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2.
PLoS One ; 15(2): e0229296, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084221

RESUMO

BACKGROUND: Barriers and motives towards physical activity (PA) in lung transplant (LTx) recipients with cystic fibrosis (CF) are largely unknown. We aimed to explore perceptions towards PA in LTx recipients with CF to better understand individuals' needs and preferences. METHODS: Participants completed an online survey at two Swiss LTx and one follow-up shared care centre between June and December 2018. RESULTS: One hundred and eleven individuals completed the survey (87.4% response rate). Overall, survey participants perceive PA as important for their daily life and health. Perceived motives of PA were improving muscle strength, endurance and quality of life (QoL), to feel better, fun, to achieve personal goals and having more energy for everyday life. Fatigue was the most common perceived barrier to PA and associated with poorer QoL (r = -0.43, p<0.001) and health status (r = -0.31, p = 0.001). Participants with lung allograft dysfunction (LAD, n = 20) reported lower habitual PA (p = 0.009) and health status (p = 0.011), and rated shortness of breath, bad weather and concerns regarding lung rejection higher than those without LAD (all p<0.05). When we asked how an optimal training programme should look like, the majority would prefer individual, non-supervised (60%), outdoor (77%), endurance training (90%), once or twice a week (47%) for 40-60 minutes (48%). Only a minority of patients (14%) would be willing to use exercise applications for their home-based training. CONCLUSIONS: LTx recipients with CF value PA as important for their health. People with CF should be encouraged individually by their multidisciplinary transplant team to implement PA in their daily life, potential barriers should be identified and addressed. Overall, knowledge on perceived barriers and motives for PA should be considered in the development of future patient-centred PA programmes.


Assuntos
Fibrose Cística/psicologia , Fibrose Cística/cirurgia , Exercício Físico , Conhecimentos, Atitudes e Prática em Saúde , Transplante de Pulmão , Transplantados/psicologia , Adulto , Fibrose Cística/fisiopatologia , Feminino , Humanos , Masculino , Motivação , Qualidade de Vida , Inquéritos e Questionários
4.
Rev. Paul. Pediatr. (Ed. Port., Online) ; 37(4): 414-418, Oct.-Dec. 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1041355

RESUMO

ABSTRACT Objective: To evaluate the association of body mass index (BMI) and albumin with pulmonary function in cystic fibrosis (CF) pediatric subjects. Methods: This is a cross-sectional study with clinically stable CF's subjects. Clinical (pulmonary function) and nutritional evaluation (body mass index and albumin) were performed. Univariate analysis was performed using simple linear correlations. Regression analysis was performed using an exit level of p<0.05. Results: Seventy-eight CF's subjects (mean age 12.8±3.8 years) with mean albumin 4.2±0.4 mg/dL, predicted forced expiratory volume in 1 second (FEV1%) 80.8±22.6 and BMI median percentile 51.2 (1.3-97.7). In the multiple regression models, albumin, age and BMI percentile were associated with pulmonary function. Subjects with lower than 25 BMI percentile had 12.2% lower FEV1%. An albumin increase of 0.1 mg was associated with 2.7% increase in predicted FEV1%, and one year increase in age was associated with reduction in 1.2% of predicted FEV1%. Conclusions: BMI percentile, albumin and age were independently associated with predicted FEV1% in a tertiary referral hospital.


RESUMO Objetivo: Avaliar a associação do Índice de Massa Corporal (IMC) e da albumina com a função pulmonar em pacientes pediátricos com fibrose cística (FC). Métodos: Estudo transversal com pacientes pediátricos com FC clinicamente estáveis. Foram realizadas avaliação clínica (função pulmonar) e nutricional (IMC e albumina). Análise univariada foi realizada usando correlação linear simples. Análise de regressão foi realizada usando o nível de significância de p<0,05. Resultados: Foram incluídos 78 pacientes com FC (média de idade 12,8±3,8 anos) com média de albumina de 4,2±0,4 mg/dL, volume expiratório forçado em um segundo (VEF1%) predito de 80,8±22,6 e mediana do percentual de IMC de 51,2 (1,3-97,7). No modelo de regressão múltipla, albumina, idade e percentual de IMC apresentaram associação com a função pulmonar. Indivíduos com IMC abaixo de 25% apresentaram VEF1% predito 12,2% menor. Um aumento de 0,1 mg de albumina teve associação com aumento de 2,7% no VEF1% predito, e um ano a mais de idade mostrou relação com a redução de 1,2% de VEF1% predito. Conclusão: O percentual de IMC, albumina e idade apresentaram associação independente com o VEF1% predito em um hospital terciário de referência.


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Índice de Massa Corporal , Fibrose Cística/fisiopatologia , Albuminas/metabolismo , Pulmão/fisiopatologia , Biomarcadores/metabolismo , Modelos Lineares , Volume Expiratório Forçado , Estudos Transversais , Fibrose Cística/metabolismo
5.
Rev. Paul. Pediatr. (Ed. Port., Online) ; 37(4): 435-441, Oct.-Dec. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1041361

RESUMO

ABSTRACT Objective: To determine the prevalence of hepatic steatosis (HS) in children and adolescents with cystic fibrosis (CF) and associate it with nutritional status. Methods: Cross-sectional study with children and adolescents with CF diagnosis. Weight and height were used to calculate the body mass index (BMI) and subsequent classification of the nutritional status. The midarm circumference (MAC), triceps skinfold thickness (TSF) and midarm muscle circumference (MAMC) were used to evaluate body composition. Abdominal ultrasonography was performed for diagnosis of HS. The statistical tests used were Student's t test, Mann-Whitney test and chi-square test with significance level of 5%. Results: 50 patients with CF were evaluated, 18 (36%) were diagnosed with HS (Group A) and 32 (64%) without HS (Group B). The mean age of Group A was 13,2±4,9 years old and Group B 11,7±4,9; for BMI, the value for Group A was 18,0±4,1 and Group B was 15,7±3,8; the TSF of Group A was 8,4±3,5 mm and Group B was 7,0±2,5 mm. For these variables, there was no significant difference between the groups. The mean of MAC and MAMC differed significantly between the groups, being higher in the HS group, with p values of 0,047 and 0,043. Conclusions: The frequency of HS in patients with CF is high and it is not related to malnutrition, according to the parameters of BMI, TSF and MAMC. The values of MAC and MAMC indicated a greater reserve of muscle mass in patients with HS.


RESUMO Objetivo: Determinar a prevalência de esteatose hepática (EH) em crianças e adolescentes com fibrose cística (FC) e associá-la com o estado nutricional. Métodos: Estudo transversal com crianças e adolescentes com diagnóstico de FC. Foram aferidos o peso e a altura para o cálculo do índice de massa corpórea (IMC) e classificação do estado nutricional. A circunferência do braço (CB), a dobra cutânea tricipital (DCT) e a circunferência muscular do braço (CMB) foram empregadas para avaliação da composição corporal. A ultrassonografia abdominal foi realizada para o diagnóstico de EH. Os testes estatísticos empregados foram o teste t de Student, o teste de Mann-Whitney e o teste do qui-quadrado, com nível de significância de 5%. Resultados: Dos 50 pacientes avaliados, 18 (36%) apresentaram EH (Grupo A) e 32 (64%) não (Grupo B). Para as médias de idade (Grupo A: 13,3±5,0 anos; e Grupo B: 11,7±5,0 anos), IMC (Grupo A: 18,0±4,1; e Grupo B: 15,7±3,8) e DCT (Grupo A: 8,4±3,5 mm; e Grupo B: 7,0±2,5 mm), não houve diferença significativa entre os grupos. A média da CB e da CMB diferiram significativamente entre os grupos, sendo mais elevada no grupo com EH, com valores p respectivos de 0,047 e 0,043. Conclusões: É alta a frequência de EH em pacientes com FC e ela não está relacionada com a desnutrição, segundo os parâmetros de IMC, DCT e CMB. Os valores de CB e CMB indicaram maior reserva de massa muscular nos pacientes com EH.


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Estado Nutricional , Fibrose Cística/complicações , Desnutrição/complicações , Hepatopatia Gordurosa não Alcoólica/etnologia , Gestão de Riscos , Prevalência , Estudos Transversais , Fibrose Cística/fisiopatologia , Desnutrição/diagnóstico , Desnutrição/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia
6.
PLoS One ; 14(12): e0225004, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31860639

RESUMO

BACKGROUND: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency, leading to fat malabsorption, malnutrition and abdominal discomfort. Until recently, no specific tool was available for assessing gastro-intestinal related quality of life (GI QOL) in patients with CF. As the Horizon2020 project MyCyFAPP aims to improve GI QOL by using a newly designed mobile application, a sensitive and reliable outcome measure was needed. We aimed to study the applicability of the existing child-specific Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Scales and Module (PedsQL GI) in children with CF. METHODS: A multicenter, prospective observational study was performed in 6 European centers to validate the PedsQL GI in children with CF during 3 months. RESULTS: In total, 248 children and their parents were included. Within-patient variability of PedsQL GI was low (24.11), and there was reasonable agreement between children and parents (ICC 0.681). Nine of 14 subscales were informative (no ceiling effect). The PedsQL GI and the median scores for 4 subscales were significantly lower in patients compared to healthy controls. Positive associations were found between PedsQL GI and age (OR = 1.044, p = 0.004) and between PedsQL GI and BMI z-score (OR = 1.127, p = 0.036). PedsQL GI correlated with most CFQ-R subscales (r 0.268 to 0.623) and with a Visual Analogue Scale (r = 0.20). CONCLUSIONS: PedsQL GI is a valid and applicable instrument to assess GI QOL in children with CF. Future research efforts should examine the responsiveness of the CF PedsQL GI to change in the context of clinical interventions and trials.


Assuntos
Fibrose Cística/fisiopatologia , Gastroenteropatias/fisiopatologia , Pais , Qualidade de Vida , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Nível de Saúde , Humanos , Masculino , Estudos Prospectivos , Psicometria , Inquéritos e Questionários
7.
N Engl J Med ; 381(19): 1809-1819, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697873

RESUMO

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).


Assuntos
Aminofenóis/administração & dosagem , Benzodioxóis/administração & dosagem , Agonistas dos Canais de Cloreto/administração & dosagem , Fibrose Cística/tratamento farmacológico , Indóis/administração & dosagem , Mutação , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Quinolonas/administração & dosagem , Adolescente , Adulto , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Agonistas dos Canais de Cloreto/efeitos adversos , Cloretos/análise , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Indóis/efeitos adversos , Masculino , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Quinolonas/efeitos adversos , Suor/química , Adulto Jovem
8.
Medicina (B Aires) ; 79(4): 303-314, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31487254

RESUMO

The chloride channels, sodium and bicarbonate channels, and aquaporin water channels are coordinated to maintain the airway surface liquid that is necessary for mucociliary clearance. The general mechanism for the transport of electrolytes and fluids depends mainly on the differential expression and distribution of ion transporters and pumps. Ions and water move through the paracellular or transcellular pathways. The transcellular route of electrolyte transport requires an active transport (dependent on ATP) or passive (following electrochemical gradients) of ions. The paracellular pathway is a passive process that is ultimately controlled by the predominant transepithelial electrochemical gradients. Cystic fibrosis is a hereditary disease that is produced by mutations in the gene that encode cystic fibrosis transmembrane conductance regulatory protein (CFTR) that acts as a chloride channel and performs functions of hydration of periciliary fluid and maintenance of luminal pH. The dysfunction of the chlorine channel in the respiratory epithelium determines an alteration in the bronchial secretions, with an increase in its viscosity and alteration of the mucociliary clearance and that associated with infectious processes can lead to irreversible lung damage. CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease, and bronchial hyperreactivity in asthma. There are drugs that exploit physiological mechanisms in the transport of ions with a therapeutic objective.


Assuntos
Transporte Biológico Ativo/fisiologia , Canais de Cloreto/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/metabolismo , Transporte de Íons/fisiologia , Depuração Mucociliar/fisiologia , Canais de Cloreto/fisiologia , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Humanos
9.
Expert Opin Investig Drugs ; 28(10): 827-833, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474120

RESUMO

Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis. Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies. Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.


Assuntos
Asma/tratamento farmacológico , Isoquinolinas/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirimidinonas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Asma/fisiopatologia , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Desenvolvimento de Medicamentos/métodos , Humanos , Isoquinolinas/farmacologia , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 3/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Pirimidinonas/farmacologia
10.
J Immunol Res ; 2019: 2180409, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396541

RESUMO

The primary purpose of pulmonary ventilation is to supply oxygen (O2) for sustained aerobic respiration in multicellular organisms. However, a plethora of abiotic insults and airborne pathogens present in the environment are occasionally introduced into the airspaces during inhalation, which could be detrimental to the structural integrity and functioning of the respiratory system. Multiple layers of host defense act in concert to eliminate unwanted constituents from the airspaces. In particular, the mucociliary escalator provides an effective mechanism for the continuous removal of inhaled insults including pathogens. Defects in the functioning of the mucociliary escalator compromise the mucociliary clearance (MCC) of inhaled pathogens, which favors microbial lung infection. Defective MCC is often associated with airway mucoobstruction, increased occurrence of respiratory infections, and progressive decrease in lung function in mucoobstructive lung diseases including cystic fibrosis (CF). In this disease, a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in dehydration of the airway surface liquid (ASL) layer. Several mice models of Cftr mutation have been developed; however, none of these models recapitulate human CF-like mucoobstructive lung disease. As an alternative, the Scnn1b transgenic (Scnn1b-Tg+) mouse model overexpressing a transgene encoding sodium channel nonvoltage-gated 1, beta subunit (Scnn1b) in airway club cells is available. The Scnn1b-Tg+ mouse model exhibits airway surface liquid (ASL) dehydration, impaired MCC, increased mucus production, and early spontaneous pulmonary bacterial infections. High morbidity and mortality among mucoobstructive disease patients, high economic and health burden, and lack of scientific understanding of the progression of mucoobstruction warrants in-depth investigation of the cause of mucoobstruction in mucoobstructive disease models. In this review, we will summarize published literature on the Scnn1b-Tg+ mouse and analyze various unanswered questions on the initiation and progression of mucobstruction and bacterial infections.


Assuntos
Obstrução das Vias Respiratórias/imunologia , Obstrução das Vias Respiratórias/fisiopatologia , Fibrose Cística/imunologia , Fibrose Cística/fisiopatologia , Modelos Animais de Doenças , Canais Epiteliais de Sódio/genética , Obstrução das Vias Respiratórias/metabolismo , Obstrução das Vias Respiratórias/microbiologia , Animais , Fibrose Cística/genética , Fibrose Cística/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Desidratação/metabolismo , Desidratação/fisiopatologia , Canais Iônicos/deficiência , Canais Iônicos/genética , Leucócitos/imunologia , Pulmão/imunologia , Pulmão/fisiopatologia , Macrófagos/imunologia , Camundongos , Camundongos Transgênicos , Depuração Mucociliar/genética , Depuração Mucociliar/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/fisiopatologia
11.
Paediatr Respir Rev ; 31: 32-34, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31288987

RESUMO

As the life expectancy of patients with cystic fibrosis has increased, greater attention has been paid towards the diagnosis and management of the longer term consequences of the condition. A recognised but rare complication of the disease is the development of secondary amyloidosis. Whilst deposition of amyloid protein has been reported in a high proportion of patients with cystic fibrosis at post-mortem [1] and Serum Amyloid A protein has been shown to correlate with disease activity and response to antibiotics [2], the manifestation of clinical disease remains extremely uncommon. The prognosis for patients with amyloid secondary to cystic fibrosis in published reports has been historically bleak [3-6], however there may be novel approaches in the era of biological therapies. The theoretical potential for an increase in the incidence of secondary amyloid amongst the population of cystic fibrosis patients who are experiencing much longer lifespans means that it is worthwhile to consider the condition and its possible treatments in more detail. We report a case and a review of the literature.


Assuntos
Amiloidose/metabolismo , Fibrose Cística/metabolismo , Síndrome Nefrótica/metabolismo , Proteína Amiloide A Sérica/metabolismo , Amiloidose/etiologia , Amiloidose/fisiopatologia , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Feminino , Humanos , Síndrome Nefrótica/etiologia , Adulto Jovem
12.
Folia Med (Plovdiv) ; 61(2): 213-222, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301654

RESUMO

BACKGROUND: Health-related quality of life (HRQoL) is a parameter that is examined in the area of clinical effectiveness. Like other chronic health conditions, paediatric cystic fibrosis (CF) impacts not only children but also their families. AIM: The present study investigates for the first time the HRQoL of children and parents in the Republic of North Macedonia. MATERIALS AND METHODS: The survey included 22 children (6 to 13 years of age) and their parents and 7 parents of children under 6 years of age by using the CFQ Revised and questions for current medical treatment. RESULTS: Children (6-13 years) reported the highest score for the digestive condition (84.85), while the lowest score was given for social activity (59.74). The highest score for digestive condition was also obtained from the parents of children from 6-13 years and under age of 6. The parents of children (6-13 years) reported the lowest score (60.56) for treatment burden activity, while the lowest score (50.0) for eating condition was obtained from the parents of children under 6 years. CONCLUSION: Nationality and gender have no significant impact on the HRQoL parameters. The highest scores for the digestive condition, respiratory function and physical condition are in a positive correlation with the fact that enzyme, antibiotic and physical therapy are given as a standard medical care. The lowest scores of the social aspect of the CF patients indicate the need for including a psychological support and support of social workers as a part of the standard medical care of these patients.


Assuntos
Fibrose Cística/fisiopatologia , Fibrose Cística/psicologia , Pais , Qualidade de Vida , Adolescente , Imagem Corporal , Criança , Efeitos Psicossociais da Doença , Fibrose Cística/complicações , Fibrose Cística/terapia , Doenças do Sistema Digestório/etiologia , Doenças do Sistema Digestório/fisiopatologia , Doenças do Sistema Digestório/psicologia , Comportamento Alimentar , Feminino , Humanos , Masculino , Doenças Respiratórias/etiologia , Doenças Respiratórias/fisiopatologia , Doenças Respiratórias/psicologia , Participação Social
13.
BMC Pulm Med ; 19(1): 128, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311524

RESUMO

BACKGROUND: In people with and without Cystic Fibrosis (CF), does side lying during nebulisation change: the proportion of the dose loaded in the nebuliser that is deposited in the lungs; the uniformity of deposition throughout the lungs; or the apical drug density as a percentage of the drug density in the remaining lung? Do these effects differ depending on the degree of lung disease present? METHODS: A randomised crossover trial with concealed allocation, intention-to-treat analysis and blinded assessors, involving 39 adults: 13 healthy, 13 with mild CF lung disease (FEV1 > 80%pred), and 13 with more advanced CF lung disease (FEV1 < 80%pred). In random order, 4 mL of nebulised radioaerosol was inhaled in upright sitting and in alternate right and left side lying at 2-min intervals, for 20 min. RESULTS: Compared to sitting upright, lung deposition and the uniformity of deposition were not significantly altered by side lying in any of the three groups. In sitting, the density of the deposition was significantly less in the apical regions than in the rest of the lung in all participants. Side lying significantly improved apical deposition in healthy adults (MD, 13%; 95% CI, 7 to 19), and in minimal CF lung disease (MD, 4%; 95% CI, 1 to 7) but not in advanced disease (MD, 4%; 95% CI, - 2 to 9). CONCLUSION: Alternating between right and left side lying during nebulisation significantly improves apical deposition in healthy adults and in adults with mild CF lung disease, without substantial detriment to overall deposition. TRIAL REGISTRATION: ACTRN12611000674932 (Healthy), ACTRN12611000672954 (CF) Retrospectively registered 4/7/2011.


Assuntos
Fibrose Cística/tratamento farmacológico , Posicionamento do Paciente/métodos , Terapia Respiratória/métodos , Administração por Inalação , Adulto , Estudos Cross-Over , Fibrose Cística/fisiopatologia , Feminino , Humanos , Modelos Lineares , Masculino , Nebulizadores e Vaporizadores , Testes de Função Respiratória , Método Simples-Cego , Fatores de Tempo , Adulto Jovem
14.
Nat Commun ; 10(1): 3124, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311920

RESUMO

Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function. Insulin producing pancreatic islets are located in close proximity to the pancreatic duct and there is a possibility of impaired cell-cell signaling between pancreatic ductal epithelial cells (PDECs) and islet cells as causative in CF. To study this possibility, we present an in vitro co-culturing system, pancreas-on-a-chip. Furthermore, we present an efficient method to micro dissect patient-derived human pancreatic ducts from pancreatic remnant cell pellets, followed by the isolation of PDECs. Here we show that defective CFTR function in PDECs directly reduced insulin secretion in islet cells significantly. This uniquely developed pancreatic function monitoring tool will help to study CF-related disorders in vitro, as a system to monitor cell-cell functional interaction of PDECs and pancreatic islets, characterize appropriate therapeutic measures and further our understanding of pancreatic function.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Células Epiteliais/patologia , Ilhotas Pancreáticas/fisiopatologia , Dispositivos Lab-On-A-Chip , Adolescente , Criança , Pré-Escolar , Técnicas de Cocultura/métodos , Fibrose Cística/patologia , Fibrose Cística/terapia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células Epiteliais/metabolismo , Feminino , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Microdissecção , Organoides , Ductos Pancreáticos/citologia , Ductos Pancreáticos/patologia , Cultura Primária de Células/métodos
15.
PLoS One ; 14(7): e0219309, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31269068

RESUMO

The lung clearance index (LCI), measured by multiple breath washout (MBW), reflects global ventilation inhomogeneity and is a sensitive marker of early obstructive airway disease. For the MBW test to accurately reflect a subject's gas mixing within the lungs, the breathing pattern should represent physiologically appropriate tidal volumes (VT) and respiratory rate (RR). We aimed to assess whether changes in VT impact MBW outcome measures with a series of prospective and retrospective studies. MBW testing was performed using the Exhalyzer ® D (EcoMedics AG, Switzerland). Healthy adult subjects performed MBW with uninstructed tidal breathing and a series of instructed tidal breathing tests, designed to isolate specific features of the breathing pattern. In addition, we retrospectively analyzed MBW data from two pediatric multi-centre interventional studies of cystic fibrosis (CF) subjects to determine the range of VT observed during uninstructed breathing, and whether breathing outside this range impacted results. The LCI was lower, but not significantly different between deep breathing at 20 ml/kg body weight and uninstructed tidal breathing; whereas LCI was significantly higher during shallow breathing compared with normal tidal breathing. For the majority of subjects with CF (80%), VT ranged from 9-15mL/kg. Within the observed VT range, LCI was similar in trials with mean VT /kg below this range compared to trials with VT /kg within the range. If subjects breathe naturally and are not instructed to use specific targets, the range of VT is within physiologically appropriate limits and normal variations observed do not impact MBW outcomes.


Assuntos
Testes Respiratórios/métodos , Adulto , Criança , Fibrose Cística/fisiopatologia , Humanos , Sobrepeso/fisiopatologia , Taxa Respiratória , Magreza/fisiopatologia , Volume de Ventilação Pulmonar
16.
Neumol. pediátr. (En línea) ; 14(2): 105-110, jul. 2019. graf, ilust, tab
Artigo em Espanhol | LILACS | ID: biblio-1015136

RESUMO

Spirometry is better pulmonary function test for evaluating preschoolers with chronic lung disease and recurrent wheeze. It is useful, accessible and very good performance. For a correct interpretation it must be under the conditions specially controlled for this age group. In this review, product of the work done during the year 2018, by the Committee on pulmonary function in pediatric pulmonology Chilean society, will be showcased aspects for the realization and interpretation of spirometry in preschool children, with emphasis on the differences in the criteria typically described for older children and adults.


La espirometría es la prueba de función pulmonar más adecuada para evaluar a preescolares con enfermedades pulmonares crónicas y sibilancias recurrentes. Es útil, accesible y de buen rendimiento. Para una correcta interpretación debe realizarse bajo las condiciones especialmente normadas para este grupo etario. En esta revisión, producto del trabajo realizado durante el año 2018, por la comisión de función pulmonar de la sociedad Chilena de Neumología Pediátrica, se expondrán los aspectos actualizados para la realización e interpretación de la espirometría en preescolares, con énfasis en las diferencias de los criterios clásicamente descritos para niños mayores y adultos.


Assuntos
Humanos , Pré-Escolar , Espirometria/métodos , Testes de Função Respiratória , Asma/diagnóstico , Asma/fisiopatologia , Índice de Gravidade de Doença , Capacidade Vital , Volume Expiratório Forçado , Fibrose Cística/diagnóstico , Fibrose Cística/fisiopatologia , Pneumopatias/diagnóstico , Pneumopatias/fisiopatologia
17.
Nat Rev Gastroenterol Hepatol ; 16(8): 497-511, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31165788

RESUMO

Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases ß-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1ß and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.


Assuntos
Doenças dos Ductos Biliares/genética , Síndrome de Alagille/fisiopatologia , Doenças dos Ductos Biliares/tratamento farmacológico , Doenças dos Ductos Biliares/etiologia , Doenças dos Ductos Biliares/fisiopatologia , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Cistos/genética , Cistos/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Humanos , Hepatopatias/genética , Hepatopatias/fisiopatologia , Terapia de Alvo Molecular/métodos , Receptores Notch/fisiologia , Transdução de Sinais/fisiologia
18.
BMC Pulm Med ; 19(1): 106, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208380

RESUMO

BACKGROUND: Treatment of patients with Cystic Fibrosis homozygous for the Phe508del gene, with Lumacaftor /Ivacaftor (LUM/IVA) improves outcomes in patients with FEV1 > 40% predicted. We set out to observe the most sensitive clinical measure that would change with treatment in terms of exercise capacity or lung function in adults with severe lung disease as defined by an FEV1 < 40% predicted when clinically stable. METHODS: 10 adults homozygous for the Phe508del received LUM/IVA. We assessed; six minute walk test (6MWT), spirometry, gas transfer (DLCO), plethysmography, and nitrogen multiple breath washout (MBW) at baseline, 4, 12, 24 and 52 weeks. Comparison was made with 10 matched historical controls that had been observed over 12 months. RESULTS: There was a significant improvement in 6MWT by 4 weeks of treatment; with a mean increase of 78 m (SD 62.3) and this increased to 118.1 m (SD 80.9) (ANOVA p = 0.006) by 52 weeks. Significant improvements were also seen in the resting heart rate and the oxygen saturation (SaO2) after 6 min walking. A significant improvement was not seen in FEV1 though until 24 weeks, though this was maintained at 52 weeks (ANOVA, p = 0.0004). There were no significant differences seen in the MBW or DLCO. After 12 months treatment with LUM/IVA, in comparison to historical controls; the 6MWT increased by 118 m (SD 80.9), but fell in the controls - 61.3 m (SD 31.1). FEV1; LUM/IVA led to an increase of 0.398 L/min, compared to a fall in the controls - 0.18 (SD 0.2). CONCLUSION: In adults homozygous for Phe508del with severe disease, treatment with LUM/IVA results in a clinically significant improvement in 6MWT that was evident at 4 weeks and maintained at 52 weeks. Improvement in exercise tolerance is an important outcome to consider in those with more severe airways disease. TRIAL REGISTRATION: This was an observational trial conducted on individuals who became eligible to receive LUM/IVA. All investigations were carried out as part of routine clinical care. The trial was registered in retrospect on the 13/5/2019 on the Australian New Zealand Clinical Trials registry; ACTRN12619000708156 .


Assuntos
Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Tolerância ao Exercício/efeitos dos fármacos , Quinolonas/uso terapêutico , Adulto , Austrália , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Testes de Função Respiratória , Teste de Caminhada , Adulto Jovem
19.
Paediatr Respir Rev ; 31: 21-24, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31153793

RESUMO

Newborn screening and extensive genetic analysis has led to the recognition of a cohort of infants with an equivocal diagnosis of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) disease. This paper reviews the comprehensive approach required for diagnosis of Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) and uses an illustrative case with p.Asp1152His (D1152H) mutation to examine the varying clinical phenotype seen amongst CFSPID patients. Whilst infants are well at diagnosis, uncertainties about cystic fibrosis (CF) disease progression indicate the importance of monitoring and early specialist involvement. However, over-medicalisation can cause significant psychosocial impact on patients' and families. The complexities underlying the surveillance and long-term management of patients with CFSPID are explored.


Assuntos
Fibrose Cística/diagnóstico , Fibrose Cística/terapia , Cloretos/análise , Efeitos Psicossociais da Doença , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Gerenciamento Clínico , Progressão da Doença , Humanos , Recém-Nascido , Mutação , Triagem Neonatal , Fenótipo , Suor/química
20.
Echocardiography ; 36(6): 1118-1122, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31148213

RESUMO

INTRODUCTION: The presence of CFTR in smooth muscle and endothelial cells, systemic inflammation, and oxidative stress could explain vascular alterations in cystic fibrosis. Aortic elastic properties are determinants of left ventricular function by means of ventriculo-arterial coupling and indicators of cardiovascular risk. OBJECTIVES: The purpose of the present study was to compare clinically stable patients affected by cystic fibrosis without overt pulmonary hypertension with controls to evaluate aortic tissue Doppler elastic properties, such as distensibility, stiffness, and strain. METHODS: A total of 22 adults affected by cystic fibrosis, and 24 healthy volunteers matched for age and sex were enrolled. None had known cardiovascular risk factors, secondary diabetes, neither aortic stenosis nor regurgitation. All people underwent blood pressure measurement and transthoracic echocardiography. RESULTS: Aortic diameter measured at Valsalva sinuses was significantly higher in patients with cystic fibrosis than healthy people, median 32.0 (interquartile range 29.8-35.0) vs 24.3 (22.2-30.0) mm; P < 0.001. Aortic distensibility was significantly lower among patients than controls, being 2.4 (1.3-3.3) vs 5.6 (3.4-8.3) per mm Hg (P < 0.001), while stiffness higher, 7.7 (6.0-14.8) vs 3.7 (2.9-6.7); P < 0.001. Finally, M-mode strain of ascending aorta was lower in patients, 4.1 (3.4-7.3)% than in controls, 13.4 (7.7-19.4)%; P < 0.001. CONCLUSION: For the first time in humans, we demonstrated subclinical alterations in aortic elastic properties in young adults affected by cystic fibrosis without pulmonary hypertension or secondary diabetes. This phenomenon could influence left ventricular function earlier by means of ventriculo-arterial coupling and may be a tool to identify patients who benefit from a closer follow-up.


Assuntos
Aorta/diagnóstico por imagem , Aorta/fisiopatologia , Fibrose Cística/fisiopatologia , Ecocardiografia Doppler/métodos , Rigidez Vascular/fisiologia , Adulto , Estudos de Casos e Controles , Elasticidade , Feminino , Humanos , Masculino , Adulto Jovem
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