High-Throughput Screening for Modulators of CFTR Activity Based on Genetically Engineered Cystic Fibrosis Disease-Specific iPSCs.

Stem Cell Reports. 2019 Apr 28;:

Authors: Merkert S, Schubert M, Olmer R, Engels L, Radetzki S, Veltman M, Scholte BJ, Zöllner J, Pedemonte N, Galietta LJV, von Kries JP, Martin U

Abstract
Organotypic culture systems from disease-specific induced pluripotent stem cells (iPSCs) exhibit obvious advantages compared with immortalized cell lines and primary cell cultures, but implementation of iPSC-based high-throughput (HT) assays is still technically challenging. Here, we demonstrate the development and conduction of an organotypic HT Cl-/I- exchange assay using cystic fibrosis (CF) disease-specific iPSCs. The introduction of a halide-sensitive YFP variant enabled automated quantitative measurement of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function in iPSC-derived intestinal epithelia. CFTR function was partially rescued by treatment with VX-770 and VX-809, and seamless gene correction of the p.Phe508del mutation resulted in full restoration of CFTR function. The identification of a series of validated primary hits that improve the function of p.Phe508del CFTR from a library of ∼42,500 chemical compounds demonstrates that the advantages of complex iPSC-derived culture systems for disease modeling can also be utilized for drug screening in a true HT format.

PMID: 31080112 [PubMed - as supplied by publisher]

Non-Cystic Fibrosis-Related Meconium Ileus: GUCY2C-Associated Disease Discovered through Rapid Neonatal Whole-Exome Sequencing.

J Pediatr. 2019 May 09;:

Authors: Woods JD, Payton KSE, Sanchez-Lara PA, Au M, Simmons CF, Graham JM

Abstract
Meconium ileus is caused by cystic fibrosis; however, mutations in the GUCY2C gene also cause this disease. We report non-cystic fibrosis meconium ileus in an infant of non-Middle Eastern origin with compound heterozygous mutations in GUCY2C.

PMID: 31079856 [PubMed - as supplied by publisher]

Inability to reduce morbidity of diarrhea by ORS: can we design a better therapy?

Pediatr Res. 2018 03;83(3):559-563

Authors: Harrell JE, Cheng SX

Abstract
Diarrheal disease is a worldwide problem that still causes significant morbidity and mortality among children. Currently, oral rehydration solution (ORS) is the standard of care for acute diarrhea in pediatric patients. Although effective in reducing mortality, ORS does not alleviate diarrheal symptoms, thus reducing caregiver compliance and therapeutic efficacy. This article will briefly review the current problem of pediatric diarrhea and the shortcomings of current therapies; however, the focus of this review is to examine the intestinal calcium-sensing receptor (CaSR). The author summarizes the evidence suggesting that targeting the CaSR will enable clinicians to address all four major pathophysiological mechanisms of diarrheal disease, and substantiates the need for future research regarding this therapy.

PMID: 29168980 [PubMed - indexed for MEDLINE]

A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis.

Sci Rep. 2019 May 10;9(1):7234

Authors: Habib AR, Kajbafzadeh M, Desai S, Yang CL, Skolnik K, Quon BS

Abstract
Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV1% predicted (ppFEV1). Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV1 favouring treatment was observed for ivacaftor (IVA) in G551D individuals (≥6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV1 in a sub-group of individuals ≥18 years old with an R117H mutation. No significant improvements in ppFEV1 were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV1 and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.

PMID: 31076617 [PubMed - in process]

Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease.

Eur J Med Chem. 2019 Apr 25;175:63-71

Authors: De Fenza M, D'Alonzo D, Esposito A, Munari S, Loberto N, Santangelo A, Lampronti I, Tamanini A, Rossi A, Ranucci S, De Fino I, Bragonzi A, Aureli M, Bassi R, Tironi M, Lippi G, Gambari R, Cabrini G, Palumbo G, Dechecchi MC, Guaragna A

Abstract
In the frame of a research program aimed to explore the relationship between chirality of iminosugars and their therapeutic potential, herein we report the synthesis of N-akyl l-deoxyiminosugars and the evaluation of the anti-inflammatory properties of selected candidates for the treatment of Pseudomonas aeruginosa infections in Cystic Fibrosis (CF) lung disease. Target glycomimetics were prepared by the shortest and most convenient approach reported to date, relying on the use of the well-known PS-TPP/I2 reagent system to prepare reactive alkoxyalkyl iodides, acting as key intermediates. Iminosugars ent-1-3 demonstrated to efficiently reduce the inflammatory response induced by P. aeruginosa in CuFi cells, either alone or in synergistic combination with their d-enantiomers, by selectively inhibiting NLGase. Surprisingly, the evaluation in murine models of lung disease showed that the amount of ent-1 required to reduce the recruitment of neutrophils was 40-fold lower than that of the corresponding d-enantiomer. The remarkably low dosage of the l-iminosugar, combined with its inability to act as inhibitor for most glycosidases, is expected to limit the onset of undesired effects, which are typically associated with the administration of its d-counterpart. Biological results herein obtained place ent-1 and congeners among the earliest examples of l-iminosugars acting as anti-inflammatory agents for therapeutic applications in Cystic Fibrosis.

PMID: 31075609 [PubMed - as supplied by publisher]

Pathophysiology of Cystic Fibrosis Liver Disease: a channelopathy leading to alterations in innate immunity and in microbiota.

Cell Mol Gastroenterol Hepatol. 2019 May 07;:

Authors: Fiorotto R, Strazzabosco M

Abstract
Cystic fibrosis (CF) is a monogenic disease caused by mutation of Cftr. Cystic fibrosis associated liver disease (CFLD) is a common non-pulmonary cause of mortality in CF and accounts for about 2.5-5% of overall CF mortality. The peak of the disease is in the pediatric population but a second wave of liver disease in CF adults has been reported in the last decade in association with an increase in the life expectancy of these patients. New drugs are available to correct the basic defect in CF but their efficacy in CFLD is not known. CFTR, expressed in the apical membrane of cholangiocytes, is a major determinant for bile secretion and CFLD has been classically considered a channelopathy. However, the recent findings of CFTR as regulator of epithelial innate immunity and the possible influence of the intestinal disease with an altered microbiota on the liver complication have open new mechanistic insight on the pathogenesis of CFLD. This review will give an overview of the current understanding of the pathophysiology of the disease and will discuss potential target for intervention.

PMID: 31075352 [PubMed - as supplied by publisher]

On the Process of Discovering Leads that Target the Heparin-Binding Site of Neutrophil Elastase in the Sputum of Cystic Fibrosis Patients.

J Med Chem. 2019 May 10;:

Authors: Morla S, Sankaranarayanan NV, Afosah DK, Kumar M, Kummarapurugu AB, Voynow J, Desai UR

Abstract
Cystic fibrosis (CF) is a disease of dysregulated salt and fluid homeostasis that results in massive accumulation of neutrophil elastase resulting in lung degradation and death. The current CF therapy relies on inhaled deoxyribonuclease and hypertonic saline, but does not address elastolytic degradation of the lung. We reasoned that allosteric agents targeting the heparin-binding site of neutrophil elastase would offer a therapeutic paradigm. Screening a library of 60 non-saccharide glycosaminoglycan mimetics (NSGMs) led to discovery of 23 hits against neutrophil elastase. To identify a lead NSGM that works in sync with the current CF relieving agents, we developed a rigorous protocol based on fundamental computational, biochemical, mechanistic, and adverse effects studies. The lead NSGM so identified neutralized neutrophil elastase present in the sputum of CF patients in the presence of deoxyribonuclease and high salt conditions. Our work presents the process for discovering potent, small, synthetic, allosteric, anti-CF agents, while also identifying a novel lead for further studies in animal models of CF.

PMID: 31074986 [PubMed - as supplied by publisher]

PDZ Scaffold Protein CAL Couples with Metabotropic Glutamate Receptor 5 to Protect Against Cell Apoptosis and Is a Potential Target in the Treatment of Parkinson's Disease.

Neurotherapeutics. 2019 May 09;:

Authors: Luo WY, Xing SQ, Zhu P, Zhang CG, Yang HM, Van Halm-Lutterodt N, Gu L, Zhang H

Abstract
Targeting mGluR5 has been an attractive strategy to modulate glutamate excitotoxicity for neuroprotection. Although human clinical trials using mGluR5 negative allosteric modulators (NAMs) have included some disappointments, recent investigations have added several more attractive small molecules to this field, providing a promise that the identification of more additional strategies to modulate mGluR5 activity might be potentially beneficial for the advancement of PD treatment. Here, we determined the role of the interacting partner CAL (cystic fibrosis transmembrane conductance regulator-associated ligand) in mGluR5-mediated protection in vitro and in vivo. In astroglial C6 cells, CAL deficiency blocked (S)-3, 5-dihydroxyphenylglycine (DHPG)-elicited p-AKT and p-ERK1/2, subsequently prevented group I mGluRs-mediated anti-apoptotic protection, which was blocked by receptor antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA), and PI3K or MEK inhibitor LY294002 or U0126. In rotenone-treated MN9D cells, both CAL and mGluR5 expressions were decreased in a time- and dose-dependent manner, and the correlation between these 2 proteins was confirmed by lentivirus-delivered CAL overexpression and knockdown. Moreover, CAL coupled with mGluR5 upregulated mGluR5 protein expression by inhibition of ubiquitin-proteasome-dependent degradation to suppress mGluR5-mediated p-JNK and to protect against cell apoptosis. Additionally, CAL also inhibited rotenone-induced glutamate release to modulate mGluR5 activity. Furthermore, in the rotenone-induced rat model of PD, AAV-delivered CAL overexpression attenuated behavioral deficits and dopaminergic neuronal death, while CAL deficiency aggravated rotenone toxicity. On the other hand, the protective effect of the mGluR5 antagonist MPEP was weakened by knocking down CAL. In vivo experiments also confirmed that CAL inhibited ubiquitination-proteasome-dependent degradation to modulate mGluR5 expression and JNK phosphorylation. Our findings show that CAL protects against cell apoptosis via modulating mGluR5 activity, and may be a new molecular target for an effective therapeutic strategy for PD.

PMID: 31073978 [PubMed - as supplied by publisher]

Incidence and risk factors of paediatric cystic fibrosis-related diabetes.

J Cyst Fibros. 2019 May 06;:

Authors: Perrem L, Stanojevic S, Solomon M, Carpenter S, Ratjen F

Abstract
INTRODUCTION: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF) directly linked to increased morbidity and mortality. Both the incidence of type I and type II diabetes has been shown to increase in the general population. In this study, we investigated the incidence and risk factors of CFRD in a paediatric CF population.
METHODS: Prospectively collected data from the Canadian CF Registry (CCFR) from 2000 to 2016 for patients ages 10 to 18 years was used to determine the incidence of CFRD. Risk factors for CFRD in the Canadian population were investigated using a nested case-control design. Conditional logistic regression analysis with a 4:1 control: case matching was used.
RESULTS: From 2000 to 2016, 2326 patients with CF aged between 10 through 18 years were included in the CCFR, during this time the overall incidence rate of CFRD was 2.1 cases per 100 patient-years (95% confidence interval 1.8 to 2.3). Incidence rates were stable in the Canadian cohort over three consecutive time periods 2000-2005, 2006-2010; 2011-2016. Worse lung function, female gender, history of allergic bronchopulmonary aspergillosis, Gastrostomy tube insertion and liver disease were statistically significant risk factors for CFRD.
CONCLUSION: The incidence of CFRD in the Canadian paediatric population has been stable over time, in contrast to the rising rates of Type 1 and Type 2 diabetes in the general paediatric population. The risk factor for CFRD in this contemporary population were consistent with previous studies.

PMID: 31072797 [PubMed - as supplied by publisher]

Azaspiracids Increase Mitochondrial Dehydrogenases Activity in Hepatocytes: Involvement of Potassium and Chloride Ions.

Mar Drugs. 2019 May 08;17(5):

Authors: Pelin M, Kilcoyne J, Florio C, Hess P, Tubaro A, Sosa S

Abstract
BACKGROUND: Azaspiracids (AZAs) are marine toxins that are produced by Azadinium and Amphidoma dinoflagellates that can contaminate edible shellfish inducing a foodborne poisoning in humans, which is characterized by gastrointestinal symptoms. Among these, AZA1, -2, and -3 are regulated in the European Union, being the most important in terms of occurrence and toxicity. In vivo studies in mice showed that, in addition to gastrointestinal effects, AZA1 induces liver alterations that are visible as a swollen organ, with the presence of hepatocellular fat droplets and vacuoles. Hence, an in vitro study was carried out to investigate the effects of AZA1, -2, and -3 on liver cells, using human non-tumor IHH hepatocytes.
RESULTS: The exposure of IHH cells to AZA1, -2, or -3 (5 × 10-12-1 × 10-7 M) for 24 h did not affect the cell viability and proliferation (Sulforhodamine B assay and 3H-Thymidine incorporation assay), but they induced a significant concentration-dependent increase of mitochondrial dehydrogenases activity (MTT reduction assay). This effect depends on the activity of mitochondrial electron transport chain complex I and II, being counteracted by rotenone and tenoyl trifluoroacetone, respectively. Furthermore, AZAs-increased mitochondrial dehydrogenase activity was almost totally suppressed in the K+-, Cl--, and Na+-free media and sensitive to the specific inhibitors of KATP and hERG potassium channels, Na+/K+, ATPase, and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels.
CONCLUSIONS: These results suggest that AZA mitochondrial effects in hepatocytes derive from an imbalance of intracellular levels of K+ and, in particular, Cl- ions, as demonstrated by the selective reduction of toxin effects by CFTR chloride channel inhibition.

PMID: 31072021 [PubMed - in process]

F508del-CFTR is not corrected by thymosin α1.

Nat Med. 2018 07;24(7):890-891

Authors: Matthes E, Hanrahan JW, Cantin AM

PMID: 29942095 [PubMed - indexed for MEDLINE]

Understanding the role of neutrophils in chronic inflammatory airway disease.

F1000Res. 2019;8:

Authors: Jasper AE, McIver WJ, Sapey E, Walton GM

Abstract
Airway neutrophilia is a common feature of many chronic inflammatory lung diseases and is associated with disease progression, often regardless of the initiating cause. Neutrophils and their products are thought to be key mediators of the inflammatory changes in the airways of patients with chronic obstructive pulmonary disease (COPD) and have been shown to cause many of the pathological features associated with disease, including emphysema and mucus hypersecretion. Patients with COPD also have high rates of bacterial colonisation and recurrent infective exacerbations, suggesting that neutrophil host defence mechanisms are impaired, a concept supported by studies showing alterations to neutrophil migration, degranulation and reactive oxygen species production in cells isolated from patients with COPD. Although the role of neutrophils is best described in COPD, many of the pathological features of this disease are not unique to COPD and also feature in other chronic inflammatory airway diseases, including asthma, cystic fibrosis, alpha-1 anti-trypsin deficiency, and bronchiectasis. There is increasing evidence for immune cell dysfunction contributing to inflammation in many of these diseases, focusing interest on the neutrophil as a key driver of pulmonary inflammation and a potential therapeutic target than spans diseases. This review discusses the evidence for neutrophilic involvement in COPD and also considers their roles in alpha-1 anti-trypsin deficiency, bronchiectasis, asthma, and cystic fibrosis. We provide an in-depth assessment of the role of the neutrophil in each of these conditions, exploring recent advances in understanding, and finally discussing the possibility of common mechanisms across diseases.

PMID: 31069060 [PubMed - in process]

Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus.

Nat Med. 2019 May;25(5):730-733

Authors: Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, Gilmour KC, Soothill J, Jacobs-Sera D, Schooley RT, Hatfull GF, Spencer H

Abstract
A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules.

PMID: 31068712 [PubMed - in process]

Can We Manipulate the Evolutionary Biology of Pathogens for Clinical Benefit?

Am J Respir Cell Mol Biol. 2018 08;59(2):143-144

Authors: Winstanley C, Brockhurst MA

PMID: 29708392 [PubMed - indexed for MEDLINE]

Intermicrobial interaction: Aspergillus fumigatus siderophores protect against competition by Pseudomonas aeruginosa.

PLoS One. 2019;14(5):e0216085

Authors: Sass G, Ansari SR, Dietl AM, Déziel E, Haas H, Stevens DA

Abstract
Pseudomonas aeruginosa and Aspergillus fumigatus are pathogens frequently co-inhabiting immunocompromised patient airways, particularly in people with cystic fibrosis. Both microbes depend on the availability of iron, and compete for iron in their microenvironment. We showed previously that the P. aeruginosa siderophore pyoverdine is the main instrument in battling A. fumigatus biofilms, by iron chelation and denial of iron to the fungus. Here we show that A. fumigatus siderophores defend against anti-fungal P. aeruginosa effects. P. aeruginosa supernatants produced in the presence of wildtype A. fumigatus planktonic supernatants (Afsup) showed less activity against A. fumigatus biofilms than P. aeruginosa supernatants without Afsup, despite higher production of pyoverdine by P. aeruginosa. Supernatants of A. fumigatus cultures lacking the sidA gene (AfΔsidA), unable to produce hydroxamate siderophores, were less capable of protecting A. fumigatus biofilms from P. aeruginosa supernatants and pyoverdine. AfΔsidA biofilm was more sensitive towards inhibitory effects of pyoverdine, the iron chelator deferiprone (DFP), or amphothericin B than wildtype A. fumigatus biofilm. Supplementation of sidA-deficient A. fumigatus biofilm with A. fumigatus siderophores restored resistance to pyoverdine. The A. fumigatus siderophore production inhibitor celastrol sensitized wildtype A. fumigatus biofilms towards the anti-fungal activity of DFP. In conclusion, A. fumigatus hydroxamate siderophores play a pivotal role in A. fumigatus competition for iron against P. aeruginosa.

PMID: 31067259 [PubMed - in process]

Patients and families experience with pharmacist care at cystic fibrosis foundation accredited clinics.

Pediatr Pulmonol. 2019 May 07;:

Authors: Young DC, Autry E, Zobell JT, Kormelink L, Homa K, Sabadosa KA, Kanga J, Anstead M, Kuhn R

Abstract
Cystic fibrosis (CF) is a complex genetic, multiorgan disease. The CF Foundation (CFF) recommends a multidisciplinary team (physician, nurse, respiratory therapist, dietitian, physical therapist, social worker, mental health coordinator, clinic coordinator, and pharmacist) to work with patients and families. The objective of our study was to describe the impact of a pharmacist involved in the care of patients and families from their perspective. The CF Patient and Family Experience of Care (PFEC) is a voluntary, 50-question telephonic or internet-based survey designed to continuously collect information from patients and their families regarding their care experience. From August of 2017 through February of 2018, five questions were added to the internet survey to assess the impact of the pharmacist on the care experience. From the 666 respondents, 54% reported that a pharmacist was involved in their CF care. At two CF clinics designated as "full access" to a pharmacist, respondents reported a higher percentage of the CF-team discussed medications compared to those from three clinics designated as "limited access" to the pharmacist (95% vs 67%). Respondents in clinics with "full access" to a pharmacist were significantly more likely to get their medications refilled on time (78% vs 63%) and reported using fewer pharmacies to fill their medications. Pharmacist involvement in CF care may improve patient's access to medication and the ability to sustain use.

PMID: 31066229 [PubMed - as supplied by publisher]

Time for a gut check: Pancreatic sufficiency resulting from CFTR modulator use.

Pediatr Pulmonol. 2019 May 07;:

Authors: Megalaa R, Gopalareddy V, Champion E, Goralski JL

Abstract
Pancreatic exocrine insufficiency in cystic fibrosis is genetically determined and generally felt to be irreversible. However, recent studies in young children started on cystic fibrosis transmembrane conductance regulator (CFTR) modulators have suggested improvement of pancreatic functioning over time. Here, we present the case of a 10-year-old child with pancreatic exocrine insufficiency since birth who regained pancreatic functioning after 4 years on the CFTR corrector drug, ivacaftor.

PMID: 31066218 [PubMed - as supplied by publisher]

Pursuing parenthood with cystic fibrosis: Reproductive health and parenting concerns in individuals with cystic fibrosis.

Pediatr Pulmonol. 2019 May 07;:

Authors: Hailey CE, Tan JW, Dellon EP, Park EM

Abstract
BACKGROUND: As life expectancy for cystic fibrosis (CF) has increased in recent decades, more individuals with CF are becoming parents. The objectives of this study were to describe the parenting and reproductive health concerns of individuals with CF and to identify the psychosocial and educational needs related to parenthood with CF.
METHODS: Twenty adults with CF, including parents and non-parents, participated in one-on-one, semi-structured interviews about reproductive health and parenting. Questions pertained to reproductive health knowledge, psychosocial adaptation to CF related to fertility and parenthood, parenting concerns in the context of CF, and psychosocial care needs. We performed thematic content analysis on interview transcripts and descriptive statistical analysis on participant demographics and health variables.
RESULTS: A majority of participants (ten women and ten men, of whom half were parents) described their health as "stable" and "good/fair"; median FEV 1 was 66% predicted (range, 30-105). Participants shared a range of experiences related to reproductive health discussions with CF care providers and expressed concerns about pregnancy, infertility, and adoption. Parents and non-parents expressed concerns about balancing roles as parent and patient, the impact of anticipated health decline and early mortality on children, and communication with children. Participants identified a need for earlier, improved education for potential parents and resources for parents with CF.
CONCLUSIONS: Individuals with CF may not receive sufficient CF-related reproductive health education, and they have wide-ranging concerns about the intersecting roles of patient and parent. Results from this study can provide guidance for CF care providers to improve their understanding and response to the needs of individuals and families affected by CF.

PMID: 31066212 [PubMed - as supplied by publisher]

Dysregulation of Circadian Rhythm Gene Expression in Cystic Fibrosis Mice.

J Circadian Rhythms. 2019 Apr 18;17:2

Authors: Barbato E, Mianzo H, Litman P, Darrah R

Abstract
Cystic fibrosis (CF) is autosomal recessive disease that affects multiple body systems. CF patients often experience sleep disturbances, altered sleep patterns, and sleep apnea. Sleep in mammals is controlled in part by circadian clock genes, including Clock, Bmal1, Period1, Period2, Cryptochrome1, and Cryptochrome2. The purpose of this study was to gain a better understanding of the biological underpinnings of disordered sleep experienced in CF. To accomplish this, we evaluated circadian clock gene expression profiles in CF and wildtype mice, divided into two subgroups each based on sleep condition. One subgroup of each genotype was permitted to maintain their sleep-wake cycle while the other was deprived of sleep for six hours prior to sacrifice. Brain, skeletal muscle, jejunum, colon, lung and adipose tissues were collected from each mouse. Quantitative polymerase chain reaction (PCR) was used to quantify expression of Clock, Bmal1, Period1, Period2, Cryptochrome1 and Cryptochrome2, and expression levels were compared between study groups. Our comparisons showed distinct differences between the CF groups and the wildtype groups under both sleep conditions. Additionally, we found the CF mice that had been sleep deprived had severely dysregulated expression of all measured genes in the lung apart from Cry1. Our findings suggest that (1) disordered sleep in CF may be caused by circadian system dysregulation and (2) the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) is a causative factor in the dysregulated circadian clock gene expression profiles of CF mice.

PMID: 31065288 [PubMed]

The Unified Airway: Does Asthma Influence Paranasal Sinus Pneumatization?

Ear Nose Throat J. 2019 May 07;:145561319848992

Authors: Marino MJ, Riley CA, Wu EL, Weinstein JE, McCoul ED

Abstract
Asthma has been implicated as a driving force in lower airway remodeling; however, its effect on upper airway development has not been studied. Clinical disease, particularly cystic fibrosis (CF), has been associated with anatomical paranasal sinus variation, although the mechanism for these variations remains unclear. The purpose of this study was to determine whether asthma is associated with altered sinus pneumatization. Five hundred ninety-one computed tomography scans, including 303 adolescents (age 13-18) and 288 adults (age > 18), were evaluated using the Assessment of Pneumatization of the Paranasal Sinuses (APPS) instrument. The APPS score is validated for assessing anatomical variation and total sinus volume. A diagnosis of asthma was ascertained from the medical record, and patients with CF were included as a positive control group. Patients with asthma had mean APPS score of 9.66, compared to 9.85 for participants without asthma ( P = .585). Subgroup analysis demonstrated similar findings among adults ( P = .817) and adolescents ( P = .585). Patients with a diagnosis of CF had significant sinus hypoplasia according to a mean APPS scores of 3.50 ( P < .001). Sinus hypoplasia persisted in both adults ( P < .001) and adolescents ( P < .001) with CF. The presence of asthma is not associated with altered paranasal sinus pneumatization. In contrast, CF is associated with significantly reduced sinus pneumatization. These findings suggest that aberrant sinus pneumatization may not be a feature of asthma and that chronic mucosal respiratory disease is not a generalizable cause for altered paranasal sinus pneumatization.

PMID: 31064242 [PubMed - as supplied by publisher]