囊性纤维化跨膜转导调节器在培养人子宫内膜上皮细胞的表达

目的　探讨雌、孕激素对体外培养人子宫内膜腺上皮细胞囊性纤维化跨膜转导调节器(CFTR)基因和蛋白质表达的影响。　方法　采用逆转录 聚合酶链反应(RT PCR)、原位杂交、免疫组织化学方法检测CFTR mRNA和蛋白质表达量的变化。　结果　RT PCR结果显示单纯雌二醇、雌二醇与孕酮合用、对照组均扩增出特异的 CFTR mRNA条带,孕酮组则未见到;原位杂交结果也证实雌二醇刺激CFTR mRNA的表达(P<0.05),孕酮则抑制CFTR mRNA的表达。免疫组织化学检测子宫内膜腺上皮细胞中CFTR蛋白质含量表明雌二醇显著刺激其生成。　结论　卵巢性激素雌二醇上调、孕酮下调体外培养人子宫内膜腺上皮细胞CFTR mRNA及蛋白质的表达,从而调节月经周期不同时相宫腔液微环境中水与电解质含量,适应不同的生殖阶段。     

Ratiometric sweat secretion optical test in cystic fibrosis,carriers and healthy subjects

We have simplified the published procedure (5) for measuring sweat rates in individual human sweat glands.Sweat secretion rates were obtained from sweat drops secreted on the forearm by multiple individual glands. We computed a ratio between CFTR-dependent (by intradermal microinjection of a β adrenergic cocktail) and CFTR-independent (by methacoline as cholinergic stimulus) sweat secretion rates.We obtained a reproducible, approximately linear readout of CFTR function with measurements performed by two different independent teams. We considered three groups (CF subjects, CF carriers and non-CF controls, n = 22 in each group); their mean ratios was respectively 0.000, 0.104 and 0.205 The average ratio of CF subjects was consistent with diagnosis in 3 additional cases clinically resembling CF. All groups were clearly discriminated, with sensibility and specificity ranging from 82% to 100%. A software was developed for detecting sweat droplets.This bioassay is suitabile for multicentre studies focusing on CFTR targeted therapies, controversial diagnosis and functional relevance of rare CFTR mutations.     

Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations

Background

The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator ivacaftor is approved for patients with CF with gating and residual function CFTR mutations. We report the results of an observational study investigating its effects in CF patients with non-G551D gating mutations.

Year to year change in FEV1 in patients with cystic fibrosis and different mutation classes

In patients with cystic fibrosis, most treatments addressing the underlying basic defect are mutation or mutation class specific. These treatments are disease modifying if they lower the year to year change in lung function. We therefore calculated the current loss of lung function, measured by year to year change in forced expired volume in 1 s in 11,417 patients included in the European Cystic Fibrosis Society Patient Registry. Whereas patients with at least one mutation of class IV or V have on average a lower year to year change, we did not find a difference between patients with a stop codon mutation, homozygous for F508del or at least one class III mutation. These data are useful background information to discuss the impact of different disease modifying treatments.     

Recovery of lung function following a pulmonary exacerbation in patients with cystic fibrosis and the G551D-CFTR mutation treated with ivacaftor

Background

Pulmonary exacerbations (PEx) are associated with acute loss of lung function that is often not recovered after treatment. We investigated lung function recovery following PEx for ivacaftor- and placebo-treated subjects.

Acute intestinal obstruction as a presentation of cystic fibrosis in infancy

Intestinal obstruction and dysmotility occur throughout life in cystic fibrosis but rarely present as an acute obstruction beyond the neonatal period. We describe the previously unreported occurrence of acute obstruction of the sigmoid colon as a presenting feature of cystic fibrosis (CF) in a 6-month infant.     

Effects of creatine supplementation in cystic fibrosis: results of a pilot study

BACKGROUND: The CF transmembrane conductance regulator (CFTR), whose mutations cause cystic fibrosis (CF), depends on ATP for activation and transport function. Availability of ATP in the cell and even more in specific cellular microcompartments often depends on a functional creatine kinase system, which provides the 'energy buffer' phosphocreatine. Creatine supplementation has been shown to increase phosphocreatine levels, thus promoting muscle growth and strength in athletes and having protective effects in neuromuscular disorders. AIM: To test clinically, if creatine supplementation improves maximal isometric muscle strength (MIMS), lung function and CFTR channel activity in patients with CF, and to determine enzymatic activity of creatine kinase in respiratory epithelial cells. METHODS: In an open-label pilot study 18 CF patients (8-18-year-old) with pancreatic insufficiency and mild to moderate lung disease received daily creatine supplementation during 12 weeks. Patients were monitored during 24-36 weeks. Enzymatic activity of creatine kinase was measured in primary epithelial cell cultures. RESULTS: After creatine supplementation, there was no change in lung function and sweat electrolyte concentrations, possibly due to the very low creatine kinase activities detected in respiratory epithelia. However, the patients consistently showed significantly increased MIMS (18.4%; P < 0.0001), as well as improved general well-being, as assessed by a standardized questionnaire. Except for one patient with transient muscle pain, no side effects were reported. CONCLUSIONS: Our pilot study suggests, that creatine supplementation should be further evaluated as a possible clinically beneficial adjuvant therapy for patients with CF to increase muscle strength, body-weight and well-being.     

Mutational spectrum of cystic fibrosis in the Lebanese population

BackgroundCystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians; it is however, considered to be rare in the Arab populations. Reports of the cystic fibrosis transmembrane regulator (CFTR) mutations from Arabs, especially from the Lebanese population, are limited.MethodsTwenty-two unrelated Lebanese families, with at least one child with CF, were studied. DNA extracts from blood samples of patients and parents were screened for CFTR gene mutations.ResultsEleven different mutations were identified. Of the 44 alleles studied, the most common mutations were: F508del (34%), N1303K (27%), W1282X (7%), and S4X (7%). Five mutations – not previously reported in the Lebanese population – were identified; these are: S549N, G542X, 2043delG, 4016insG, and R117H-7T.ConclusionsThe most common CFTR mutations in addition to five mutations not previously described in the Lebanese population were identified. Identification of CFTR mutations in the Lebanese population is important for molecular investigations and genetic counseling.     

Continuous glucose monitoring in youth with cystic fibrosis treated with lumacaftor-ivacaftor

Background

The effects of lumacaftor-ivacaftor therapy on glycemia have not been thoroughly investigated. Continuous glucose monitoring (CGM) provides detailed information about glycemic patterns and detects glucose abnormalities earlier than traditional screening tools for diabetes.

肺移植治疗囊性纤维化1例并文献复习

目的 探讨肺移植治疗囊性纤维化（CF）的疗效和预后。 方法 回顾性分析行同种异体双肺移植术治疗1例终末期CF受者的临床资料,对CF受者的临床特点、诊断方法及治疗策略进行总结。 结果 本例受者幼年发病,反复咳嗽、咳浓痰30年,肺部反复感染合并急性加重、慢性鼻窦炎及极重度营养不良,肺移植术前因呼吸肌无力难以脱离有创呼吸机,长期入住重症监护室（ICU）。影像学检查提示双肺多发囊柱状支气管扩张伴感染,经汗液测试和基因检测进一步确诊为CF。该受者2017年8月17日接受双肺移植术后经过康复治疗,肺功能逐渐恢复正常,康复后至投稿日已2年余,享有与同龄健康人同等的生活质量。 结论 肺移植术作为终末期CF的有效治疗手段,不仅能挽救患者生命,而且还能显著提高患者的生活质量。     

先天性双侧输精管缺如患者囊性纤维化跨膜转运调节物基因⊿F508突变的研究

目的研究男性先天性双侧输精管缺如(CBAVD)患者其囊性纤维化跨膜转运调节物(CFTR)基因第10号外显子区域上△F508的突变情况。方法应用聚合酶链反应(PCR)及PCR产物直接测序的方法检测了32例CBAVD患者和32例健康生育男性CFTR基因第10号外显子区域上△F508的突变情况。结果两组检查均没有发现△F508突变。结论△F508突变是国外白种人CBAVD患者最常见的一种基因突变,而对中国人来说检测该突变意义可能不大。     

Prevalence and diversity of filamentous fungi in the airways of cystic fibrosis patients – A Dutch,multicentre study

Background

Progressive lung injury in Cystic Fibrosis (CF) patients can lead to chronic colonization with bacteria and fungi. Fungal colonization is obtained from the environment which necessitates locally performed epidemiology studies. We prospectively analyzed respiratory samples of CF patients during a 3-year period, using a uniform fungal culture protocol, focusing on filamentous fungi and azole resistance in Aspergillus fumigatus.

Worsening anxiety and depression after initiation of lumacaftor/ivacaftor combination therapy in adolescent females with cystic fibrosis

In both phase III studies of LUM/IVA, as well as an extension study, worsening of mental health was not reported as a common side effect. Here we describe five cases in adolescent female patients that suggest a worsening of anxiety or depression associated with its use. In these five patients, two experienced suicidal ideation and three made suicide attempts that resulted in psychiatric hospitalizations.     

双肺移植治疗儿童囊性纤维化的多学科综合诊疗

目的  通过多学科综合诊疗（MDT）模式提高双肺移植治疗儿童囊性纤维化的外科疗效。方法  对1例国内罕见的终末期囊性纤维化10岁患儿进行肺移植术前MDT讨论,制定对应治疗方案。结果  患儿确诊囊性纤维化5年,肺移植指征明确,经过MDT讨论决定行Clam-shell切口下双肺移植术,术中维持生命体征稳定,术后给予呼吸机辅助通气、抗感染、免疫抑制、抑酸和预防应激性溃疡等治疗,并根据患儿特点给予个体化治疗方案,术后恢复良好。结论  通过肺移植术前MDT讨论,肺移植治疗儿童囊性纤维化的手术效果满意,减少了术后并发症的发生风险,值得临床推广。     

Genetics of CFTR and male infertility

Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as an ion transporter on the epithelium of exocrine glands, regulating secretion viscosity. The CFTR gene, encoded on chromosome 7, is required for the production and trafficking of the intact and functional CFTR protein. Literally thousands of human CFTR allelic mutations have been identified, each with varying impact on protein quality and quantity. As a result, individuals harboring CFTR mutations present with a spectrum of symptoms ranging from CF to normal phenotypes. Those with loss of function but without full CF may present with CFTR-related disorders (CFTR-RDs) including male infertility, sinusitis, pancreatitis, atypical asthma and bronchitis. Studies have demonstrated associations between higher rates of CFTR mutations and oligospermia, epididymal obstruction, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic ejaculatory duct obstruction (EDO). Genetic variants are detected in over three-quarters of men with CBAVD, the reproductive abnormality most classically associated with CFTR aberrations. Likewise, nearly all men with clinical CF will have CBAVD. Current guidelines from multiple groups recommend CFTR screening in all men with clinical CF or CBAVD though a consensus on the minimum number of variants for which to test is lacking. CFTR testing is not recommended as routine screening for men with other categories of infertility. While available CFTR panels include 30 to 96 of the most common variants, complete gene sequencing should be considered if there is a high index of suspicion in a high-risk couple (e.g., partner is CFTR mutation carrier). CF treatments to date have largely targeted end-organ complications. Novel CFTR-modulator treatments aim to directly target CFTR protein dysfunction, effectively circumventing downstream complications, and possibly preventing symptoms like vasal atresia at a young age. Future gene therapies may also hold promise in preventing or reversing genetic changes that lead to CF and CFTR-RD.     

High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France

In this report, we present updated spectrum and frequency of mutations of the CFTR gene that are responsible for cystic fibrosis (CF) in Languedoc-Roussillon (L-R), the southwestern part of France. A total of 75 different mutations were identified by DGGE in 215 families, accounting for 97.6% of CF genes and generating 88 different mutational genotypes. The frequency of p.F508del was 60.23% in L-R versus 67.18% in the whole country and only five other mutations (p.G542X, p.N1303K, p.R334W, c.1717-1G>A, c.711+1G>T) had a frequency higher than 1%. The mutations were scattered over 20 exons or their border. This sample representing only 5.7% of French CF patients contributed to 24% of CFTR mutations reported in France. This is one of the highest molecular allelic heterogeneity reported so far in CF. We also present the result of a neonatal screening program based on a two-tiered approach "IRT/20 mutations/IRT" analysis on blood spots, implemented in France with the aim to improve survival and quality of life of patients diagnosed before clinical onset. This 18-month pilot project showed an unexpected low incidence of CF (1/8885) in South of France, with only six CF children detected among 43,489 neonates born in L-R, and 13 among 125,339 neonates born in Provence-Alpes-C?te-d'Azur (PACA).     

Risk factors for persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis

Background

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as an important pathogen in cystic fibrosis (CF). Over 25% of individuals in the United States with CF are found to have MRSA in respiratory culture specimens, and persistent MRSA infection has been associated with more rapid decline in lung function and increased mortality. The objective of this study was to investigate clinical and demographic characteristics that are associated with the development of persistent MRSA infection in a CF population.

Rational approach to genetic testing of cystic fibrosis (CF) in infertile men

Male infertility as a result of isolated congenital bilateral absence of the vas deferens (CBAVD) is one primary genital form of cystic fibrosis (CF) and occurs in 1-2% of infertile men. Assisted fertilization in patients with CBAVD increases the risk of transmitting mutations in the CF gene. We developed a rational approach to genetic CF testing in infertile men. A total of 282 infertile male patients were screened for the most common CF mutations (DeltaF508, R117H, IVS8-5T). Clinical data including medical history, examination, semen analysis, sweat tests, karyotypes and hormonal values were analysed. We identified 23 patients carrying mutations in the CF gene (DeltaF508: 10 patients; R117H: six patients; IVS8-5T: 11 patients). Two patients were compound heterozygote for DeltaF508/R117H, two others for DeltaF508/IVS8-5T. Correlating these molecular analyses with the clinical data pertaining to serum follicle-stimulating hormone concentration, semen pH, sperm count and total testicular volume, we were able to develop a score with a high specificity (98.4) for the presence of a cystic fibrosis transmembrane conductance regulator (CFTR) mutation, but only with a low sensitivity (positive post-test likelihood: 62.5%; negative post-test likelihood: 6.3%). With regard to the low sensitivity and the high number of CFTR mutations found in this heterogeneous group of infertile men, we still recommend genetic CF testing before assisted fertilization.