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Cystic fibrosis [keywords]
- Stoichiometry and novel gating mechanism within the cystic fibrosis transmembrane conductance regulator (CFTR) channel. [JOURNAL ARTICLE]
- Exp Physiol 2014 Oct 16.
Despite its fundamental importance to the molecular mechanism underlying the disease of cystic fibrosis (CF), many details of the structural basis for the cystic fibrosis transmembrane conductance regulator (CFTR) remain unknown. In addition, the possible interactions among the CFTR proteins have not been clearly demonstrated. To identify whether the CFTR channel pore is formed as monomer or multimer, we analyzed the single-channel properties in patches of cell membrane that co-expressed selected CFTR mutants having significantly different single-channel properties. No hybrid channel opening patterns were observed. We therefore propose that the CFTR channel pore is indeed composed of a monomer. However, we also observed that co-existing CFTR monomers in the cell membrane facilitated the activation of individual CFTR channels. The functional upregulation of this CFTR channel opening probability and the different gating behavior suggest dynamic conformational changes among the interacting CFTR proteins within the multimeric CFTR complex. Our findings regarding: (ⅰ) the CFTR monomer channel pore and (ⅱ) the novel synergistic gating behavior within the CFTR channel complex will help to resolve remaining contradictions among previous studies regarding whether CFTR is a monomer or a multimer. This article is protected by copyright. All rights reserved.
- Complications of Intralesional Bleomycin in the Treatment of Orbital Lymphatic Malformations. [JOURNAL ARTICLE]
- Semin Ophthalmol 2014 Nov; 29(5-6):450-455.
Abstract Purpose: Lymphatic malformations (LM) are associated with significant morbidity, and in the orbit, can lead to vision loss. Treatment of these lesions is complicated by their infiltrative nature, making surgical excision challenging. Bleomycin has been used since the 1970s for sclerosis of LM to reduce the need for or improve the success of surgical excision. This paper reviews the complications associated with intralesional bleomycin in the treatment of orbital LM. Methods: A comprehensive literature search was performed on PubMed. Thirty full-length English articles were reviewed. Results: The pathophysiology and imaging characteristic of LM were first reviewed. The head and neck literature was heavily cited given the dearth of specific orbital data. This review highlights the common techniques and dosages for injection, the overall success rate of this treatment, and its common side effects. The orbital data were then reviewed, and differentiated from the head and neck literature. Conclusion: Sclerotherapy of most LM with bleomycin appears to be safe and effective, but the lack of specific orbital data means we must extrapolate LM data from other fields to orbital LM with caution. Additional research is warranted, though the risk-benefit ratio remains unknown.
- The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis. [REVIEW]
- Nat Chem Biol 2014 Nov; 10(11):902-910.
Proteins that traffic through the eukaryotic secretory pathway are commonly modified with N-linked carbohydrates. These bulky amphipathic modifications at asparagines intrinsically enhance solubility and folding energetics through carbohydrate-protein interactions. N-linked glycans can also extrinsically enhance glycoprotein folding by using the glycoprotein homeostasis or 'glycoproteostasis' network, which comprises numerous glycan binding and/or modification enzymes or proteins that synthesize, transfer, sculpt and use N-linked glycans to direct folding and trafficking versus degradation and trafficking of nascent N-glycoproteins through the cellular secretory pathway. If protein maturation is perturbed by misfolding, aggregation or both, stress pathways are often activated that result in transcriptional remodeling of the secretory pathway in an attempt to alleviate the insult (or insults). The inability to achieve glycoproteostasis is linked to several pathologies, including amyloidoses, cystic fibrosis and lysosomal storage diseases. Recent progress on genetic and pharmacologic adaptation of the glycoproteostasis network provides hope that drugs of this mechanistic class can be developed for these maladies in the near future.
- Characterization by phenotypic and genotypic methods of metallo-β‑lactamase‑producing Pseudomonas aeruginosa isolated from patients with cystic fibrosis. [JOURNAL ARTICLE]
- Mol Med Rep 2014 Oct 16.
Pseudomonas aeruginosa continues to be a predominant cause of infections with high intrinsic resistance to antibiotics, resulting in treatment failure. P. aeruginosa is the leading cause of respiratory infections among cystic fibrosis (CF) patients. Resistance to carbapenem antibiotics among P. aeruginosa has been reported. Thus, this study was undertaken to characterize the metallo‑β‑lactamase (MBL) production of P. aeruginosa by phenotypic and genotypic methods. A total of 572 sputum samples were collected from cystic fibrosis patients along with the patient demographic details in a questionnaire. In total, 217 P. aeruginosa isolates were collected and an antibiogram revealed that 159 (73.3%) and 141 (64.9%) of these colonies exhibited resistance to imipenem and meropenem, respectively. Ceftazidime and tobramycin resistance were both identified in 112 (51.6%) isolates, and resistance to piperacillin‑tazobactam, gatifloxacin and netilmicin was detected in 96 (44.2%) respective samples. A total of 62 (28.6%) respective samples were resistant to cefoperazone, cefepime and ceftriaxone. The least antibiotic resistance was shown to amikacin and ceftizoxime with 51 (23.5%) and 32 (14.7%) respective colonies resistant to the antibiotics. The minimum inhibitory concentration (MIC) for imipenem revealed a reduction in the MIC values. MBL screening by the zone enhancement method using ceftazidime plus EDTA discs demonstrated that 63 (56.25%) of the colonies were positive for MBL. A total of 53 (84.1%) samples expressed blaVIM and 48 (76.1%) expressed blaIMP genes, as detected by duplex polymerase chain reaction. In conclusion, carbapenem resistance is of great clinical concern in cystic fibrosis patients with P. aeruginosa infection. Therefore, mandatory regular screening and monitoring the resistance in P. aeruginosa among CF patients is required.
- Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores. [JOURNAL ARTICLE]
- Thorax 2014 Oct 16.
The Quality of Life-Bronchiectasis (QOL-B), a self-administered, patient-reported outcome measure assessing symptoms, functioning and health-related quality of life for patients with non-cystic fibrosis (CF) bronchiectasis, contains 37 items on 8 scales (Respiratory Symptoms, Physical, Role, Emotional and Social Functioning, Vitality, Health Perceptions and Treatment Burden).Psychometric analyses of QOL-B V.3.0 used data from two double-blind, multicentre, randomised, placebo-controlled, phase III trials of aztreonam for inhalation solution (AZLI) in 542 patients with non-CF bronchiectasis and Gram-negative endobronchial infection.Excellent internal consistency (Cronbach's α ≥0.70) and 2-week test-retest reliability (intraclass correlation coefficients ≥0.72) were demonstrated for each scale. Convergent validity with 6 min walk test was observed for Physical and Role Functioning scores. No floor or ceiling effects (baseline scores of 0 or 100) were found for the Respiratory Symptoms scale (primary endpoint of trials). Baseline Respiratory Symptoms scores discriminated between patients based on baseline FEV1% predicted in only one trial. The minimal important difference score for the Respiratory Symptoms scale was 8.0 points. AZLI did not show efficacy in the two phase III trials. QOL-B responsivity to treatment was assessed by examining changes from baseline QOL-B scores at study visits at which protocol-defined pulmonary exacerbations were reported. Mean Respiratory Symptoms scores decreased 14.0 and 14.2 points from baseline for placebo-treated and AZLI-treated patients with exacerbations, indicating that worsening respiratory symptoms were reflected in clinically meaningful changes in QOL-B scores.Previously established content validity, reliability and responsivity of the QOL-B are confirmed by this final validation study. The QOL-B is available for use in clinical trials and routine clinical practice.
- Inhaled antibiotics: dry or wet? [REVIEW]
- Eur Respir J 2014 Oct 16.
Dry powder inhalers (DPIs) delivering antibiotics for the suppressive treatment of Pseudomonas aeruginosa in cystic fibrosis patients were developed recently and are now increasingly replacing time-consuming nebuliser therapy. Noninferiority studies have shown that the efficacy of inhaled tobramycin delivered by DPI was similar to that of wet nebulisation. However, there are many differences between inhaled antibiotic therapy delivered by DPI and by nebuliser. The question is whether and to what extent inhalation technique and other patient-related factors affect the efficacy of antibiotics delivered by DPI compared with nebulisers. Health professionals should be aware of the differences between dry and wet aerosols, and of patient-related factors that can influence efficacy, in order to personalise treatment, to give appropriate instructions to patients and to better understand the response to the treatment after switching. In this review, key issues of aerosol therapy are discussed in relation to inhaled antibiotic therapy with the aim of optimising the use of both nebulised and DPI antibiotics by patients. An example of these issues is the relationship between airway generation, structural lung changes and local concentrations of the inhaled antibiotics. The pros and cons of dry and wet modes of delivery for inhaled antibiotics are discussed.
- Nasal nitric oxide screening for primary ciliary dyskinesia: systematic review and meta-analysis. [JOURNAL ARTICLE]
- Eur Respir J 2014 Oct 16.
Nasal nitric oxide (nNO) concentrations are low in patients with primary ciliary dyskinesia (PCD) providing a noninvasive screening test. We conducted a systematic review of the literature to examine the utility of nNO in screening for PCD, in particular 1) different respiratory manoeuvres during sampling (velum closure, tidal breathing, etc.), 2) accuracy in screening young/uncooperative children, 3) stationary versus portable analysers, and 4) nNO in "atypical" PCD. 96 papers were assessed according to modified PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and 22 were included in this review. Meta-analysis of 11 studies comparing nNO during a velum closure breath hold gave a mean±sd nNO of 19.4±18.6 nL·min(-1) in PCD (n = 478) and 265.0±118.9 nL·min(-1) in healthy controls (n = 338). Weighted mean difference for PCD versus healthy controls was 231.1 nL·min(-1) (95% CI 193.3-268.9; n = 338) and 114.1 nL·min(-1) (95% CI 101.5-126.8; n = 415) for PCD versus cystic fibrosis. Five studies of nNO measurement during tidal breathing demonstrated that this is an acceptable manoeuvre in young children where velum closure is not possible, but the discriminatory value was reduced. Four small studies of portable NO analysers suggest these are reliable tools for screening for PCD. However, nNO must be interpreted alongside clinical suspicion. Future studies should focus on standardising sampling techniques and reporting.
- [Practical guideline for the use of colistin.] [JOURNAL ARTICLE]
- Ned Tijdschr Geneeskd 2014; 158(0):A7445.
- Colistin (polymyxin E) binds to the cell wall of gram-negative bacteria, leading to osmotic destruction of the cell.- Since its introduction in 1959, colistin has been little used parenterally due to a high incidence of reversible nephrotoxicity and, to a lesser extent, neurotoxicity.- Colistin use remained limited to combating Pseudomonas aeruginosa in cystic fibrosis patients. In addition, oral colistin is part of the recently introduced regime of selective digestive tract decontamination in ICU patients.- Intravenous administration of colistin is now increasingly prescribed for the control of multi-resistant microorganisms. Colistin monotherapy, however, rapidly selects resistant subpopulations. Therefore, only combination therapy is advised. - The prodrug colistimethate sodium is less toxic and is hydrolyzed in vivo to active colistin; colistin is renally cleared.- Clinical practice remains hampered by lack of uniformity and standardization of names, dosage units, dosing recommendations and methods of concentration and susceptibility testing.
- Early Respiratory Infection is Associated with Reduced Spirometry in Children with Cystic Fibrosis. [JOURNAL ARTICLE]
- Am J Respir Crit Care Med 2014 Oct 16.
Rationale: Pulmonary inflammation, infection and structural lung disease occur early in life in children with cystic fibrosis. Objectives: We hypothesised that the presence of these markers of cystic fibrosis lung disease in the first two years of life would be associated with reduced lung function in childhood. Methods: Lung function (FEV0.75, FVC) was assessed in individuals with cystic fibrosis diagnosed following newborn screening and healthy subjects during infancy (0 - 2 years) and again at early school-age (4 - 8 years). Individuals with cystic fibrosis had annual bronchoalveolar lavage fluid, and chest computed tomography. We examined which clinical outcomes (pulmonary inflammation, infection, structural lung disease, respiratory hospitalisations, antibiotic prophylaxis) measured in the first two years of life were associated with reduced lung function in infants and young children with cystic fibrosis using a mixed effects model. Measurements and Main Results: Children with cystic fibrosis (n=56) had 8.3% (95% confidence interval (CI) -15•9, -6•6; p = 0•04) lower FEV0.75 compared with healthy subjects (n=18). Detection of pro-inflammatory bacterial pathogens (Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Aspergillus species, Streptococcus pneumoniae) in BAL fluid was associated with clinically significant reductions in FEV0.75 (ranging between 11.3% and 15.6%). Conclusions: The onset of lung disease in infancy, specifically the occurrence of lower respiratory tract infection is associated with low lung function in young children with cystic fibrosis. Deficits in lung function measured in infancy persist into childhood emphasising the need for targeted therapeutic interventions in infancy to maximise functional outcomes later in life.
- Characterization of N-Acyl-homoserine Lactones (AHLs)-Deficient Clinical Isolates of Pseudomonas aeruginosa. [Journal Article]
- Indian J Microbiol 2014 Jun; 54(2):158-62.
Pseudomonas aeruginosa is an opportunistic pathogen causing severe respiratory infections. Acylated homoserine lactones (AHLs) are self-generated diffusible signal molecules that mediate population density dependent gene expression (quorum sensing, QS) in a variety of Gram-negative bacteria, and several virulence genes of bacterial pathogens are known to be controlled by QS. Hence, fitness mutant of virulent factors is beneficial for natural selection. In this study, strains of P. aeruginosa isolated from chronic lung infection of cystic fibrosis patients, were screened for AHLs production by using indicator strains of Chromobacterium violaceum CV026 and Agrobacterium tumefaciens strain At136. Four AHLs defective strains were selected from fifty-three clinical isolates. PCR analysis revealed that only one isolate was negative for lasR gene. These four AHLs defective isolates produced less virulence factors and forming less biofilm than PAO1. Only isolate PA41 produce little more pyocyanin than PAO1. The results indicate that, despite the pivotal role of QS in the pathogenesis of P. aeruginosa infections, AHLs-deficient strains are still capable of causing infections in human.