 15 days and assessed 21 (± 5) days later. Results: There were significant and negative correlations between TNR and V5 in all groups and evaluation situations. The r values ranged from -0.73 to -0.32, and the association found in rhinitis group, at baseline, to evaluate the strongest and most obstructed nostril (r = -0.727). For the nasal cavity, of no significant correlation between OS and TNR and between OS and V5 at all studied times. Regarding the most obstructed nostril, we found significant negative correlation for OS and TNR (r = -0.51) and significant and positive for OS and V5 (r = 0.29), evaluating the total group at baseline. There were no clear differences in the coefficients of correlation found in patients and controls. The correlation coefficients were not changed after the induction of nasal obstruction and after treatment with nasal corticosteroids. Similarly, younger children showed a correlation coefficient similar to those of older adolescents. Conclusions: As has been described for adults, the objective assessment of nasal obstruction ARM (V5) and RMAA (TNR) showed no significant correlation in relation to the subjective evaluation (obstruction score) in children and adolescents, when assessing the nasal cavity as a whole, which has been seen in the assessment of unilateral nasal cavity. There was strong correlation between the objective evaluations. The presence of chronic nasal disease (allergic rhinitis) did not affect the correlation between objective and subjective assessments of nasal obstruction. The acute induction of nasal obstruction, nasal corticosteroid treatment and age also seem to induce changes in this correlation. It is suggested, therefore, usefulness in adding an objective method for evaluating nasal obstruction in the polls in rhinology and, failing which, the evaluation of the nostrils separately. / TEDE / BV UNIFESP: Teses e dissertações

The KCNE1 and KCNE3 type I transmembrane-spanning β-subunits assemble with the KCNQ1 voltage-gated K+ channel to afford membrane-embedded complexes with dramatically different properties. Assembly with KCNE1 produces the very slowly activating and deactivating IKs current that shapes the repolarization phase of cardiac action potentials. Genetic mutations in KCNQ1 or KCNE1 that reduce IKs current cause long QT syndrome and predispose affected individuals to potentially fatal cardiac arrhythmias. In contrast, complexes formed between KCNQ1 and KCNE3 produce rapidly activating and mostly voltage-independent currents, properties that are essential for function in K+ recycling and Cl−secretion in gastrointestinal epithelia. This thesis addresses how these two homologous accessory peptides impart their distinctive effects on KCNQ1 channel gating by examining two important protein regions: 1) a conserved C-terminal motif in the β-subunits themselves, and 2) the voltage sensing domain of KCNQ1 channels. Sequences in both the transmembrane domain and C-terminus of KCNE1 and KCNE3 have been identified as contributing to the divergent modulatory effects that these β-subunits exert. The homology of transmembrane-abutting C-terminal residues within the KCNE family and the presence of long QT-causing mutations in this region highlight its importance. A bipartite model of modulation was proposed that suggests the transmembrane domain of KCNE1 is passive, allowing the C-terminal domain to control modulation. Chapter II builds on this model by investigating the effect of mutating specific amino acids in the KCNE1 C-terminal domain. Point mutants that produce ‘high impact’ perturbations in gating were shown to cluster in a periodic fashion, suggesting an alpha-helical secondary structure that is kinked by a conserved proline residue and interacts with the Q1 channel complex. In Chapter III, the voltage sensing domain of Q1 channels is examined in the presence of either KCNE1 or KCNE3. To determine the influence of these two peptides on voltage sensing, the position of the S4 voltage sensor was monitored using cysteine accessibility experiments. In the slowly opening KCNQ1/KCNE1 complexes, voltage sensor activation appears to occur much faster than the onset of current, suggesting that slow channel activation is not due to slowly moving voltage sensors. KCNE3, on the other hand, shifts the voltage sensor equilibrium to favor the active state, producing open channels even at negative voltages. Taken together, these findings provide mechanistic detail to illustrate how two homologous peptides radically alter the gating properties of the same K+ channel and present a structural scaffold to map protein-protein interactions.