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Cystic fibrosis [keywords]
- Genetic relatedness and host specificity of Pseudomonas aeruginosa isolates from cystic fibrosis and non-cystic fibrosis patients. [JOURNAL ARTICLE]
- Infect Drug Resist 2014.:309-316.
Pseudomonas aeruginosa is one of the primary pathogens isolated more frequently in cystic fibrosis (CF) and it exhibits innate resistance to a wide range of antibiotics.We sought to determine whether the highly prevalent genotypes of P. aeruginosa are specifically linked to CF patients and have any related multidrug antibiotic resistance. Isolates from hospitalized non-CF patients and from environmental sources were also genotypically analyzed.Collections of P. aeruginosa from lower respiratory secretions (n=45) were genotyped using pulsed-field gel electrophoresis (PFGE). Phenotypic screening for antibiotic susceptibility was performed for the common antimicrobial agents by E-test and automated Phoenix method.P. aeruginosa isolates from CF (n=32), hospitalized non-CF patients (n=13), and environment sources (n=5) were analyzed. The population structure of P. aeruginosa is highly diverse and population-specific. All PFGE results of P. aeruginosa isolates fall among four major clusters. Cluster 1 contained 16 P. aeruginosa isolates from CF patients and two from environmental sources; cluster 2 contained 11 P. aeruginosa isolates from CF and one each from non-CF and environmental sources; cluster 3 contained 12 P. aeruginosa isolates from hospitalized non-CF patients and two P. aeruginosa isolates from one CF patient and one environmental source; and cluster 4 consisted of three isolates from CF patients and one from the environment. The majority of multidrug-resistant P. aeruginosa isolates were in clusters 3 and 4. P. aeruginosa isolates from CF patients were resistant to ciprofloxacin (34.4%) followed by resistance to amikacin and gentamicin (each 28%), whereas the majority of isolates from non-CF patients were resistant to meropenem (69%) and were grouped in cluster 3.PFGE of P. aeruginosa isolates from CF patients shows a high degree of similarity, suggesting specific adaptation of these clones to CF-affected lungs. The hospitalized non-CF cluster has a different clonal origin, indicating specific clustering in a specific location, suggesting hospital-acquired P. aeruginosa infections.
- Multi-physiopathological consequences of the c.1392G>T CFTR mutation revealed by clinical and cellular investigations. [JOURNAL ARTICLE]
- Biochem Cell Biol 2014 Sep 17.:1-10.
This study combines a clinical approach and multiple level cellular analyses to determine the physiopathological consequences of the c.1392G>T (p.Lys464Asn) CFTR exon 10 mutation, detected in a CF patient with a frameshift deletion in trans and a TG(11)T(5) in cis. Minigene experiment, with different TG(m)T(n) alleles, and nasal cell mRNA extracts were used to study the impact of c.1392G>T on splicing in both in cellulo and in vivo studies. The processing and localization of p.Lys464Asn protein were evaluated, in cellulo, by western blotting analyses and confocal microscopy. Clinical and channel exploration tests were performed on the patient to determine the exact CF phenotype profile and the CFTR chloride transport activity. c.1392G>T affects exon 10 splicing by inducing its complete deletion and encoding a frameshift transcript. The polymorphism TG(11)T(5) aggravates the effects of this mutation on aberrant splicing. Analysis of mRNA obtained from parental airway epithelial cells confirmed these in cellulo results. At the protein level the p.Lys464Asn protein showed neither maturated form nor membrane localization. Furthermore, the in vivo channel tests confirmed the absence of CFTR activity. Thus, the c.1392G>T mutation alone or in association with the TG repeats and the poly T tract revealed obvious impacts on splicing and CFTR protein processing and functionality. The c.[T(5); 1392G>T] complex allele contributes to the CF phenotype by affecting splicing and inducing a severe misprocessing defect. These results demonstrate that the classical CFTR mutations classification is not sufficient: in vivo and in cellulo studies of a possible complex allele in a patient are required to provide correct CFTR mutation classification, adequate medical counseling, and adapted therapeutic strategies.
- Non-surgical interventions for treating heavy menstrual bleeding (menorrhagia) in women with bleeding disorders. [JOURNAL ARTICLE]
- Cochrane Database Syst Rev 2014 Nov 26.:CD010338.
Heavy menstrual bleeding without an organic lesion is mainly due to an imbalance of the various hormones which have a regulatory effect on the menstrual cycle. Another cause of heavy menstrual bleeding with no pelvic pathology, is the presence of an acquired or inherited bleeding disorder. The haemostatic system has a central role in controlling the amount and the duration of menstrual bleeding, thus abnormally prolonged or profuse bleeding does occur in most women affected by bleeding disorders. Whereas irregular, pre-menarchal or post-menopausal uterine bleeding is unusual in inherited or acquired haemorrhagic disorders, severe acute bleeding and heavy menstrual bleeding at menarche and chronic heavy menstrual bleeding during the entire reproductive life are common.To determine the efficacy and safety of non-surgical interventions versus each other, placebo or no treatment for reducing menstrual blood loss in women with bleeding disorders.We searched the Cochrane Cystic Fibrosis Haemoglobinopathies Trials Register (13 March 2014), Embase (May 2013), LILACS (February 2013) and the WHO International Clinical Trial registry (February 2013).Randomised controlled studies of non-surgical interventions for treating heavy menstrual bleeding (menorrhagia) in women of reproductive age suffering from a congenital or acquired bleeding disorder.Two authors independently assessed studies for inclusion, extracted data and assessed the risk of bias.Three cross-over studies, with 175 participants were included in the review. All three studies had an unclear risk of bias with regards to trial design and overall, the quality of evidence generated was judged to be poor.Two of the studies (n = 59) compared desmopressin (1-deamino-8-D-arginine vasopressin) with placebo. Menstrual blood loss was the primary outcome for both of these studies. Neither study found clear evidence of a difference between groups. The first of these reported a mean difference in menstrual blood loss in the desmopressin versus placebo group of 21.20 mL (95% confidence interval -19.00 to 61.50)The second study reported that even though there was an improvement of pictorial bleeding assessment chart scores with desmopressin and placebo when compared to pretreatment assessment, there was no clear evidence of difference in these scores when the two were compared to each other (results presented graphically, P = 0.51). The data from these studies could not be combined.The third study (n = 116) compared desmopressin with tranexamic acid (n = 116). This study found a decrease in pictorial bleeding assessment chart scores after both treatments as compared to baseline. The decrease in these scores was greater for tranexamic acid than for desmopressin, with a mean difference of 41.6 mL (95% confidence interval 19.6 to 63) (P < 0.0002).In relation to adverse events, across two studies, there was no clear evidence of a difference when placebo was compared to desmopressin, risk ratio 1.17 (95% confidence interval 0.41 to 3.34) . The same was also true when desmopressin was compared to tranexamic acid, risk ratio 1.17 (95% confidence interval 0.41 to 3.34).Only the study that compared desmopressin to tranexamic acid assessed quality of life. However, we are unable to present any data from this study, since no differences in this outcome between the two intervention groups were reported.Evidence from randomised controlled studies on the effect of desmopressin when compared to placebo in reducing menstrual blood loss is very limited and inconclusive. Two studies, each with a very limited number of participants, have shown uncertain effects in menstrual blood loss and adverse effects. A non-randomised comparison in one of the studies points to the value of combining desmopressin and tranexamic acid, which needs to be tested in a formal randomised controlled study comparison.When tranexamic acid was compared to desmopressin, a single study showed a reduction in menstrual blood loss with tranexamic acid use compared to desmopressin.There is a need to evaluate non-surgical methods for treating of menorrhagia in women with bleeding disorders through randomised controlled studies. Such methods would be more acceptable than surgery for women wishing to retain their fertility. Given that women may need to use these treatments throughout their entire reproductive life, long-term side-effects should be evaluated.
- Feasibility and Acceptability of an Internet-Based Program to Promote Physical Activity in Adults with Cystic Fibrosis. [JOURNAL ARTICLE]
- Respir Care 2014 Nov 25.
Lifelong physical activity is an important component of the therapeutic management of patients with cystic fibrosis (CF). Use of the internet to monitor and encourage participation in physical activity has not been assessed in adults with CF. We aimed to establish the feasibility and acceptability of a specifically developed internet-based program to monitor and encourage physical activity participation in adults with CF.Subjects were recruited at hospital discharge to trial an internet-based physical activity program (ActivOnline) for 8 weeks, which incorporated fortnightly telephone consultation to support physical activity behavior change. Acceptability of the program was assessed by semistructured interview, as well as subject-rated system usability and perceived benefit using Likert scales. Feasibility was assessed by frequency of access of the online site and number of physical activity sessions recorded.Ten subjects were recruited who rated system usability and perceived benefit favorably (median score usability of 89% [interquartile range of 84-95%]; median score of perceived benefit (maximum of 5) of 4 [interquartile range of 3-4.8]). During interviews, subjects described a positive reaction to receiving graphical representation of their activity participation; however, 80% would have preferred a more mobile interface such as an app. Subjects accessed ActivOnline on a mean ± SD of 13 ± 11 occasions over 8 weeks and recorded a mean of 35 (range of 15-57) physical activity sessions.Use of an internet-based program to encourage participation in physical activity was both feasible and acceptable to adults with CF. Feasibility may be further improved with the ability to access the program through a mobile application.
- Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. [JOURNAL ARTICLE]
- Clin Infect Dis 2014 Nov 25.
Ivacaftor improves outcomes in CF patients with the G551D mutation; however effects on respiratory microbiology are largely unknown. This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response. The G551D Observational Study enrolled a longitudinal observational cohort of US CF patients 6 and older with at least one copy of the G551D mutation. Results were linked with retrospective and prospective culture data in the US CF Foundation's National Patient Registry. P. aeruginosa infection category in the year before and after ivacaftor were compared and correlated with clinical findings. Among 151 participants prescribed ivacaftor, 29% (26/89) who were P. aeruginosa culture positive the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected. The odds of P. aeruginosa positivity in the year after ivacaftor compared to the year prior were reduced by 35% (OR=0.65, p<0.001). Ivacaftor was also associated with reduced odds of mucoid P. aeruginosa (OR=0.77, p=0.013) and aspergillus (OR=0.47, p=0.039), but not Staphylococcus aureus or other common CF pathogens. Patients with intermittent culture positivity and higher FEV1 were most likely to turn culture negative. Reduction in P. aeruginosa was not associated with change in FEV1, BMI, or hospitalizations. P. aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease.
- Cystic fibrosis newborn screening: A model for neuromuscular disease screening? [JOURNAL ARTICLE]
- Ann Neurol 2014 Nov 26.
Congenital neuromuscular disorders, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and Pompe disease (acid maltase deficiency, AMD) are candidates for universal newborn screening (NBS). In this paper, we discuss the future path of NBS for these disorders with particular emphasis on DMD-NBS, because of the likely approval of new gene modifying treatments, the possible benefits of earlier treatment with corticosteroids, and the recently demonstrated feasibility of a two tiered approach to NBS with screening by creatine kinase (CK) levels in dried blood spots followed by mutation detection in those with elevated CK. The cystic fibrosis newborn screening (CF-NBS) program is a successful model for NBS. Cystic fibrosis (CF) outcomes have consistently improved into adulthood following introduction of CF-NBS because considerable resources have been devoted to practices that include: attention to improving laboratory screening; consistent confirmatory testing and immediate referral of all newly diagnosed infants to designated CF care centers that follow established practice guidelines; and, ongoing evaluation of CF care centers via a centralized clinical database. Like CF, DMD, SMA, and infantile AMD are inexorably debilitating and require lifetime multidisciplinary clinical management. NBS would address the delays in diagnosis that prevent patients from receiving timely treatments. Standardized care following early diagnosis would reduce disparities in clinical care and outcomes. NBS in these neuromuscular disorders should be implemented, utilizing lessons learned from the past 20 years of CF-NBS: standardized protocols for all patients identified by DMD-NBS; longitudinal follow-up in multidisciplinary clinics; and coordinated oversight of these clinics. This article is protected by copyright. All rights reserved.
- Duodenal perforation: an unusual complication of sickle cell anemia. [Journal Article]
- Pan Afr Med J 2014.:217.
Duodenal perforation in childhood is a rare condition with a high mortality rate if not treated surgically. Primary gastroduodenal perforation is frequently associated with peptic ulcer and exhibits a positive family history. Helicobacter pylorus is the most significant agent. Secondary gastroduodenal perforation may be a finding of specific diseases, such as Crohn disease, or more rarely may be associated with diseases such as cystic fibrosis or sickle cell anemia. A 14-year-old boy presented with abdominal and back pain. The patient was operated on for acute abdomen and diagnosed with duodenal perforation. Helicobacter pylorus was negative. There was no risk factor to account for duodenal perforation other than sickle cell anemia. Surgical intervention was successful and without significant sequelae. Duodenal perforation is a rare entity described in patients with sickle cell anemia. To our knowledge, this is the first report of duodenal perforation in a patient sickle cell anemia.
- The Environment of Mycobacterium avium subsp. hominissuis Microaggregates Induces the Synthesis of Small Proteins Associated with Efficient Infection of the Respiratory Epithelial Cells. [JOURNAL ARTICLE]
- Infect Immun 2014 Nov 24.
Mycobacterium avium subsp. hominissuis (MAH) is an opportunistic environmental pathogen that causes respiratory illness in immunocompromised patients such as those with cystic fibrosis as well as other chronic respiratory diseases. Currently, there is no efficient approach to prevent or treat MAH infection in the lungs. During initial colonization of the airways, MAH form microaggregates composed of 3-20 bacteria on human respiratory epithelial cells, which provides an environment for phenotypic changes leading to efficient mucosal invasion in vitro and in vivo. DNA microarray was employed to identify genes associated with the microaggregate phenotype. The gene encoded for MBP-1 (Microaggregate Binding Protein-1, MAV_3013) is highly expressed during microaggregate formation. When expressed in non-invasive Mycobacterium smegmatis, MBP-1 increased the ability of the bacteria to bind to HEp-2 epithelial cells. Using anti-MBP-1 immune serum, microaggregate binding to HEp-2 cells was significantly reduced. By a Far-Western blot, and verified by co-immunoprecipitation, we observed that MBP-1 interacts with the host cytoskeletal protein vimentin. As visualized by confocal microscopy, microaggregates, as well as MBP-1, induced vimentin polymerization at the site of bacteria-host cell contact. Binding of microaggregates to HEp-2 cells was inhibited by treatment with an anti-vimentin antibody, suggesting that MBP-1 expression is important for MAH adherence to the host cell. MBP-1 immune serum significantly inhibited MAH infection throughout the respiratory tract of mice. This study characterizes a pathogenic mechanism utilized by MAH to bind and invade the host respiratory epithelium, suggesting new potential targets for the development of anti-virulence therapy.
- Lobar lung transplantation from deceased donors: a valid option for small-sized patients with cystic fibrosis. [Journal Article]
- Transplant Proc 2014; 46(9):3154-9.
Small-sized patients with cystic fibrosis usually face long waiting times for a suitable lung donor. Reduced-size lung transplantation (LTx) was promoted to shorten waiting times. We compared donor and recipient characteristics and outcome in lobar ([L]) versus full-size ([FS]) lung recipients.Between July 1, 1991, and February 28, 2011, 535 isolated LTx were performed, including 74 in cystic fibrosis patients (8 L, 66 FS). Patients were followed up until September 2012.[L] recipients were younger, smaller, and lighter. Sex, waiting times, and donor data (age, sex, height, weight, PaO2/FiO2, and ventilation time) were comparable. Cardiopulmonary bypass was used more often in [L]; cold ischemia was comparable for first lung but longer in [L] for second lung; implantation times were comparable. In-hospital mortality rate was 0% in [L] versus 3% in [FS]. Both intensive care unit and hospital stay were longer in [L]. Grade 3 primary graft dysfunction was more pronounced in [L] at T0 and at T48. FEV1 increased significantly in both groups from preoperative value. Bronchiolitis obliterans syndrome was absent in [L] and diagnosed in 18 patients in [FS], accounting for 6 of 15 late deaths. All [L] are still alive. No differences in survival were found between the groups.Although hindered by a higher incidence of primary graft dysfunction, L-LTx is a viable option with excellent survival and pulmonary function comparable to FS-LTx.
- Quality of life assessment in two consecutive years of patients in a waiting list for lung transplantation. [Journal Article]
- Transplant Proc 2014; 46(9):3060-3.
Patients on a waiting list for lung transplantation (LT) have physical and emotional setbacks due to limiting symptoms such as dyspnea and cough. Time on a waiting list may worsen the conditions of these patients and affect their quality of life (QoL).Our objective was to evaluate QoL components in patients in 2 consecutive years who were waiting for transplantation.We studied patients who remained on a waiting list for transplantation in the first 2 years after inclusion on the list. Evaluation was performed using the Short-Form-36 (SF-36) Questionnaire and the Saint George's Respiratory Questionnaire (SGRQ).Fifty-six patients were included (38.5 ± 15 years), 33 women (59%) and 23 men (41%). Of these, 18 had bronchiectasis, 14 had cystic fibrosis, 9 had lung fibrosis, 8 had lung emphysema, and 7 had other diseases. The domains with greater involvement in the first and second year were Functional Capacity and Physical Aspects. In the second year there was a significant worsening in Physical Aspects (2.5-0 points; P = .032). The domains related to the emotional component did not have significant changes.The progression of the disease and progressive worsening of symptoms of patients on a transplantation waiting list led to less physical exercise, worsening the effects of inactivity. After 1 year on a waiting list for LT, patients had a significant loss of functionality, which had an impact on QoL.