Thesis (M.Sc.)--University of Alberta, 1997. / Submitted to the Faculty of Graduate Studies and Research in partial fulfilment of the requirements for the degree of Master of Science, Department of Agricultural, Food and Nutritional Science. Also available online.

Theses (Ph. D.)--Marshall University, 2006. / Title from document title page. Includes abstract. Document formatted into pages: contains xv, 153 p. Bibliography: p. 141-151.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Thesis (Ph.D.)--University of Florida, 2004. / Typescript. Title from title page of source document. Document formatted into pages; contains 94 pages. Includes Vita. Includes bibliographical references.

Hepatic fibrosis is a serious health problem in many parts of the world. However, its treatment remains severely limited because of inadequate target specificity. HSC are the largest reservoir of vitamin A in the body. They are also the principal players responsible for the pathogenesis of liver fibrosis. Targeting HSC is an effective strategy for treatment of liver fibrosis. The specific association of BMP4 with various liver diseases including liver fibrosis makes it an ideal candidate for targeting HSC cells using siRNA. The objective of this study is to develop and characterize vitamin A (VA)-coupled liposomes for the targeted delivery of BMP4-siRNA to cultured HSC. DOTAP/DOPE liposomes surfaces were prepared by thin film hydration and their surfaces were decorated with VA (1:2 mol/mol). Particle size and zeta potential were determined using ZetaPALS. In addition, the siRNA binding efficiency was determined by ultra-centrifugation and fluorescence assays. The cytotoxicity of VA-conjugated liposomes was evaluated by the WST-1 cytotoxicity assay. Inhibition of BMP4 and α-SMA was determined by real time PCR and ELISA. Their average particle size was in the range of 100-120 nm and they exhibited zeta potential around +45 mV. VA-coated liposomes were mixed with BMP4-siRNA, forming lipoplexes with particle sizes less than 200 nm and zeta potential around +25 mV. The presence of VA did not alter the siRNA binding efficiency, it also had no effect on cytotoxicity, but resulted in enhanced cellular uptake of siRNA as shown by flow cytometry. There was a significant reduction in BMP4 mRNA with VA-coupled liposomes carrying BMP4-siRNA. Moreover, BMP4 gene silencing was accompanied by a significantly reduced the expression of the potent fibrinogenic α-SMA at mRNA and protein levels. In conclusion, VA-coated liposomes were successfully able to target and deliver BMP4-siRNA to HSC. This could offer an interesting perspective for the treatment of liver fibrosis. / February 2016

Cystic Fibrosis (CF) is a life threatening autosomal recessive disorder caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, leading to irregular secretions and inflammation in tubular organs. Disease manifestations of CF are heterogeneous in severity and can be present in the sinopulmonary, hepatic, gastrointestinal, and genitourinary tract. Since the 1960’s, physicians and scientists have described a less severe form of CF known as atypical CF, usually seen in adults. Patients with atypical CF tend to have one severe CF mutation on one chromosome, and one less common, mild CF mutation on their other chromosome; or have one severe mutation on one chromosome and an abnormal number of trinucleotide repeats in the CFTR gene on their other chromosome. Today, of the approximately 1000 patients diagnosed with CF per year in the United States, roughly 10% are diagnosed with the atypical presentation of the disease as adults. Patients suffering from atypical CF typically have only one organ system that is dysfunctional, and their clinical symptoms may be less severe than those of a classical case where there are two severe CF mutations. Common symptoms include idiopathic bronchiectasis, chronic sinusitis, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic pancreatitis. Unlike patients suffering from the classical presentation of the disease, most are pancreatic sufficient – however the possibility of pancreatic insufficiency still exists. Patients with atypical CF represent a diagnostic challenge for physicians due to the mild, slowly progressing array of clinical symptoms, the general lack of knowledge about atypical CF, and the general association of CF as a childhood disease. Increasing physician awareness of the adult population with CF is a paramount in improving the diagnosis, care and treatment of patients with atypical CF. Missed diagnoses can result in hospital admissions and morbidity that may have been avoidable. The goal of this thesis is to describe the causes of CF, the common symptoms seen in both CF and atypical CF, the proper diagnosis of atypical CF, and to identify the therapies, both current and in development, used to treat atypical CF.

Pericytes represent a population of potential mesenchymal stem cells (MSC) that reside within a perivascular niche until they are required in normal homeostasis and the response to injury. Their mesenchymal capacities for multipotent differentiation, immune modulation and release of trophic factors hold great promise for regenerative therapies. Pathological expression of these potentials has been described in disease states, while acute or chronic inflammation following injury can lead to the production of signalling molecules that ultimately drive these progenitors to a fibrotic fate. The aim of this work was to explore how fate decisions of pericytes are regulated by their niche (in the setting of osteogenesis), and in the response to acute and chronic injury (in the setting of fibrosis). It was hypothesized that interactions between pericytes and endothelial cells (EC) within their perivascular niche are responsible for regulating mesenchymal differentiation. The osteogenic, adipogenic and chondrogenic potential of pericytes following isolation from multiple human organs was confirmed. The interactions between pericytes and EC in 2D and 3D coculture and the production of basement membrane proteins in these settings were confirmed. The osteogenic differentiation of pericytes was accelerated by EC but no influence of EC on the adipogenic and chondrogenic differentiation of pericytes was detected. Furthermore, data indicated that the influence on pericyte osteogenic potential by EC may occur through wnt signaling. The activation of TGFβ (transforming growth factor beta) through αv integrins has been suggested as central mediator of fibrosis in multiple organs. We hypothesized that selective αv integrin deletions in PDGFRβ (platelet derived growth factor receptor beta) expressing pericytes identifies a targetable pathway regulating fibrosis in skeletal muscle. We report that PDGFRβ-Cre inactivates genes in murine skeletal muscle pericytes with high efficiency. Deletion of the αv integrin subunit in pericytes protected mice from chemical injury induced skeletal muscle fibrosis. Pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated muscle fibrosis, even when administered after fibrosis was established.

Orientador: Márjorie de Assis Golim / Resumo: Vírus da Hepatite C (VHC) é uma das principais causas de doença inflamatória crônica do fígado, com progressão variável para a fibrose e cirrose hepática. Cerca de 30 a 40% dos pacientes com hepatite C crônica tem manifestações extra-hepáticas, sendo uma variedade destas descritas como associadas ao VHC. Quando a produção da medula é incapaz de manter as necessidades do organismo, em reação secundária a doença mieloproliferativa (policitemia vera, leucemia granulocítica crônica), ou até mesmo de origem idiopática, pode ocorrer hematopoese extramedular (HEM), presente mais comumente no fígado, baço e gânglios linfáticos, os quais passam a exercer função hematopoiética. Com o objetivo de avaliar a existência de hematopoese extramedular hepática em pacientes com hepatite C crônica e sua influência na gênese da fibrose hepática, foram avaliados 69 pacientes VHC positivos, os quais foram submetidos à biópsia hepática percutânea, e estratificados em grupos conforme a classificação METAVIR, conforme descrição abaixo: G1 – n = 19: pacientes no estágio F1 (fibrose portal sem septos); G2 – n = 16: pacientes no estágio F2 (septos poucos); G3 – n = 17: pacientes em estágio F3 (septos numerosos sem cirrose); G4 – n = 17: pacientes em estágio F4 (cirrose); G5 - n = 15: indivíduos saudáveis (grupo controle). Foram realizadas quantificações plasmáticas de quimiocinas (CXCL8, CCL5, CXCL9, CCL2 e CXCL10) e fatores de crescimento (TGF-beta, VEGF, FGF, PDGF) e investigada a presença de HEM em co... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Hepatitis C Virus (HCV) is a major cause of chronic liver inflammatory disease with variable progression for fibrosis and cirrhosis. About 30 to 40% of patients with chronic hepatitis C has extrahepatic manifestations and a variety of these described as an association with HCV. When the production of the bone marrow is not able to maintain the homeostasis due a secondary reaction to myeloproliferative disease (polycythemia vera, chronic granulocytic leukemia), or idiopathic causes, it may occur an extramedullary hematopoiesis (EMH), most commonly in the liver, spleen and lymph nodes, which can start the development of hematopoietic function. The purpose of this study is the evaluation of existence of liver extramedullary hematopoiesis in patients with chronic hepatitis C, and the influence in the pathogenesis of liver fibrosis. It was evaluated 69 liver biopsy from HCV positive patients and stratified into groups according to METAVIR rating as described below: G1 - n = 19: patients in the F1 stage (portal fibrosis without septa); G2 - n = 16: patients in stage F2 (few septa); G3 - n = 17: patients with stage F3 (numerous septa without cirrhosis); G4 - n = 17: patients in stage F4 (cirrhosis); G5 - n = 15: healthy individuals (control group). It was quantifed the chemokines (CXCL8, CCL5, CXCL9, CCL2 and CXCL10) and growth factors (TGF-, VEGF, FGF, PDGF) from plasma and investigated the presence of EMH in the liver tissue sections by immunohistochemistry use of CD61 / CD34... (Complete abstract click electronic access below) / Mestre

Orientador: José Dirceu Ribeiro / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-16T17:48:38Z (GMT). No. of bitstreams: 1 Dentini_Priscila_M.pdf: 10675938 bytes, checksum: afc138751a1f11e6991384ca9bbee25c (MD5) Previous issue date: 2010 / Resumo: Objetivos: Determinar a prevalência da colonização/infecção pelo Complexo Burkholderia cepacia (CBc) e os respectivos genomovares em pacientes com fibrose cística (FC) e comparar os indicadores clínicos, nutricionais, tomográficos e funcionais de gravidade da lesão pulmonar em dois grupos de pacientes: GI: pacientes colonizados/infectados pelo CBc e GII: pacientes sem colonização/infecção pelo CBc, com a finalidade de avaliar o impacto deste microrganismo na deterioração pulmonar. Métodos: Foi realizado um estudo clínico-laboratorial, prospectivo, com 222 pacientes com FC, acompanhados nos ambulatórios pediatria e adultos da UNICAMP. Os pacientes foram divididos em 2 grupos: GI (n=50) e GII (n=134). Os microrganismos foram identificados por meio de testes bioquímicos convencionais, pelo Vitek2®Compact, PCR do gene recA, e nested-PCR com primers espécie-específicos. O seqüenciamento do gene recA foi realizado para cepas com PCR inconclusivas. Os pacientes foram classificados pelo escore clínico de Schwachman e as medidas de peso/idade, estatura/idade e IMC/idade foram utilizadas para avaliar o estado nutricional. As alterações tomográficas foram classificadas pelo escore de Bhalla e a função pulmonar foi avaliada por espirometria. Os dados foram comparados entre os grupos com a finalidade de avaliar o impacto do CBc na lesão pulmonar. Resultados: A prevalência do CBc foi de 22,5% e dos genomovares: Bukholderia multivorans (30,0%), seguido de Burkholderia cepacia (24,0%), Burkholderia cenocepacia IIIA (10,0%), Burkholderia cenocepacia IIIB (2%) e Burkholderia vietnamiensis (2,0%). No grupo I, 26,0% dos pacientes estavam infectados, 18,0% apresentaram colonização transitória e 56,0% colonização intermitente pelo CBc. Não houve diferença estatística na média de pontos do escore de Schwachman (p=0,07), nem na classificação da gravidade (p=0,611), porém houve diferença nas variáveis: estado nutricional (p=0,020) e atividade geral (p=0,026). Houve diferença estatística na média de pontos do escore de Bhalla (p=0,04) e entre os parâmetros: gravidade da bronquiectasia (p=0,007), espessamento peribrônquico (p=0,013), extensão das bronquiectasias (p=0,010), generalidades da árvore bronquial (p=0,020). O teste de função pulmonar mostrou: CVF(%) (p=0,076), VEF1(%) (p=0,066), FEF25-75% no (p=0,312) e VEF1/CVF (p=0,312). Classificação dos distúrbios ventilatórios: DVO no GI=4,8% e GII=23,8%, DVR no GI e GII=9,5%, DVM no GI=19,0% e GII=1,6% e DVM com CVF reduzida no GI=47,6% e GII=30,2%. Na avaliação nutricional houve diferença significante entre as médias de peso(kg) e estatura(cm) (p=0,02). Conclusões: A prevalência do CBc em nosso centro é significativamente superior aos dados apresentados pela literatura nacional e internacional. A maior prevalência da Burkholderia multivorans difere da maioria dos estudos. Há a suspeita de que possa ter ocorrido infecção cruzada entre os pacientes ou que seja uma característica regional. Os escore de Shwachman, escore de Bhalla, espirometria e dados nutricionais mostraram que o CBc tem sério impacto na deterioração pulmonar e na piora clínica. Os métodos fenotípicos são úteis para a identificação presuntiva do CBc. O Vitek® apresentou boa acurácia na identificação do CBc, porém com alguns erros decorrentes de limitações do método/equipamento. O PCR, nested-PCR e seqüenciamento do gene recA apresentaram boa especificidade na identificação do CBc e dos genomovares, entretanto, ainda ocorrem algumas limitações, decorrentes da variedade genotípica, sendo necessária a utilização de métodos mais abrangentes, como o MSLT / Abstract: Objectives: Determine the Burkholderia cepacia complex (BCC) colonization/infection and genomovar prevalence in cystic fibrosis patients and compare the clinical, tomographic and functional severity indicators of lung injury in two groups of patients: GI - patients colonized or infected with BCC and GII - patients without BCC colonization or infection, with the aim of assessing the impact of this microorganism in pulmonary deterioration. Methods: A clinical-laboratory and prospective study was conducted with 222 CF patients seen in the CF outpatient (pediatrics and adults) in UNICAMP. Patients were divided into two groups: GI (n = 50) and GII (n = 134). Microorganisms were identified by conventional biochemical tests, Vitek2®Compact, recA-PCR and recA-nested-PCR with species-specific primers. The recA gene sequencing was performed for strains with inconclusive PCR reactions. Patients were classified by Schwachman's clinical score and measures of weight/age, height/age and BMI/age were used to assess nutritional status. The tomography changes were classified by Bhalla's score and lung function was assessed by spirometry. Data were compared between groups with the aim of assessing the CBC impact in lung injury. Results: The BCC prevalence was 22.5% and the most prevalent genomovars was: Bukholderia multivorans (30.0%), followed by Burkholderia cepacia (24.0%), Burkholderia cenocepacia IIIA (10.0%), Burkholderia cenocepacia IIIB (2%) and Burkholderia vietnamiensis (2.0%). In group I, 26.0% of patients were infected, 18.0% had transient colonization and 56.0% intermittent colonization by BCC. There was no statistical difference in the average point of Schwachman's score (p = 0.07) or in the severity classification (p = 0.611) but had differences in variables: nutritional status (p = 0.020) and general activity (p = 0.026). In the average point Bhalla's score was statistical difference (p = 0.04) and between the parameters: severity of bronchiectasis (p = 0.007), peribronchial thickening (p = 0.013), extent of bronchiectasis (p = 0.010), general the bronchial tree (p = 0.020). The pulmonary function test showed: FVC (%) (p = 0.076), FEV1 (%) (p = 0.066), FEF25-75% (p = 0.312) and FEV1/FVC (p = 0.312). Respiratory disorders classification: DVO in GI and GII = 4.8% = 23.8%, DVR in GI and GII = 9.5%, DVM in GI and GII = 19.0% = 1.6% and with DVM FVC decreased in GI and GII = 47.6% = 30.2%. Nutritional assessment was significant difference between the mean weight (kg) and height (cm) (p = 0.02.) CCoonncclluussiioonnss:: The BCC prevalence in our center is significantly higher than the dates provided by national and international literature. The increased Burkholderia multivorans prevalence differs from the most studies. It is suspected that may have been cross-infection between patients or is a regional characteristic. The Shwachman's and Bhalla score, spirometry and nutritional data showed that the BCC has serious impact on the deterioration and worsening pulmonary clinic. The phenotypic methods are useful for the presumptive BCC identification. The Vitek2®Compact showed good accuracy in BCC identification of, but with some errors due to limitations of the method/equipment. PCR, nested-PCR and recA sequencing showed good specificity in BCC genomovars identifying, however, there are still some limitations, stemming from different genotype, being necessary to use more comprehensive methods, such as the MSLT / Mestrado / Saude da Criança e do Adolescente / Mestre em Saude da Criança e do Adolescente

Disrupted sleep and nocturnal hypoxia are common in cystic fibrosis (CF). However, the predictors of nocturnal hypoxia in CF are still controversial. In order to identify the risk factors for nocturnal desaturation and sleep disturbances, we carried out a clinical and polysomnographic investigation of CF patients. We studied 30 clinically stable CF cases with clinical lung disease (mean age=12.8; mean forced expiratory volume in 1 second FEV1=65.2), 10 CF cases without significant lung disease (mean age=13.3; mean FEV1=99.8), and 20 controls (mean age=15.5). Patients were evaluated by spirometry, 6-min walk test (6MWT), the ShwachmanâKulczycki (SâK) score, and full overnight polysomnography. Cases with clinical lung disease had lower body mass index, forced vital capacity, and SâK scores. During sleep, five CF cases with clinical lung disease (15%) had SaO2 <90% during more than 30% of total sleep timeand 11 cases (36.6%) had a nadir SaO2 below 85%. FEV1 values for CF cases with clinical lung disease were related to nadir SaO2 (P<0.03) and to mean oxygen saturation SaO2 (P=0.02). A receiver operating characteristic (ROC) analysis determined FEV1 at 64% to be predictive of nocturnal desaturation as defined by minimum SaO2 <85% (sensitivity=92.3%; specificity=77.3%) or SaO2<90% for 30% of sleep time (sensitivity=81.8%; specificity=85.2%). Frequency of impaired sleep was not different in CF cases with (N=5) and without significant lung disease (N=2, P=0.53). Sleep architecture was not significantly different between the two groups. Sleep apnea was present in three CF cases with clinical lung disease and in one case without significant lung disease. In summary, desaturation during sleep can be predicted by FEV1<64%with good sensitivity and specificity. There are no significant differences in sleep architecture between clinically stable CF cases with and without significant lung disease. The recognition of biological markers that can predict clinical deterioration in cystic fibrosis (CF) is a key issue in everyday care of these patients. The (S-K) scores and (FEV1) have been considered the best independent predictors of impairment/disability. The aim of this study was to evaluate the role of high-resolution computed tomography of the chest (HRCT) and the use of the Bhalla score in the detection of functional disability in CF. Cases of both genders, aged older than six years, with CF clinically stable were studied with spirometry, basal oxygen saturation SpO2, the 6MWT, HRCT and the S-K score. Twenty-five patients (15 male, mean age 14.2Â5.6) with FEV1 (range 28.6-98.0; mean 62.5Â21.8) were studied. Nine patients had severe/moderate respiratory insufficiency (40<FEV1&#8804;59), nine had mild (59<FEV1&#8804;79) and six had normal function (FEV1>79). Bronchiectasis was the most frequent finding. Peribronchial thickening, mucus plugging and emphysema, despite being less severe, were also commonly observed. None of the cases presented bullae. Total scores of CT abnormalities varied from 7 to 25 (13.8Â4.4). The ROC curve showed the high sensitivity/specificity for Bhalla and S-K scores in the prediction of clinical disability as measured by the FEV1. By comparison, the Bhalla scores showed higher sensitivity than the S-K scores. SpO2 and the 6MWT were not good predictors of disability as measured by functional pulmonary tests. Melatonin, a natural hormone secreted by the pineal gland, has an important function in the synchronization of circadian rhythms, including the sleepâwake cycle, and has been shown to possess significant anti-oxidant properties. To evaluate the effects of exogenous melatonin on sleep and inflammation and oxidative stress markers in CF we conducted a randomized double-blind placebo controlled study initially involving 20 patients with CF. One case failed to conclude the study. All subjects were clinically stable when studied and without recent infectious exacerbation or hospitalization in the last 30 days. Groups were randomized for placebo (N= 10; mean age 12.10Â6.0) or melatonin 3.0 mg (N=9; mean age 16.62Â8.26) during 21 days. Actigraphy was performed during 6 days before start of medication and in the third week (days 14 to 20) of treatment. Isoprostane and nitrite levels were determined in exhaled breath condensate (EBC) at baseline (day 0) and after treatment (Day 21). Melatonin improved sleep efficiency (p=0.01) and tended to improve sleep latency (p= 0.08). Melatonin reduced EBC nitrite (p=0.01) but not isoprostane. In summary, melatonin administration reduces nitrite levels in EBC and improves sleep measures in clinically stable CF patients. / A Fibrose CÃstica (FC) à uma doenÃa crÃnica e progressiva acompanhada por episÃdios repetidos de infecÃÃes respiratÃrias. Neste trabalho, realizaram-se investigaÃÃes relacionadas aos aspectos polissonogrÃficos, de tomografia computadorizada de alta resoluÃÃo do tÃrax (TCAR) e um estudo sobre os efeitos da melatonina em pacientes com FC, que serÃo descritos a seguir. Na FC, as alteraÃÃes do sono e a dessaturaÃÃo noturna da oxi-hemoglobina sÃo comuns, no entanto, os preditores dessa dessaturaÃÃo ainda sÃo controversos e a indicaÃÃo para a realizaÃÃo de polissonografia ainda nÃo foi definida. Com o objetivo de identificar os fatores de risco associados com hipÃxia noturna e com as alteraÃÃes do sono, realizou-se uma investigaÃÃo clÃnica e polissonogrÃfica de pacientes com FC com e sem envolvimento pulmonar. Trata-se de um estudo transversal de pacientes clinicamente estÃveis com (N=30; mÃdia de idade = 12,8 anos; mÃdia de volume expiratÃrio forÃado no primeiro segundo (VEF1= 65,2%) e sem (N=10; mÃdia de idade =13,3; mÃdia de VEF1 = 99,8%) doenÃa pulmonar e controles (N=20; mÃdia de idade =15,5). Os pacientes foram avaliados por meio das provas de funÃÃo pulmonar (PFP), teste da caminhada de seis minutos (TC6min), pelo escore Swhachman-Kulczycki (S-K) e polissonografia de noite inteira. Os pacientes com doenÃa pulmonar apresentavam Ãndices mais baixos de massa corpÃrea, VEF1, capacidade vital forÃada e escore S-K. Durante o sono, entre os pacientes com FC e doenÃa pulmonar, cinco (15%) tinham SpO2 <90% durante mais de 30% do tempo total de sono e 11 (36,6%) tinham SpO2 mÃnima. Observou-se uma correlaÃÃo entre os nÃveis de VEF1 e os nÃveis mÃdios de SpO2 (p=0,02) e valores mÃnimos da SpO2 (p<0,03). A Receiver Operating Curve (ROC) mostrou que o VEF1 < 64% à um preditor da dessaturaÃÃo noturna ao se considerar o nadir, SpO2 menor que 85% (sensibilidade = 92,3% e especificidade = 77,3%) ou SpO2 < 90% durante mais de 30% (sensibilidade = 81,8% e especificidade = 85,2%). A frequÃncia das alteraÃÃes do sono, quando se considerou a qualidade subjetiva do sono (IQSP), nÃo foi diferente entre os casos de FC com (N=5) e sem comprometimento pulmonar (N=2, P=0.53). A arquitetura do sono nÃo foi significativamente diferente entre os casos de FC com e sem doenÃa pulmonar. Apneia obstrutiva do sono estava presente em trÃs casos com doenÃa pulmonar e em um caso sem doenÃa pulmonar. Em conclusÃo, a dessaturaÃÃo durante o sono pode ser prevista por um VEF1 < 64% com boa sensibilidade e especificidade. NÃo hà diferenÃas significantes entre os casos de FC clinicamente estÃveis com e sem envolvimento pulmonar. Sugere-se que a polissonografia pode ser Ãtil em casos selecionados de FC com e sem doenÃa pulmonar quando hà suspeita de apneia obstrutiva do sono. Em relaÃÃo ao estudo com TCAR do tÃrax, deve ser enfatizado que o reconhecimento de marcadores de gravidade, capazes de predizer a deterioraÃÃo clÃnica na fibrose cÃstica à de fundamental importÃncia para o manuseio terapÃutico dos pacientes. O escore de S-K e o VEF1 sÃo considerados os melhores preditores independentes do prognÃstico em FC. O objetivo desse estudo foi avaliar o papel da TCAR e o escore de Bhalla na avaliaÃÃo da gravidade de pacientes com FC. Casos de ambos os sexos, com idade superior a seis anos, clinicamente estÃveis, foram avaliados mediante espirometria, nÃveis basais de saturaÃÃo de oxigÃnio (SpO2), TC6min, TCAR e escores S-K e Bhalla. Vinte e cinco pacientes (15 homens, idade mÃdia 14,2  5,6) com VEF1 (variaÃÃo 28,6-98,0; mÃdia 62,5  21,8) foram estudados. Nove pacientes apresentavam insuficiÃncia respiratÃria moderada/grave (40 < VEF1 &#8804; 59), nove tinham insuficiÃncia respiratÃria leve (59 < VEF1 &#8804; 79) e seis tinham funÃÃo normal (VEF1 > 79). As bronquiectasias foram o achado tomogrÃfico mais frequente. Espessamento peribrÃnquico, rolha de muco e enfisema, apesar de menor gravidade, foram tambÃm comumente observados. Nenhum dos casos apresentava bolhas. Os escores totais das anormalidades tomogrÃficas variaram de 7 a 25 (13,8  4,4). A curva (ROC) mostrou alta sensibilidade/especificidade para o escore Bhalla na prediÃÃo da gravidade da doenÃa medida pelo VEF1. De forma comparativa, os escores Bhalla apresentaram maior sensibilidade do que os escores S-K. Os nÃveis basais de SpO2 e o TC6min nÃo foram bons preditores de gravidade avaliada pelos testes de funÃÃo pulmonar. Realizou-se um estudo sobre os efeitos da melatonina na FC. A melatonina à um hormÃnio natural secretado pela glÃndula pineal, tem uma funÃÃo importante na sincronizaÃÃo do ritmo circadiano, incluindo o ciclo vigÃlia-sono e tem propriedades antioxidantes. Com o objetivo de avaliar os efeitos da melatonina no sono, na inflamaÃÃo e no estresse oxidativo pulmonar realizou-se um estudo randomizado, duplo-cego e controlado por placebo. Vinte pacientes com FC foram inicialmente avaliados. Um paciente nÃo concluiu o estudo. Todos os indivÃduos estavam clinicamente estÃveis por ocasiÃo do estudo, ou seja, nÃo tinham apresentado exacerbaÃÃes infecciosas ou hospitalizaÃÃes nos Ãltimos 30 dias. Os grupos foram randomizados para o uso de placebo (N= 10; mÃdia da idade 12,10  6,0) ou melatonina 3,0 mg (N=9; mÃdia da idade 16,62  8,26) durante 21 dias. Um registro actigrÃfico foi realizado durante seis dias, antes do inÃcio da medicaÃÃo e na terceira semana (dias 14 a 20) do tratamento. Os nÃveis de isoprostano e nitrito foram determinados no condensado de ar exalado (CAE) no inÃcio do estudo (dia 0) e depois do tratamento (dia 21). A melatonina melhorou a eficiÃncia do sono (p=0,01) e nitrito do CAE, porÃm nÃo reduziu o isoprostano. Em conclusÃo, em pacientes com FC clinicamente estÃveis, a administraÃÃo de melatonina reduz os nÃveis de nitrito e melhora os parÃmetros de sono.