Airway profile of bioactive lipids predicts early progression of lung disease in cystic fibrosis.

J Cyst Fibros. 2020 Feb 10;:

Authors: Horati H, Janssens HM, Margaroli C, Veltman M, Stolarczyk M, Kilgore MB, Chou J, Peng L, Tiddens HAMW, Chandler JD, Tirouvanziam R, Scholte BJ

Abstract
BACKGROUND: Previously, we showed that abnormal levels of bioactive lipids in bronchoalveolar lavage fluid (BALF) from infants with cystic fibrosis (CF) correlated with early structural lung damage.
METHOD: To extend these studies, BALF bioactive lipid measurement by mass spectrometry and chest computed tomography (CT, combined with the sensitive PRAGMA-CF scoring method) were performed longitudinally at 2-year intervals in a new cohort of CF children (n = 21, aged 1-5 yrs).
RESULTS: PRAGMA-CF, neutrophil elastase activity, and myeloperoxidase correlated with BALF lysolipids and isoprostanes, markers of oxidative stress, as well as prostaglandin E2 and combined ceramide precursors (Spearman's Rho > 0.5; P < 0.01 for all). Multiple protein agonists of inflammation and tissue remodeling, measured by Olink protein array, correlated positively (r = 0.44-0.79, p < 0.05) with PRAGMA-CF scores and bioactive lipid levels. Notably, levels of lysolipids, prostaglandin E2 and isoprostanes at first BALF predicted the evolution of PRAGMA-CF scores 2 years later. In wild-type differentiated primary bronchial epithelial cells, and in CFTR-inducible iCFBE cells, treatment with a lysolipid receptor agonist (VPC3114) enhanced shedding of pro-inflammatory and pro-fibrotic proteins.
CONCLUSIONS: Together, our findings suggest that bioactive lipids in BALF correlate with and possibly predict structural lung disease in CF children, which supports their use as biomarkers of disease progression and treatment efficacy. Furthermore, our data suggest a causative role of airway lysolipids and oxidative stress in the progression of early CF lung disease, unveiling potential therapeutic targets.

PMID: 32057679 [PubMed - as supplied by publisher]

Evaluation of increased arterial stiffness in pediatric patients with cystic fibrosis by augmentation index and pulse wave velocity analysis.

Pediatr Pulmonol. 2020 Feb 14;:

Authors: Kartal Öztürk G, Conkar S, Eşki A, Gülen F, Keskinoğlu A, Demir E

Abstract
With the increase in life expectancy, cardiovascular complications of cystic fibrosis (CF) have come to the forefront. Increased arterial stiffness is a marker of increased cardiovascular risk. The aim of this study was to compare both pulse wave velocity (PWV) and augmentation index (Aix) measurements in children with CF and to compare them with healthy controls. We hypothesized that children with CF had increased arterial stiffness, although traditional risk factors for CVD were not observed. Forty-four patients and age and sex-matched 30 healthy controls were included in the study. Hemodynamic measurements were compared in both groups, together with traditional risk factors. Peripheral blood pressure parameters of CF and control groups were similar (P > .05). Bodyweight and BMI were significantly lower in the CF group (P < .001). Serum cholesterol, HDL, and LDL levels were significantly lower in the CF group, whereas fasting blood glucose and triglyceride levels were significantly higher than the control group (P < .05). Mean ± SD Aix was significantly higher in the CF group (33.22 ± 13.87%) compared with the control group (24.93 ± 10.58%), respectively (P < .05), while PWV was similar. No significant correlation between PWV and Aix and fasting blood glucose and lipid profile in both groups (P > .05). Children with CF have been shown to have increased arterial stiffness compared to healthy children. Although there are not many traditional risk factors, increased arterial stiffness have been demonstrated in children with CF. The effects of this process starting from childhood on the development of CVD in adulthood are not known. Therefore, further studies are needed.

PMID: 32057197 [PubMed - as supplied by publisher]

Respiratory viral infections in Western Australians with cystic fibrosis.

Respir Med. 2020 Jan;161:105854

Authors: Brestovac B, Lawrence C, Speers DJ, Sammels LM, Mulrennan S

Abstract
BACKGROUND: Viral respiratory infections (VRI) in people living with Cystic fibrosis (CF) is less well understood than respiratory bacterial infections, particularly adults with CF and few studies have compared children with adults. This study evaluated the frequency of respiratory viruses in patients with cystic fibrosis (CF) in Western Australia (WA). We determined the VRI in CF and compared them with non-CF patients. Further, we compared CF patients that were hospitalised with those that were not.
PATIENTS/METHODS: Nucleic acid from sputum of 157 CF and 348 non-CF patients was analysed for influenzavirus A (Flu A) and B, (Flu B), respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human rhinovirus (RV), and parainfluenza viruses (PIV 1-3) by RT-PCR, during the 2016 winter respiratory season.
RESULTS: No significant difference in the frequency of respiratory virus detection between CF and non-CF patients was found. RV was the most frequently detected virus in CF patients, and in hospitalised CF. RSV and hMPV were found less frequently in CF patients and RSV was not found in any hospitalised CF patient. A trend for fewer influenzavirus detections in adult CF patients was observed, however the trend was opposite for paediatric patients. RV and Flu A were the most common viruses detected in hospitalised CF patients.
CONCLUSION: There was no significant difference in VRI between CF and non-CF patients. RV and influenza A were most commonly found in hospitalised CF patients, suggesting that infection with these viruses may contribute to hospitalisation for CF respiratory exacerbations.

PMID: 32056728 [PubMed - in process]

The year's new drugs and biologics 2019.

Drugs Today (Barc). 2020 Jan;56(1):47-103

Authors: Graul AI, Pina P, Tracy M, Sorbera L

Abstract
Highlights of our annual review of new approvals and launches on global drug markets include the approval and launch of Trikafta, the most widely applicable treatment to date for cystic fibrosis; approval of the first Ebola vaccine for general (rather than emergency) use; the pilot rollout in three African countries of the world's first malaria vaccine; approval of a new treatment option for multidrug-resistant bacterial infections; and the approval and launch in China of the first new drug to treat Alzheimer's disease in more than a decade. Several new immune checkpoint inhibitors and antibody-drug conjugates were approved for cancer indications, confirming continued industry enthusiasm for cancer immunotherapy. The most notable trend of 2019 was the granting by the Food and Drug Administration (FDA) of a record number of accelerated approvals, many of which were issued several months ahead of the expected action date.

PMID: 32055805 [PubMed - in process]

Effect of short-term inhalation of warm saline atomised gas on patients with non-cystic fibrosis bronchiectasis.

ERJ Open Res. 2020 Jan;6(1):

Authors: Zhong L, Xiong Y, Zheng Z, Liu N, Hu J, Yang F, Chen R

Abstract
Objective: Secretion clearance is advocated in non-cystic fibrosis bronchiectasis, but is often neglected in clinical treatment. The present study aimed to investigate the effect of inhaled 0.9% normal saline by ultrasonic nebuliser with warming (UNW) in stable non-cystic fibrosis bronchiectasis patients with purulent sputum.
Methods: 27 stable patients were enrolled in a randomised crossover trial comprising 3 months of daily UNW aerosol therapy compared with 3 months of daily oral expectorant treatment. The outcomes were quality of life (assessed via the Leicester cough questionnaire (LCQ)), sputum characteristics, pulmonary function, 6-min walk distance (6MWD) and acute exacerbation frequency.
Results: Compared with baseline, the sputum viscosity, sputum colour, LCQ score and 6MWD were significantly improved with UNW (p<0.05), and the improvements in sputum colour, LCQ score, 6MWD and inspirational capacity with UNW were significantly better than those achieved via treatment with oral expectorant (p<0.05). There were no significant differences between treatments in pulmonary function, sputum cytology classification and inflammatory factors of sputum.
Conclusion: UNW aerosol therapy in non-cystic fibrosis bronchiectasis has small yet significant benefits. However, UNW does not improve the degree of inflammation.

PMID: 32055629 [PubMed]

Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs.

Chem Sci. 2019 Nov 14;10(42):9663-9672

Authors: Li H, Valkenier H, Thorne AG, Dias CM, Cooper JA, Kieffer M, Busschaert N, Gale PA, Sheppard DN, Davis AP

Abstract
Defective anion transport is a hallmark of the genetic disease cystic fibrosis (CF). One approach to restore anion transport to CF cells utilises alternative pathways for transmembrane anion transport, including artificial anion carriers (anionophores). Here, we screened 22 anionophores for biological activity using fluorescence emission from the halide-sensitive yellow fluorescent protein. Three compounds possessed anion transport activity similar to or greater than that of a bis-(p-nitrophenyl)ureidodecalin previously shown to have promising biological activity. Anion transport by these anionophores was concentration-dependent and persistent. All four anionophores mediated anion transport in CF cells, and their activity was additive to rescue of the predominant disease-causing variant F508del-CFTR using the clinically-licensed drugs lumacaftor and ivacaftor. Toxicity was variable but minimal at the lower end. The results provide further evidence that anionophores, by themselves or together with other treatments that restore anion transport, offer a potential therapeutic strategy for CF.

PMID: 32055336 [PubMed]

HMGB1 is increased in adolescents with polycystic ovary syndrome (PCOS) and decreases after treatment with myo-inositol (MYO) in combination with alpha-lipoic acid (ALA).

Gynecol Endocrinol. 2020 Feb 13;:1-6

Authors: Cirillo F, Catellani C, Lazzeroni P, Sartori C, Tridenti G, Vezzani C, Fulghesu AM, Madeddu E, Amarri S, Street ME

Abstract
PCOS treatment should be based on pathophysiology. High-mobility-group-box-1 (HMGB1) was shown to increase in PCOS patients as a consequence of reduced cystic-fibrosis-transmembrane-conductance-regulator (CFTR) expression in the ovary, and was associated with insulin resistance and inflammation, both features of PCOS. Inositols and ALA derivatives could have positive effects on insulin sensitivity, reduce androgens, and improve ovulation rhythm. The aim of this study was to verify changes in HMGB1, in metabolic and endocrine parameters in adolescents with PCOS compared with controls and after treatment with a combination of MYO + ALA. Twenty-three PCOS adolescents and 21 controls matched for age and BMI were enrolled. In all subjects, metabolic and hormonal parameters were assayed. Homeostatic index (HOMA-IR) and the triglyceride/HDL-cholesterol ratio were calculated. Ovarian volumes were evaluated. Patients were treated with MYO + ALA for 6 months. HMGB1 was measured using a specific ELISA assay. HMGB1 was increased in PCOS compared with controls (19.76 ± 5.99 versus 5.65 ± 1.88 ng/ml; p < .05) and normalized after treatment (2.27 ± 0.36 ng/ml, p < .05). Treatment significantly reduced insulin (24.0 ± 4.11 versus 12.13 ± 2.13 uU/ml), HOMA-IR (3.91 ± 0.41 versus 2.42 ± 0.45), and 17-hydroxyprogesterone (1.20 ± 0.15 versus 0.78 ± 0.11 ng/ml). Cholesterol, luteinizing hormone, 17-β-estradiol, delta 4-androstenedione, and testosterone were unchanged. Circulating HMGB1 was increased in PCOS adolescents, and treatment was effective in normalizing HMGB1.

PMID: 32054355 [PubMed - as supplied by publisher]

Triple Therapy for Cystic Fibrosis with a Phe508del CFTR Mutation. Reply.

N Engl J Med. 2020 Feb 13;382(7):684

Authors: Jain R, Middleton PG, Rowe SM

PMID: 32053311 [PubMed - in process]

Triple Therapy for Cystic Fibrosis with a Phe508del CFTR Mutation.

N Engl J Med. 2020 Feb 13;382(7):

Authors: McGarry ME

PMID: 32053310 [PubMed - in process]

Making the invisible visible: the availability and desirability of adherence data in routine CF care- findings from a national questionnaire survey.

F1000Res. 2019;8:1904

Authors: Robinson L, Maguire C, Hoo ZH, Wildman MJ

Abstract
Background: Inhaled medications for cystic fibrosis (CF) are effective but adherence is low. Clinicians find it difficult to estimate how much treatment people with CF (PWCF) take, whilst objective adherence measurement demonstrates that patients are poorly calibrated with a tendency to over-estimate actual adherence. The diagnostic approach to a PWCF with deteriorating clinical status and very low adherence is likely to be different to the approach to a deteriorating patient with optimal adherence. Access to objective adherence data in routine consultations could help to overcome diagnostic challenges for clinicians and people with CF. Attitudes of clinicians to the use and importance of routinely available adherence data is unknown. Methods: We conducted an online questionnaire survey with UK CF centres. We asked five questions relating to the current use and perception of objective measurements of adherence in routine care. Results: A total of eight CF centres completed the questionnaire. Few of the responding centres have adherence data readily available in routine clinics (13% of centres use medicines possession ratio; of centres with access to I-nebs® it was estimated that 17% of patients had I-neb data regularly available in clinics). All centres considered the availability of objectively measured adherence data to be important. Respondents identified that systems developed to provide adherence data in clinical practice must provide data to both clinicians and patients that is readily understood and easy to use. Conclusions: Centres perceived the availability of adherence data in routine care to be important but objective measures of adherence is rarely available at present.

PMID: 32051757 [PubMed - in process]

Discovery of a novel chalcone derivative inhibiting CFTR chloride channel via AMPK activation and its anti-diarrheal application.

J Pharmacol Sci. 2019 Jul;140(3):273-283

Authors: Yibcharoenporn C, Chusuth P, Jakakul C, Rungrotmongkol T, Chavasiri W, Muanprasat C

Abstract
Secretory diarrhea is one of the most common causes of death world-wide especially in children under 5 years old. Isoliquiritigenin (ISLQ), a plant-derived chalcone, has previously been shown to exert anti-secretory action in vitro and in vivo by inhibiting CFTR Cl- channels. However, its CFTR inhibition potency is considerably low (IC50 > 10 μM) with unknown mechanism of action. This study aimed to identify novel chalcone derivatives with improved potency and explore their mechanism of action. Screening of 27 chalcone derivatives identified CHAL-025 as the most potent chalcone analog that reversibly inhibited CFTR-mediated Cl- secretion in T84 cells with an IC50 of ∼1.5 μM. As analyzed by electrophysiological and biochemical analyses, the mechanism of CFTR inhibition by CHAL-025 is through AMP-activated protein kinase (AMPK), a negative regulator of CFTR activity. Furthermore, Western blot analyses and molecular dynamics (MD) results suggest that CHAL-025 activates AMPK by binding at the allosteric site of an upstream kinase calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ). Interestingly, CHAL-025 inhibited both cholera toxin (CT) and bile acid-induced Cl- secretion in T84 cells and prevented CT-induced intestinal fluid secretion in mice. Therefore, CHAL-025 represents a promising anti-diarrheal agent that inhibits CFTR Cl- channel activity via CaMKKβ-AMPK pathways.

PMID: 31444000 [PubMed - indexed for MEDLINE]

Does Circadian Rhythm affect the Pharmacokinetics of Once-Daily Tobramycin in Adults with Cystic Fibrosis?

Ther Drug Monit. 2020 Feb 11;:

Authors: van Maarseveen EM, van der Meer R, Neef C, Heijerman HGM, Touw DJ

Abstract
BACKGROUND: In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated.
METHODS: In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 h. Pharmacokinetic and kidney function parameters were compared between the two groups.
RESULTS: Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 vs. 1.43 mL/h*kg (p=0.50) and mean volumes of distribution were 0.25 vs. 0.27 L/kg (p=0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 vs. 0.2 mmol/L, p=0.015).
CONCLUSIONS: The time of administration (8:00 vs 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

PMID: 32049889 [PubMed - as supplied by publisher]

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases.

Drug Dev Res. 2020 Feb 12;:

Authors: Chellappan DK, Yee LW, Xuan KY, Kunalan K, Rou LC, Jean LS, Ying LY, Wie LX, Chellian J, Mehta M, Satija S, Singh SK, Gulati M, Dureja H, Da Silva MW, Tambuwala MM, Gupta G, Paudel KR, Wadhwa R, Hansbro PM, Dua K

Abstract
Neutrophils are essential effector cells of immune system for clearing the extracellular pathogens during inflammation and immune reactions. Neutrophils play a major role in chronic respiratory diseases. In respiratory diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, lung cancer and others, there occurs extreme infiltration and activation of neutrophils followed by a cascade of events like oxidative stress and dysregulated cellular proteins that eventually result in apoptosis and tissue damage. Dysregulation of neutrophil effector functions including delayed neutropil apoptosis, increased neutrophil extracellular traps in the pathogenesis of asthma, and chronic obstructive pulmonary disease enable neutrophils as a potential therapeutic target. Accounting to their role in pathogenesis, neutrophils present as an excellent therapeutic target for the treatment of chronic respiratory diseases. This review highlights the current status and the emerging trends in novel drug delivery systems such as nanoparticles, liposomes, microspheres, and other newer nanosystems that can target neutrophils and their molecular pathways, in the airways against infections, inflammation, and cancer. These drug delivery systems are promising in providing sustained drug delivery, reduced therapeutic dose, improved patient compliance, and reduced drug toxicity. In addition, the review also discusses emerging strategies and the future perspectives in neutrophil-based therapy.

PMID: 32048757 [PubMed - as supplied by publisher]

Bacterial dominance is due to effective utilisation of secondary metabolites produced by competitors.

Sci Rep. 2020 Feb 11;10(1):2316

Authors: Morgan BG, Warren P, Mewis RE, Rivett DW

Abstract
Interactions between bacteria govern the progression of respiratory infections; however, the mechanisms underpinning these interactions are still unclear. Understanding how a bacterial species comes to dominate infectious communities associated with respiratory infections has direct relevance to treatment. In this study, Burkholderia, Pseudomonas, and Staphylococcus species were isolated from the sputum of an individual with Cystic Fibrosis and assembled in a fully factorial design to create simple microcosms. Measurements of growth and habitat modification were recorded over time, the later using proton Nuclear Magnetic Resonance spectra. The results showed interactions between the bacteria became increasingly neutral over time. Concurrently, the bacteria significantly altered their ability to modify the environment, with Pseudomonas able to utilise secondary metabolites produced by the other two isolates, whereas the reverse was not observed. This study indicates the importance of including data about the habitat modification of a community, to better elucidate the mechanisms of bacterial interactions.

PMID: 32047185 [PubMed - in process]

Human Metapneumovirus Infection in Hospitalized Children.

Respir Care. 2020 Feb 11;:

Authors: Holzemer NF, Hasvold JJ, Pohl KJ, Ashbrook MJ, Meert KL, Quasney MW

Abstract
BACKGROUND: Most children are exposed to human metapneumovirus (HMPV) by the age of 5 y. This study aimed to describe the morbidity associated with HMPV infections in a cohort of children in the Midwest of the United States.
METHODS: This was a retrospective 2-center cohort study including children (0-17 y old) hospitalized with HMPV infections at 2 tertiary care pediatric hospitals from 2009 to 2013. Demographics, chronic medical conditions, viral coinfections, and hospitalization characteristics, including the need for respiratory support, high-flow nasal cannula, CPAP, bi-level positive airway pressure, invasive mechanical ventilation, pediatric ICU admission, acute kidney injury (AKI), use of extracorporeal membrane oxygenation, and length of stay, were collected.
RESULTS: In total, 131 subjects were included. Those with one or more comorbidities were older than their otherwise healthy counterparts, with a median age of 2.8 y (interquartile range [IQR] 1.1-7.0) compared to 1.3 y (IQR 0.6-2.0, P < .001), respectively. Ninety-nine (75.6%) subjects required respiratory support; 72 (55.0%) subjects required nasal cannula, simple face mask, or tracheostomy mask as their maximum support. Additionally, 1 (0.8%) subject required high-flow nasal cannula, 1 (0.8%) subject required CPAP, 2 (1.5%) subjects required bi-level positive airway pressure, 15 (11.5%) subjects required invasive mechanical ventilation, 4 (3.1%) subjects required high-frequency oscillatory or jet ventilation, and 4 (3.1%) subjects required extracorporeal membrane oxygenation. Fifty-one (38.9%) subjects required pediatric ICU admission, and 16 (12.2%) subjects developed AKI. Subjects with AKI were significantly older than those without AKI at 5.4 y old (IQR 1.6-11.7) versus 1.9 y old (IQR 0.7-3.5, P = .003). After controlling for the presence of at least one comorbidity and cystic fibrosis, each year increase in age led to a 16% increase in the odds of AKI (P = .01). The median length of stay for the entire cohort was 4.0 d (IQR 2.7-7.0).
CONCLUSIONS: Children hospitalized with HMPV may be at risk for AKI. Risk of HMPV-associated AKI appears to increase with age regardless of severity of respiratory illness or presence of comorbidities.

PMID: 32047124 [PubMed - as supplied by publisher]

Determinants of Exercise Capacity Assessed With the Modified Shuttle Test in Individuals With Cystic Fibrosis.

Respir Care. 2020 Feb 11;:

Authors: Vendrusculo FM, Aquino ES, Campos NE, de Almeida IS, Heinzmann-Filho JP, Queiroz KCV, Leite LR, Donadio MVF

Abstract
BACKGROUND: Patients with cystic fibrosis develop decreased exercise capacity. However, the main factors responsible for this decline are still unclear. Thus, the objective of this study was to evaluate the factors influencing exercise capacity assessed with the modified shuttle test (MST) in individuals with cystic fibrosis.
METHODS: A cross-sectional study was carried out in subjects with a diagnosis of cystic fibrosis who were 6-26 y old and were regularly monitored at 2 cystic fibrosis reference centers in Brazil. Individuals who were unable to perform the tests or who exhibited hemodynamic instability and exacerbation of respiratory symptoms were excluded. Anthropometric, clinical, and genotype data were collected. In addition, lung function and exercise capacity were evaluated with the MST.
RESULTS: 73 subjects (mean age 12.2 ± 4.9 y and FEV1 76.8 ± 23.3%) were included. The mean distance achieved in the MST was 765 ± 258 m (71.6% of predicted). The distance achieved on the MST correlated significantly with age (r = 0.49, P < .001), body mass index (r = 0.41, P < .001), resting heart rate (r = -0.51, P < .001), and FEV1 (r = 0.24, P = .042). Subjects with FEV1 > 67% of predicted (P = .02) and those with resting heart rate < 100 beats/min (P = .01) had a greater exercise capacity. Resting heart rate, age, and FEV1 (%) were found as significant variables to explain the distance achieved on the MST (R2 = 0.48, standard error = 191.0 m).
CONCLUSIONS: The main determinants of exercise capacity assessed with the MST in individuals with cystic fibrosis were resting heart rate, age, and lung function.

PMID: 32047118 [PubMed - as supplied by publisher]

Unilateral temporary diaphragmatic paralysis secondary to bronchial artery embolization in a girl with cystic fibrosis and massive hemoptysis: a case report.

BMC Pulm Med. 2020 Feb 11;20(1):38

Authors: Terlizzi V, Botti M, Gabbani G, Fanelli F, De Martino M, Taccetti G

Abstract
BACKGROUND: Massive hemoptysis is a serious complication in Cystic Fibrosis (CF), occurring commonly in older patients. Bronchial artery embolization (BAE) can be performed to stop the bleeding. BAE is generally safe and effective, but can sometimes lead to serious complications. We report the first case of temporary unilateral diaphragmatic paralysis associated to lung consolidation following BAE in a pediatric CF female patient. This complication worsened the lung function of the patient who underwent lung transplantation after 9 months.
CASE PRESENTATION: A 14 years old female CF patient followed by the CF center of Florence presented low-grade fever, cough increase and recurrent episodes of major hemorrhages such as to carry out a BAE. Within 24 h the patient started to complain of severe thoracic pain in the right hemithorax, increased dyspnea and fever. A computed tomographic angiography and a dynamic fluoroscopic evaluation revealed the right diaphragmatic paralysis, not present before the procedure. After 4 days the clinical condition and radiological imaging had improved with restored mobility of the right hemidiaphragm. Nine months later, she required mechanical ventilation, and subsequently the initiation of extracorporeal membrane oxygenation (ECMO) for a pulmonary exacerbation with septic shock. Lung transplantation in ECMO was performed with success.
CONCLUSION: Clinicians should be aware of the possibility of phrenic nerve injury with BAE in pediatric CF patients.

PMID: 32046694 [PubMed - in process]

Eradication of Pseudomonas aeruginosa in cystic fibrosis patients with inhalation of dry powder tobramycin.

Ther Adv Respir Dis. 2020 Jan-Dec;14:1753466620905279

Authors: Akkerman-Nijland AM, Yousofi M, Rottier BL, Van der Vaart H, Burgerhof JGM, Frijlink HW, Touw DJ, Koppelman GH, Akkerman OW

Abstract
BACKGROUND: Pseudomonas aeruginosa (Pa) is the predominant pulmonary pathogen in patients with cystic fibrosis (CF). Tobramycin nebulization is used for the eradication of Pa infection. Nowadays, tobramycin dry powder inhalation (DPI) is available as well. This study reports the results of eradicating Pa with tobramycin DPI versus nebulization.
METHODS: Adult CF patients with a Pa isolation between September 2010 and September 2017 from the University Medical Centre Groningen (UMCG), the Netherlands, were included in this retrospective study.
RESULTS: In total 27 Pa isolations were recorded. In 13 of these, eradication was attempted with tobramycin, 7 with DPI and 6 with nebulization. DPI eradicated Pa successfully in six isolations (85.7%). Of these, one patient received additional oral ciprofloxacin and one received intravenous ceftazidime. Nebulization eradicated three Pa isolations (50.0%), in two of these, additional oral ciprofloxacin was given.
CONCLUSION: Eradication rates of DPI tobramycin are comparable with those for nebulized tobramycin reported in the literature. This study suggests that DPI tobramycin is an alternative to nebulized tobramycin for eradication of Pa.
TRIAL REGISTRATION: The Medical Ethics Committee of the UMCG granted a waiver (METC2017-349), as they concluded that this study was not subject to the Medical Research Involving Human Subjects Act. The reviews of this paper are available via the supplemental material section.

PMID: 32046620 [PubMed - in process]

Peptide Nucleic Acids and Gene Editing: Perspectives on Structure and Repair.

Molecules. 2020 Feb 08;25(3):

Authors: Economos NG, Oyaghire S, Quijano E, Ricciardi AS, Saltzman WM, Glazer PM

Abstract
Unusual nucleic acid structures are salient triggers of endogenous repair and can occur in sequence-specific contexts. Peptide nucleic acids (PNAs) rely on these principles to achieve non-enzymatic gene editing. By forming high-affinity heterotriplex structures within the genome, PNAs have been used to correct multiple human disease-relevant mutations with low off-target effects. Advances in molecular design, chemical modification, and delivery have enabled systemic in vivo application of PNAs resulting in detectable editing in preclinical mouse models. In a model of β-thalassemia, treated animals demonstrated clinically relevant protein restoration and disease phenotype amelioration, suggesting a potential for curative therapeutic application of PNAs to monogenic disorders. This review discusses the rationale and advances of PNA technologies and their application to gene editing with an emphasis on structural biochemistry and repair.

PMID: 32046275 [PubMed - in process]

Ion Channels in The Pathogenesis of Endometriosis: A Cutting-Edge Point of View.

Int J Mol Sci. 2020 Feb 07;21(3):

Authors: Riemma G, Laganà AS, Schiattarella A, Garzon S, Cobellis L, Autiero R, Licciardi F, Della Corte L, La Verde M, De Franciscis P

Abstract
BACKGROUND: Ion channels play a crucial role in many physiological processes. Several subtypes are expressed in the endometrium. Endometriosis is strictly correlated to estrogens and it is evident that expression and functionality of different ion channels are estrogen-dependent, fluctuating between the menstrual phases. However, their relationship with endometriosis is still unclear.
OBJECTIVE: To summarize the available literature data about the role of ion channels in the etiopathogenesis of endometriosis.
METHODS: A search on PubMed and Medline databases was performed from inception to November 2019.
RESULTS: Cystic fibrosis transmembrane conductance regulator (CFTR), transient receptor potentials (TRPs), aquaporins (AQPs), and chloride channel (ClC)-3 expression and activity were analyzed. CFTR expression changed during the menstrual phases and was enhanced in endometriosis samples; its overexpression promoted endometrial cell proliferation, migration, and invasion throughout nuclear factor kappa-light-chain-enhancer of activated B cells-urokinase plasminogen activator receptor (NFκB-uPAR) signaling pathway. No connection between TRPs and the pathogenesis of endometriosis was found. AQP5 activity was estrogen-increased and, through phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT), helped in vivo implantation of ectopic endometrium. In vitro, AQP9 participated in extracellular signal-regulated kinases/p38 mitogen-activated protein kinase (ERK/p38 MAPK) pathway and helped migration and invasion stimulating matrix metalloproteinase (MMP)2 and MMP9. ClC-3 was also overexpressed in ectopic endometrium and upregulated MMP9.
CONCLUSION: Available evidence suggests a pivotal role of CFTR, AQPs, and ClC-3 in endometriosis etiopathogenesis. However, data obtained are not sufficient to establish a direct role of ion channels in the etiology of the disease. Further studies are needed to clarify this relationship.

PMID: 32046116 [PubMed - in process]