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1.
BMC Pulm Med ; 24(1): 307, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38956524

RESUMEN

Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy.


Asunto(s)
Aminofenoles , Benzodioxoles , Fibrosis Quística , Combinación de Medicamentos , Enfermedad de Gilbert , Hiperbilirrubinemia , Indoles , Pirazoles , Piridinas , Quinolonas , Humanos , Enfermedad de Gilbert/genética , Enfermedad de Gilbert/tratamiento farmacológico , Masculino , Aminofenoles/efectos adversos , Aminofenoles/uso terapéutico , Femenino , Adulto , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/complicaciones , Piridinas/efectos adversos , Piridinas/uso terapéutico , Indoles/efectos adversos , Benzodioxoles/efectos adversos , Benzodioxoles/uso terapéutico , Quinolonas/efectos adversos , Quinolonas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Hiperbilirrubinemia/inducido químicamente , Adulto Joven , Pirroles/efectos adversos , Adolescente , Glucuronosiltransferasa/genética , Pirrolidinas , Quinolinas
2.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33468668

RESUMEN

Epistasis refers to the dependence of a mutation on other mutation(s) and the genetic context in general. In the context of human disorders, epistasis complicates the spectrum of disease symptoms and has been proposed as a major contributor to variations in disease outcome. The nonadditive relationship between mutations and the lack of complete understanding of the underlying physiological effects limit our ability to predict phenotypic outcome. Here, we report positive epistasis between intragenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)-the gene responsible for cystic fibrosis (CF) pathology. We identified a synonymous single-nucleotide polymorphism (sSNP) that is invariant for the CFTR amino acid sequence but inverts translation speed at the affected codon. This sSNP in cis exhibits positive epistatic effects on some CF disease-causing missense mutations. Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity. The most robust effect was observed when the sSNP was present in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon. Functional studies revealed that synergistic alteration in ribosomal velocity is the underlying mechanism; alteration of translation speed likely increases the time window for establishing crucial domain-domain interactions that are otherwise perturbed by each individual mutation.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Epistasis Genética , Biosíntesis de Proteínas , Secuencia de Aminoácidos/genética , Codón/genética , Fibrosis Quística/patología , Humanos , Mutación Missense/genética , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genética
3.
Acta Paediatr ; 112(4): 861-867, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36653956

RESUMEN

AIM: Chronic conditions can influence the situation of healthy siblings of affected children. We investigated the opinion of the affected child about the situation of their healthy sibling and the sibling relationship. METHODS: We performed a semi-structured interview with epilepsy or asthma patients aged 6-18 years and asked them to draw a picture: "Epilepsy/Asthma, my siblings and me." RESULTS: Of the 58 children with epilepsy, 67%, and of the 40 children with asthma, 60% thought that their siblings were worried about the condition. Among other aspects, they addressed helplessness during a seizure. Of the children with epilepsy, 83% and of those with asthma, 95% assumed that their siblings were not disadvantaged because of the participant's condition. Of the patients with epilepsy, 91% and of those with asthma, 93% thought that the sibling relationship would not be different without the condition. Of the participants with epilepsy, 86% and of those with asthma, 93% drew a picture; 30% with epilepsy and 14% with asthma visualised an interaction with their siblings in context of a seizure or episode of dyspnoea. CONCLUSION: According to the affected children, the condition worries their siblings but does not affect the siblings' lives or the sibling relationship.


Asunto(s)
Asma , Epilepsia , Humanos , Niño , Adolescente , Hermanos , Relaciones entre Hermanos , Convulsiones
4.
BMC Pulm Med ; 21(1): 131, 2021 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-33882893

RESUMEN

BACKGROUND: The extend of lung disease remains the most important prognostic factor for survival in patients with cystic fibrosis (CF), and lack of adherence is the main reason for treatment failure. Early detection of deterioration in lung function and optimising adherence are therefore crucial in CF care. We implement a randomized controlled trial to evaluate efficacy of telemonitoring of adherence, lung function, and health condition in combination with behavior change interventions using innovative digital technologies. METHODS: This is a multi-centre, randomized, controlled, non-blinded trial aiming to include 402 patients ≥ 12 years-of-age with CF. A standard-of-care arm is compared to an arm receiving objective, continuous monitoring of adherence to inhalation therapies, weekly home spirometry using electronic devices with data transmission to patients and caring physicians combined with video-conferencing, a self-management app and professional telephone coaching. The duration of the intervention phase is 18 months. The primary endpoint is time to the first protocol-defined pulmonary exacerbation. Secondary outcome measures include number of and time between pulmonary exacerbations, adherence to inhalation therapy, changes in forced expiratory volume in 1 s from baseline, number of hospital admissions, and changes in health-related quality of life. CF-associated medical treatment and care, and health care related costs will be assessed by explorative analysis in both arms. DISCUSSION: This study offers the opportunity to evaluate the effect of adherence interventions using telemedicine capable devices on adherence and lung health, possibly paving the way for implementation of telemedicine in routine care for patients with CF. TRIAL REGISTRATION: This study has been registered with the German Clinical Trials Register (Identifier: DRKS00024642, date of registration 01 Mar 2021, URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024642 ).


Asunto(s)
Fibrosis Quística/terapia , Monitoreo Ambulatorio/métodos , Educación del Paciente como Asunto , Telemedicina , Adolescente , Adulto , Niño , Humanos
5.
Klin Padiatr ; 232(4): 210-216, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32176935

RESUMEN

BACKGROUND: Oral glucose tolerance (OGT) deteriorates progressively in cystic fibrosis (CF). Clinical registries provide a unique basis to study real-world data. PATIENTS & METHODS: OGT tests (OGTTs) documented in the German CF-registry in 2016 were classified according WHO, modified by ADA: normal glucose tolerance (NGT), indeterminate glycaemia (INDET), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, diabetes mellitus (DM). To study the association with lung function, multivariable regression adjusted for age, sex, and CFTR mutation was performed. RESULTS: Overall, OGTT screening was done in 35% of CF patients ≧10 years. Of the 996 patients (46.4% females; median age (IQR): 19 (14-27) years) with evaluable OGTTs, 56.2% had either NGT or INDET, whereas 34% had a pre-diabetic OGTT (IFG; IGT; IFG+IGT) and 9.8% a diabetic OGTT. 7 patients had glucose tolerance abnormalities <10 years. DM was more common in females or patients with F508del homozygote mutation, whereas IFG was more frequent in males (all p<0.05). Nearly 75% of patients after transplantation and about half with enteral/parental nutrition and/or steroid use had either a pre-diabetic or diabetic glucose tolerance. In the adjusted model, age (p<0.001) and OGTT category (p=0.013) had both a significant impact on %FEV1. CONCLUSION: Our data of the German CF-registry highlights incidence of glucose tolerance abnormalities in second decade of life in CF patients. However, it also underlines the need for improvement of the documentation and/or performance of OGTT screening in real-world CF care. HINTERGRUND: Bei Mukoviszidose (zystischer Fibrose: CF) verschlechtert sich die orale Glukosetoleranz (OGT) im Krankheitsverlauf. PATIENTEN & METHODEN: OGT Tests (OGTTs), die 2016 im Deutschen CF-Register dokumentiert waren, wurden gemäß WHO (modifiziert nach ADA) kategorisiert: Normale Glukosetoleranz (NGT), intermittierende Glykämie (INDET), eingeschränkte Nüchternglukosetoleranz (IFG), gestörte Glukosetoleranz (IGT), IFG+IGT, Diabetes Mellitus (DM). Um den Zusammenhang mit der Lungenfunktion zu analysieren, wurde eine multivariable Regressionsanalyse adjustiert für Alter, Geschlecht und CFTR Mutation durchgeführt. ERGEBNISSE: Insgesamt wurden 35% der CF-Patienten ≥10 Jahre mittels OGTT gescreent. Von den 996 Patienten (46,4% weiblich, medianes Alter (IQR): 19 (14-27) Jahre) mit auswertbaren OGTTs hatten 56,2% entweder NGT oder INDET, wohingegen bei 34% ein prädiabetischer (IFG; IGT; IFG+IGT) und bei 9,8% ein diabetischer OGTT beobachtet wurde. Bei 7 Patienten zeigten sich vor dem 10. LJ Abnormalitäten im Glukosestoffwechsel. DM war häufiger bei Frauen und Patienten mit homozygoter F508del Mutation, wobei IFG öfters bei Männern vorlag (alle p<0,05). Ca. 75% der Patienten mit Transplantation und etwa die Hälfte der Patienten mit künstlicher Ernährung und/oder Steroidgabe hatten eine prädiabetische oder diabetische Glukosetoleranz. Das Alter (p<0,001) und die OGTT Kategorie (p=0,013) zeigten im adjustierten Modell eine signifikante Assoziation mit %FEV1. SCHLUSSFOLGERUNG: Unsere Daten unterstreichen das Auftreten von Abnormalitäten im Glukosestoffwechsel bei CF im 2. Lebensjahrzehnt. Jedoch weißt es auf die Notwendigkeit eines regelmäßigen Diabetesscreenings und/oder Dokumentation von OGTTs bei CF hin.


Asunto(s)
Fibrosis Quística/fisiopatología , Prueba de Tolerancia a la Glucosa , Adolescente , Adulto , Fibrosis Quística/complicaciones , Diabetes Mellitus , Femenino , Alemania , Glucosa , Humanos , Masculino , Estado Prediabético/complicaciones , Sistema de Registros , Adulto Joven
6.
Am J Respir Crit Care Med ; 188(1): 83-9, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23631796

RESUMEN

RATIONALE: Glutathione is the major antioxidant in the extracellular lining fluid of the lungs and depleted in patients with cystic fibrosis (CF). OBJECTIVES: We aimed to assess glutathione delivered by inhalation as a potential treatment for CF lung disease. METHODS: This randomized, double-blind, placebo-controlled trial evaluated inhaled glutathione in subjects with CF 8 years of age and older and FEV1 of 40-90% of predicted. Subjects were randomized to receive 646 mg glutathione in 4 ml (n = 73) or placebo (n = 80) via an investigational eFlow nebulizer every 12 hours for 6 months. MEASUREMENTS AND MAIN RESULTS: FEV1 (absolute values), both as pre-post differences (P = 0.180) and as area under the curves (P = 0.205), were the primary efficacy endpoints, and were not different between the glutathione group and the placebo group over the 6-month treatment period. Exploratory analysis showed an increase of FEV1 from baseline over placebo of 100 ml or 2.2% predicted; this was significant at 3 months, but not later. Subjects receiving glutathione had neither fewer pulmonary exacerbations, nor better scores for quality of life. Whereas increased glutathione and metabolites in sputum demonstrated significant delivery to the lungs, there was no indication of diminished oxidative stress to proteins or lipids, and no evidence for anti-inflammatory or antiproteolytic actions of glutathione supplemented to the airways. The adverse event incidence was similar between glutathione and placebo. CONCLUSIONS: Inhaled glutathione in the dose administered did not demonstrate clinically relevant improvements in lung function, pulmonary exacerbation frequency, or patient-reported outcomes. Glutathione delivery to the airways was not associated with changes in markers of oxidation, proteolysis, or inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT00506688) and https://eudract.ema.europa.eu/index.html (EudraCT 2005-003870-88).


Asunto(s)
Antioxidantes/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Glutatión/administración & dosificación , Administración por Inhalación , Adulto , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Pruebas de Función Respiratoria/métodos , Pruebas de Función Respiratoria/estadística & datos numéricos , Resultado del Tratamiento , Adulto Joven
7.
BMC Pulm Med ; 14: 26, 2014 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-24571729

RESUMEN

BACKGROUND: Health-related and disease-specific quality of life (HRQoL) has been increasingly valued as relevant clinical parameter in cystic fibrosis (CF) clinical care and clinical trials. HRQoL measures should assess - among other domains - daily functioning from a patient's perspective. However, validation studies for the most frequently used HRQoL questionnaire in CF, the Cystic Fibrosis Questionnaire (CFQ), have not included measures of physical activity or fitness. The objective of this study was, therefore, to determine the cross-sectional and longitudinal relationships between HRQoL, physical activity and fitness in patients with CF. METHODS: Baseline (n = 76) and 6-month follow-up data (n = 70) from patients with CF (age ≥12 years, FEV1 ≥35%) were analysed. Patients participated in two multi-centre exercise intervention studies with identical assessment methodology. Outcome variables included HRQoL (German revised multi-dimensional disease-specific CFQ (CFQ-R)), body composition, pulmonary function, physical activity, short-term muscle power, and aerobic fitness by peak oxygen uptake and aerobic power. RESULTS: Peak oxygen uptake was positively related to 7 of 13 HRQoL scales cross-sectionally (r = 0.30-0.46). Muscle power (r = 0.25-0.32) and peak aerobic power (r = 0.24-0.35) were positively related to 4 scales each, and reported physical activity to 1 scale (r = 0.29). Changes in HRQoL-scores were directly and significantly related to changes in reported activity (r = 0.35-0.39), peak aerobic power (r = 0.31-0.34), and peak oxygen uptake (r = 0.26-0.37) in 3 scales each. Established associates of HRQoL such as FEV1 or body mass index correlated positively with fewer scales (all 0.24 < r < 0.55). CONCLUSIONS: HRQoL was associated with physical fitness, especially aerobic fitness, and to a lesser extent with reported physical activity. These findings underline the importance of physical fitness for HRQoL in CF and provide an additional rationale for exercise testing in this population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00231686.


Asunto(s)
Fibrosis Quística/fisiopatología , Actividad Motora , Aptitud Física , Calidad de Vida , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Encuestas y Cuestionarios , Adulto Joven
8.
BMC Pediatr ; 14: 70, 2014 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-24620855

RESUMEN

BACKGROUND: Diabetes mellitus may be present in patients with cystic fibrosis starting in the second decade of life. The prevalence increases rapidly with increasing age. As life-expectancy increases in cystic fibrosis, cystic fibrosis related diabetes will be diagnosed more frequently in the future.Up to date, no data are available to answer the question if cystic fibrosis related diabetes should always initially be treated by insulin therapy. Missing data regarding oral antidiabetic treatment of newly diagnosed cystic fibrosis related diabetes are an important reason to recommend insulin treatment. Several centres report the successful management of cystic fibrosis related diabetes using oral anti-diabetic drugs at least for some years. Oral therapies would be less invasive for a patient group which is highly traumatized by a very demanding therapy. Based on an initiative of the German Mukoviszidosis-Foundation, the present study tries to answer the question, whether oral therapy with repaglinide is as effective as insulin therapy in cystic fibrosis patients with early diagnosed diabetes mellitus. METHODS/DESIGN: In all cystic fibrosis patients with an age of 10 years or older, an oral glucose tolerance test is recommended. The result of this test is classified according to the WHO cut off values. It is required to have two diabetes positive oral glucose tolerance tests for the diagnosis of diabetes mellitus.This study is a multi-national, multicentre, open labelled, randomized and prospective controlled parallel group's trial, with 24 months treatment.The primary objective of this trial is to compare the glycaemic control of oral therapy with Repaglinide with insulin injections in patients with cystic fibrosis related diabetes after 2 years of treatment.The trial should include 74 subjects showing cystic fibrosis related diabetes newly diagnosed by oral glucose tolerance test during annual screening for cystic fibrosis related diabetes.Patients are randomised by central fax randomisation.Primary endpoint is mean HbA1c after 24 months of treatment. Secondary endpoints are change in FEV1% predicted and change in BMI-Z-score. DISCUSSION: There is only one prospective study comparing oral antidiabetic drugs to insulin in the treatment of CFRD without fasting hyperglycaemia. The results regarding BMI after 6 months and 12 months showed an improvement for the insulin treated patients and were inconsistent for those treated with repaglinide. HbA1c and lung function (FEV1%pred) were unchanged for either group. The authors compared the changes -12 months to baseline and baseline to +12 months separately for each group. Therefore a direct comparison of the effect of repaglinide versus insulin on BMI, HbA1c and FEV1%pred was not presented. According to our protocol, we will directly compare treatment effects (HbA1c, BMI, FEV1%pred) in between both groups. The actual Cochrane report regarding "Insulin and oral agents for managing CFRD" stated that further studies are needed to establish whether there is clear benefit for hypoglycemic agents. We expect that the results of our study will help to address this clinical need. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00662714.


Asunto(s)
Carbamatos/uso terapéutico , Fibrosis Quística/complicaciones , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/etiología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Piperidinas/uso terapéutico , Adolescente , Algoritmos , Niño , Diabetes Mellitus/diagnóstico , Diagnóstico Precoz , Humanos , Estudios Prospectivos
9.
Curr Eye Res ; 49(7): 759-767, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38557392

RESUMEN

PURPOSE: Patients with cystic fibrosis (CF) are at risk to develop CF related diabetes (CFRD) and subsequently even diabetic neuro- and/or vasculopathy. We sought to determine if there are typical signs of diabetes-related retinal alterations present in CF patients with preserved and impaired glycemic control. METHODS: During routine annual examination CF patients were offered an additional 7-day period of real time continuous glucose monitoring (rtCGM) and an ophthalmological examination including retinal optical coherence tomography (OCT). Patients were categorized according to the glycemic control, i.e. the results of an oral glucose tolerance test (OGTT) and rtCGM were taken into consideration. OCT data was analyzed by our previously published visual analysis software generating dedicated and spatially resolved deviation maps for visualization and quantification of differences in total retinal thickness and thickness of retinal nerve fiber layer (RNFL) as well as ganglion cell layer (GCL) in comparison to age-matched healthy controls and patients with either type 1 or type 2 diabetes mellitus. RESULTS: Results of the rtCGM and/or OGTT enabled discrimination between patients with normal glycemic control (CFNG; n = 6), with abnormal glycemic control (CFAG; n = 6) and overt CFRD (n = 4). OCT data indicates gradually increasing retinal thinning in all 3 groups, depending on the degree of glucose metabolism disorder compared to healthy controls. At the foveal region total retinal thickness and GCL thickness were significantly thinner in CFRD patients compared to CFNG patients (total retinal thickness: 260.4 µm (239.3-270.8) vs. 275.4 µm (254.3-289.5); GCL: 11.82 µm (11.16-15.25) vs. 17.30 µm (13.95-19.82); each p < 0.05). CONCLUSION: Although we investigated a rather small number of patients, we obtained evidence that intraretinal neurodegenerative changes occur in each of our subgroups (CFNG, CFAG, CFRD). Beyond this, our results favor the detrimental role of additional diabetes, as the deviations from healthy controls were most pronounced in the CFRD group and are similar to those seen in patients suffering from type 1 or type 2 diabetes.


Asunto(s)
Glucemia , Fibrosis Quística , Prueba de Tolerancia a la Glucosa , Fibras Nerviosas , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Fibrosis Quística/complicaciones , Masculino , Femenino , Glucemia/metabolismo , Adulto , Fibras Nerviosas/patología , Células Ganglionares de la Retina/patología , Adulto Joven , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/etiología , Hemoglobina Glucada/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Persona de Mediana Edad , Adolescente
10.
Cancers (Basel) ; 16(11)2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38893208

RESUMEN

Background: Immune checkpoint blockade (ICB) has presented a breakthrough in the treatment of malignant tumors and increased the overall survival of patients with various tumor entities. ICB may also cause immune-related adverse events, such as pneumonitis or interstitial lung disease. The lung clearance index (LCI) is a multiple-breath washout technique offering information on lung pathology in addition to conventional spirometry. It measures the degree of pulmonary ventilation inhomogeneity and allows early detection of pulmonary damage, especially that to peripheral airways. Methods: This cross-sectional study compared the lung function of patients with melanoma or metastatic cutaneous squamous cell carcinoma who received programmed cell death 1 (PD-1) and cytotoxic T-Lymphocyte-associated Protein 4 (CTLA-4) antibodies, alone or in combination, to age- and sex-matched controls. Lung function was assessed using spirometry, according to American Thoracic Society and European Respiratory Society standards, the LCI, and a diffusion capacity of carbon monoxide (DLCO) measurement. Results: Sixty-one screened patients and thirty-eight screened controls led to nineteen successfully included pairs. The LCI in the ICB-treated patients was 8.41 ± 1.15 (mean ± SD), which was 0.32 higher compared to 8.07 ± 1.17 in the control group, but the difference was not significant (p = 0.452). The patients receiving their ICB therapy for under five months showed a significantly lower LCI (7.98 ± 0.77) compared to the ICB patients undergoing therapy for over five months (9.63 ± 1.22) at the point of testing (p = 0.014). Spirometric analysis revealed that the forced expiratory volume between 25 and 75% of the forced vital capacity (FEF25-75%) in the ICB-treated patients was significantly reduced (p = 0.047) compared to the control group. DLCO (%predicted and adjusted for hemoglobin) was 94.4 ± 19.7 in the ICB patients and 93.4 ± 21.7 in the control group (p = 0.734). Conclusions: The patients undergoing ICB therapy showed slightly impaired lung function compared to the controls. Longer periods of ICB treatment led to deterioration of the LCI, which may be a sign of a subclinical inflammatory process. The LCI is feasible and may be easily integrated into the clinical daily routine and could contribute to early detection of pulmonary (auto-)inflammation.

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