Int J Mol Sci. 2022 Jul 2;23(13):7384. doi: 10.3390/ijms23137384.

ABSTRACT

Mesenchymal stromal/stem cells and their derivates are the most promising cell source for cell therapies in regenerative medicine. The application of extracellular vesicles (EVs) as cell-free therapeuticals requires particles with a maximum regenerative capability to enhance tissue and organ regeneration. The cargo of mRNA and microRNA (miR) in EVs after hypoxic preconditioning has not been extensively investigated. Therefore, the aim of our study was the characterization of mRNA and the miR loading of EVs. We further investigated the effects of the isolated EVs on renal tubular epithelial cells in vitro. We found 3131 transcripts to be significantly regulated upon hypoxia. Only 15 of these were downregulated, but 3116 were up-regulated. In addition, we found 190 small RNAs, 169 of these were miRs and 21 were piwi-interacting RNAs (piR). However, only 18 of the small RNAs were significantly altered, seven were miRs and 11 were piRs. Interestingly, all seven miRs were down-regulated after hypoxic pretreatment, whereas all 11 piRs were up-regulated. Gene ontology term enrichment and miR-target enrichment analysis of the mRNAs and miR were also performed in order to study the biological background. Finally, the therapeutic effect of EVs on human renal tubular epithelial cells was shown by the increased expression of three anti-inflammatory molecules after incubation with EVs from hypoxic pretreatment. In summary, our study demonstrates the altered mRNA and miR load in EVs after hypoxic preconditioning, and their anti-inflammatory effect on epithelial cells.

PMID:35806391 | DOI:10.3390/ijms23137384

Int J Environ Res Public Health. 2022 Jun 28;19(13):7923. doi: 10.3390/ijerph19137923.

ABSTRACT

BACKGROUND: The aim of this study was to investigate the effects of a monitored exercise program on aerobic fitness in children with cystic fibrosis (CF).

METHODS: Six children (2f/4m) with ages ranging from 6 to 14 years (11.3 ± 3.3 years.) and a mean ppFEV1 102.5 ± 13.5% pred. participated in the partially monitored 12-month exercise program. VO2peak and Wpeak were used as parameters of aerobic fitness. Incremental Cardio-Pulmonary Exercise Tests (CPETs) were performed before the program began (T1), after 6 months (T3) of monitoring, and after a further 6 months (T4) without monitoring. Habitual physical activity (HPA) was assessed with accelerometry.

RESULTS: The values of VO2peak and Wpeak improved slightly from T1 to T3 (p > 0.05), without a further increase after monitoring was stopped (T4). However, the VO2peak and Wpeak values were higher after monitoring was stopped compared to at T1. The exercise program with and without monitoring (p > 0.05) had no or only a slight effect on the FEV1 values, steps/day, and the intensity of HPA.

CONCLUSIONS: Monitoring seems to facilitate the achievement of beneficial effects on physical fitness in CF children. For that reason, continuous individual exercise monitoring programs that involve close contact with an exercise therapist should be provided to maintain long-term motivation and participation in physical activities and sport activities during leisure time.

PMID:35805585 | DOI:10.3390/ijerph19137923

J Cyst Fibros. 2022 Jul 5:S1569-1993(22)00599-9. doi: 10.1016/j.jcf.2022.06.012. Online ahead of print.

ABSTRACT

BACKGROUND: Previous studies have reported differences in aerobic exercise capacity, expressed as peak oxygen uptake (VO2peak), between people with and without cystic fibrosis (CF) related diabetes (CFRD). However, none of the studies controlled for the potential influence of physical activity on VO2peak. We investigated associations between CFRD and VO2peak following rigorous control for confounders including objectively measured physical activity.

METHODS: Baseline data from the international multicenter trial ACTIVATE-CF with participants ≥12 years performing up to 4 h per week of vigorous physical activity were used for this project. Multivariable models were computed to study associations between CFRD and VO2peak (mL.min-1) adjusting for a set of pre-defined covariates: age, sex, weight, forced expiratory volume in 1 s (FEV1), breathing reserve index, Pseudomonas aeruginosa infection, and physical activity (aerobic step counts from pedometry). Variables were selected based on their potential confounding effect on the association between VO2peak and CFRD.

RESULTS: Among 117 randomized individuals, 103 (52% female) had a maximal exercise test and were included in the analysis. Participants with (n = 19) and without (n = 84) CFRD did not differ in FEV1, physical activity, nutritional status, and other clinical characteristics. There were also no differences in VO2peak (mL.min-1 or mL.kg-1.min-1 or% predicted). In the final multivariable model, all pre-defined covariates were significant predictors of VO2peak (mL.min-1), however CFRD [coefficient 82.1, 95% CI -69.5 to 233.8, p = 0.28] was not.

CONCLUSIONS: This study suggests no meaningful differences in VO2peak between people with and without CFRD given comparable levels of physical activity.

PMID:35803884 | DOI:10.1016/j.jcf.2022.06.012

J Cyst Fibros. 2022 Jul 5:S1569-1993(22)00597-5. doi: 10.1016/j.jcf.2022.06.010. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic inflammation and excessive cytokines secretion in the lung. Isogenic human CF bronchial epithelial (CFBE41o-) cell lines stably expressing wt-CFTR (WTBE) or F508del mutant (CFBE) are widely used tools in understanding responses to stimuli or drugs and CF pathogenesis in vitro. However, the intrinsic cellular differences in culture are unknown.

METHODS: We performed integrative analyses of these isogenic cells at the protein, mRNA, and chromatin levels in the submerged and air-liquid interface (ALI) conditions to determine cell intrinsic effects of mutant versus complemented CFTR expression.

RESULTS: CFBE and WTBE cells displayed different cytokine secretion patterns, including IL-6, IL-8, CXCL1, CXCL10, and CCL5. The ALI culture dramatically increased cytokine secretion in both cells. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) result showed different chromatin landscapes upon polarization and CFBE cells, compared to WTBE cells, exhibited higher genome-wide chromatin accessibility under both culture methods. At the transcriptome level, differentially expressed genes identified by mRNA sequencing between two cell lines were highly concentrated in immunity-related pathways.

CONCLUSIONS: This multilayered study shows that expression of wild-type CFTR has an epithelial cell intrinsic effect on the cell's epigenome and transcriptome particularly in immunity relevant activities. These data will serve as a resource for the CF community and may serve as epithelial biomarkers for CFTR mRNA therapy.

PMID:35803883 | DOI:10.1016/j.jcf.2022.06.010

BMJ Open. 2022 Jul 8;12(7):e059186. doi: 10.1136/bmjopen-2021-059186.

ABSTRACT

INTRODUCTION: Non-cystic fibrosis bronchiectasis (NCFB) brought a heavy healthcare burden worldwide. Macrolide maintenance therapy was proved to be helpful in reducing exacerbation of NCFB. However, the optimal dosing regimens of macrolides have not been determined, and its efficacy in Chinese NCFB population has not been validated. This protocol describes a head-to-head clinical trial designed to compare the efficacy of two dosing regimens of azithromycin in Chinese NCFB population.

METHODS AND ANALYSIS: This prospective, open-label and randomised controlled trial will be conducted in the First People's Hospital of Jiashan, China. Eligible patients with high-resolution CT defined NCFB will be randomly divided into three groups, which will receive either 250 mg daily azithromycin, or 500 mg three-times-weekly azithromycin or no treatment for 6 months. They will be followed up for another 6 months without treatment. The primary outcome is the mean rate of protocol-defined pulmonary exacerbation at 6 months.

ETHICS AND DISSEMINATION: Ethical approval was obtained from the First People's Hospital of Jiashan Ethics Committee. The findings will be disseminated in peer-reviewed publications.

TRIAL REGISTRATION NUMBER: ChiCTR2100052906.

PMID:35803624 | DOI:10.1136/bmjopen-2021-059186

J Immunol. 2021 Dec 15;207(12):2901-2912. doi: 10.4049/jimmunol.2100424.

ABSTRACT

The highly complex and variable genotype-phenotype relationships observed in cystic fibrosis (CF) have been an area of growing interest since the discovery of the CF transmembrane conductance regulator (CFTR) gene >30 y ago. The consistently observed excessive, yet ineffective, activation of both the innate and adaptive host immune systems and the establishment of chronic infections within the lung, leading to destruction and functional decline, remain the primary causes of morbidity and mortality in CF. The fact that both inflammation and pathogenic bacteria persist despite the introduction of modulator therapies targeting the defective protein, CFTR, highlights that we still have much to discover regarding mucosal immunity determinants in CF. Gene modifier studies have overwhelmingly implicated immune genes in the pulmonary phenotype of the disease. In this context, we aim to review recent advances in our understanding of the innate and adaptive immune systems in CF lung disease.

PMID:35802761 | DOI:10.4049/jimmunol.2100424

Cochrane Database Syst Rev. 2022 Jul 8;7:CD011808. doi: 10.1002/14651858.CD011808.pub3.

ABSTRACT

BACKGROUND: In people with sickle cell disease, sickled red blood cells cause the occlusion of small blood vessels, which presents as episodes of severe pain known as pain crises or vaso-occlusive crises. The pain can occur in the bones, chest, or other parts of the body, and may last several hours to days. Pain relief during crises includes both pharmacologic and non-pharmacologic treatments. The efficacy of inhaled nitric oxide in pain crises has been a subject of controversy; hypotheses have been made suggesting a beneficial response due to its vasodilator properties, yet no conclusive evidence has been presented. This review aimed to evaluate the available randomised controlled studies addressing this topic.

OBJECTIVES: To capture the body of evidence evaluating the efficacy and safety of the use of inhaled nitric oxide in treating pain crises in people with sickle cell disease, and to assess the relevance, robustness, and validity of the treatment to better guide medical practice in the fields of haematology and palliative care (since the recent literature seems to favour the involvement of palliative care for such people).

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register. We searched for unpublished work in the abstract books of the European Haematology Association conference, the American Society of Hematology conference, the British Society for Haematology Annual Scientific Meeting, the Caribbean Health Research Council Meetings, and the National Sickle Cell Disease Program Annual Meeting. The most recent search was conducted on 1 September 2021. We also searched ongoing study registries on 19 November 2021.

SELECTION CRITERIA: Randomised and quasi-randomised trials comparing inhaled nitric oxide with placebo for treating pain crises in people with sickle cell disease.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data (including adverse event data), with any disagreements resolved by consulting a third review author. When the data were not reported in the text, we attempted to extract the data from available tables or figures. We contacted trial authors for additional information. We assessed the certainty of the evidence using the GRADE criteria.

MAIN RESULTS: We included three trials involving a total of 188 participants in the review. There were equal numbers of males and females. Most participants were adults, although one small trial was conducted in a children's hospital and recruited children over the age of 10 years. All three parallel trials compared inhaled nitric oxygen (80 parts per million (ppm)) to placebo (nitrogen gas mixed with oxygen or room air) for four hours; one trial continued administering nitric oxide (40 ppm) for a further four hours. This extended trial had an overall low risk of bias; however, we had concerns about risk of bias for the remaining two trials due to their small sample size, and additionally a high risk of bias due to financial conflicts of interest in one of these smaller trials. We were only able to analyse some limited data from the eight-hour trial, reporting the remaining results narratively. Evidence from one trial (150 participants) suggested that inhaled nitric oxide may not reduce the time to pain resolution: inhaled nitric oxide median 73.0 hours (95% confidence interval (CI) 46.0 to 91.0) and with placebo median 65.5 hours (95% CI 48.1 to 84.0) (low-certainty evidence). No trial reported on the duration of the initial pain crisis. Only one large trial reported on the frequency of pain crises in the follow-up period and found there may be little or no difference between the inhaled nitric oxide and placebo groups for return to the emergency department (risk ratio (RR) 0.73, 95% CI 0.31 to 1.71) and rehospitalisation (RR 0.53, 95% CI 0.25 to 1.11) (150 participants; low-certainty evidence). There may be little or no difference between treatment and placebo in terms of reduction in pain score at any time point up to eight hours (150 participants). The two smaller trials reported a beneficial effect of inhaled nitric oxide in reducing the visual analogue pain score after four hours of the intervention. Analgesic use was reported not to differ greatly between the inhaled nitric oxide group and placebo group in any of the three trials, but no analysable data were provided. Two trials reported the median duration of hospitalisation: in the largest trial the placebo group had the shorter duration, whilst in the second smaller (paediatric) trial hospitalisation was shorter in the treatment group. Only the largest trial (150 participants) reported serious adverse events, with no increase in the inhaled nitric oxide group during or after the intervention compared to the control group (acute chest syndrome occurred in 5 out of 75 participants from each group, pyrexia in 1 out of 75 participants from each group, and dysphagia and a drop in haemoglobin were each reported in 1 out of 75 participants in the inhaled nitric oxide group) (low-certainty evidence).

AUTHORS' CONCLUSIONS: The currently available evidence is insufficient to determine the effects (benefits or harms) of using inhaled nitric oxide to treat pain (vaso-occlusive) crises in people with sickle cell disease. Large-scale, long-term trials are needed to provide more robust data in this area. Patient-important outcomes (e.g. measures of pain and time to pain resolution and amounts of analgesics used), as well as use of healthcare services, should be measured and reported in a standardised manner.

PMID:35802341 | DOI:10.1002/14651858.CD011808.pub3

Pol Merkur Lekarski. 2022 Jun 24;50(297):190-194.

ABSTRACT

The involvement of commensals and opportunistic pathogens and the role of protective mechanisms in the development of dental diseases in children with cystic fibrosis require more detailed study.

AIM: The aim of the study was to determine the ecological characteristics of the oral microbiota and some antimicrobial factors of saliva in children with mucoviscidosis.

MATERIALS AND METHODS: The study involved an assessment of oral microbiota as complex ecological system that protects the human body from colonization by pathogenic flora in children with cystic fibrosis. Bacteriological studies have been performed on clinical material from 30 children with mucoviscidosis diagnosed with dental and periodontal diseases.

RESULTS: In the microbiological study of plaque microbiota, 70 strains of opportunistic pathogens were isolated in patients with mucoviscidosis. The most significant were alpha-hemolytic Streptococci (40%). The proportion of bacteria of Neisseria genus in patients with cystic fibrosis was lower and amounted to 24.3%. C. albicans fungi were isolated in comparable values (18.5%), S. aureus (8.5%), as well as gram-negative strains of E. aerogenes (4.3%) and E. coli (4.3%) significantly dominated. The results indicate that opportunistic pathogens S. aureus, E. aerogenes and E. coli partially replaced the representatives of the normal oral microbiota alpha-hemolytic streptococci and non-pathogenic species of Neisseria genus in patients with mucoviscidosis.

CONCLUSIONS: Microbiota of plaque in children with mucoviscidosis is characterized by an expansion of the spectrum of opportunistic pathogens due to Staphylococcus aureus, enterobacteria and C. albicans fungi, which indicates a violation of the microbiocenosis due to reduced mucosal immunity. Mucosal immunity of the oral cavity in children with mucoviscidosis is characterized by a 1.5-fold decrease in lysozyme activity and the level of secretory IgA in the saliva of children.

PMID:35801603

Eur Clin Respir J. 2022 Jun 30;9(1):2095104. doi: 10.1080/20018525.2022.2095104. eCollection 2022.

ABSTRACT

PURPOSE: Patients with bronchiectasis (BE) who suffer frequent exacerbations are likely to experience negative effects on quality of life (QoL) and require more healthcare utilization. We aimed to discover, in a cohort of Finnish BE patients, those risk factors that influence QoL.

METHODS: Non-cystic fibrosis BE patients of a Helsinki University Hospital cohort were examined with high-resolution computed tomography (HRCT) of the chest. They completed a disease-specific quality of life-bronchiectasis (QoL-B) questionnaire in Finnish translation. We considered scores in the lowest quarter (25%) of that QoL-B scale to indicate poor QoL. The bronchiectasis severity index (BSI), FACED score, and modified Medical Research Council (mMRC) dyspnoea scale were used.

RESULTS: Overall, of 95 adult BE patients, mean age was 69 (SD ± 13) and 79% were women. From the cohort, 82% presented with chronic sputum production and exacerbations, at a median rate of 1.7 (SD ± 1.6). The number of exacerbations (OR 1.7), frequent exacerbations (≥3 per year) (OR 4.9), high BSI score (OR 1.3), and extensive disease (≥3 lobes) (OR 3.7) were all predictive of poor QoL. Frequent exacerbations were associated with bronchial bacterial colonisation, low forced expiratory volume in 1 s (FEV1), and radiological disease severity. Based on the BSI, 34.1% of our cohort had severe disease, with 11.6% classified as severe according to their FACED score. The mMRC dyspnoea score (r = -0.57) and BSI (r = -0.60) correlated, in the QoL-B questionnaire, negatively with physical domain.

CONCLUSION: The strongest determinants of poor QoL in the cohort of Finnish BE patients were frequent exacerbations, radiological disease severity, and high BSI score. Neither comorbidities nor BE aetiology appeared to affect QoL. Reduced physical capacity correlated with dyspnoea and severe disease.

STUDY REGISTRATION: University of Helsinki, Faculty of Medicine, 148/16.08.2017.

PMID:35800900 | PMC:PMC9255225 | DOI:10.1080/20018525.2022.2095104

Diabetes. 2022 Jul 7:db220399. doi: 10.2337/db22-0399. Online ahead of print.

ABSTRACT

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in CF is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n=16) or GIP (n=16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions with either incretin or placebo infused by randomized, double-blind, cross-over fashion. Another 4 adults with PI-CF and normal glucose tolerance (NGT) and 4 matched non-CF controls underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion, but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in non-CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

PMID:35796669 | DOI:10.2337/db22-0399

Nanoscale. 2022 Jul 7. doi: 10.1039/d2nr01003h. Online ahead of print.

ABSTRACT

Persister cells are responsible for relapses of infections common in cystic fibrosis and chronic suppurative otitis media (CSOM). Yet, there are no Food and Drug Administration (FDA) approved antibiotics to eradicate persister cells. Frustratingly, the global preclinical bacterial pipeline does not contain antibacterial agents targeting persister cells. Therefore, we report a nontraditional antimicrobial chemotherapy strategy based on gold nanoclusters adjuvant to eradicate persister cells by existing antibiotics belonging to that different class. Compared to killing with antibiotics alone, combining antibiotics and AuNC@CPP sterilizes persister cells and biofilms. Enhanced killing of up to 4 orders of magnitude in a validated mouse model of CSOM with Pseudomonas aeruginosa infection was observed when combining antibiotics and AuNC@CPP, informing a potential approach to improve the treatment of CSOM. We established that the mechanism of action of AuNC@CPP is due to disruption of the proton gradient and membrane hyperpolarization. The method presented here could compensate for the lack of new antibiotics to combat persister cells. This method could also benefit the current effort to slow resistance development because AuNC@CPP abolished the emergence of drug-resistant strains induced by antibiotics.

PMID:35796201 | DOI:10.1039/d2nr01003h

J Cyst Fibros. 2022 Jul 3:S1569-1993(22)00596-3. doi: 10.1016/j.jcf.2022.06.009. Online ahead of print.

ABSTRACT

BACKGROUND: Liver disease in Cystic Fibrosis (CFLD) is an early complication of CF. Evidence of CFLD is often subclinical and screening is recommended. Screening includes a biochemical work-up and an ultrasound investigation. Non-invasive methods measuring liver stiffness such as shear wave elastography could be beneficial. This study describes the use of 2D Shear Wave Elastography (2D SWE) in screening for CFLD in a clinical setting and explores its correlation to other indicators of CFLD. Furthermore, a relationship between liver stiffness and nutritional status, lung function and glucose tolerance was explored.

MATERIAL AND METHODS: A retrospective cohort study was performed at a pediatric CF center. Information was gathered from the patients' charts and the Swedish national CF registry. The patients included had been evaluated for the presence of CFLD by ultrasound and 2D SWE during 2018-2020. Demographic data as well as data concerning nutritional status, lung function and glucose tolerance were collected.

RESULTS: Fifty-one subjects were included with a median age of 11 years. Four children who had biopsy confirmed liver cirrhosis had significantly increased liver stiffness. There was a statistically significant negative correlation between liver stiffness and vitamin D levels and FEV1% predicted respectively. Children with abnormal glucose tolerance had increased liver stiffness compared to their normal glucose tolerant counterparts.

CONCLUSION: Measuring liver stiffness by 2D SWE is a reliable addition to CFLD screening with data comparable to the more conventional ultrasound investigation. Increased liver stiffness is associated with lower vitamin D levels, lower FEV1% predicted and abnormal glucose tolerance.

PMID:35794060 | DOI:10.1016/j.jcf.2022.06.009

PLoS One. 2022 Jul 6;17(7):e0269897. doi: 10.1371/journal.pone.0269897. eCollection 2022.

ABSTRACT

BACKGROUND: Non-cystic fibrosis bronchiectasis (NCFB) is a heterogeneous disease, which assessment and severity can't be defined by one particular instrument but using a multidimensional score. Thus, in additional to traditional methods, alternative tools have been developed to assist these patients' evaluation.

OBJECTIVE: To correlate functional and morphological indexes with severity and dyspnea in NCFB patients, focusing on the correlation between the impulse oscillometry system (IOS) and the quantitative analysis of computed tomography (CT).

METHODS: Clinically stable NCFB patients, between 18 and 80 years old were submitted to clinical, functional and morphological evaluations assessed by Bronchiectasis Severity Index (BSI) and Medical Research Council (MRC) scale; spirometry and IOS; and subjective and quantitative Chest CT scans analysis, respectively.

RESULTS: This study included 38 patients. The best correlations obtained between functional and morphological airway indexes were: resistance at 5 Hz-R5 and the normalized thickness of bronchial walls-Pi10 (r = 0.57), and the mean forced expiratory flow (FEF25-75%) and CT score (r = -0.39). BSI as well as MRC showed higher correlations with the quantitative automated analysis of CT (BSI and Pi10: r = 0.41; MRC and Pi10: r = 0.35) than with subjective CT score (BSI and CT score: r = 0.41; MRC and CT score: r = 0.15); and moderate and weak correlations were obtained on both functional airway indexes (BSI and peripheral airways resistance - R5-R20: r = 0.53; BSI and forced expiratory volume at the first second-FEV1: R = -0,64; MRC and R5-R20: r = 0.42; and MRC and VEF1: r = -0.45).

CONCLUSION: In NCFB patients, compartmentalized methods for assessing the respiratory system (IOS and the automated quantitative CT analysis) have a good correlation with severity and dyspnea.

PMID:35793286 | DOI:10.1371/journal.pone.0269897

Curr Opin Pharmacol. 2022 Jul 2;65:102262. doi: 10.1016/j.coph.2022.102262. Online ahead of print.

ABSTRACT

This review guides the reader through the current understanding of the dynamic changes that occur within the cystic fibrosis (CF) lung that allow Pseudomonas aeruginosa to become the dominant pathogen associated with CF. Although recent studies provide some insight, the mechanisms that drive the changing landscape of the lung environment throughout an individual's lifetime that prime P. aeruginosa to take over and establish chronic infection within the lungs, remain poorly understood. We explore how the CF lung environment shapes the ability of P. aeruginosa to persist in spite of intense antimicrobial therapy. We also highlight the pioneering use of a triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, Trikafta, to restore CFTR function and how it influences P. aeruginosa persistence in the CF lung. We utilize existing data for single modulator therapies to extrapolate the potential future of pathogen infection in the era of Trikafta therapy.

PMID:35792519 | DOI:10.1016/j.coph.2022.102262

Indian J Ophthalmol. 2022 Jul;70(7):2641-2643. doi: 10.4103/ijo.IJO_2927_21.

NO ABSTRACT

PMID:35791184 | DOI:10.4103/ijo.IJO_2927_21

Pediatr Pulmonol. 2022 Jul 5. doi: 10.1002/ppul.26063. Online ahead of print.

ABSTRACT

Airway inflammation in cystic fibrosis (CF) involves an early and non-resolving activation of the innate immune system, characterised by neutrophil infiltration, production of serine proteases such as neutrophil elastase (NE), oxidative stress and high levels of pro-inflammatory cytokines, even in the absence of infection1 . This article is protected by copyright. All rights reserved.

PMID:35791043 | DOI:10.1002/ppul.26063

BMC Pulm Med. 2022 Jul 5;22(1):263. doi: 10.1186/s12890-022-02054-3.

ABSTRACT

BACKGROUND: Aspergillus fumigatus is the most common filamentous fungus isolated from the airways of people with cystic fibrosis (CF). The aim of this study was to investigate how chronic A. fumigatus colonization affects lung function in people with CF, to identify risk factors for colonization, and to evaluate antifungal treatment of asymptomatic Aspergillus colonization.

METHODS: Data from 2014-2018 was collected from the Swedish CF registry and medical records. Baseline data before the start of A. fumigatus colonization was compared with the two succeeding years to evaluate how colonization and treatment affected lung function and other clinical aspects.

RESULTS: A total of 437 patients were included, of which 64 (14.6%) became colonized with A. fumigatus during the study period. Inhaled antibiotics was associated with A. fumigatus colonization (adjusted OR 3.1, 95% CI 1.6-5.9, p < 0.05). Fungal colonization was not associated with a more rapid lung function decline or increased use of IV-antibiotics compared to the non-colonized group, but patients with A. fumigatus had more hospital days, a higher increase of total IgE, and higher eosinophil counts. In the Aspergillus group, 42 patients were considered to be asymptomatic. Of these, 19 patients received antifungal treatment. Over the follow up period, the treated group had a more pronounced decrease in percent predicted Forced Expiratory Volume in one second (ppFEV1) compared to untreated patients (- 8.7 vs - 1.4 percentage points, p < 0.05).

CONCLUSION: Inhaled antibiotics was associated with A. fumigatus colonization, but no association was found between persistent A. fumigatus and subsequent lung function decline. No obvious benefits of treating asymptomatic A. fumigatus colonization were demonstrated.

PMID:35790954 | DOI:10.1186/s12890-022-02054-3

Psychol Res Behav Manag. 2022 Jun 28;15:1601-1605. doi: 10.2147/PRBM.S322425. eCollection 2022.

ABSTRACT

OBJECTIVE: This exploratory study examines the prevalence of adverse childhood experiences (ACEs) in adults with cystic fibrosis (CF).

DESIGN: Childhood exposure to 16 ACEs was measured during an annual review assessment (N = 80).

METHODS: CF patients (n = 80) attending the All Wales Adult CF Service for a routine annual review assessment completed an adapted version of the Centers for Disease Control and Prevention (CDC) short-form ACE questionnaire alongside measures of psychological well-being.

RESULTS: In this sample, 65 (78%) reported at least one type of childhood adversity and 11 (14%) experienced four or more ACEs. Parental divorce or separation and verbal abuse were the most frequently reported ACEs. Illness related trauma in childhood was also prevalent with 52 (64%) reporting having experienced a painful or frightening medical procedure and 23 (28%) feeling forced to have treatment or a procedure.

CONCLUSION: Individuals with CF reported a number of childhood traumas including trauma relating to medical procedures. Those with a history of ACEs may have increased risks of emotional and physical difficulties and may benefit from additional support from the CF psychosocial team.

PMID:35789731 | PMC:PMC9250325 | DOI:10.2147/PRBM.S322425

BMJ Case Rep. 2022 Jul 4;15(7):e250643. doi: 10.1136/bcr-2022-250643.

ABSTRACT

A man in his 50s was admitted with 4 months of myalgia, headaches, hypercalcaemia and declining renal function on a background of lung transplantation for cystic fibrosis 5 years prior. MRI confirmed myositis and a muscle biopsy revealed invasive muscular microsporidial infection. Positron emission tomography(PET)/CT revealed widespread dissemination of the infection. Albendazole was commenced and after a 1 week systemic inflammatory response syndrome, the patient made a significant recovery and was discharged home. PCR testing confirmed the species as Anncaliia algerae, which is known to infect mosquitoes, larvae and contaminate water supplies. This case highlights the need to relentlessly pursue a diagnosis and to consider atypical pathology in immune compromised patients. A tissue sample yielded highly beneficial and unexpected results. A multispecialty approach was essential given the varied infection manifestations, which included myositis, keratitis and possible central nervous system, vocal cord, parapharyngeal and renal involvement.

PMID:35787491 | DOI:10.1136/bcr-2022-250643

Biomed Pharmacother. 2022 Jul 1;153:113373. doi: 10.1016/j.biopha.2022.113373. Online ahead of print.

ABSTRACT

Anoctamin 1 (ANO1) is a calcium-activated chloride channel found in various cell types and is overexpressed in non-small cell lung cancer (NSCLC), a major cause of cancer-related mortality. With the rising interest in development of druggable compounds for NSCLC, there has been a corresponding rise in interest in ANO1, a novel drug target for NSCLC. However, as ANO1 inhibitors that have been discovered simultaneously exhibit both the functions of an inhibition of ANO1 channel as well as a reduction of ANO1 protein levels, it is unclear which of the two functions directly causes the anticancer effect. In this study, verteporfin, a chemical compound that reduces ANO1 protein levels was identified through high-throughput screening. Verteporfin did not inhibit ANO1-induced chloride secretion but reduced ANO1 protein levels in a dose-dependent manner with an IC50 value of ~300 nM. Moreover, verteporfin inhibited neither P2Y receptor-induced intracellular Ca2+ mobilization nor cystic fibrosis transmembrane conductance regulator (CFTR) channel activity, and molecular docking studies revealed that verteporfin bound to specific sites of ANO1 protein. Confirming that verteporfin reduces ANO1 protein levels, we then investigated the molecular mechanisms involved in its effect on NSCLC cells. Interestingly, verteporfin decreased ANO1 protein levels, the EGFR-STAT3 pathway as well as ANO1 mRNA expression. Verteporfin reduced the viability of ANO1-expressing cells (PC9, and gefitinib-resistant PC9) and induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage. However, it did not affect hERG channel activity. These results show that the anticancer mechanism of verteporfin is caused via the down-regulation of ANO1.

PMID:35785700 | DOI:10.1016/j.biopha.2022.113373