Exogenous alginate protects Staphylococcus aureus from killing by Pseudomonas aeruginosa.

J Bacteriol. 2019 Dec 02;:

Authors: Price CE, Brown DG, Limoli DH, Phelan VV, O'Toole GA

Abstract
Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are mono-infected with either P. aeruginosa or S. aureus We showed previously that mucoid strains of P. aeruginosa can co-exist with S. aureus in vitro due to transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm co-culture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to transcriptional downregulation of pvdA, a gene required for the production of the iron scavenging siderophore pyoverdine, as well as down-regulation of the PQS (Pseudomonas quinolone signal; 2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that co-culture of mucoid P. aeruginosa with non-mucoid P. aeruginosa can mitigate the killing of S. aureus by the non-mucoid strain of P. aeruginosa, indicating that the mechanism we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability to kill S. aureus at late time points, and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the S. aureus-protective effects of mucoidy in a strain-specific manner.IMPORTANCE CF patients are chronically infected by polymicrobial communities. The two dominant bacterial pathogens that infect the lungs of CF patients are P. aeruginosa and S. aureus, with ∼30% of patients co-infected by both species. Such co-infected individuals have worse outcomes than mono-infected patients, and both species persist within the same physical space. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus co-existence, despite evidence that P. aeruginosa kills S. aureus when these organisms are co-cultured in vitro Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to co-exist in proximal physical space, will lead to better informed treatments for chronic polymicrobial infections.

PMID: 31792010 [PubMed - as supplied by publisher]

Improved pulmonary 129 Xe ventilation imaging via 3D-spiral UTE MRI.

Magn Reson Med. 2019 Dec 01;:

Authors: Willmering MM, Niedbalski PJ, Wang H, Walkup LL, Robison RK, Pipe JG, Cleveland ZI, Woods JC

Abstract
PURPOSE: Hyperpolarized 129 Xe MRI characterizes regional lung ventilation in a variety of disease populations, with high sensitivity to airway obstruction in early disease. However, ventilation images are usually limited to a single breath-hold and most-often acquired using gradient-recalled echo sequences with thick slices (~10-15 mm), which increases partial-volume effects, limits ability to observe small defects, and suffers from imperfect slice selection. We demonstrate higher-resolution ventilation images, in shorter breath-holds, using FLORET (Fermat Looped ORthogonally Encoded Trajectories), a center-out 3D-spiral UTE sequence.
METHODS: In vivo human adult (N = 4; 2 healthy, 2 with cystic fibrosis) 129 Xe images were acquired using 2D gradient-recalled echo, 3D radial, and FLORET. Each sequence was acquired at its highest possible resolution within a 16-second breath-hold with a minimum voxel dimension of 3 mm. Images were compared using 129 Xe ventilation defect percentage, SNR, similarity coefficients, and vasculature cross-sections.
RESULTS: The FLORET sequence obtained relative normalized SNR, 40% greater than 2D gradient-recalled echo (P = .012) and 26% greater than 3D radial (P = .067). Moreover, the FLORET images were acquired with 3-fold-higher nominal resolution in a 15% shorter breath-hold. Finally, vasculature was less prominent in FLORET, likely due to diminished susceptibility-induced dephasing at shorter TEs afforded by UTE sequences.
CONCLUSION: The FLORET sequence yields higher SNR for a given resolution with a shorter breath-hold than traditional ventilation imaging techniques. This sequence more accurately measures ventilation abnormalities and enables reduced scan times in patients with poor compliance and severe lung disease.

PMID: 31788858 [PubMed - as supplied by publisher]

Use of low field nuclear magnetic resonance to monitor lung inflammation and the amount of pathological components in the sputum of cystic fibrosis patients.

Magn Reson Med. 2019 Dec 01;:

Authors: Abrami M, Maschio M, Conese M, Confalonieri M, Di Gioia S, Gerin F, Dapas B, Tonon F, Farra R, Murano E, Zanella G, Salton F, Torelli L, Grassi G, Grassi M

Abstract
PURPOSE: To develop a novel approach to monitor lung ventilation/inflammation in cystic fibrosis (CF) patients. Lung assessment in CF patients is relevant given that most patients succumb to respiratory failure. Respiratory functional tests (forced expiratory volume in the first second; FEV1 ) and inflammatory markers are used to test pulmonary ventilation/inflammation, respectively. However, FEV1 is effort dependent and might be uncomfortable for CF patients. Furthermore, inflammatory marker detection is costly and not rapid. To overcome these limitations, we propose the measurement, by means of low field nuclear magnetic resonance, of the spin-spin relaxation time (T2m ) of water hydrogens present in CF patient sputum. In CF sputum, different biological components are pathologically increased and inversely related to lung functionality. Moreover, we showed that these components alter in a dose-dependent manner the T2m in synthetic CF sputum.
METHODS: Sputum samples were obtained from 42 CF subjects by voluntary expectoration; FEV1 , C-reactive protein (CRP), blood neutrophil counts together with cytokine (tumor necrosis factor alpha [TNFα], interleukin [IL]-1β, IL-4, and vascular endothelial growth factor) quantifications were then evaluated.
RESULTS: In sputum samples, we observe that T2m directly correlates (rFEV1 = 0.44; P < 10-4 ; 169 samples) with FEV1 . Moreover, T2m inversely correlates with the circulating inflammation markers CRP/neutrophil number (rCRP = -0.44, P < 10-4 ; rNC = -0.37, P < 2 * 10-4 ; 103 and 86 samples, respectively) and with the sputum inflammatory cytokines TNFα/IL-β1 (rTNFα = -0.72, P < 10-4 ; rIL-1β = -0.685, P < 10-4 ; 27 samples). T2m variations also correspond to FEV1 values over time in defined patients.
CONCLUSION: These findings, together with the fast, reliable, and simple determination of T2m , make our approach a novel tool potentially usable in the real world of CF patients.

PMID: 31788856 [PubMed - as supplied by publisher]

Intestinal organoids for Cystic Fibrosis research.

J Cyst Fibros. 2019 Nov 28;:

Authors: de Poel E, Lefferts JW, Beekman JM

Abstract
Significant progress has been made in the development of CFTR modulator therapy; however, current CFTR modulator therapies are only available for a minority of the CF-patient population. Additionally, heterogeneity in in vivo modulator response has been reported among individuals carrying homozygous F508del-CFTR, adding to the desire for an optimal prediction of response-to-therapy on an individual level. In the last decade, a lot of progress has been made in the development of primary cell cultures into 3D patient-derived disease models. The advantage of these models is that the endogenous CFTR function is affected by the patient's mutation as well as other genetic or environmental factors. In this review we focus on intestinal organoids as in vitro model for CF, enabling for CF disease classification, drug development and treatment optimization in a personalized manner, taking into account rare CFTR mutations and clinical heterogeneity among individuals with CF.

PMID: 31787574 [PubMed - as supplied by publisher]

CFTR-deficient pigs display alterations of bone microarchitecture and composition at birth.

J Cyst Fibros. 2019 Nov 28;:

Authors: Braux J, Jourdain ML, Guillaume C, Untereiner V, Piot O, Baehr A, Klymiuk N, Winter N, Berri M, Buzoni-Gatel D, Caballero I, Guillon A, Si-Tahar M, Jacquot J, Velard F

Abstract
BACKGROUND: The lack of cystic fibrosis transmembrane conductance regulator (CFTR) function causes cystic fibrosis (CF), predisposing to severe lung disease, reduced growth and osteopenia. Both reduced bone content and strength are increasingly recognized in infants with CF before the onset of significant lung disease, suggesting a developmental origin and a possible role in bone disease pathogenesis. The role of CFTR in bone metabolism is unclear and studies on humans are not feasible. Deletion of CFTR in pigs (CFTR -/- pigs) displays at birth severe malformations similar to humans in the intestine, respiratory tract, pancreas, liver, and male reproductive tract.
METHODS: We compared bone parameters of CFTR -/- male and female pigs with those of their wild-type (WT) littermates at birth. Morphological and microstructural properties of femoral cortical and trabecular bone were evaluated using micro-computed tomography (μCT), and their chemical compositions were examined using Raman microspectroscopy.
RESULTS: The integrity of the CFTR -/- bone was altered due to changes in its microstructure and chemical composition in both sexes. Low cortical thickness and high cortical porosity were found in CFTR -/- pigs compared to sex-matched WT littermates. Moreover, an increased chemical composition heterogeneity associated with higher carbonate/phosphate ratio and higher mineral crystallinity was found in CFTR -/- trabecular bone, but not in CFTR -/- cortical bone.
CONCLUSIONS: The loss of CFTR directly alters the bone composition and metabolism of newborn pigs. Based on these findings, we speculate that bone defects in patients with CF could be a primary, rather than a secondary consequence of inflammation and infection.

PMID: 31787573 [PubMed - as supplied by publisher]

Energy-Optimized Pharmacophore Coupled Virtual Screening in the Discovery of Quorum Sensing Inhibitors of LasR Protein of Pseudomonas aeruginosa.

J Biomol Struct Dyn. 2019 Dec 02;:1-25

Authors: Nain Z, Sayed SB, Karim MM, Islam A, Adhikari UK

Abstract
Pseudomonas aeruginosa is an emerging opportunistic pathogen responsible for cystic fibrosis and nosocomial infections. In addition, empirical treatments are become inefficient due to their multiple-antibiotic resistance and extensive colonizing ability. Quorum sensing (QS) plays a vital role in the regulation of virulence factors in P. aeruginosa. Therefore, attenuation of virulence by QS inhibition could be an alternative and effective approach to control the infections. In this study, we sought to discover new QS inhibitors (QSIs) against LasR receptor in P. aeruginosa using chemoinformatics. Initially, a structure-based high-throughput virtual screening was performed using the LasR active site that identified 61404 relevant molecules. The e-pharmacophore (ADAHH) screening of these molecules rendered 72 QSI candidates. In standard-precision docking, only 7 compounds were found as potential QSIs based on their higher binding affinity to LasR receptor (-7.53 to -10.32 kcal/mol compared to -7.43 kcal/mol of native ligand). The ADMET properties of these compounds were suitable to be QSIs. Later, extra-precision docking and binding energy calculation suggested ZINC19765885 and ZINC72387263 as the most promising QSIs. The dynamic simulation of the docked complexes showed stable binding affinity and molecular interactions. The current study suggested that these two compounds could be used in P. aeruginosa QS inhibition to combat bacterial infections.

PMID: 31787031 [PubMed - as supplied by publisher]

Natural Perspiration Sampling and in Situ Electrochemical Analysis with Hydrogel Micropatches for User-Identifiable and Wireless Chemo/Biosensing.

ACS Sens. 2019 Dec 01;:

Authors: Lin S, Wang B, Zhao Y, Shih R, Cheng X, Yu W, Hojaiji H, Lin H, Hoffman C, Ly D, Tan J, Chen Y, Di Carlo D, Milla C, Emaminejad S

Abstract
Recent advances in microelectronics, microfluidics, and electrochemical sensing platforms have enabled the development of an emerging class of fully integrated personal health monitoring devices that exploit sweat to noninvasively access biomarker information. Despite such advances, effective sweat sampling remains a significant challenge for reliable biomarker analysis, with many existing methods requiring active stimulation (e.g., iontophoresis, exercise, heat). Natural perspiration offers a suitable alternative as sweat can be collected with minimal effort on the part of the user. To leverage this phenomenon, we devised a thin hydrogel micropatch (THMP), which simultaneously serves as an interface for sweat sampling and a medium for electrochemical sensing. To characterize the performance of the THMP, caffeine and lactate were selected as two representative target molecules. We demonstrated the suitability of the sampling method to track metabolic patterns, as well as to render sample-to-answer biomarker data for personal monitoring (through coupling with an electrochemical sensing system). To inform its potential application, this biomarker sampling and sensing system is incorporated within a distributed terminal-based sensing network, which uniquely capitalizes on the fingertip as a site for simultaneous biomarker data sampling and user identification.

PMID: 31786928 [PubMed - as supplied by publisher]

Ramachandran Conformational Energy Maps for Disaccharide Linkages found in Burkholderia multivorans Biofilm Polysaccharides.

Int J Biol Macromol. 2019 Nov 28;:

Authors: Jou IA, Caterino M, Schnupf U, Rizzo R, Cescutti P, Brady JW

Abstract
Ramachandran conformational energy maps have been prepared for all of the glycosidic linkages found in the C1576 exopolysaccharide that constitutes the biofilms of the bacterial species Burkholderia multivorans, a member of the Burkholderia cepacian complex that was isolated from a cystic fibrosis patient. This polysaccharide is a rhamnomannan with a tetrasaccharide repeat unit containing two mannose residues and two rhamnose residues, -[3-α-D-Man-(1→2)- α -D-Man-(1→2)- α -D-Rha-(1→3)- α -D-Rha-(1→]n-, where approximately 50% of the rhamnoses are randomly methylated on their O3 hydroxyl groups, further increasing the overall hydrophobicity of the chains. Because of the methylation, the tetrasaccharide repeat unit actually contains six possible linkages. The conformational energy maps are fully adiabatic relaxed maps in which the energy for each (ϕ,ψ) grid point on the map represents the lowest possible energy for the molecule in that conformation, considering all the combinations of the other degrees of freedom, such as hydroxyl orientations. Molecular dynamics simulations were used to verify that these maps indeed describe the conformational dynamics of these linkages. All six linkages were found to be quite restricted in possible ϕ angles, but to exhibit several possible low-energy ψ angles, suggesting that these chains could be quite flexible.

PMID: 31786294 [PubMed - as supplied by publisher]

Improvement in contraceptive coverage and gynecological care of adult women with cystic fibrosis following the implementation of an on-site gynecological consultation.

Contraception. 2019 Nov 28;:

Authors: Rousset-Jablonski C, Reynaud Q, Perceval M, Nove-Josserand R, Durupt S, Ray-Coquard I, Golfier F, Durieu I

Abstract
OBJECTIVE: Our study aimed to evaluate the impact of the introduction of a new gynecologic referral service in our adult Cystic Fibrosis (CF) center on contraceptive coverage, gynecological follow-up regularity, and cervical cancer screening coverage.
STUDY DESIGN: We implemented an on-site gynecological consultation in our adultCF center in 2015. We compared the results of two surveys conducted successively in 2014 and in 2017 in a cohort of women with CF attending the Lyon CF center. Women completed the same self-report written questionnaire as in 2014. Main outcome measures were the comparisons of contraceptive coverage, gynecological follow-up regularity, and cervical cancer screening coverage between 2014 and 2017.
RESULTS: All the 136 women (100%) who attended the clinic in 2017 participated. Contraceptive prevalence rate increased from 69%(CI95%:60.3-78.1) to 86%(CI95%:79.6-92.9) between 2014 and 2017 (p=0.005). Among transplanted patients, the contraceptive prevalence rate was 92.3%(CI95%:82.0-100) in 2017. Long acting reversible contraceptive use markedly increased from 10% to 21.6% (p=0.005). The proportion of women that reported an access to gynecological care increased between 2014 and 2017 (74%(CI95%:66.3-82.0) vs 91%(CI95%:86.9-95.4), p<0.005) and reached 100% among transplanted patients. Cervical cancer screening improved (55%(CI95%:51.2-68.8) vs 85%(CI95%:78.6-90.6) women ever screened) (p<0.0005) and reached 100% among transplanted patients.
CONCLUSIONS: We observed an improvement in contraceptive coverage and gynecological care of adult women with CF following the implementation of a dedicated gynecological consultation in the CF center.
IMPLICATIONS: Service linkages and formal links between CF centers and gynecologists can facilitate access to disease-specific contraceptive counseling, adequate gynecological management and cervical cancer screening.

PMID: 31786201 [PubMed - as supplied by publisher]

Colonisation of Staphylococcus aureus in patients with Nasal Polyposis.

Neuro Endocrinol Lett. 2019 Oct 01;40(Suppl1):37-42

Authors:

Abstract
BACKGROUND: Nasal polyps (NPs) are one of the most common inflammatory mass lesions of the nose, affecting up to 0.5-4% of the population. The pathogenesis of NPs has been studied widely, but it is not clearly understood. A possible role of S. aureus in nasal polyposis has been suggested by numerous studies. This study aimed to map S.aureus colonisation in NP patients in the nose in comparison to healthy controls.
MATERIAL AND METHODS: We identified Staphylococcus aureus in nasal mucosal swab, collected from 58 patients with nasal polyposis from the out-patient ENT clinic of the Faculty Hospital in Nitra. We compared them to 50 patients without symptoms of nasal obstruction or NP. Isolated bacterial strains were then further identified.
RESULTS: In nasal mucosa membrane, results were not statistically significant. The selected population consisted of 108 patients, of which 58 (54%) had nasal polyps and 50 (46%) didnt. We collected the following information about patients from both groups: age, gender, smoker, presence of asthma, allergy and presence of Staphylococcus aureus by cultivation from nasal mucosa. In addition, for patients with nasal polyposis we have following variables, such as: presence inflammatory diseases, allergy to acylpyrine, cystic fibrosis. Out of 58 patients with nasal polyposis 15% (n=9) were found to have S.aureus in nasal mucosa membrane, compared to the healthy controls where 6% (n=3) of patients had S. aureus.
CONCLUSION: Our results did not show that S. aureus found in nasal mucosa membrane is significantly different in patients with or without NP. However, association of the presence of S. aureus in patients with nasal polyposis with asthma, allergy and inflammation has been shown.

PMID: 31785225 [PubMed - as supplied by publisher]

Elexacaftor/Ivacaftor/Tezacaftor: First Approval.

Drugs. 2019 Nov 29;:

Authors: Hoy SM

Abstract
A fixed-dose combination tablet of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector tezacaftor and the CFTR potentiator ivacaftor with the next-generation CFTR corrector elexacaftor (hereafter referred to as elexacaftor/ivacaftor/tezacaftor) [Trikafta™] has been developed by Vertex Pharmaceuticals Inc. to treat patients with the most common cystic fibrosis mutation (F508del). Its use has been associated with statistically significant and/or clinically meaningful improvements in lung function and respiratory-related quality of life compared with comparator regimens (placebo or ivacaftor/tezacaftor) in multinational phase II and III studies, and in October 2019 elexacaftor/ivacaftor/tezacaftor was approved by the US FDA for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene. A regulatory assessment for elexacaftor/ivacaftor/tezacaftor as a treatment for cystic fibrosis is underway in the EU. This article summarizes the milestones in the development of elexacaftor/ivacaftor/tezacaftor leading to this first approval for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene.

PMID: 31784874 [PubMed - as supplied by publisher]

Two Distinct Types of Sweat Profile in Healthy Subjects While Exercising at Constant Power Output Measured by a Wearable Sweat Sensor.

Sci Rep. 2019 Nov 29;9(1):17877

Authors: Choi DH, Kitchen G, Kim JS, Li Y, Kim K, Jeong IC, Nguyen J, Stewart KJ, Zeger SL, Searson PC

Abstract
Wearable sweat sensors have enabled real-time monitoring of sweat profiles (sweat concentration versus time) and could enable monitoring of electrolyte loss during exercise or for individuals working in extreme environments. To assess the feasibility of using a wearable sweat chloride sensor for real-time monitoring of individuals during exercise, we recorded and analyzed the sweat profiles of 50 healthy subjects while spinning at 75 Watts for 1 hour. The measured sweat chloride concentrations were in the range from 2.9-34 mM. The sweat profiles showed two distinct sweat responses: Type 1 (single plateau) and Type 2 (multiple plateaus). Subjects with Type 2 profiles had higher sweat chloride concentration and weight loss, higher maximum heart rate, and larger changes in heart rate and rating of perceived exertion during the trial compared to subjects with Type 1 profiles. To assess the influence of level of effort, we recorded sweat profiles for five subjects at 75 W, 100 W, and 125 W. While all five subjects showed Type 1 sweat profiles at 75 W, four of the subjects had Type 2 profiles at 125 W, showing an increase in sweat chloride with exercise intensity. Finally, we show that sweat profiles along with other physiological parameters can be used to predict fluid loss.

PMID: 31784588 [PubMed - in process]

Ivacaftor in cystic fibrosis with residual function: Lung function results from an N-of-1 study.

J Cyst Fibros. 2019 Nov 26;:

Authors: Nick JA, St Clair C, Jones MC, Lan L, Higgins M, VX12-770-113 Study Team

Abstract
BACKGROUND: Ivacaftor shows benefit in patients with cystic fibrosis (CF) and CFTR mutations associated with residual CF transmembrane conductance regulator (CFTR) function. Here we further assess the effect of ivacaftor in such patients using an N-of-1 study design.
METHODS: Patients aged ≥12 years with CF with clinical or molecular evidence of residual CFTR function were randomized to 1 of 4 treatment sequences for two 4-week, double-blind crossover cycles (each divided into 2 weeks of ivacaftor treatment and placebo) followed by 8 weeks of open-label ivacaftor treatment. The primary endpoint was absolute change from cycle baseline of percent predicted forced expiratory volume in 1 s (ppFEV1) after 2 weeks of treatment with ivacaftor relative to placebo.
RESULTS: Absolute change (SD) from study baseline in ppFEV1 favored ivacaftor by 2.3 (1.0) percentage points (95% credible interval, 0.4-4.1) after 2 weeks of treatment. Absolute mean change (SD) from open-label baseline (defined as day 1 of the open-label ivacaftor treatment period) in ppFEV1 after 8 weeks of treatment was 4.7 (4.2) percentage points (P<.0001). Safety of ivacaftor was consistent with that observed in prior studies.
CONCLUSIONS: Ivacaftor improved lung function during the double-blind and open-label treatment periods in patients with CF and CFTR mutations associated with residual CFTR function (ClinicalTrials.gov, NCT01685801).

PMID: 31784217 [PubMed - as supplied by publisher]

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Feedback controlled photolytic gas phase nitric oxide delivery from S-nitrosothiol-doped silicone rubber films.

J Control Release. 2019 Nov 25;:

Authors: Lautner G, Lautner-Csorba O, Stringer B, Meyerhoff ME, Schwendeman SP

Abstract
Constant therapeutic gas phase nitric oxide (NO) delivery is achieved from S-nitrosothiol (RSNO) type NO donor doped silicone rubber films using feedback-controlled photolysis. For photo-release of the NO gas, the intensity of the LED light source is controlled via a PID (proportional-integral-derivative) controller implemented on a microcontroller. The NO concentration within the emitted gas phase is monitored continuously with a commercial amperometric NO gas sensor. NO release was accurately adjustable up to 10 ppm across a broad range of setpoints with response times of roughly 1 min or less. When NO is generated into an air recipient stream, lower NO yields and a comparable level of toxic nitrogen dioxide (NO2) formation is observed. However, NO gas generated into an N2 recipient gas stream can be blended into pure O2 with very low NO2 formation. Following scale-up, this technology could be used for point-of-care gas phase NO generation as an alternative for currently used gas cylinder technology for treatment of health conditions where inhaled NO is beneficial, such as pulmonary hypertension, hypoxemia, and cystic fibrosis.

PMID: 31778741 [PubMed - as supplied by publisher]

Protein Misfolding and ER stress in Chronic Lung Disease: Will Cell-Specific Targeting be the Key to the Cure?

Chest. 2019 Nov 25;:

Authors: Naiel S, Tat V, Padwal M, Vierhout M, Mekhael O, Yousof T, Ayoub A, Abed S, Dvorkin-Gheva A, Ask K

Abstract
Chronic lung disease accounts for a significant global burden with respect to death, disability and healthcare costs. Due to the heterogeneous nature and limited treatment options for these diseases, it is imperative that the cellular and molecular mechanisms underlying the disease pathophysiology are further understood. The lung is a complex organ with a diverse cell population, and each cell type will likely have different roles in disease initiation, progression and resolution. The effectiveness of a given therapeutic agent may depend on the net effect on each of these cell types. Over the past decade, it has been established that endoplasmic reticulum stress and the unfolded protein response are involved in the development of several chronic lung diseases. These conserved cellular pathways are important for maintaining cellular proteostasis, but their aberrant activation can result in pathology. This review will discuss the current understanding of endoplasmic reticulum stress and the unfolded protein response at the cellular level in the development and progression of various chronic lung diseases. We highlight the need for increased understanding of the specific cellular contributions of UPR activation to these pathologies and suggest that the development of cell-specific targeted therapies is likely required to further decrease disease progression and to promote resolution of chronic lung disease.

PMID: 31778676 [PubMed - as supplied by publisher]

[Adherence of adolescents with cystic fibrosis to enzyme replacement therapy: associated factors].

Cien Saude Colet. 2019 Dec;24(12):4717-4726

Authors: Ferreira DP, Chaves CRMM, Costa ACCD

Abstract
This article sets out to evaluate the prevalence and factors associated with adherence to enzyme replacement therapy among adolescents with cystic fibrosis. It is a cross-sectional, descriptive and observational study. Sociodemographic and clinical data were collected. The instruments used to assess adherence were: the Morisky-Green questionnaire and medication dispensation at the pharmacy, and interviews with structured questionnaires for the associated factors. Forty-four adolescents were interviewed. According to the method of the pharmacy medication dispensation analysis and the Morisky-Green questionnaire, the adherence of 45.5% and 11.4% was found, respectively. The higher adherence was observed in those with early diagnosis and the lowest in older adolescents and girls. The factors with the highest prevalence of non-adherence were: not taking enzymes when eating out of the home; only taking enzymes with major meals; normal lung function; with severe and very severe obstruction. The prevalence of adhesion to enzymes was low. Information related to the disease and treatment should be improved, especially among older adolescents and with impairment of lung function, with the creation of strategies and longitudinal studies to identify factors that interfere with adherence.

PMID: 31778521 [PubMed - in process]

Lung ultrasound assessment of response to antibiotic therapy in cystic fibrosis exacerbations: a study of two cases.

J Bras Pneumol. 2019 Nov 25;45(6):e20190128

Authors: Peixoto AO, Marson FAL, Souza TH, Fraga AMA, Ribeiro JD

PMID: 31778425 [PubMed - in process]

Novel intermicrobial molecular interaction: Pseudomonas aeruginosa Quinolone Signal (PQS) modulates Aspergillus fumigatus response to iron.

Microbiology. 2019 Nov 28;:

Authors: Nazik H, Sass G, Ansari SR, Ertekin R, Haas H, Déziel E, Stevens DA

Abstract
Pseudomonas aeruginosa (Pa) and Aspergillus fumigatus (Af), the commonest bacterium and fungus in compromised host airways, compete for iron (Fe). The Pseudomonas quinolone signal (PQS), a Pa quorum sensing molecule, also chelates Fe, and delivers Fe to the Pa cell membrane using Pa siderophores. In models of Af biofilm formation or preformed biofilms, PQS inhibited Af in a low Fe environment. AfΔsidA (mutant unable to produce siderophores) biofilm was more sensitive to PQS inhibition than wild-type (WT), as was planktonic AfΔsidA growth. PQS decreased WT Af growth on agar. All these inhibitory actions were reversed by Fe. The Pa siderophore pyoverdin, or Af siderophore inhibitor celastrol, act cooperatively with PQS in Af inhibition. These findings all indicate PQS inhibition is owing to Fe chelation. Remarkably, in high Fe environments, PQS enhanced Af biofilm at 1/100 to 1/2000 Fe concentration required for Fe alone to enhance. Planktonic Af growth, and on agar, Af conidiation, were also enhanced by PQS+Fe compared to Fe alone. In contrast, neither AfΔsidA biofilm, nor planktonic AfΔsidA, were enhanced by PQS-Fe compared to Fe. When Af siderophore ferricrocin (FC),+PQS, were added to AfΔsidA, Af was then boosted more than by FC alone. Moreover, FC+PQS+Fe boosted AfΔsidA more than Fe, FC, FC+Fe, PQS+FC or PQS+Fe. Thus PQS-Fe maximal stimulation requires Af siderophores. PQS inhibits Af via chelation under low Fe conditions. In a high Fe environment, PQS paradoxically stimulates Af efficiently, and this involves Af siderophores. PQS production by Pa could stimulate Af in cystic fibrosis airways, where Fe homeostasis is altered and Fe levels increase, supporting fungal growth.

PMID: 31778108 [PubMed - as supplied by publisher]

Recapitulation of polymicrobial communities associated with cystic fibrosis airway infections: a perspective.

Future Microbiol. 2019 Nov 28;:

Authors: O'Brien TJ, Welch M

Abstract
The airways of persons with cystic fibrosis are prone to infection by a diverse and dynamic polymicrobial consortium. Currently, no models exist that permit recapitulation of this consortium within the laboratory. Such microbial ecosystems likely have a network of interspecies interactions, serving to modulate metabolic pathways and impact upon disease severity. The contribution of less abundant/fastidious microbial species on this cross-talk has often been neglected due to lack of experimental tractability. Here, we critically assess the existing models for studying polymicrobial infections. Particular attention is paid to 3Rs-compliant in vitro and in silico infection models, offering significant advantages over mammalian infection models. We outline why these models will likely become the 'go to' approaches when recapitulating polymicrobial cystic fibrosis infection.

PMID: 31778075 [PubMed - as supplied by publisher]